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Indian J Crit Care Med
Indian J Crit Care Med
IJCCM
Indian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine
0972-5229
1998-359X
Jaypee Brothers Medical Publishers

39234229
10.5005/jp-journals-10071-24677
Guidelines
Guidelines for Antibiotics Prescription in Critically Ill Patients
Khilnani Gopi C 1https://orcid.org/0000-0003-0820-0624

Tiwari Pawan 2https://orcid.org/0000-0002-5136-4221

Mittal Saurabh 3https://orcid.org/0000-0002-7979-6405

Kulkarni Atul P 4https://orcid.org/0000-0002-5172-7619

Chaudhry Dhruva 5https://orcid.org/0000-0001-5138-2908

Zirpe Kapil G 6https://orcid.org/0000-0002-8140-727X

Todi Subhash K 7https://orcid.org/0000-0003-2306-6080

Mohan Anant 8https://orcid.org/0000-0002-2383-9437

Hegde Ashit 9https://orcid.org/0000-0003-4342-122X

Jagiasi Bharat G 10https://orcid.org/0000-0002-3068-1201

Krishna Bhuvana 11https://orcid.org/0000-0002-0003-6797

Rodrigues Camila 12https://orcid.org/0000-0002-6105-6660

Govil Deepak 13https://orcid.org/0000-0002-4624-1614

Pal Divya 14https://orcid.org/0000-0002-1607-3816

Divatia Jigeeshu V 15https://orcid.org/0000-0001-7384-4886

Sengar Manju 16https://orcid.org/0000-0002-3509-5682

Gupta Mansi 17https://orcid.org/0000-0001-9506-1911

Desai Mukesh 18https://orcid.org/0000-0002-9253-7934

Rungta Narendra 19https://orcid.org/0009-0009-9836-9466

Prayag Parikshit S 20https://orcid.org/0000-0003-2102-7627

Bhattacharya Pradip K 21https://orcid.org/0000-0002-0219-385X

Samavedam Srinivas 22https://orcid.org/0000-0001-6737-8663

Dixit Subhal B 23https://orcid.org/0000-0002-1441-0807

Sharma Sudivya 24https://orcid.org/0000-0003-0608-8819

Bandopadhyay Susruta 25https://orcid.org/0000-0001-5732-5461

Kola Venkat R 26https://orcid.org/0000-0002-6971-1236

Deswal Vikas 27https://orcid.org/0000-0002-5758-2262

Mehta Yatin 28https://orcid.org/0000-0002-0888-4774

Singh Yogendra P 29https://orcid.org/0000-0002-5026-9978

Myatra Sheila N 30https://orcid.org/0000-0001-6761-163X

1 Department of Pulmonary, Critical Care and Sleep Medicine, PSRI Hospital, New Delhi, India
2,3,8 Department of Pulmonary, Critical Care and Sleep Medicine, AIIMS, New Delhi, India
4 Division of Critical Care Medicine, Department of Anaesthesia, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
5 Department of Pulmonary and Critical Care Medicine, University of Health Sciences, Rohtak, Haryana, India
6 Department of Neuro Trauma Unit, Grant Medical Foundation, Pune, Maharashtra, India
7 Department of Critical Care, AMRI Hospital, Kolkata, West Bengal, India
9 Department of Medicine & Critical Care, P D Hinduja National Hospital, Mumbai, India
10 Department of Critical Care, Kokilaben Dhirubhai Ambani Hospital, Navi Mumbai, Maharashtra, India
11 Department of Critical Care Medicine, St John's Medical College and Hospital, Bengaluru, India
12 Department of Microbiology, P D Hinduja National Hospital, Mumbai, India
13,14,28 Department of Critical Care and Anesthesia, Medanta – The Medicity, GuruGram, Haryana, India
15,24,30 Department of Anaesthesiology, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
16 Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, Maharashtra, India
17 Department of Pulmonary Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
18 Department of Immunology, Pediatric Hematology and Oncology Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India
19 Department of Critical Care & Anaesthesiology, Rajasthan Hospital, Jaipur, India
20 Department of Transplant Infectious Diseases, Deenanath Mangeshkar Hospital, Pune, Maharashtra, India
21 Department of Critical Care Medicine, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
22 Department of Critical Care, Ramdev Rao Hospital, Hyderabad, Telangana, India
23 Department of Critical Care, Sanjeevan and MJM Hospital, Pune, Maharashtra, India
25 Department of Critical Care, AMRI Hospitals Salt Lake, Kolkata, West Bengal, India
26 Department of Critical Care Medicine, Yashoda Hospitals, Hyderabad, Telangana, India
27 Consultant, Infectious Diseases, Medanta - The Medicity, Gurugram, Haryana, India
29 Department of Critical Care, Max Super Speciality Hospital, Patparganj, New Delhi, India
Gopi C Khilnani, Department of Pulmonary, Critical Care and Sleep Medicine, PSRI Hospital, New Delhi, India, Phone: +91 9810353696, e-mail: gckhil@gmail.com
8 2024
10 8 2024
28 Suppl 2 S104S216
14 2 2024
20 3 2024
Copyright © 2024; The Author(s).
2024
https://creativecommons.org/licenses/by-nc/4.0/ © The Author(s). 2024 Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
How to cite this article: Khilnani GC, Tiwari P, Mittal S, Kulkarni AP, Chaudhry D, Zirpe KG, et al. Guidelines for Antibiotics Prescription in Critically Ill Patients. Indian J Crit Care Med 2024;28(S2):S104–S216.

Keywords

Antibiotics
Guidelines
Intensive care unit
Infections
Prescription
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pmcExecutive Summary

Pharmacokinetics and Pharmacodynamics

Evidence Statement

Time-dependent antibiotics require drug concentrations greater than the minimum inhibitory concentration (MIC) for a certain time period between doses, which usually ranges from 40 to 50% of inter-dose interval for their best action. Continuous infusions are preferred over extended infusions for beta-lactam antibiotics and are associated with clinical benefits like decrease in hospital stay, cost of therapy and mortality. For vancomycin, continuous infusion is associated with reduced toxicity and cost of therapy but no mortality benefit.

Newer Diagnostics Including Multiplex PCR

Recent times have seen a surge in rapid culture-independent novel assays and molecular diagnostics for common respiratory pathogens, as well as the availability of updated tests for newer strains of pathogens. These include antigen detection assays, reverse transcription–quantitative polymerase chain reaction (RT-qPCR) testing, multiplex PCR panels targeting multiple organisms, plasma cell-free DNA, next-generation sequencing (NGS), etc. on blood, and upper and lower respiratory tract specimens to detect viral, bacterial, fungal, and mycobacterial infections. Appropriate use of these newer methods leads to reduced antibiotic usage.

Community-acquired Pneumoniae in the Intensive Care Unit

What are the Common Organisms Causing Community-acquired Pneumoniae in Intensive Care Unit Worldwide and in India?

Evidence Statement

Viruses (including influenza), Streptococcus pneumoniaee, gram-negative bacilli (including klebsiella), Haemophilus influenzae and atypical organisms (Mycoplasma pneumoniaee) and are common causes of community-acquired pneumoniae (CAP) in intensive care unit (ICU). Staphylococcus aureus, Legionella and Mycobacterium tuberculosis are less common causes of CAP in ICU. Pseudomonas aeruginosa is an important pathogen causing CAP in patients with structural lung disease. Methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant gram-negative organisms are relatively infrequent causes of CAP in India and are associated with risk factors such as structural lung disease and previous antimicrobial intake. Anaerobic organisms may cause CAP or co-infection in patients with risk factors for aspiration like elderly, altered sensorium, dysphagia, head and neck malignancy. S. pneumoniaee remains sensitive to beta-lactams and macrolides. Haemophilus influenzae has good sensitivity to beta-lactam with beta-lactamase inhibitors and fluoroquinolones. Recent studies show increasing prevalence of extended spectrum β-lactamase (ESBL) producing enterobacteriaceae. Newer agents like omadacycline, delafloxacin and Lefamulin have added advantages of being effective against MRSA and anaerobes. Omadacycline and delafloxacin are effective against GNBs, whereas only Delafloxacin has good sensitivity against pseudomonas. Nafcillin and oxacillin are preferred agents for MSSA whereas agents effective against MRSA pneumoniae include linezolid, vancomycin and teicoplanin.

What are the Risk Factors for Multidrug-resistant (MDR) Pathogens for CAP in ICU?

Evidence Statement

Risk factors for multidrug-resistant (MDR) organisms include age > 65 years, antimicrobial therapy in the preceding 3 months, high frequency of antibiotic resistance in the community, hospitalization for ≥48 h in the preceding 3 months, home infusion therapy including antibiotics, home wound care, chronic dialysis within 1 month, family member with MDR pathogen and ongoing immunosuppressive treatment.

Recommendation

All patients admitted with CAP in ICU should be evaluated for risk factors for infection with MDR organisms (2A).

Antibiotic therapy should be individualized to cover the commonly implicated organisms according to risk factors, including Pseudomonas, ESBL producing enterobacteriaceae or MRSA (3A).

If antipseudomonal, MRSA specific or non-standard antibiotics are initiated emperically, early microbiologic diagnosis of respiratory secretions (Gram stain, PCR or multiplex PCR) and blood cultures should be sought for early de-escalation or narrowing down antimicrobial therapy (3A).

Should Serum Procalcitonin Levels be Done at Baseline in Patients Admitted with CAP in ICU?

Evidence Statement

Serum procalcitonin has moderate sensitivity and specificity in differentiating bacterial and viral etiology in CAP. Serial measurements of procalcitonin are useful in limiting antibiotic exposure in ICU patients with lower respiratory tract infections, predominantly by early cessation.

Recommendation

Serum Procalcitonin should not be used to differentiate bacterial and viral etiology in CAP in ICU (1A).

Serum procalcitonin levels should be measured at baseline and serially for use in antibiotic de-escalation for CAP in ICU (1A).

How Early should the Antibiotics be Initiated in Patients with CAP Who Require ICU Admission?

Evidence Statement

Early initiation of antibiotics has been associated with reduction in all-cause mortality in community-acquired pneumoniae, including severe pneumoniae with sepsis or septic shock.

Recommendation

Appropriate antimicrobial therapy should be initiated as early as possible in patients of CAP requiring ICU admission, preferably within the first hour after obtaining necessary microbiologic samples (3A).

Respiratory samples should be sent for Gram stain, bacterial culture, and other investigations as clinically indicated, as early as possible (3A).

Multiplex PCR may be used to obtain precise microbiologic diagnosis in patients with CAP admitted to ICU if feasible (2B).

Should CAP in ICU Receive Empirical Antimicrobials or Upfront Targeted Antimicrobial Therapy?

Evidence Statement

Early institution of targeted antibiotic therapy in severe CAP based on urinary antigen testing is associated with higher relapse rate without any mortality benefit in prospective randomized studies. Retrospective studies have shown mortality benefit with narrowing down of antibiotic therapy based on results from cultures of respiratory specimens, blood cultures as well as Legionella and pneumococcal urinary antigen testing. Multiplex PCR based diagnostic testing of respiratory specimens leads to more appropriate and focused antimicrobial therapy administration.

Recommendations

Empirical therapy covering common etiologic organisms should be initiated for severe CAP requiring ICU admission (2A).

Investigations including culture of respiratory secretions (sputum, endotracheal aspirate), blood cultures, urinary antigen testing for pneumococcus and Legionella may be performed to narrow down therapy. (UPP)

Multiplex polymerase chain reaction (PCR) testing of respiratory specimens, if available, should be performed for CAP in ICU for microbiologic diagnosis and subsequent antibiotic modification or de-escalation (3A).

PCR testing for viral etiology (e.g., influenza, SARS-Cov2) should be performed based on seasonality and local guidelines (3A).

Bronchoscopic BAL or protected specimen brush samples may be performed for microbiologic diagnosis on case by case basis (3A).

What is the Current Role of Radiologic Investigations in Guiding Antibiotic Therapy for CAP in ICU?

Evidence Statement

Lung ultrasound has high sensitivity and specificity in diagnosis of pneumoniae, and better diagnostic accuracy as compared to chest X ray. Addition of lung ultrasound aids in improving confidence in diagnosis of CAP and leads to significant treatment modification. CT Chest leads to early diagnosis of CAP in ICU and modification of treatment in significant proportion of cases, though there is insufficient evidence in impact on short term outcomes.

Recommendations

Bedside chest ultrasound should be done for all suspected CAP patients in ICU at baseline, and at frequent intervals as indicated (1A).

CT Chest may be done for diagnosis of CAP in ICU in cases where diagnosis is in doubt, alternate causes (heart failure, pulmonary embolism) are suspected, to rule out rarer causes (e.g., tuberculosis, nocardia) or to decide on site of invasive sampling (bronchoscopy or image guided sampling) (3A).

For Empirical Therapy in Patients with CAP in ICU, Should Combination Therapy be Preferred Over Monotherapy?

Evidence Statement

Empirical combination therapy covering common organisms causing community-acquired pneumoniae improves survival without any significant increase in microbial resistance.

Recommendation

Patients with CAP requiring ICU admission should initially receive combination of empirical antimicrobial agents covering common causative organisms (2A).

What should be the Preferred Combination Therapy for CAP in ICU?

Evidence Statement

For patients with severe CAP requiring ICU admission without risk factors for pseudomonal infection, a combination of beta-lactams along with macrolides is better as compared to beta-lactam fluoroquinolone combination in terms of mortality benefit and length of hospital stay.

Recommendation

For patients with CAP requiring ICU admission, a non-pseudomonal beta-lactam (cefotaxime, ceftriaxone, or amoxicillin–clavulanic acid) plus a macrolide (azithromycin or clarithromycin) should be preferred if there are no risk factors for Pseudomonas aeruginosa infection (1A).

For penicillin-allergic patients, a respiratory fluoroquinolone (levofloxacin, moxifloxacin or ciprofloxacin) and aztreonam may be used (3A).

If macrolides cannot be used, a fluoroquinolone may be used if there is no clinical suspicion of tuberculosis, after sending sputum or endotracheal aspirate for AFB and Genexpert (3A).

When should Anti-pseudomonal Cover be Added for CAP in ICU? If Required, which are the Preferred Antimicrobials for Anti-pseudomonal Cover?

Evidence Statement

For patients with severe CAP requiring ICU admission, risk factors for infection with Pseudomonas aeruginosa include chronic pulmonary disease (chronic obstructive pulmonary disease, asthma, bronchiectasis), frequent systemic corticosteroid use, prior antibiotic therapy, old age, immunocompromised states, enteral tube feeding, cerebrovascular or cardiovascular disease. Prior antibiotic therapy is a risk factor for multidrug-resistant pseudomonal infection.

Recommendation

If P. aeruginosa is an etiological consideration, antipneumococcal, antipseudomonal antibiotic (like ceftazidime, cefoperazone, piperacillin–tazobactam, cefoperazone–sulbactam, imipenem, meropenem or cefepime) should be used (2A).

Combination therapy should be considered with addition of aminoglycosides or antipseudomonal fluoroquinolones (e.g., ciprofloxacin) (3A).

If empiric antipseudomonal treatment is started, a culture of respiratory specimens (sputum, miniBAL or BAL) should be obtained to confirm pseudomonal infection or subsequent de-escalation (3A).

When should MRSA Cover be Added to Empiric Regimen for CAP in ICU?

Evidence Statement

Risk factors for MRSA in CAP in ICU include close contact with MRSA carrier or patient, influenza, prisoners, professional athletes, army recruits, men having sex with men (MSM), intravenous (IV) drug abusers, regular sauna users and those with recent antibiotic use. MRSA pneumoniae should be suspected after influenza or in previously healthy young patients, if there is cavitation or necrotizing pneumoniae, along with rapid increase of pleural effusion, massive hemoptysis, neutropenia or erythematous rashes. Vancomycin, teicoplanin, linezolid and tigecycline are effective antibiotics against MRSA.

Recommendation

All patients admitted with CAP in ICU should be evaluated for presence of risk factors associated with MRSA (3A).

If MRSA is a consideration, empiric linezolid (1A), vancomycin (1A) or teicoplanin (2A) should be added to the regimen. Linezolid should be used for vancomycin intolerant patients, vancomycin-resistant Staphylococcus aureus (VRSA), or patients with renal failure (1A).

PCR and Gram stain of nasal swab, along with Gram stain and culture of respiratory specimens should be obtained for microbiologic diagnosis of MRSA if empiric MRSA treatment is initiated, for future de-escalation or targeted antimicrobial therapy (3A).

When should Anaerobic Cover be Added to Empiric Antibiotic Regimen for CAP in ICU?

Evidence Statement

Risk factors for aspiration pneumoniae in patients admitted with CAP in ICU include dysphagia, altered sensorium, coma, witnessed aspiration, putrid discharge, presence of lung abscess, empyema, or necrotizing pneumoniae. There is no significant difference in anaerobic flora of CAP patients with or without aspiration. Severe aspiration related CAP has increased prevalence of GNBs and decreased prevalence of GPCs.

Recommendation

Empirical antibiotics with anaerobic coverage should be considered for treatment of CAP in ICU in presence of witnessed aspiration, lung abscess, empyema, or necrotizing pneumoniae (2A).

Specific antibiotics with anaerobic coverage (such as clindamycin and metronidazole) should not be routinely prescribed in severe CAP (UPP).

Which Antibiotic should be Preferred for Anaerobic Coverage for CAP in ICU?

Evidence Statement

Commonly prescribed empirical antibiotics for CAP in ICU such as ampicillin-sulbactam, amoxicillin-clavulanic acid, piperacillin-tazobactam and carbapenems have excellent anaerobic coverage. Clindamycin and moxifloxacin are effective against aspiration pneumoniae and lung abscess caused by anaerobic organisms. Lung abscess and necrotizing pneumoniae may require prolonged treatment up to 4 to 6 weeks.

Recommendation

Patients with CAP due to anaerobic infection should be initiated on antibiotics with anaerobic activity such as amoxicillin-clavulanate, clindamycin or moxifloxacin (1A).

Piperacillin-tazobactam or carbapenems can be used for empirical therapy in CAP due to anaerobes if otherwise indicated (3A).

Duration of treatment should be individualized according to response and severity of disease (3A).

What should be the Optimal Duration of Antibiotics for CAP in ICU?

Evidence Statement

For CAP in ICU, there is limited evidence regarding duration of treatment, with no significant mortality benefit beyond 7 days of antimicrobial therapy in uncomplicated cases. However, CAP due to GNB, enterobacteriaceae, P. aeruginosa, S. aureus bacteremia and L. pneumophila requires prolonged treatment. Necrotizing pneumoniae, lung abscess, empyema or extrapulmonary infective complications like meningitis or infective endocarditis also require longer duration of treatment.

Recommendation

Patients with CAP requiring ICU admission should receive antibiotics for 7 to 10 days (2A).

Patients with CAP due to Pseudomonas or aspiration pneumoniae should be treated for 14 days (3A).

Necrotizing pneumoniae due to GNB, MRSA or anaerobes also require treatment for 14 to 21 days (3A).

Duration of treatment should be individualized according to causative organism, response, severity of disease and complications (3A).

What is the Role of Adjunctive Therapy, i.e., Systemic Corticosteroids and Inhaled Antibiotics for CAP in ICU?

Evidence Statement

Short course of systemic corticosteroids has been associated with reduced risk of mortality, need for endotracheal intubation and inotrope initiation in severe CAP. Systemic corticosteroids are associated with reduced need for ICU admission and endotracheal intubation in patients hospitalized with CAP, albeit with higher risk of readmission rates. However, large trials have excluded patients with septic shock, pregnancy, immunodeficiency, viral infections (influenza, herpes, acute viral hepatitis), tuberculosis and invasive fungal infections. Hydrocortisone 200 mg to 240 mg daily infusion was most commonly used regimen in CAP trials for 7 to 10 days.

The evidence for inhaled antibiotics is predominantly from hospital-acquired and ventilator-associated pneumoniae, with better odds of clinical cure and microbiologic eradication in adjunct inhaled antibiotic therapy.

Recommendation

Short courses of systemic steroids should be given for patients with severe CAP after careful risk-benefit analysis (1A).

Hydrocortisone 200 mg infusion over 24 hours for 5 to 7 days should be used for systemic corticosteroid administration in severe CAP patients (2A).

Inhaled antibiotics may be used in severe CAP patients on a case-to-case basis. (UPP)

Should Procalcitonin be Used to Determine Duration of Antibiotic Administration for CAP in ICU?

Evidence Statement

Serial procalcitonin levels can be used to de-escalate antibiotics for CAP in the ICU without increasing mortality or recurrence rates.

Recommendation

Procalcitonin levels can be used along with clinical judgement for de-escalation of antibiotics in CAP in ICU in patients treated beyond 5-7 days (1A).

Hospital-acquired Pneumoniae and Ventilator-associated Pneumoniae

What are the Common Organisms Causing HAP/VAP in ICU and What is their Antibiotic Susceptibility Pattern?

Evidence Statement

Ventilator-associated pneumoniae (VAP) and hospital-acquired pneumoniae (HAP) are commonly caused by aerobic gram-negative bacilli, such as Acinetobacter baumannii, klebsiella pneumoniaee, Pseudomonas aeruginosa, or by gram-positive cocci (Staphylococcus aureus). In Indian ICUs, gram-negative organisms are most common etiologic agents (i.e., Acinetobacter, Klebsiella and Pseudomonas spp). Most of these pathogens have been found to be multidrug-resistant. Frequency of specific MDR pathogens causing HAP and VAP may vary by hospital, patient population, type of ICU patient, and change over time. Pan resistant organisms are increasingly being reported. Invasive sampling (including bronchoalveolar lavage) leads to better microbiologic diagnosis in HAP and VAP, but has not been associated with improved outcomes.

Should Baseline Serum Procalcitonin be Measured in Patients with Suspected VAP?

Evidence Statement

Baseline serum procalcitonin has moderate sensitivity and specificity for the diagnosis of ventilator and hospital-acquired pneumoniae, and cannot reliably differentiate between ventilator-associated tracheobronchitis and ventilator-associated pneumoniae. An 80% decline from baseline procalcitonin levels has been used along with absolute value of less than 0.5 mL to make decisions regarding antibiotic de-escalation.

Recommendation

Serum procalcitonin should not be used for diagnosis of Ventilator-associated or Hospital-acquired Pneumoniae or for decision making regarding antibiotic initiation (1A).

Baseline procalcitonin levels may be measured in VAP, for future use in antibiotic de-escalation (2B).

What are the Risk Factors for MDR Pathogens in VAP in ICU?

Evidence Statement

The risk factors for VAP due to MDR organisms include age >60 years, duration of mechanical ventilation ≥7 days, prior antibiotic use within 3 months, presence of severe sepsis or septic shock at time of VAP, ARDS preceding VAP, renal replacement therapy prior to VAP, systemic corticosteroid therapy and high prevalence (>25%) of MDR organisms in the hospital setting.

What should be the Initial Combination of Empiric Antibiotic Therapy for VAP in ICU?

Evidence Statement

Use of combination therapy for VAP has better outcomes in patients who are at risk for MDR pathogens. Commonly used antimicrobial agents include piperacillin-tazobactam, cefepime, levofloxacin, imipenem and meropenem. Among antimicrobial agents, carbapenems have a higher chance of clinical cure than non-carbapenems. Patients with high risk of MDR HAP or VAP, i.e., those admitted in ICUs with high prevalence of MDR organisms, prior isolation of MDR GNBs from respiratory secretions have been treated with combination therapy of carbapenems or beta-lactams with colistin or polymyxin. Monotherapy with newer beta-lactam-beta-lactamase combinations (e.g., ceftazidime-avibactam) or carbapenem-beta-lactamase combination (e.g., Imipenem-cilastatin-relebactam, meropenem-vaborbactam) have better outcomes and less toxicity as compared to other available regimens or polymyxins. Polymyxin B and colistin have been found to be efficacious in treatment of carbapenem resistant Klebsiella and Acinetobacter, but colistin has a higher incidence of nephrotoxicity. Tigecycline and minocycline are alternative options for CRE infections when pseudomonas is not a consideration. Aztreonam as a part of combination therapy is an alternative when newer beta-lactam-beta lactamase combinations are not available, or in presence of metalloproteinases like NDM. For treatment of VAP due to MRSA, glycopeptides and linezolid have similar clinical success, however, linezolid may be associated with higher chance of thrombocytopenia and gastrointestinal adverse events. Adjunct nebulized antibiotics (colistin, aminoglycosides) have been found to increase microbiologic eradication without any mortality benefit in VAP and HAP.

Gram staining of respiratory secretions can lead to lesser prescription of anti-pseudomonal and anti-MRSA antibiotics without compromising clinical cure rates in ICUs with low MDR organism prevalence. Molecular techniques like multiplex PCR have a very less turnaround time and can be used to effectively modify empiric regimen for HAP and VAP.

Recommendation

Among patients with VAP who are at high risk of MDR pathogens or are in ICU with high prevalence of MRSA (>15%) and resistant gram-negative organisms (>10%), an agent active against MRSA and at least two agents active against gram-negative organisms including P. aeruginosa is recommended (3A).

Among patients with VAP who are not at high risk of MDR pathogens and are in ICU with high prevalence of resistant gram-negative organisms (>15%) but low prevalence of MRSA (<10%), two agents active against gram-negative organism including P. aeruginosa is recommended (3A).

Linezolid, vancomycin or teicoplanin should be used for empiric MRSA coverage in patients at high risk of MRSA (1A).

In patients with high risk for MDR GNBs and prior isolation of MDR or carbapenem resistant GNBs from respiratory secretions, monotherapy with newer agents (Ceftazidime-avibactam, Ceftolozane-tazobactam, Imipenem-cilastatin-relebactam or Meropenem-vaborbactam) should be preferred to combination therapy (2A).

Polymyxin B (preferred) or colistin as part of empiric combination regimen can be used in the ICUs with high prevalence of carbapenem-resistant enterobacteriaceae (>20%) in patients with risk factors for MDR or XDR gram-negative pathogens (2A).

In patients with high risk for MDR GNBs or prior isolation of MDR/carbapenem resistant GNBs from respiratory secretions, tetracyclines (tigecycline or minocycline) may be used as part of combination therapy if no alternate drugs can be given, in patients without bacteremia, and pseudomonas is not a consideration (3B).

In patients with high risk for MDR GNBs, aztreonam can be used as part of combination regimen if no alternate drugs are available or pseudomonal coverage is needed (3A).

In ICU where distribution of pathogen and antibiotic resistance pattern is known, empiric treatment should be designed accordingly, based upon patient risk factors for MDR pathogens (UPP).

Adjunct nebulized antibiotics (colistin, aminoglycosides) can be used in combination with systemic therapy for empiric treatment of VAP on case-to-case basis or microbiologic sensitivity (3A).

Invasive sampling (Nonbronchoscopic BAL or bronchoscopic BAL, protected specimen brushing) should be performed in VAP for microbiologic diagnosis and definitive antibiotic therapy (2A).

Multiplex PCR of respiratory specimens (non-bronchoscopic BAL, or bronchoscopic BAL) should be used for early identification of causative organisms and appropriate modification of antibiotic therapy (2A).

Gram stain of respiratory specimens can be used for early de-escalation of empiric anti-MRSA therapy (2A).

In our country or in areas with high endemicity of tuberculosis, use of linezolid may be restricted unless no suitable alternative is available (UPP).

Fluoroquinolones and aminoglycosides should be cautiously used as monotherapy in VAP in our country as well as in other areas with high endemicity of tuberculosis. (UPP)

When to Give Antipseudomonal Drugs for VAP in ICU?

Evidence Statement

Prior use of antibiotics (most consistent association), prolonged duration of mechanical ventilation, and chronic obstructive pulmonary disease (COPD) have been identified as risk factors for MDR P. aeruginosa infection.

Recommendation

Empiric treatment should be given to cover Pseudomonas if there are risk factors for MDR Pseudomonas infection (2A).

In ICUs where gram-negative isolate resistance rate is high (>10 % gram-negative isolate resistant to agent being considered for monotherapy or not known), two anti-pseudomonal antibiotics from different class to be given (3A).

What should be the Duration of Antibiotic Treatment for HAP/VAP?

Evidence Statement

Short-course regimens for VAP are associated with significantly more antibiotic-free days without any significant difference in duration of ICU or hospital stay, recurrence of VAP and mortality. Short-course regimens are associated with more recurrences in VAP due to non-fermenting gram-negative bacilli (NF-GNB).

Recommendation

Short course (7-8 days) of antibiotic therapy should be used, in case of VAP with good clinical response to therapy (1A).

Longer duration (14 days) of antibiotic therapy should be considered, in case of VAP caused by NF-GNBs or is associated with severe immunodeficiency, structural lung disease (COPD, bronchiectasis, and interstitial lung disease), empyema, lung abscess, necrotizing pneumoniae and inappropriate initial antimicrobial therapy (3A).

When should Anaerobic Cover be Added for VAP and Which is the Preferred Antimicrobial Agent?

Evidence Statement

Incidence of anaerobic bacteria as causative agent of VAP is 2 to 7%. Risk factors for VAP due to anaerobes are altered consciousness, aspiration pneumonitis and high simplified acute physiology score (SAPS).

Recommendation

Empirical antibiotic regimen for VAP should not include coverage for anaerobic organisms routinely (2A).

In the presence of risk factors for VAP due to anaerobic pathogens, anaerobic antimicrobial coverage should be added in empirical regimen (2B).

In patients with risk factors for anaerobic organisms, clindamycin or metronidazole should be added to empirical antibiotics regimen for VAP, if it does not include carbapenems (meropenem or imipenem) or piperacillin-tazobactam in the ongoing empirical regimen (UPP).

When to Give Atypical Cover for VAP and Which is the Preferred Agent?

Evidence Statement

Incidence of a typical bacteria as causative agents of VAP is low (5 to 7.5%). Risk factors for VAP due to Legionella are Legionella colonization in hospital water supply, prolonged use of corticosteroids, cytotoxic chemotherapy, elderly, chronic renal failure, previous antibiotic use, granulocytopenia and poor Glasgow coma score.

Recommendation

Empirical antibiotic regimen for VAP should not include coverage for atypical organisms routinely (2A).

In the presence of risk factors for VAP due to atypical bacterial pathogens, atypical antimicrobial coverage should be added to empirical regimen (2B).

The preferred atypical coverage in combination antibiotics regimen is fluoroquinolones (levofloxacin or moxifloxacin) or macrolides (azithromycin or clarithromycin) (UPP).

Can Serum Procalcitonin be Used for De-escalation of Antibiotic Therapy in VAP?

Evidence Statement

Use of procalcitonin to guide de-escalation of antibiotic treatment in patients with VAP is effective in reducing antibiotic exposure, without an increase in the risk of mortality or treatment failure.

Recommendation

Serum procalcitonin may be used to guide the de-escalation of antibiotics in VAP, when the anticipated duration of therapy is >7–8 days (1B).

Serum procalcitonin levels (together with clinical response) should be used for de-escalation of antibiotic therapy in VAP in specific clinical conditions (severely immunocompromised patients, drug resistant pathogens-NF-GNB, initial inappropriate therapy) (3A).

How to Approach a Patient of Non-responding VAP?

Evidence Statement

Re-evaluation at 48 to 72 hours after the initial diagnosis of VAP is the most suitable time. By then the results of the initial microbial investigation are usually available and treatment modification can be done. Evaluation of treatment response for VAP should be on the basis of clinical, laboratory, radiograph and microbiological results. Factors associated with treatment failure in VAP includes host factors (advanced age, immunosuppressed, chronic lung disease, ventilator dependence), bacterial factors (drug resistant pathogens, opportunistic pathogens), therapeutic factors (inappropriate antibiotics, delayed initiation of therapy, insufficient duration of therapy, suboptimal dosing, inadequate local concentration of drugs), complications of initial VAP episode (lung abscess, empyema), other non-pulmonary infections or non-infectious mimics of pneumoniae.

Recommendation

Non-responding VAP should be evaluated for non-infectious mimics of pneumoniae, unsuspected or drug-resistant pathogens, extrapulmonary sites of infection, and complications of pneumoniae or its therapy and diagnostic testing should be directed to whichever of these causes is likely (2A).

CT Chest and other indicated imaging modalities should be performed to clarify diagnosis in non-responding VAP and HAP (3A).

Microbiologic analysis of blood, respiratory specimen (non-bronchoscopic or bronchoscopic BAL) and other samples like pleural fluid should be performed using conventional culture and molecular methods for identification of pathogens in non-responding HAP and VAP (3A).

Catheter-related Bloodstream Infections (CRBSI)

What is the Incidence of Catheter Colonization and CRBSI?

Evidence Statement

The global incidence of CC ranges from 1.4 % to 19.4 % whereas CRBSI incidence ranges from 2.4 % to 12.5 %. The incidence of CC is higher in Indian ICUs ranging from 18 % to as high as 59 %, whereas incidence of CRBSI is up to 16.1 per 1000 catheter days.

What are the Risk Factors for CRBSI?

Evidence Statement

Longer indwelling catheter duration, immunosuppression, diabetes mellitus, sepsis at the time of insertion, multilumen catheters and APACHE >23 are important risk factors for CRBSI. APACHE at admission, renal failure, central venous catheterization and steroid therapy are important risk factors for fungal CRBSI.

What are the Common Organisms Causing CRBSI and their Antibiotic Susceptibility?

Evidence Statement

Coagulase-negative staphylococci (CONS), S. aureus, enterococcus and Candida species are the common organisms accounting for majority of the CRBSIs. Large proportion of Staphylococcus aureus and CONS are methicillin resistant ranging from 11 % to 87 %. There is an increased incidence of CRBSI due to gram-negative organisms (most of which are ESBL producers) and Candida especially the non-albicans Candida.

What is/are the Empiric Antibiotic(s) of Choice for CRBSI in ICU?

Evidence Statement

Vancomycin, teicoplanin, linezolid and daptomycin are effective in treatment of CRBSI due to MRSA and MR-CONS. Fourth-generation cephalosporin, carbapenem or beta-lactam/beta-lactamase combination like piperacillin-tazobactam and aminoglycosides might be used for gram-negative organisms causing CRBSI. Caspofungin and fluconazole have been equally effective as amphotericin-B for treatment of candidemia. However, increasingly fluconazole resistant Candida are becoming more common, and echinocandins are preferred as initial therapy in suspected catheter-related bloodstream infections due to Candida.

Recommendation

Empirical antibiotic regimen for CRBSI should include coverage for both gram-positive and gram-negative organisms. (2A)

Vancomycin or teicoplanin is the recommended first line drug for the empiric treatment of CRBSI for MRSA and MR-CONS while linezolid and daptomycin are good alternative agents. (2A)

Empiric coverage for gram-negative bacilli should include a fourth-generation cephalosporin, a carbapenem, or a β-lactam/β-lactamase inhibitor combination, newer agents (like ceftazidime-avibactam) or without an aminoglycoside. (UPP)

An echinocandin should be used as empirical antifungal agent for treatment of suspected central line-associated candidemia. (2A)

What should be the Duration of Antibiotic Treatment for CRBSI?

Evidence Statement

Short duration (<14 days) of antibiotics is as effective as longer duration (>14 days) for uncomplicated Staphylococcus aureus bacteremia. Complicated bacteremia due to S. aureus or those associated with endocarditis should receive longer duration. For gram-negative bacteremia, seven days of antibiotics is sufficient. In responding patient with uncomplicated CONS infection, 5-7 days therapy is considered optimum. Minimum 14 days treatment with antifungals is required for fungal CRBSI.

Recommendation

Minimum 2 weeks antibiotics should be given for uncomplicated and 4-6 weeks for complicated Staphylococcus aureus CRBSI and infective endocarditis (2A).

Minimum 7 days of antibiotics should be given for gram-negative CRBSI (2A).

Five to seven days antibiotics are recommended for CONS bacteremia (3A).

For suspected fungal CRBSI, antifungal therapy for at least 14 days is recommended (UPP).

Empirical Antibiotics for Urinary and Urogenital Sepsis in ICU

What is the Incidence of UTI in I Evidence Statement ICU? What are the Common Organisms and Risk Factors for UTI in ICU?

Evidence Statement

Incidence of CA-UTI ranges from 5-30% of all ICU admissions. The most common organism causing UTI in ICU are gram-negative bacteria (E. coli, Klebsiella) and fungi (especially Candida). Risk factors for UTI in ICU include duration of catheterization, length of ICU stay, prior antibiotic use, higher disease severity score, and female gender.

What is the Empirical Antimicrobial Agent of Choice for Treating UTI in ICU?

Evidence Statement

There has been a trend towards increasing prevalence of extended spectrum beta-lactamase producing gram-negative bacteria in the urinary cultures of catheter associated UTI. Aminoglycosides, beta-lactams along with a beta-lactamase inhibitor as well as carbapenems and fosfomycin have good efficacy in catheter associated UTI. The susceptibility for fluoroquinolones is decreasing over time among organisms isolated from nosocomial UTI. Candida species isolated from the patients with UTI show sensitivity to fluconazole, but increasingly fluconazole resistance is being reported.

Recommendations

Initial choice of antibiotics should cover for ESBL producing gram-negative organisms and includes aminoglycosides, beta-lactam along with a beta-lactamase inhibitor or carbapenems (2A).

In initial empirical regimen for UTI, antibiotics against gram-positive organisms is not recommended (3A).

In appropriate clinical settings antifungals should be considered in the empirical regimen. Fluconazole is preferred, amphotericin deoxycholate is an alternative if fluconazole resistance is suspected (3B).

Catheter removal, if no longer indicated, or intermittent catheterization should be done in patients with catheter associated urinary tract infection (3A).

Acute infective diarrhea, Antibiotic-induced Diarrhea, and Clostridium difficile-associated Diarrhea in the ICU

What are the Common Organisms Causing Acute Infective Diarrhea in the ICU?

Evidence Statement

The incidence of diarrhea in the ICU ranges from 12.9 to 38%. Majority of the cases of diarrhea in ICU are non-infectious in etiology. Clostridium difficile is responsible for majority of infectious cases of diarrhea in ICU.

What are the Empirical Antibiotics of Choice for Treating Acute Infective Diarrhea in the ICU?

Evidence Statement

Empirical use of metronidazole in patients with diarrhea suspected due to Clostridium difficile in ICU setting results in significant symptomatic improvement.

Recommendation

We recommend that empiric metronidazole be used for therapy of patients with acute diarrhea in the ICU with suspected Clostridium difficile infection (3A).

What are the Risk Factors for the Development of CDI or CDAD?

Evidence Statement

Risk factors for development of CDI include prior antibiotic therapy, advanced age, prolonged ICU/hospital stay, immunosuppression, proton pump inhibitors and enteral feeding. Cephalosporins, clindamycin, fluoroquinolones, carbapenems and penicillin derivatives are the commonly implicated antibiotics for CDAD/CDI.

What is the Recommended Treatment for CDI/CDAD: Which Antibiotics and Duration? Should Offending Antibiotics be Stopped? What is the Role of Probiotics in the Treatment of CDAD? How Should Recurrent Clostridium difficile Infection be Treated?

Evidence Statement

Both metronidazole and oral vancomycin have similar efficacy in clinical and bacteriologic cure of CDI. Use of implicated antibiotic after completing the treatment of CDI is associated with increased risk of recurrence of CDI. There is insufficient evidence to justify the use of probiotics as an adjunct to antibiotics in the treatment of CDAD. In a single RCT, fecal microbiota transplantation was found to be highly efficacious for treatment of recurrent CDI.

Recommendations

We recommend metronidazole as the first line treatment of mild to moderate CDI/CDAD (1A).

We recommend oral vancomycin as the first line treatment of microbiologically proven severe CDI/CDAD (1A).

We recommend oral vancomycin as the treatment of recurrent CDI/CDAD infection (2A).

We recommend fecal microbiota transplantation as an alternate treatment of recurrent CDI/CDAD infection (2A).

We recommend that implicated antibiotics should be discontinued as soon as clinically feasible (2A).

We recommend against the use of probiotics as an adjunct for the treatment of CDI/CDAD (2A).

We recommend addition of vancomycin to a patient with microbiologically proven CDI/CDAD, if the patient is already on metronidazole or has no clinical response to metronidazole within 3-4 days (UPP).

Abdominal Infections in ICU Acute pancreatitis and Infected Pancreatic Necrosis

What is the Incidence, Risk Factors and Microbiology of Pancreatic Infection Following Acute Pancreatitis?

Evidence Statement

Incidence of pancreatic infection following acute pancreatitis ranges from 12-37%. Presence of pancreatic necrosis of >50% is a major risk factor for pancreatic infection following acute pancreatitis. Primary organ failure predicts development of infective pancreatic infection in patients with acute pancreatitis.

Evidence Statement

Gram-negative organisms are the most common organisms isolated from infected pancreatic necrosis following acute pancreatitis in Indian patients. Prophylactic antibiotic use in patients of AP to prevent IPN has been associated with increased risk of infection with gram-positive organisms. Resistance to carbapenems, beta-lactam /beta- lactamase inhibitors and quinolones in gram-negative organisms isolated from IPN has increased, however, with maintain sensitivity to colistin and tigecycline.

What are the Empirical Antibiotics if Choice for Treatment of Pancreatic Infection Following Acute Pancreatitis?

Evidence Statement

Prophylactic use of antibiotics in patients with necrotizing pancreatitis has not been shown to reduce incidence of pancreatic infection and mortality. The presence of persistent fever, leukocytosis, multiorgan failure and presence of air within pancreatic necrosis suggest infected pancreatic necrosis. Cephalosporins, piperacillin-tazobactam, quinolones and carbapenems have the highest whereas aminoglycosides have the lowest penetration into necrotic pancreatic tissue. Response to antibiotic therapy is assessed by clinical and radiological parameters.

Recommendation

Routine use of prophylactic antibiotics to prevent pancreatic infection following acute pancreatitis of any severity is not recommended (1A).

Empirical antibiotic regimen in patients with infected pancreatic necrosis should be guided by local microbiological data, susceptibility pattern, pharmacokinetic property of antibiotics and previous antibiotic exposure (UPP).

In treatment-naïve patients with evidence of infected pancreatic necrosis, we recommend empirical treatment with either carbapenems, piperacillin-tazobactam or cefoperazone- sulbactam (2A).

In patients not responding or already exposed to the piperacillin-tazobactam, cefoperazone- sulbactam or carbapenems, colistin should be added to the empirical regime (3B).

Duration of antibiotic therapy should be guided by clinical, radiological and laboratory parameters (UPP).

Patients not responding to antibiotics should undergo necrosectomy and drainage (3B).

Biliary Sepsis, Acute Cholangitis

What are the Incidence, Risk Factors, and Microbiology of Biliary Infection in ICU?

Evidence Statement

Incidence of acute cholangitis varies with underlying etiology and ranges from 0.2 to 10%. Cholelithiasis, choledocholithiasis, benign and malignant common bile duct (CBD) strictures, CBD interventions, and stenting are the most common risk factors for cholangitis.

Evidence Statement

Gram-negative organisms are the most common organisms isolated from patients with acute cholangitis. Most of the pathogens isolated are susceptible to third-generation cephalosporins (such as cefoperazone-sulbactam), aminoglycosides, quinolones, ureidopenicillins, and carbapenems. Risk factors for multidrug drug resistance organisms causing acute cholangitis include an indwelling biliary stent, malignant biliary obstruction, previous hospitalization, and antibiotic use within 90 days.

What is the Empirical Antibiotic Regimen for Acute Cholangitis?

Evidence Statement

The empirical antibiotic regime in patients with acute cholangitis is guided by the severity of the disease, local antibiotic susceptibility pattern, and biliary penetration of the antibiotics. The duration of antibiotics depends on the severity of cholangitis and adequacy of source control. Biliary drainage (percutaneous or endoscopic) is required in addition to antibiotic use in the management of acute cholangitis.

Recommendation

Empirical antibiotic therapy should be guided by the severity of the cholangitis, local microbiological susceptibility patterns, biliary penetration of antibiotics, and previous antibiotic exposure (UPP).

We recommend either beta-lactam/beta-lactamase inhibitor (such as cefoperazone-sulbactam or piperacillin/tazobactam) or carbapenems (imipenem/meropenem) as monotherapy in patients with moderate to severe cholangitis (3B).

We recommend antibiotic duration for 4-7 days in patients with acute cholangitis after adequate source control (2B).

Biliary drainage should be considered in all patients with cholangitis in addition to empirical antibiotic therapy (1A).

Anti-anaerobic therapy (such as metronidazole, tinidazole, or clindamycin) is required if a biliary-enteric anastomosis is present and the primary antibiotic therapy does not include carbapenems, piperacillin/tazobactam, or cefoperazone/sulbactam as these drugs have sufficient anti-anaerobic activity. (3A)

Liver Abscess

What are the Most Common Organisms Causing Liver Abscess in ICU?

Evidence Statement

Amoebic liver abscess is the most common cause of liver abscess in Indian setup. The incidence of pyogenic liver abscess varies from 2.3 to 446 per 100000 hospital admissions per year. Gram-negative organisms (E. coli and Klebsiella) are the most common organisms causing pyogenic liver abscess. Risk factors for pyogenic liver abscess include diabetes mellitus, older age, male gender, biliary diseases, biliary procedures, alcoholism, malignancy, intra-abdominal infection, and cystic lesions in the liver.

What are the Empirical antibiotics of Choice for Treating Liver Abscess in ICU?

Amoebic Liver Abscess

Evidence Statement

Metronidazole is the drug of choice for the treatment of amoebic liver abscess. The optimum duration of treatment in patients with amoebic liver abscess is 7-10 days. Routine needle aspiration of amoebic liver abscess is controversial. Addition of aspiration to drug therapy in patients with amoebic liver abscess of >5 cm in size hastens clinical improvement.

Recommendation

We recommend metronidazole as an initial antibiotic of choice in patients with amoebic liver abscess (2A).

We recommend antibiotic treatment for a period of 7-10 days in patients with amoebic liver abscess (3B).

Needle aspiration of amoebic liver abscess is recommended in patients with a lack of clinical improvement in 48-72 hours, left lobe abscess, abscess more than 5-10 cm or thin rim of liver tissue around the abscess (<10 mm) (UPP).

The luminal agents used to remove any intraluminal cysts (paromomycin, diiodohydroxyquin or diloxanide furoate) should be used even if the stool microscopy is negative (UPP).

Pyogenic Liver Abscess

Evidence Statement

Beta-lactam/beta-lactamase inhibitors, metronidazole, and carbapenems are effective antibiotics for management of pyogenic liver abscess. Carbapenems are effective in case of suspected infection with ESBL producing organisms or melioidosis. Antibiotics are required for prolonged periods ranging from 4-6 weeks. Clinical and radiological assessment is required to guide the adequate treatment duration. Initial 2-4 weeks therapy may be parenteral while oral therapy may be given for rest of the duration.

Recommendation

We recommend beta lactam/beta lactamase inhibitors with metronidazole in patients with pyogenic liver abscess for a duration of 4-6 weeks (2A).

We recommend carbapenems in case of infection with ESBL-producing organisms or melioidosis (2B).

The empiric regimen should also cover E. histolytica until the causative pathogen is found or amebic abscess is excluded (UPP).

Peritonitis

What are the Most common Organisms Causing Peritonitis in ICU?

Evidence Statement

The risk factors for development of primary peritonitis are decompensated cirrhosis, nephrotic syndrome and peritoneal dialysis. The risk factors for development of secondary peritonitis include intra-abdominal organ perforation, post intra-abdominal surgery, and trauma. Longer ICU stay, urgent operation on hospital admission, total parenteral nutrition, and stomach-duodenum as primary infection site are associated with the development of tertiary peritonitis. Gram-negative enteric organisms (such as E. coli, and Klebsiella pneumoniae) are the common causes of primary and secondary peritonitis. Other organisms include gram-positive as well as anaerobic bacteria. The organisms commonly isolated in tertiary peritonitis are Candida, Enterococcus faecium and Staphylococcus epidermidis.

What are the Empirical Antibiotics of Choice for Treating Peritonitis in ICU?

Primary Peritonitis

Evidence Statement

Third-generation cephalosporins are the most effective antibiotic therapy for primary peritonitis. Antibiotics are usually required for 7-10 days for adequate treatment. Most of the organisms isolated in secondary peritonitis are sensitive to beta-lactam/beta-lactamase inhibitors or carbapenems. For gram-positive organisms, vancomycin and linezolid are effective treatment options. Short duration of antibiotic treatment (4 days) is as effective as a longer duration after adequate source control.

Recommendation

We recommend third generation cephalosporins (such as cefotaxime and ceftriaxone) for a duration of 7-10 days in patients with primary peritonitis (2A).

We recommend either beta-lactam/beta-lactamase inhibitor or carbapenems with an anaerobic cover (using metronidazole) for the treatment of secondary peritonitis (2A).

For secondary peritonitis, antibiotic treatment is required for at least 4 days after an adequate source control; however, longer treatment is required if adequate source control is not achieved (2A).

CNS Infections in ICU

What are the Most Common Organisms Causing Acute Bacterial Meningitis in ICU?

Community-acquired Meningitis Evidence Statement

The incidence of community-acquired pyogenic meningitis ranges from 2 to 7.40 per lakh population and data suggest higher incidence in children. The common causative organisms include Streptococcus pneumoniaee, Neisseria meningitidis, other streptococci, Haemophilus influenzae and Listeria monocytogenes. Other causative organisms are staphylococcus species, gram-negative bacilli, and Pseudomonas. Common risk factors for community-acquired bacterial meningitis are otitis media, elderly population, depressed immune status and prior use of antibiotics.

Nosocomial Meningitis

Evidence Statement

Incidence of post-ventricular drain or catheter meningitis ranges from 2% to 27%. Commonly implicated organisms are CONS (especially staphylococcus epidermidis), Staphylococcus aureus, Acinetobacter, pseudomonas, and Enterobacteriaceae. Risk factors are repeated catheterization, higher catheter duration, CSF sampling, presence of concomitant systemic infection, and surgical technique i.e., subcutaneously tunneled extraventricular drain (EVD), Rickham reservoir with percutaneous CSF drainage. The incidence of post craniotomy or post neurosurgery meningitis is 0.02% to 9.5%. Most commonly implicated organisms are Staphylococcus aureus, coagulase-negative staphylococci (especially S. epidermidis), Enterobacteriaceae, Acinetobacter, and pseudomonas. Risk factors include CSF leak, EVD, longer duration of drainage, multiple operations, lack of antibiotic prophylaxis, and emergency surgery. The incidence of post-neuroaxial blockade meningitis is 0.2 per 10000 with Viridans streptococci and Staphylococcus aureus being common organisms. Exogenous inoculation is the main risk factor. Post-head trauma meningitis incidence ranges from 1.39% to 2% with CONS, Acinetobacter, and Enterobacteriaceae as common microbes and prolonged hospitalization, and insertion of a lumbar and ventricular drain as common risk factors. Post-internal ventricular drain infection incidence ranges from 5.9% to 15.2%. The most common causative organisms are CONS, Staphylococcus aureus, gram-negative bacilli, group D streptococci, and Propionibacterium acnes. CSF leak, single gloves use, and number of times shunt exposed to breached surgical gloves are the risk factors.

What are the Empirical Antibiotics of Choice for Treating Acute Bacterial Meningitis in ICU? What should be the Duration of Antibiotic Treatment?

Community-acquired Meningitis

Evidence Statement

Choice of antibiotics depends on the most likely causative microorganisms, local antibiotics sensitivity patterns, mechanism of infection, and patient's predisposing condition. Most commonly recommended empirical antibiotic regimens include third-generation cephalosporin plus vancomycin, third-generation cephalosporin monotherapy and penicillin monotherapy. Addition of amoxicillin, ampicillin or benzyl-penicillin has been recommended in patients older than 50 years. However, antibiotic therapy should be modified according to the isolated organisms since MDR organisms are being reported from community as well.

Recommendation

We recommend third-generation cephalosporin (preferably ceftriaxone) plus vancomycin as empirical antibiotics of choice for community-acquired meningitis (3A).

We recommend adding ampicillin or amoxicillin if the age >50 years (3A).

If beta-lactams are contraindicated, we recommend chloramphenicol plus vancomycin as the antibiotic of choice, and to add cotrimoxazole if age >50 years (3A).

We recommend ciprofloxacin or aztreonam plus vancomycin as an alternative regimen and to add cotrimoxazole, if age greater than 50 years (UPP).

We recommend the duration of antibiotics based on suspected or isolated organisms i.e., 10 to 14 days for Streptococcus pneumoniaee, 14 to 21 days for Streptococcus agalactiae, 7 days for Neisseria meningitidis or Haemophilus influenzae, 21 days for aerobic gram-negative bacilli, and 21 days or more for Listeria monocytogenes (3A).

If no microorganism is identified, antibiotics should be given for at least 10 to 14 days (3A).

Nosocomial Meningitis

Evidence Statement

Vancomycin in combination with cefepime, ceftazidime or meropenem is a commonly recommended empirical antibiotic regimen for nosocomial meningitis. Alternative regimens include third-generation cephalosporin or meropenem monotherapy or ceftriaxone plus flucloxacillin or cloxacillin combination therapy. Limited available evidence shows the efficacy of intraventricular or intrathecal antibiotics in the management of nosocomial meningitis poorly responsive to systemic antibiotics.

Recommendation

We recommend vancomycin plus cefepime or ceftazidime or meropenem as empirical antibiotics of choice for nosocomial meningitis (3A).

Colistin may be given if the incidence of CRE or drug-resistant Acinetobacter is high in the specific unit (UPP).

If beta-lactams are contraindicated, we recommend replacing beta-lactam with aztreonam or ciprofloxacin (3A).

Intraventricular or intrathecal antibiotics should be considered if infection responds poorly to appropriate systemic antibiotics clinically or microbiologically (3A).

What are the Most Common Organisms Causing Brain Abscess in ICU?

Evidence Statement

Incidence of brain abscess ranges from 1.3 to 2.6 cases per lakh population. Most commonly involved micro-organisms include streptococcus (especially S. viridans), staphylococcus (especially S. aureus), gram-negative bacilli, anaerobes (bacteroides, Peptostreptococcus, Fusobacterium), pseudomonas and H. influenzae. Polymicrobial etiology accounts for 23-26% cases. Risk factors include otitis media, sinusitis, head trauma, congenital heart diseases, hematogenous spread, surgery, immunocompromised status, pulmonary disease, meningitis and odontogenic infections.

What are the Empirical Antibiotics of Choice for Treating Brain Abscess in ICU? What should be the Duration of Antibiotic Treatment?

Evidence Statement

The most common empiric treatment consists of a third-generation cephalosporin combined with metronidazole. Antibiotic duration ranges from 4 to 8 weeks.

Recommendation

We recommend third-generation cephalosporins plus metronidazole as the empirical antibiotic of choice for brain abscess (3A).

We recommend adding vancomycin if there is a high likelihood of MRSA (3A)

We recommend vancomycin plus ciprofloxacin if beta-lactams are contraindicated (3A).

We recommend aztreonam if ciprofloxacin cannot be given or contraindicated (UPP).

We recommend a minimum 4 weeks of therapy; however, duration may be extended according to clinic-radiological response irrespective of aspiration or excision of abscess (3A).

Skin and Soft Tissue Infections in ICU

What are the Most Common Organisms and Risk Factors for SSTI in ICU?

Evidence Statement

Older age, diabetes mellitus, obesity, malignancy, cirrhosis and longer ICU stay are risk factors for SSTIs. Gram-positive organisms (Staphylococcus aureus) are the most common organism responsible for the SSTIs. E. coli and pseudomonas are common pathogens among gram-negative organisms. MRSA and ESBL producing gram-negative organisms are the most common causative agents for SSTIs in ICU. Monomicrobial necrotizing fasciitis is commonly caused by Streptococcus pyogenes; mixed coliforms, anaerobes and staphylococci are common causes of polymicrobial necrotizing fasciitis.

What are the Empirical Antibiotics of Choice for Treating SSTI in ICU ? For Empirical Therapy, should Combination Therapy be Preferred over Monotherapy?

Evidence Statement

Vancomycin, teicoplanin, daptomycin and linezolid are effective in SSTIs caused by MRSA. Piperacillin-tazobactam and carbapenems are the most effective antibiotics for ESBL producing gram-negative organisms. Penicillin plus clindamycin are most effective antibiotics in monomicrobial necrotizing fasciitis, whereas a combination of piperacillin-tazobactam, fluoroquinolone and clindamycin is effective for polymicrobial necrotizing fasciitis.

Recommendation

For moderate non-purulent SSTI, we recommend intravenous penicillin or clindamycin as first choice of antibiotics (2A).

Severe non-purulent SSTI should be treated with a combination of piperacillin-tazobactam along with coverage for MRSA (vancomycin, teicoplanin, daptomycin or linezolid) (2A).

Concomitant surgical inspection or debridement should be considered for severe non-purulent SSTIs (2A).

For severe purulent SSTI, incision and drainage followed by empiric antibiotics including piperacillin tazobactam, along with MRSA coverage (vancomycin, teicoplanin, daptomycin or linezolid) is recommended (3A).

Penicillin plus clindamycin is recommended for monomicrobial necrotizing infection caused by Streptococcus pyogenes or clostridial species. For polymicrobial necrotizing fasciitis, a combination of piperacillin-tazobactam, fluoroquinolone and clindamycin is recommended (3A).

What should be the Duration of Antibiotic Treatment for SSTI?

Evidence Statement

Shorter course of antibiotic therapy is adequate for uncomplicated SSTIs while complicated SSTIs require longer duration of antibiotic therapy.

Recommendation

Severe nonpurulent SSTIs should be treated with at least 5 days of antibiotics. (3A)

Severe SSTIs with organ dysfunction should be treated with a prolonged course of antibiotics of 2-3 weeks duration. (3A)

Sepsis of Unknown Cause in ICU

What is the Empirical Treatment for Sepsis of Unknown Cause in ICU?

Evidence Statement

Empirical therapy with dual class (with different mechanisms of action) combination antimicrobial therapy for sepsis of unknown cause in ICU is associated with have better clinical outcomes. Empirical therapy with either piperacillin-tazobactam or carbapenems in combination with aminoglycoside or fluoroquinolone has been shown to give appropriate broad coverage leading to better clinical outcomes as compared to monotherapy.

Recommendation

We recommend empirical antimicrobial therapy with combination of ceftriaxone and doxycycline or macrolide for community-acquired sepsis of unknown origin in ICU (UPP).

We recommend empirical antimicrobial therapy with combination of beta-lactam/beta-lactamase inhibitor and fluoroquinolone or aminoglycoside for nosocomial sepsis of unknown origin in ICU (UPP).

Empiric therapy should attempt to provide antimicrobial activity against the most likely pathogens based upon clinical features along with local patterns of infection and resistance (UPP).

Duration of therapy is 7 to 10 days, though longer courses may be appropriate in patients with slow response (3B).

Empirical Antifungals for Non-neutropenic Patients in ICU

What are the Risk Factors for Invasive Fungal Infections in ICU?

Evidence Statement

Risk factors for invasive fungal infections in non-neutropenic patients in ICU are surgery, total parenteral nutrition, renal replacement therapy, cardiopulmonary bypass >120 minutes, diabetes mellitus, central venous catheters, urinary catheters, Candida colonization with colonization index >0.5, use of broad-spectrum antibiotics, acute renal failure, mechanical ventilation >3 days and APACHE II score >16.

What is the Role of Empirical Antifungals in Non-neutropenic Patients in ICU?

Evidence Statement

Empirical antifungals for non-neutropenic patients in ICU routinely has not been associated with decrease in mortality or hospital length of stay. Empirical antifungals in patients at high risk for invasive fungal infections in ICU has been shown to reduce incidence of subsequent proven invasive fungal infections.

Recommendation

We do not recommend the routine use of empirical antifungals in non-neutropenic patients in ICU (1A).

Empirical antifungals may be considered in critically ill patients with high risk of invasive fungal infections to reduce the incidence of subsequent invasive fungal infections (1B).

What is the Antifungal Agent of Choice and Duration of Empirical Therapy in Non-neutropenic Patients in ICU?

Evidence Statement

Fluconazole and caspofungin are useful as empirical antifungal therapy in non-neutropenic ICU patients at high risk of Invasive fungal infection. In India, rate of fluconazole resistance is up to 7%, especially in non-albicans Candida species.

Recommendation

We recommend fluconazole or caspofungin as preferred empirical antifungal agents in non- neutropenic ICU patients at risk for invasive fungal infection (1A).

Caspofungin may be preferred in areas with high prevalence of fluconazole resistance (1B).

Micafungin or anidulafungin may be used as alternative agents (3A).

Recommended duration of empirical antifungal therapy is 2 weeks (3A).

Antibiotic Stewardship

Does Antibiotic Stewardship Improve Patient Outcome in ICU?

Evidence Statement

Antibiotic stewardship programs in hospitalized patients are associated with reduction in number of antibiotic days, duration of hospital stay and all-cause mortality.

Recommendation

All hospitals should have an antibiotic stewardship program including the intensive care units (1A).

What are the Essential Strategies of Antibiotic Stewardship in an ICU Setting?

Evidence Statement

Antibiotic stewardship requires a multidisciplinary approach with integration of infectious disease physician, microbiologist with logistic and financial support from hospital administration. Both enablement and restrictive strategies are useful in improving adherence to antibiotic stewardship programs. Restrictive strategies give immediate results. Enablement practices are more resource intensive. Most studies have used a combination of both the methods and have shown additive effects. Providing feedback to the treating team improves adherence. A single RCT has shown that restrictive strategy alone may cause delay in initiation of antibiotics.

Recommendation

Prospective audit of antibiotic use and/or preauthorization (if feasible) along with feedback to the treating team is recommended as part of antibiotic stewardship program (1A).

What is the Role of Antibiotic Cycling, Intravenous to Oral Switch and De-escalation in the ICU?

Evidence Statement

Antibiotic cycling in the intensive care unit has not been adequately studied in randomized controlled trials. Non-randomized studies show significant heterogeneity in terms of site of study, method of cycling and confounders like simultaneous infection control measures being employed. Evidence of benefit of antibiotic cycling is lacking, with few studies demonstrating reduction in colonization though mortality and length of hospital stay remain unchanged.

Recommendation

Antibiotic cycling should not be used as a method of antibiotic stewardship program (2A).

Scheduled Intravenous to Oral Switch

Evidence Statement

Early intravenous to oral transition of antibiotics reduce hospital length of stay and cost of care. There is no increase in mortality or other adverse events when this is done after assessing as to which patients can be safely transitioned to oral therapy.

Recommendation

Antibiotic stewardship programs should implement strategies to improve timely transition from parenteral to oral antibiotic therapy (2A).

De-escalation in Intensive Care Unit

Evidence Statement

Pooled results from observational studies in an ICU setting do not show any increase in mortality with antibiotic de-escalation while significantly reducing antibiotic exposure days and ICU length of stay.

Recommendation

Antibiotic de-escalation in the ICU is recommended as part of antibiotic stewardship program (2A).

What is the Role of Procalcitonin in Antibiotic De-escalation in ICU?

Evidence Statement

Implementation of antibiotic de-escalation algorithm based on serial procalcitonin measurements has been shown to reduce mortality, length of ICU stay, total duration of antibiotic days and health care costs.

Recommendation

Procalcitonin based algorithms may be used for antibiotic de-escalation (1A).

Antimicrobial Prescription in Critically Ill Immunocompromised Patients

What should be the Empiric Antibiotic Therapy in Critically Ill Febrile Neutropenic Patients with Suspected Bloodstream Infection?

Evidence Statement

Gram-positive and gram-negative organisms are common causes of febrile neutropenia, with gram-negative organisms predominating in India. The commonly isolated GNBs include Enterobacteriaceae (E. coli and Klebsiella species) and Pseudomonas aeruginosa to be the most common among gram-negative organisms. Staphylococcus aureus and Coagulase negative staphylococcus are most common gram-positive isolates. Recent studies have reported increasing prevalence of MDR organisms. Choice of antibiotics depends on local epidemiology, focus of infection and host and disease characteristics. Current evidence shows carbapenem resistance among Enterobacteriaceae is 35-50 %, Pseudomonas spp 47% and Acinetobacter spp 62%. Acute leukemia patients presenting to the ICU, patient already on carbapenem shifted to ICU from ward, previous multidrug-resistant infections in the last 1 month and patients on vasopressors are at risk of harboring carbapenem resistant organisms. Empiric upfront vancomycin has not been shown to improve clinical outcomes or mortality in febrile neutropenia. Patients at risk of MRSA infections include suspected indwelling catheter infection (rigors following infusion, cellulitis at exit site), skin and soft tissue infection, severe mucositis, culture growing gram-positive cocci pending identification, previous MRSA colonization/infection and hemodynamic instability at admission.

Recommendation

In a critically ill febrile neutropenic patient presenting to the ICU with organ failure, empiric antibiotic therapy should be initiated with or escalated to a broad-spectrum carbapenem like imipenem or meropenem (UPP).

Empiric combination of Meropenem and Colistin/Polymyxin B should be considered in patients having high risk of infection with resistant gram-negative organisms (3A). Following risk factors should be assessed:

– Critically Ill patients with underlying acute leukemia (on induction or consolidation therapy) presenting to the ICU.

– Patients of acute leukemia/lymphomas on beta-lactam/beta lactamase inhibitor±aminoglycosides, shifted to ICU from ward.

– Previous history of infection with multidrug-resistant organism in last 1 month.

– Hypotensive patients requiring vasopressor infusions (refractory septic shock).

– Patient shifted to the ICU on carbapenem therapy.

We strongly caution against the use of empiric combination of Meropenem and Colistin/Polymyxin B or Colistin/Polymyxin B alone in patients who are not high risk of infection with carbapenem resistant gram-negative organisms as defined above (3A).

We caution against use of other carbapenems like Doripenem and Ertapenem due to lack of positive evidence and inadequate spectrum respectively (2A).

Vancomycin/Teicoplanin should be added as empiric therapy in critically ill febrile neutropenic patient with risk factors for MRSA infection (3A). These include:

– Suspected indwelling vascular catheter infection.

– Skin and soft-tissue infection.

– Previous colonization/infection with methicillin-resistant Staphylococcus aureus.

– Blood Culture growing gram-positive cocci awaiting identification.

– Severe mucositis.

– Hemodynamic instability(hypotension) at admission from home or outpatient department (UPP).

Empiric MRSA coverage should be avoided in absence of risk factors for MRSA and in ICUs with low prevalence of MRSA(UPP).

After the initiation of empiric therapy based on the factors listed above, the subsequent therapy should be based on the organisms isolated and sensitivity patterns. In patients with no isolates, the treatment should be continued as per the response to ongoing antibiotics and appearance of any new focus of infection (UPP).

What Methods should be Used for Early Identification of Causative Organisms in Febrile Neutropenia Patients?

Evidence Statement

Two sets of blood cultures drawn prior to antibiotic administration yields microbiologic diagnosis in 30% cases. Addition of multiplex PCR techniques can aid in early diagnosis and has high sensitivity and specificity as compared to culture-based methods.

Recommendation

We recommend collection of at least 2 sets of blood cultures, with a set collected simultaneously from peripheral site and one central. In case of multi lumen catheter, one set per lumen should be collected (1A).

Two blood culture sets from separate venepunctures should be sent if no central venous catheter is present (1A).

One set includes one aerobic and one anaerobic culture bottle. Blood culture volume should be at least 10 mL/bottle (1A).

The use of molecular methods for identification of multidrug-resistant organisms and their antibiotic sensitivity pattern can be considered in critically ill patients, however, the availability and cost may be a concern along with risk of false negativity and false positivity (2B).

What should be the Approach to Empiric Antifungal Therapy in Febrile Neutropenia in Critically Ill Immunocompromised Patients?

Evidence Summary

Patients with febrile neutropenia are at risk of developing invasive fungal infections. IFIs have high mortality in patients with febrile neutropenia. Persistent or recurrent febrile neutropenia and development of lung infiltrates may be clues to fungal etiology of febrile neutropenia. Yeast (primarily Candida species) and molds are common etiologic agents. In patients with persisting fever without any localization, empiric antifungals targeting Candida species are initiated. Chest radiograph has poor sensitivity for pneumoniae detection in patients with febrile neutropenia, and CT Chest is preferred. Galactomannan assay is highly specific for Aspergillus species with some cross-reactivity with Histoplasma capsulatum and Penicillium species. False-positive reaction can occur with concomitant use of b-lactam/b-lactamase combinations, such as piperacillin/tazobactam. Use of Beta-D Glucan alone has limited sensitivity for the diagnosis of invasive candidiasis. Invasive aspergillosis should be suspected in patients with persistent febrile neutropenia with the development of signs of pneumoniae including lung infiltrate.

The echinocandins have demonstrated significant fungicidal activity and treatment success against most of the Candida species in randomized clinical trials. Individual echinocandins namely caspofungin, micafungin and anidulafungin have similar efficacy and are interchangeable. Echinocandins have poor penetration in eye, CNS, and urine. Echinocandins are not active against Zygomycosis. Voriconazole is the preferred agent for invasive aspergillosis, whereas liposomal amphotericin B is preferred for zygomycosis. Echinocandins have been useful in salvage therapy of aspergillosis. Guidelines advise to continue treatment for candidemia for at least two weeks after 2 weeks after documented clearance of Candida from the bloodstream, and resolution of neutropenia and symptoms attributable to candidemia. Recommended duration of invasive pulmonary aspergillosis is 6-12 weeks based on the resolution of symptoms and neutropenia. Combination antifungal treatments have limited evidence for added efficacy.

Recommendation

Following patients should be considered for initiation of antifungal therapy when they present to ICU with shock or respiratory distress especially when they have persistent or recurrent fever or clinical deterioration after >3 days of broad-spectrum antibiotics (2A).

– Allogenic HSCT.

– Severe mucositis with diarrhea.

– Prolonged/anticipated duration of neutropenia >10 days.

– Worsening on broad-spectrum antibiotics like BL/BLI and Carbapenems.

– More than 2 weeks of high-dose steroids (more than 15-20 mg of prednisolone or equivalent).

– History of invasive fungal infection.

– New onset lung infiltrate. (Since chest x ray has low sensitivity, HRCT should be done in these patients).

We recommend the use of caspofungin (echinocandin group) as initial antifungal therapy. Caspofungin should be avoided in patients with chronic liver disease (Child-Pugh C) (2A).

Anidulafungin and Micafungin can be considered if there are contraindications to use of caspofungin (3A).

Voriconazole is the drug of choice for proven, probable or possible aspergillosis. Due to its variable bioavailability voriconazole should be administered IV. In patients with renal dysfunction caspofungin can be given instead of IV voriconazole (1A).

Liposomal Amphotericin B is the drug of choice for suspected or confirmed Mucormycosis (1A).

All efforts should be made to confirm presence of invasive fungal infection with the use of tests including CT Chest/suspected site (abdomen for hepatosplenic candidiasis or mucormycosis/paranasal sinus for mucormycosis), β –D- glucan, serum and BAL Galactomannan, fungal culture. Tissue (lung/other clinically involved sites) biopsy should be performed if required, whenever feasible and safe (1A).

We do not recommend routine use of combination antifungal therapy for probable or proven Invasive aspergillosis (IA) due to lack of strong evidence (3A).

Which Patients should be Considered for Empiric Treatment against Pneumocystis jirovecii Pneumoniae?

Evidence Statement

HSCT, high dose corticosteroids, T-cell depleting agents and rituximab predispose to PCP infection. Hypoxemia and characteristic radiologic abnormalities indicate PCP pneumoniae, though chest radiograph might be normal in early disease. Empiric treatment with trimethoprim-sulfamethoxazole is indicated in suspected PCP pneumoniae.

Recommendations

Treatment with sulfamethoxazole/trimethoprim should be considered in high risk patients such as allogenic HSCT, high-dose corticosteroid therapy administration of T-cell-depleting agents such as fludarabine/purine analogues and rituximab when such patients present with hypoxemic respiratory failure with or without radiological evidence of Pneumocystis carinii pneumoniae especially if they are not on PCP prophylaxis (3A).

Every attempt should be made to confirm PCP infection (3A).

What is the Role of Empiric Antiviral Therapy in Immunocompromised Patients with Febrile Neutropenia?

Evidence Statement

Antiviral therapy in febrile neutropenia is given according to treatment guidelines of the etiologic agent. There are no effective agents for treatment of parainfluenza and respiratory syncytial virus infection at present.

Recommendations

There is no role of empirical antiviral therapy with febrile neutropenia. Active HSV or VZV infections in neutropenic patients indicated by clinical or laboratory evidence should be treated with Acyclovir (3A)

Immunoglobulin tests should not be used to diagnose VZV or HSV infection (3A).

Ganciclovir is recommended for the empiric therapy for CMV in patients with high risk of CMV reactivation (3A):

– Administration of T-cell-depleting agents such as fludarabine/purine analogues, rituximab

– Patients on high dose steroids who develop diarrhea

– Pneumoniae not responding to antibiotics & antifungals.

No specific treatment for infections with RSV and parainfluenza viruses due to lack of specific evidence (3A).

What is the Role for Empiric Antimicrobial Therapy for Tropical Infections like Malaria, Leptospirosis in Patients with Febrile Neutropenia?

Evidence Statement

There is insufficient evidence regarding tropical infections in patients with hematologic or solid organ malignancies and febrile neutropenia.

Recommendation

There is no role for empirical antimicrobial therapy against tropical infections like malaria, leptospirosis in febrile neutropenia patients (3A).

Documented tropical infections in neutropenic patients in ICU should be treated similar as they are treated in non-neutropenic patients (UPP).

What is the Role of Surveillance Cultures in Guiding Therapy in Febrile Neutropenia Patients?

Evidence Statement

Surveillance cultures have not been shown to correlate with subsequent causative organisms in immunocompromised patients.

Recommendation

We strongly recommend against repeated surveillance cultures as these do not help to guide antibiotic therapy (3A).

What is the Role of Source Control in the Treatment of a Febrile Neutropenic Patient?

Evidence Statement

Source control at the earliest possible time reduces microbiologic burden and improves outcomes. Source control includes debridement, drainage of collections, removal of incriminated indwelling catheters and implanted devices.

Recommendations

We recommend that in patients with febrile neutropenia with clinically documented source of infection (as defined below), immediate intervention should be undertaken for source control (3A).

What should be the Approach to Antibiotic De-escalation in Patients with Febrile Neutropenia?

Evidence Statement

Antibiotic de-escalation to definitive therapy is feasible after identification of causative organism or in patients who remain afebrile for >48 hours with evidence of marrow recovery.

Recommendations

Antibiotic de-escalation should be considered in the following situations (3A):

Once and if a pathogen is identified, we recommend de- escalation to an antibiotic that the organism is susceptible to.

Treat with appropriate agents based on the site and pathogen until the patient is afebrile for at least 48 hours and there is evidence of marrow recovery (neutrophil count ≥500 cells/mm3).

In patients without microbiologically documented infection continue empirical antimicrobials until the patient is afebrile for at least 48 hours and there is evidence of marrow recovery (neutrophil count ≥500 cells/mm3)

Which Antibiotics should be Used for Febrile Neutropenia due to Multidrug-resistant Bacteria?

Evidence Statement

Antibiotics like fosfomycin, tigecycline and minocycline have activity against variety of MDR gram-negative organisms. For MRSA, vancomycin, teicoplanin and linezolid have most evidence. Linezolid is effective against vancomycin-resistant enterococci. However, good quality RCTs for MDR infections are lacking in immunocompromised patients.

Recommendation

Antibiotics like Fosfomycin, tigecycline and minocycline may be considered in infection with multidrug-resistant bacteria in presence of in vitro susceptibility after considering the in vivo penetration at source of sepsis, and if alternate agents with proven efficacy are not available or contraindicated (3A).

Vancomycin or linezolid can be used in cases of MRSA (1A).

Antimicrobial Guidelines in Solid Organ Transplant Recipients

What are the Common Infections in Post-solid Organ Transplant Patients? What should be the Preferred Approach to Empiric Therapy and Diagnostic Evaluation?

Evidence Statement

Incidence of sepsis in solid organ recipients ranges from 20% to 60% and is associated with in-hospital mortality of 5% to 40%. Nosocomial infections predominate in the first month, opportunistic infections till six months posttransplant and subsequently community-acquired infections become most common. In the Most of these infections are of bacterial followed by fungal etiology. Most common site remains urinary tract infection, followed by line related infections, and E. coli the most common etiology. CMV is most common infection from 1 month up to 3 months, whereas tuberculosis reactivation is more common from 3 months to 1 year posttransplantation. Pneumocystis and aspergillus infections are common after 1 year. MDR GNB isolates are increasing in prevalence, especially in nosocomial infections. Risk for developing sepsis with bacteremia can be lowered significantly by antibiotic prophylaxis. Prophylaxis is governed by type of transplant and risk of specific infections. Liver transplant patients often receive antibiotics covering skin flora, enterobacteriaceae, enterococci and anaerobes whereas post-lung transplant, prophylaxis is against molds, gram-negative bacteria or colonizers. Post-kidney transplantation trimethoprim-sulfamethoxazole given for PJP prophylaxis reduces UTI and bacteremia. Alternatives include nitrofurantoin and cephalexin. Fluoroquinolones increase risk of resistant infections like pseudomonas, and should be used with caution. Opportunistic infections have decreased due to anti-infective prophylaxis for CMV and PJP. TMP-SMX provides protection against toxoplasma, and protects against UTI, Listeria meningitis and nocardial infections.

Recommendation

Anti-infective Prophylaxis

Prophylaxis in first month posttransplant should depend upon the nosocomial infections, colonization of donor and recipient, and the organ transplanted (1A).

Trimethoprim-sulfamethoxazole (TMP-SMX) for primary prophylaxis for urinary tract infection (UTI) in renal transplant patients is recommended; TMP-SMX usually given for 6 months for PJP prophylaxis decreases UTI and bacteremia in renal transplant recipients (1A).

Primary prophylaxis for UTI with agents other than TMP-SMX may be limited to the first month after transplant (3B).

Approach to Diagnosis and Treatment of Infection

Infections in the first month (0–30 days) of post SOT period should be investigated and treated similarly to those of non-immunocompromised postoperative patient (1A).

Infections in the first month (0–30 days) of post SOT period should be investigated and treated on the lines of nosocomial infections/donor derived infections (1A).

Complete blood count with differential, liver and renal function tests, serum electrolytes should be obtained in all patients with suspected infection (3A).

We recommend obtaining blood cultures at presentation and preferably prior to initiation of antibiotics in all patients presenting with features suggestive of infection (3A).

Antimicrobials should be administered considering prior cultures, local antibiogram and susceptibility patterns (1A).

Asymptomatic bacteriuria (AB) should not be treated (1A) unless same pathogen has been isolated twice consecutively >105 CFU/mL in first 2 months post SOT (2B) or AB is found in Post-kidney transplant recipients. (1B).

Multidrug-resistant (MDR) urinary tract infection (UTI) with gram-negative bacteria such as Pseudomonoas spp and Klebsiella spp, newer agents like ceftazidime-avibactam can be considered as alternatives to colistin or aminoglycosides. (1B).

Approach to Diagnosis and Treatment of Respiratory Infection

Evidence Statement

Acute respiratory failure (ARF) following SOT can be due to variety of infective and noninfective causes. Patterns of involvement on chest radiograph or CT scan can help to narrow down diagnosis. Ground glass opacities and micronodular infiltrates can suggest PJP or CMV, whereas lobar consolidation suggests bacterial etiology. Nodular infiltrates suggest fungal, tubercular or malignant etiology. Majority of cases of community-acquired pneumoniae have been seen after 6 months posttransplantation. Early initiation of antibiotics after sending blood cultures in patients with septic shock leads to better outcomes. Organisms responsible for CAP include viruses, bacteria, fungal and mycobacteria. Streptococcus pneumoniaee has been reported to be most common bacteria causing CAP, whereas P. aeruginosa was the most common microorganism isolated in nosocomial pneumoniae. Bronchoscopic BAL leads to microbiologic diagnosis in up to 77% cases. CT Guided biopsy has been used for diagnosis of patients with lung nodules. Open lung biopsy has been reported to have high yield (85%) but with increased risk of complications. Empiric antimicrobial therapy for pneumoniae in SOT patients would depend upon the net state of immunosuppression, the epidemiological exposures, the clinical and radiological profile of the patient, and the local antibiogram.

Recommendation

We recommend obtaining chest radiograph in all patients with suspected pneumoniae (2A).

We recommend performing a chest computerized tomography (CT) scan in all SOT patients with pneumoniae (I,A) and high resolution CT (HRCT) scan in patients with nodular infiltrates with suspected invasive aspergillosis (1A).

We recommend obtaining nasopharyngeal swab for influenza virus testing by PCR if seasonally appropriate and high suspicion for viral pneumoniae(1A).

Early BAL should be considered in SOT patients with suspected pneumoniae admitting to ICU (1A).

We recommend BAL in patients with pulmonary infiltrates not improving on empiric antimicrobial therapy or in whom there is diagnostic uncertainty on non-invasive testing (1A).

– BAL fluid should be tested for:

- Stains and immunohistochemistry- Gram stain, KOH/Calcofluor white, Auramine-rhodamine, auramine-o, or ziehl-neelson, Modified acid-fast stain, Silver methenamine stain, Galactomannan assay (<0.5 Negative predictive value, >3 positive predictive value).

- Polymerase chain reaction (PCR)- Mycobacterium tuberculosis (Cartridge Based Nucleic Acid Amplification Test (CB-NAAT or GeneXpert), Multiplex PCR assay [(Including Respiratory viruses, CMV)(Quantitative or semiquantitative detection- particularly bacterial)].

- Culture- Aerobic culture for bacteria, mycobacterial growth indicator tube (MGIT) for Mycobacterium tuberculosis, fungal culture.

Following organisms are diagnostic of infections. If identified, they are less likely to be the contaminants/colonizers and should be treated: Pneumocystis carinii, Toxoplasma gondii, Strongyloides stercoralis, Legionella pneumophila, Cryptococcus neoformans, Histoplasma capsulatum, Mycobacterium tuberculosis, Mycoplasma pneumoniaee, Influenza a and b viruses, Respiratory syncytial virus. (2A)

Open/Video-assisted thoracoscopy (VATS)/CT guided/transbronchial biopsy should be done in patients with lung infiltrates where the non-invasive testing/BAL haven't been able to provide the diagnosis and who have failed to respond to therapy, after risk-benefit assessment on case to case basis (2A).

Any prior microbial colonization or antimicrobial resistance pattern of particular organisms should be considered while deciding empiric treatment for pneumoniae in SOT patients, particularly so in case of colonization of airway in lung transplant patients (3A).

Empiric antibiotic therapy with carbapenem based on local susceptibility patterns for suspected community-acquired bacterial pneumoniae along with coverage of atypical /intracellular pathogens like Mycoplasma pneumoniaee, Chlamydia pneumoniae, and Legionella spp. is recommended (2A). For the coverage of latter, among macrolides, consider using azithromycin instead of clarithromycin or erythromycin because of its relatively less likelihood to interact with immunosuppressants.

For suspected viral pneumoniae, adding antiviral for influenza should be considered (2A).

We recommend empiric treatment of recipients requiring hospitalization for pneumoniae with broad-spectrum antibiotics (carbapenem ± antipseudomonal ± anti MRSA) depending on local flora and resistance patterns, along with coverage for atypical organisms (2A).

Antipseudomonal agent/polymyxin should be added if the patient is admitted in the hospital for ≥48 hours before symptoms (nosocomial pneumoniae) (2A), visited medical care (hemodialysis, wound care, immunosuppressants) within the previous 30 days, or hospitalized in an acute care hospital ≥2 days within the prior 90 days (UPP).

Empiric antifungal therapy may be initiated where there is strong suspicion based on the clinical and radiological profile of the patient (3B).

Empiric therapy should be initiated/modified as per clinical, radiological and microbiological findings and response (2A).

CMV Management

Evidence Statement

CMV reactivation risk is increased in post SOT patients due to immunosuppression induced lymphopenia and lymphocyte anergy. Preoperative CMV-IgG serology of donor and recipient can be used to assess risk and guide prophylaxis. In posttransplant period, CMV DNA using quantitative nucleic acid amplification is the diagnostic modality of choice. Detection of CMV by QNAT in BAL fluid and cerebrospinal fluid (CSF) is feasible. For end organ CMV disease, histopathologic diagnosis is the gold standard. CMV retinitis is diagnosed based on ophthalmologic examination. RT-PCR was a more reliable tool to monitor the response to therapy. Pre-emptive therapy is used for most SOT recipients, however, lung transplant patients should receive prophylaxis. Valganciclovir and intravenous ganciclovir have good efficacy and are used for prophylaxis and disease respectively. Letermovir has been shown to be noninferior to valganciclovir for prophylaxis in post renal transplant patients. Post prophylaxis delayed onset CMV disease occurs in donor positive recipient negative SOT recipients three to six months after completion of antiviral prophylaxis and should be treated with pre-emptive therapy. High dose ganciclovir or foscarnet are effective in empiric reatment of refractory disease, along with cautious reduction in immunosuppression. Immunoglobulins as adjunct therapy have been used in refractory disease.

Recommendation

Antiviral Prophylaxis

Antiviral prophylaxis should be initiated within 10 days post SOT in all at-risk recipients for prevention of CMV infection/disease (1A).

Valganciclovir (oral 900 mg once daily) or intravenous ganciclovir (5 mg/kg IV once daily) should be used for prophylaxis in all SOT recipients. Only in Post-kidney transplant patients, high dose oral valacyclovir (2Gram qid) may be used as an alternative agent (1A).

The duration of prophylactic therapy depends upon the CMV serostatus of the donor (D) and recipient (R) pre-transplant and the specific organ transplanted (Table 5).

For patients receiving lymphocyte‐depleting anti‐lymphocyte antibodies (e.g. anti-thymocyte globulin ATG) for rejection, antiviral prophylaxis with valganciclovir or intravenous ganciclovir should be initiated (1A).

Pre-emptive Therapy

Pre-emptive therapy for prevention of CMV disease in asymptomatic CMV infection in SOT patients (tested weekly post-transplant for up to 12 weeks or longer) with valganciclovir 900mg twice daily or intravenous ganciclovir (5 mg/kg twice daily) should be initiated once the predefined viral load threshold has been achieved, and duration be guided by viral load monitoring (ie, CMV DNAemia or antigenemia below the predefined threshold or not detected) (1A).

Antiviral prophylaxis is preferred over pre-emptive therapy for prevention of CMV disease heart transplant patients (1A).

Preemptive therapy is not recommended for prevention of CMV disease in lung transplant patients (1A).

Therapy for CMV Disease

We recommend CMV DNA by QNAT as the laboratory method of choice for rapid diagnosis of CMV infection in blood after SOT (1A).

We recommend treatment of CMV disease with intravenous ganciclovir (5mg/kg 12th hourly) or oral valganciclovir (900 mg twice daily) (in renally adjusted dosages) (1A).

For severe or life‐threatening CMV disease, very high viral load, and doubtful gastrointestinal absorption, use of intravenous ganciclovir is recommended (1A).

Oral valganciclovir is an effective initial therapy for mild to moderate CMV disease (I, A), or as a step down to intravenous ganciclovir after clinical improvement (2B).

Foscarnet and cidofovir can be used only as second‐line agents for SOT recipients (due to high risk of nephrotoxicity associated) who are unable to tolerate intravenous ganciclovir or valganciclovir (2A).

We recommend against use of acyclovir, valacyclovir, and oral ganciclovir for treatment of CMV disease (1A).

We recommend a duration of treatment with antiviral for a minimum of two weeks and till there is resolution of clinical signs along with viral clearance as tested by weekly CMV quantitative NAT (QNAT: polymerase chain reaction- PCR) (1A).

After completion of full-dose antiviral treatment, a 1 to 3 months course of secondary prophylaxis may be considered depending on the clinical situation (2B).

We recommend monitoring complete blood count with differential and serum creatinine weekly for assessment of potential hematologic and renal toxicity (1A).

The drug dosage of antiviral should be adjusted as per the renal function test (1A).

The drug dosage of antiviral should not be decreased due to neutropenia or pancytopenia (1A). Hematopoietic growth factors may be used to counter the myelosuppressive effect of the drugs.

Cautious reduction in immunosuppression should be considered in SOT patients presenting with CMV disease, especially if the disease is moderate to severe, or with severe lymphopenia or with refractory/resistant CMV disease (2B).

Empiric treatment of suspected resistant CMV disease include high‐dose intravenous ganciclovir (up to 10 mg/kg q12 hours, renally adjusted) or foscarnet. Definitive antiviral treatment should be guided by results of genotypic testing (2B).

CMV immunoglobulin or IVIg may be used as an adjunct to antiviral drugs in transplant recipients with life-threatening disease, CMV pneumonitis or resistant CMV disease (2B).

Tuberculosis (TB) in SOT Recipient

Evidence Summary

Incidence of tuberculosis is higher as compared to general population. Up to 50% cases of tuberculosis can bre disseminated or extrapulmonary in post SOT patients. Atypical clinical presentations, less sputum positivity and false negative tuberculin and IGRA tests lead to delays in diagnosis. Radiological investigations like CT scan along with bronchoscopy, BAL or histopathologic evaluation from involved site are needed for prompt diagnosis. Rifampin containing regimens reduce serum concentrations of tacrolimus, cyclosporine, sirolimus and everolimus, whereas rifampin free regimens increase the duration of antitubercular therapy.

Recommendation

The diagnosis of active TB in transplant recipients requires a high index of suspicion. Although the diagnostic modalities and treatment of TB in SOT patients remains the same as that in immunocompetent hosts, these individuals often require an invasive procedure, such as bronchoscopy with BAL or lung biopsy (1A).

Rifamycins, particularly rifampin, reduce serum concentrations of tacrolimus, cyclosporine, rapamycin (sirolimus), and everolimus via induction of the cytochrome p450 isoenzyme CYP3A4, necessary dose adjustments, and therapeutic drug monitoring are warranted to avoid development of rejection (II, A). When rifampin is not used, a longer than usual duration of treatment is required (2B).

Infective Diarrhea in SOT Recipient

Evidence Statement

Diarrhea in posttransplant patients can be due to infectious and non-infectious causes. Drug induced diarrhea and infections are most common reported causes. Bacterial infections, parasitic infections (giardiasis) and viral infections (CMV, norovirus) are common infectious causes. Due to frequent exposure to antibiotics and frequent hospitalization, Clostridium difficile-associated diarrhea is also common. Stool investigations should be performed for all suspected organisms. The initial management of C. difficile infection (CDI) remains similar to non-transplant patients.

Recommendation

We recommend empiric management of gastrointestinal infections/diarrhea with ceftriaxone iv + ganciclovir 5mg/kg BD IV and vancomycin 125mg PO QID (if the patient is already on antibiotics to cover CDI) till definitive diagnosis is made (1A).

If the patient is in septic shock, based on local resistance pattern, and previous drug history of patient consider carbapenems (UPP).

We recommend cessation of the inciting antimicrobial agent whenever possible (2A).

We recommend using a NAAT alone or a multistep algorithm for testing (ie, GDH plus toxin; or NAAT plus toxin) rather than a toxin test alone for the diagnosis in stool specimens likely to be having Clostridium difficile infection CDI (2A).

For treatment of CDI in adults, either vancomycin (125mg given 4 times daily orally for adults; 40 to 50mg/kg/day divided QID for pediatric patients, not to exceed adult dosing; for 10-14 days) or fidaxomicin (200mg given twice daily orally for 10 days) is recommended over metronidazole (1A). If these agents aren't available, metronidazole 500 mg 3 times daily by mouth can be used as an alternative.

We recommend oral vancomycin up to 500 mg orally QID in adults for the treatment of severe/fulminant CDI (I,A). If ileus, consider adding rectal instillation of vancomycin 500 mg in 100 mL normal saline as retention enema 4 times a day (2B).

Intravenous metronidazole 500 mg intravenously every 8 hours may be administered together with oral or rectal vancomycin (1B).

In cases of multiple recurrences of CDI, we recommend prolonged courses of oral vancomycin, either in a tapering or pulse dose schedule (2A). Fidaxomicin can be used if available (2B).

Fecal microbiota transplant (FMT) may be considered in recurrent or relapsing CDI (2B).

We suggest consideration for surgical intervention in cases of complicated CDI (2B).

Invasive Fungal Infection in SOT Recipients

Evidence Statement

SOT recipients are at increased risk of fungal infections, highest risk in small bowel transplant, followed by lung, liver, heart, pancreas and kidney transplant. Invasive candidiasis is most common fungal infection, followed by aspergillosis, cryptococcosis, non-aspergillus molds, endemic fungi and zygomycosis. Emerging Candida strains that are drug resistant are a cause for concern and pose challenge in the management. India data is limited, and mucormycosis is the commonest infection. Candida infections are most commonly bloodstream infections followed by intraabdominal infections. Aspergillus colonization and infection is associated with increased mortality in lung transplant recipients. Various diagnostic modalities including serum markers such as beta-D glucan, galactomannan, imaging (CT scan), bronchoscopic evaluation or histologic evaluation of involved site lead to early diagnosis.

Voriconazole remains the drug of choice for treatment of IA, isavuconazole and lipid formulations AmpB being the alternative agents. Echinocandins can be used as salvage therapy. Isavuconazole is non‐inferior to voriconazole for the primary treatment of invasive mold disease caused by Aspergillus and other filamentous fungi. Therapeutic drug monitoring (TDM) for azole antifungals (especially voriconazole and posaconazole) improves clinical efficacy and is preferred. For IC or candidemia, echinocandins remain the drug of choice and in a clinically stable patient it can be switched to fluconazole if the Candida isolate is susceptible to fluconazole. Duration is dependent on culture negativity and resolution of features of invasive candidiasis.

Recommendation

Invasive Aspergillosis (IA) Treatment

It is recommended not to use serum galactomannan (GM) to diagnose IA in SOT patients (1A).

Serum or BAL beta-D-glucan should not be used to screen or diagnose SOT patients for IA (1B).

BAL GM is the preferred parameter for diagnosis of invasive pulmonary aspergillosis and a value of ≥1.0 in combination with other fungal diagnostic methods is used to diagnose IA in SOT recipients (1A).

For IA or positive BAL galactomannan, we recommend voriconazole in the dose of 6mg/kg bd for 1 day f/b 3mg/kg bd (1A).

Isavuconazole and lipid formulations of Amphotericin B (AmB) can be used as alternative agents (1A).

As a salvage therapy, posaconazole can be used where patients fail to respond or are intolerant to first line agents (1B).

Echinocandins are not recommended as a primary therapy (1B) and can be used only as a salvage therapy or as a second agent where combination therapy is being considered (3B).

We recommend therapeutic drug level monitoring (TDM) for voriconazole when using it for the treatment of IA (1A).

We recommend that treatment be continued for minimum 12 weeks, if tolerated, and guided by clinical and radiological response (1A).

Other Emerging Fungal Infections

For infection by mucormycetes, lipid formulations of AmB is the drug of choice for induction therapy (1A).

Posaconazole or isavuconazole can be used as alternative agents for induction and for maintenance therapy (2B).

Surgical excision or debridement is recommended for all wherever feasible, particularly for mucormycetes infection outside of lungs (2A).

For trichosporon, azoles are the recommended first line agents (3A), subject to the susceptibility.

Pneumocystis Jirovecii Infection Management

Evidence Statement

Incidence of PJP infections in SOT recipients ranges from 0.6% to 9% in various studies. Risk depends on degree of immunosuppression. PJP infection, in turn, leads to more episodes of rejection and increased need for steroids and immunosuppression. TMP-SMX has high efficacy and availability in both oral and IV preparation with good oral bioavailability. The optimal duration of therapy is usually 14 days which can be extended to 21 days in severe cases with slow clinical improvement. Adjunctive glucocorticoids are recommended for moderate to severe PCP. PJP prophylaxis reduces incidence of PJP in the first year after transplant.

Recommendation

Anti-pneumocystis Prophylaxis

We recommend anti-pneumocystis prophylaxis to all SOT recipients for 6 to 12 months posttransplant, particularly for centers with incidence ≥3%-5% among transplant recipients (1A).

Longer duration of prophylaxis may be considered in patients with prior history of PJP (Pneumocystis jirovecii pneumoniae) infection, chronic CMV infection, higher intensity of immunosuppression, lung and small bowel transplant recipients, prolonged neutropenia (1A).

Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for prophylaxis of PJP, in a (adult) dose of either 80mg TMP/400 mg SMX (single strength) daily or 160mg TMP/800 mg SMX (double strength) orally three times weekly (1A).

PJP Treatment

We recommend TMP-SMX as the first-line agent and drug of choice with the Trimethoprim component being 15-20 mg/kg /day in 3 to 4 divided doses (1A).

In severe infections, if available, intravenous pentamidine probably remains the second-line agent after TMP-SMX (2A). Its usage should be avoided in pancreas transplant recipients (1B).

Primaquine and clindamycin in combination may be used as alternative in mild to moderate infection. However, primaquine should be avoided in G6PD deficient patients, and association of clostridium difficile-associated diarrhea (CDAD) with long term usage of clindamycin should be considered (2B).

In patients with hypoxemia (PaO2 <70 mmHg on room air), adjunctive corticosteroids should be administered with antimicrobial therapy, ideally within 72 hours of initiating antimicrobial therapy for maximum benefit (2A). The dose of steroids should be 1 mg/kg/day prednisone (or equivalent) given in two divided doses daily for 5 to 7 days (2A). Steroids should be tapered over a period of 7 to 14 days (2B).

Duration of antimicrobial therapy should be for at least 14 days (1B).

CNS Infections in SOT Recipients

Evidence Statement

SOT patients with altered sensorium have multifactorial causes and need extensive work up, with MRI being the initial preferred imaging modality. Empirical regimens with bactericidal or fungicidal agents having CNS penetration are initiated at admission, until definitive diagnosis. Common pathogens causing CNS infections in SOT are viral followed by fungal and bacterial agents. Viral meningoencephalitis is most common CNS disease in large prospective studies. Thus, antibiotics covering both gram-positive and gram-negative pathogens along with Acyclovir is part of initial empiric regimen. Amphotericin B plus 5‐flucytosine is used as initial treatment of cryptococcal meningitis.

Recommendation

We recommend initial workup for suspected CNS infections should include (1A)

– MRI over CT scan.

– CSF analysis including India ink preparation.

– Rapid multiplex PCR on CSF.

– Serum cryptococcal antigen.

We recommend empiric treatment to be started with Ceftriaxone + Vancomycin + Acyclovir (1A).

We recommend liposomal Amphotericin B or AmB lipid complex (ABLC) plus flucytosine as the initial treatment for Cryptococcus for minimum 2 weeks for CNS disease, disseminated disease, or moderate‐to‐severe pulmonary disease (1A). Alternatively, liposomal AmB or ABLC can be used for minimum duration of 4 to 6 weeks (1B).

Nocardia in SOT Recipients

Evidence Statement

Nocardia infection can occur post solid organ transplants. Lung transplant patients seem to be at highest risk. TMP-SMX, carbapenems and linezolid have efficacy against nocardia. Combination therapy is recommended in critically ill patients with pulmonary, cerebral and disseminated nocardial infection.

Recommendation

We recommend the following regimens for treatment of post-transplant nocardia infections

Pulmonary: TMP-SMX (1A) (TMP‐SMX 15 mg/kg in 3‐4 divided doses, for 6 to12 months)

Disseminated or CNS, Critically Ill: Imipenem plus TMP-SMX or Amikacin (2A)

Alternative: Linezolid, Meropenem (1A)

Multidrug-resistant (MDR) Infections in SOT Recipients

Evidence Statement

Carbapenems are effective for treatment of ESBL‐producing Enterobacteriaceae. For Carbapenem‐resistant Enterobacteriaceae (CRE), preferred antibiotics are ceftazidime/avibactam is preferred, whereas and ceftazidime/avibactam plus aztreonam or cefiderocol monotherapy are useful in metallo‐β‐lactamase producing CRE. Tigecycline is useful in treatment of CRE infections outside the urinary tract, and in absence of bacteremia, as combination therapy. For MDR pseudomonas, effective drugs are antipseudomonal β‐lactam or Ceftolozane/tazobactam or Ceftazidime/avibactam. For carbapenem resistant acinetobcacter, high dose ampicillin-sulbactam, tetracycline derivatives (minocycline/tigecycline), polymyxin B, or cefiderocol are options for combination therapy. For MDR Stenotrophomonas maltophilia, combination therapy with two agents (TMP- SMX, minocycline/tigecycline, cefiderocol, or levofloxacin) is effective. However, critically ill patients can be treated with ceftazidime-avibactam plus aztreonam. For MRSA, vancomycin with therapeutic drug monitoring has most evidence. Linezolid can be used for skin and soft tissue infection (SSTI) and nosocomial pneumoniae. Teicoplanin is another efficacious alternative.

Recommendation

Empiric antibiotics for MDR pathogens should be chosen to cover the suspected pathogen spectrum and local microbiology (2A).

The Human Immunodeficiency Virus (HIV)-positive Patient in the Intensive Care Unit

Evidence Statement

Respiratory failure is the most important cause of ICU admission among HIV patients. Causes of community-acquired pneumoniae are similar to non-HIV patients. However, tuberculosis, and opportunistic infections (like Pneumocystis Jirovecii, cryptococcus, CMV) are also common, and can present with respiratory failure. Viral infections like influenza and covid-19 are other important causes. Increasing age, comorbidities, severity of illness, extent of organ dysfunction and cART naivety are predictors of increased mortality.

Recommendation

Patients with severe pneumoniae who require intensive care and without risk of Pseudomonas aeruginosa should be empirically treated with an IV β-lactam plus IV macrolide (2A). Preferred β-lactams are ceftriaxone, cefotaxime, or amoxicillin-clavulanic acid. In patients who are allergic to penicillin, aztreonam plus azithromycin should be used (3A).

If patients with HIV/AIDS develop acute respiratory failure and they have any of the risk factors (Table 1) for Pseudomonas infection we recommend dual antipseudomonal coverage such as anti-pseudomonal β-lactam plus aminoglycoside (examples of anti-pseudomonal β-lactams include ceftazidime, cefoperazone, cefoperazone-sulbactam, piperacillin-tazobactam, imipenem-cilastatin, or meropenem (3A). Table 1 Criteria for level of evidence and grading of strength of recommendations used in formulation of current guidelines

Quality of evidence	Level	
Evidence from ≥1 good quality and well conducted randomized control trial(s) or meta-analysis of RCT's.	1	
Evidence from at least 1 RCT of moderate quality, or well-designed clinical trial without randomization; or from cohort or case-controlled studies.	2	
Evidence from descriptive studies, reports of expert committees, or opinions respected authorities based on clinical experience.	3	
Not backed by sufficient evidence; however, a consensus reached by the working group based on clinical experience and expertise.	Useful practice point (UPP)	
Strength of Recommendation	Grade	
Strong recommendation to do (or not to do) where the benefits clearly outweigh the risk (or vice versa) for most, if not all patients.	A	
Weak recommendation, where benefits and risk are more closely balanced or are more uncertain.	B	

In patients who are allergic to penicillin, aztreonam can be used in place of the β-lactam. Combination therapy may be considered with the addition of aminoglycosides or antipseudomonal fluoroquinolones (e.g., levofloxacin, ciprofloxacin) (3A).

We recommend continuing Azithromycin along with anti-pseudomonal therapy for coverage of atypical pathogens (2B).

We recommend against using fluoroquinolones empirically to avoid development of drug-resistant TB. Patients should also undergo sputum testing for acid-fast bacilli simultaneously if fluoroquinolones are being used (3A).

In patients who have risk factors for methicillin-resistant Staphylococcus aureus (MRSA) infection–empiric treatment should include vancomycin or linezolid (3A).

Empiric therapy should cover P. aeruginosa or MRSA if previously isolated from sputum cultures (3A).

Steroids are not indicated except in cases of refractory shock (2A).

We suggest the addition of clindamycin (to vancomycin, but not to linezolid) in cases of severe necrotizing pneumoniae to minimize bacterial toxin production (3B).

Those with CD4 counts <200/mm3 and without signs of focal consolidation may be suspected to have PCP (2A).

All diagnosed cases of HIV should receive cART and trimethoprim-sulfamethoxazole (TMP-SMX) for PCP prophylaxis to reduce the risk of pneumoniae (1A).

A switch to oral therapy should be considered in patients with community-acquired pneumoniae (CAP) on IV antibiotic therapy who have improved clinically, can swallow, and tolerate oral medications, and have intact gastrointestinal function (2A).

cART should be initiated promptly within 2 weeks of initiating therapy for the pneumoniae if not started (2A).

Diagnostic work up of acute respiratory failure in HIV patient should consist of: (3A)

– Complete blood count with CD4 cell count.

– Sputum microscopy and culture especially for acid fast bacilli (AFB), Nucleic acid amplification tests (NAATs) for TB.

– Chest imaging, lung ultrasound.

– Bronchoalveolar lavage (BAL) for culture, staining with Gomori-Grocott or Giemsa or direct fluorescence antibody for PCP, PCR.

– Blood culture.

– BAL 1, 3 beta-D-glucan (BDG).

– Urine antigen for L. pneumophila and S. pneumoniaee.

– Serum LDH, BDG.

Rule out non-infectious causes of respiratory failure- COPD, Bronchiectasis, lung cancer, heart failure, lung fibrosis, interstitial pneumonitis, drug toxicity, asthma, pulmonary embolism (3A).

Hiv-positive Patient Presenting with Signs of CNS Infection in ICU

Evidence Statement

Patients with HIV and low CD4 counts are prone to opportunistic CNS infections like toxoplasmosis, tuberculosis, cryptococcosis. Less common opportunistic CNS infections are CMV, nocardiosis, aspergillosis, and neurosyphilis. CNS mass lesions and lymphoma are also common with low CD4 counts, Multiple etiologies can often co-exist. Clinical and laboratory evaluation and prompt management is associated with improved outcomes.

Immune reconstitution inflammatory syndrome (IRIS) is another differential if cART is started in undiagnosed or partially treated opportunistic infections.

cART should be continued in the HIV patients admitted to intensive care unit as much as possible.

Recommendation

For a patient coming to ICU with altered CNS function and suspicion of meningitis, we recommend a third-generation cephalosporin- known to penetrate the blood-brain barrier - at higher doses, e.g., Ceftriaxone 2 gm BD intravenously (1A).

We suggest the addition of vancomycin empirically to the initial treatment regime (1B).

We recommend de-escalating antibiotics after culture reports are available (1A).

In patients above 50 years of age, we suggest the use of additional ampicillin at high doses of 2 gm every 6th hourly (1B).

In very young infants of age <1 month, we suggest Ampicillin plus cefotaxime or ampicillin plus an aminoglycoside as the initial management (1B).

Diagnostic work up for CNS infection in HIV patient should consist of: (3A)

– Complete blood count with CD4 cell count.

– Lumbar puncture, CSF (Cerebrospinal fluid) for cell count, glucose, protein, ADA (Adenosine deaminase), lactate, culture, PCR.

– For immunocompromised host–Toxoplasma gondi IgG antigen and antibodies, cryptococcal antigen (serum and CSF).

– Brain imaging preferably MRI (Magnetic resonance Imaging).

HIV-positive Patients Presenting with Suspected Bloodstream Infections or Sepsis of Unknown Origin

Evidence Statement

Lack of cART, low CD4 count, alcohol abuse, smoking, and comorbidities such as liver disease are risk factors associated with bacteremia in HIV patients. Common organisms seem to be non-typhoid Salmonellae, Streptococcus pneumoniaee, Escherichia coli, Staphylococcus aureus, and coagulase-negative Staphylococci. Unidfferentiated fever in patients with low CD4 counts may be due to viral syndromes such as CMV, Disseminated mycobacterial disease, disseminated fungal disease or noninfectious etiology. Disseminated opportunistic infections may trigger hemophagocytic lymphohistiocytosis. Drug-resistant organisms are also seen more commonly in HIV patients. Extensive diagnostic work up is needed in HIV patients with sepsis of unknown origin. In-hospital mortality in HIV patients depends on age, underlying comorbidities and extent of organ dysfunctions and not HIV related parameters such as viral load, CD4 cell count, admission for AIDS-related diagnoses, and prior cART use.

Recommendation

In the presence of sepsis or septic shock, we recommend following the surviving sepsis guidelines like the management of other patients with sepsis (UPP).

In the absence of septic shock or absence of risk factors for Pseudomonas a monotherapy with a third-generation cephalosporin or a cephalosporin, the b-lactamase inhibitor is sufficient (2A).

In more severe disease states, such as in the presence of organ dysfunction or septic shock–a combination of broad-spectrum antibiotics may be used for initial empiric therapy (3A).

Empiric gram-positive coverage is suggested for those who have risk factors for MRSA (UPP).

Anti-fungal agents may be considered only if there is no clinical improvement or there is clinical deterioration even after 72 hours of appropriate empirical antibiotics therapy and CD4 counts <200/mm3 (2A).

We recommend against the use of routine empirical antifungal therapy (2A).

Congenital and Acquired Hyposplenism and Asplenia

What should be the Approach to Empiric Therapy in Patients with Hyposplenism or Asplenia who Develop Sepsis?

Evidence Statement

Patients with congenital and acquired hyposplenism/asplenia are at high risk for encapsulated bacterial infections like Neisseria meningitidis, Streptococcus pneumoniaee and Haemophilus influenzae type b. These patients are more likely to have severe sepsis, and overwhelming post-splenectomy infection (OPSI). OPSI can present with flu-like illness at onset, and rapidly progress to septic shock and death, and therefore needs prompt institution of antibiotics covering for both gram-positive and gram-negative organisms under close observation in high dependency or intensive care units.

Recommendation

If an asplenic or hyposplenic patient is suspected to have sepsis we recommend administration of IV ceftriaxone before transferring the patient to a higher center (2A).

We recommend that all patients with Overwhelming Post-Splenectomy Infection (OPSI) be treated in the ICU (UPP).

We recommend empiric antibiotic therapy for aslpenic patients with a combination of ceftriaxone and vancomycin (1A).

In case of allergy to β-lactams, we recommend vancomycin with aztreonam or fluoroquinolones in adults. Do not delay administration of antibiotics, be prepared to treat reaction (UPP).

We recommend to add clarithromycin or erythromycin in case of respiratory symptoms (3A).

We recommend empiric therapy with IV Cefotaxime + vancomycin+ ampicillin, if the patient age <2 months (3A).

All febrile asplenic patients should be screened for malaria with peripheral smears. Start artesunate based antimalarial therapy, if the history is suggestive of Malaria (UPP).

If gram staining of peripheral blood smear shows gram-negative bacilli, we recommend addition of antipseudomonal coverage to the therapy (3A).

We recommend that urine be checked for urinary antigen for streptococcus pneumoniae. (2A).

We suggest RT-PCR test for simultaneous identification of 3 main encapsulated bacteria (Str pneumoniae, H. influenzae type B and N. meningitidis) (3B).

We recommend that all asplenic patients should receive immunization against encapsulated bacteria (S. pneumoniaee, H. influenzae, and N. meningitidis) (1A).

Immunization against seasonal flu is recommended for patients over 6 months of age (1A).

Vaccination programs should be started no sooner than 14 days after splenectomy (1A).

If the patient is discharged before 15 days after splenectomy or angioembolization, where the risk to miss vaccination is deemed high, we suggest that patient be vaccinate before discharge (1B).

Antibiotic prophylaxis is indicated in patients for 1-2 years after splenectomy and lifelong for patient had an episode of overwhelming infection or immunocompromised (2B).

We recommend self-administration of one dose of, in stock “pill in pocket”, prescribed antibiotics in the event of any sudden onset of unexplained fever, malaise, chills or other constitutional symptoms, when medical consultation not readily accessible within 2 hours (2A).

We suggest that any patient with sepsis having risk factor for hyposplenia, the peripheral smear should be checked for Howell-Jolly bodies. (2B)

We recommend formulation of Spleen registry. (UPP).

Patients with Primary Immune Deficiency in the ICU

Evidence Statement

A diagnosis of primary immunodeficiency should be considered in patients with serious infections. Significant family history, hematologic abnormalities like neutropenia, lymphopenia, recurrent infections, or infections with uncommon organisms can lead to evaluation for primary immunodeficiency. Recurrent sinopulmonary infections are seen with humoral immunodeficiencies. Recurrent infections with organisms like tuberculosis or endemic fungi should lead to evaluation for cell mediated immunodeficiency. Microbiologic diagnosis is important in patients with suspected immunodeficiency due to higher incidence of co-infections and drug resistant infections. In patients with primary immunodeficiency with serious infections, empiric coverage for causative organisms, including viruses and invasive fungal infections is practiced. Treatment for underlying immunodeficiency (e.g., intravenous immunoglobulin therapy) and comorbid autoimmune conditions improves outcomes.

Recommendations

PID should be suspected when the following history/symptoms or signs are present: (UPP).

– Family history of sibling death.

– Four or more ear infections within 1 year.

– Two or more serious sinus infections or pneumoniaes within 1 year.

– Two or more months on antibiotics with little effect.

– Two or more deep seated infections including septicemia.

– Persistent thrush in mouth or fungal infection on skin.

– Infections in multiple anatomic locations.

– Increasing frequency and severity of infections with age.

– Recurrent serious infections with common pathogens.

– Serious infections with unusual pathogens.

We recommend that when PID is suspected, HIV infection should also be considered, and testing should be performed for HIV (UPP).

– We recommend that patient should be investigated for PID when: (3A).

– In neonates, Absolute lymphocyte count (ALC) of <2000/mm3 in cord blood or in an infant an ALC of <4000/mm3.

– Severe hypogammaglobulinemia with IgG <1 50 mg/dL.

– Absolute lymphocyte count <4000/mm3 (In non-chemotherapy setting).

– Unusual organism picked up on microbiology.

– Unexplained neutropenia.

We recommend that Initial laboratory screening should include a complete blood count with differential counts (including Absolute Lymphocyte Count, Absolute Neutrophil Count, Absolute Monocyte Count) and measurement of serum immunoglobulin and complement levels (UPP).

We recommend Severe Combined Immune deficiency (SCID) be considered as a pediatric emergency and attention be paid to Absolute Lymphocyte Count, at all time in ICU. If the Absolute Lymphocyte Count is less than normal for the age, we recommend to take immunology reference, use irradiated blood products, and avoid live vaccines till diagnosis is confirmed or ruled out (UPP).

We recommend that patient be investigated for Combined Variable Immuno-deficiency (CVID) when patient has any of the following: (UPP)

– Recurrent bacterial infections.

– Serum IgG, IgM, IgA levels (at least two of the three) with a marked decrease (at least 2 SD below the mean for age).

– Onset of immunodeficiency at more than 2 years of age.

– Absence of isohemagglutinins and or poor response to vaccines.

We recommend that immunology consult be obtained for these patients and the patient be investigated to diagnose specific form of immunodeficiency (UPP)

– Lymphocyte subpopulations by Flow cytometry (CD3, CD4, CD8, CD19, CD20, CD16 & CD56).

– Naive T cells, Memory B cells, Memory T cells.

– T-cell response to mitogens.

– Nitroblue Tetrazolium-NBT test.

– Complement levels.

– Bone Marrow and Genetic tests.

We recommend for all critically ill patients with suspicion of PID the empirical antimicrobial treatment with IV Carbapenems with IV Vancomycin/Teicoplanin for broad-spectrum coverage. (UPP, A). Voriconazole is the preferred antifungal in case of proven, possible or probable invasive fungal infection with aspergillus (IA).

In critically ill patients diagnosed with Combined B and T cell deficiency the antimicrobial drug of choice is IV Carbapenems with Vancomycin/Teicoplanin and Trimethoprim-Sulfamethoxazole (UPP).

In critically ill patients diagnosed with Combined B and T cell deficiency with suspicion of viral infections, we recommend: (UPP)

– IV Acyclovir if herpes group of infection is suspected.

– Oral oseltamivir if Influenza virus is suspected.

– IV Ganciclovir if CMV is suspected radiologically or by laboratory tests.

In critically ill patients diagnosed with B cell deficiency, based on the organisms expected (Capsulated), we recommend IV ceftriaxone with IV Vancomycin/Teicoplanin (UPP).

We recommend IV Immunoglobulin (IVIg) at dose of 1 gm/kg weekly in cases of severe infections especially ECHO /Enterovirus / Polio virus induced encephalitis (UPP).

In critically ill patients diagnosed with Phagocyte disorder we recommend.

Antimicrobial drug of choice to be IV Carbapenems with IV Vancomycin/Teicoplanin and Voriconazole (UPP).

We recommend the use of Granulocyte colony stimulating factor (GCSF) in patients of congenital Neutropenia (UPP).

In critically ill patients diagnosed with complement deficiency the antimicrobial drug of choice is IV Cephalosporin (UPP).

We recommend appropriate cultures, and PCRs; for organisms likely to cause infections pertinent to the conditions they are suffering from (UPP).

Attempt should be made to identify the microorganisms directly or on PCRs as serological tests in infectious diseases could give false-negative results if there is an antibody defect (UPP).

We recommend the use of Multiplex PCR to help diagnose infections (UPP).

We recommend intravenous Immunoglobulin for treatment of all antibody deficiency diseases, at doses of 400 mg/kg/doses every 4 weekly. We recommend 2 gm/kg single dose (Severe Infections) or 1 gm/kg weekly till infection subsides (UPP).

We recommend to maintain serum IgG trough levels above 500 mg/dL and above 700 mg/dL in bronchiectasis (3A).

We recommend thoracic computed axial tomography, lung function tests with spirometry and DLCO every 6 months after discharge (UPP).

We recommend hematopoietic stem cell transplantation in cellular and macrophage immunodeficiency (UPP).

We recommend monoclonal antibodies such as rituximab only in autoimmune complications related to CVID (UPP).

We recommend Rituximab be given in PID complicated with EBV viremia (UPP).

What should be the Approach to Vaccinations and Antimicrobial Prophylaxis at Discharge for Patients with Primary Immunodeficiency Requiring Intensive Care?

Evidence Statement

Live vaccines are contraindicated in SCID whereas all vaccines are safe and effective in complement deficiency. Antifungal prophylaxis and PCP prophylaxis are important to prevent invasive life-threatening infections in patients with PID.

Recommendations

All forms of live vaccines, viral and bacterial, are contraindicated in patients with SCID (UPP).

We recommend vaccination for diagnosed patients with complement deficiency at time of discharge (UPP).

We recommend avoiding BCG vaccination in Chronic Granulomatous Disease /MSMD patient (UPP).

We recommend antifungal and anti PCP prophylaxis for all patients diagnosed with PID shifted from ICU (UPP).

PID patients with chronic granulomatous disease should be treated with Itraconazole (IA) and Trimethoprim-Sulfamethoxazole (2A).

PCP prophylaxis should be given to all patients with Combined B and T or T cell deficiency with drug of choice being Trimethoprim-Sulfamethoxazole (1A).

We recommend antifungal prophylaxis in all patients with T cell defects (3A).

Introduction

Severe infections are common indications requiring admission to intensive care units (ICU). For these patients, effective antibiotic therapy is lifesaving. The resistance to currently available antibiotics has increased over the last few years. Secondly, only a few new antibiotics have been marketed over the last few years and will be available in the coming years. Another issue is the ever-increasing number of admissions of immunocompromised patients in the intensive care units due to the availability of effective treatment options for acquired immunodeficiency states and cancer, resulting in prolonged survival and cure, use of multiple lines of myelosuppressive therapies at diagnosis and relapse, and better outcomes in these patients. The best way to preserve the efficacy of existing antibiotics is to use these drugs appropriately. One way to do this may be to increase awareness and develop guidelines for the prescription of antibiotics. International guidelines on antibiotic prescription in ICUs have been framed. The Indian Society of Critical Care Medicine also formulated guidelines for empiric antibiotics in intensive care units and immunocompromised patients. 1,2 Regular updation of guidelines is important with arrival of new research and evidence.

Scope of the Guidelines

The scope of these guidelines includes antibiotic prescription for common bacterial infections for pneumoniae (community-acquired, hospital-acquired and ventilator-associated), bloodstream infections, abdominal infection (hepato-biliary, pancreatic, urogenital), central nervous system, skin and soft tissue infections in patients admitted in ICU. These guidelines also include recommendations for use of empiric antimicrobials in immunocompromised patients.

Methodology

This document is the latest effort to improve existing antibiotic prescription guidelines in the intensive care unit (ICU) and antimicrobial prescription guidelines in critically ill immunocompromised patients under the aegis of Indian Society of Critical Care Medicine.1,2 The committee was composed of experts from various fields specializing in ICU infections and was divided into five groups. The team updated the evidence by extensively reviewing the literature through various electronic databases, including PubMed and Embase. The team also reviewed cross-references from articles and all major international guidelines on the topic. The experts in each group exchanged and reviewed relevant literature, and consensus was reached on the scope and questions that needed to be addressed in formulating the guidelines. After thorough discussions and review, the guidelines were framed to ensure their reliability and relevance in clinical practice. Modified Grade System was utilized to classify the quality of evidence and the strength of recommendations (Table 1). Draft document thus formulated was reviewed by all committee members; comments and suggestions were incorporated after discussion, and a final document was prepared. The final document was reviewed and accepted by all expert committee members.

Pharmacokinetics and Pharmacodynamics

Pharmacokinetics deals with the time course of drug absorption, distribution, metabolism, and excretion while pharmacodynamics involves relationship between drug concentration and its effects including toxicity. Each antibiotic has its own pharmacokinetic profile though each class of antibiotics has its class specific properties as well. Each class of antimicrobials has a different pharmacodynamic profile based on different inhibitory characteristics on bacteria.

Individualized dosing regimens using known pharmacokinetics and pharmacodynamic characteristics are important to optimize patient outcomes and minimize antimicrobial resistance. Pharmacokinetic profiles change over time in critically ill patients, warranting periodic reconsideration of dosing regimens.

The factors determining metabolism and effects of an antibiotic include basic antibiotic characteristics such as lipophilic or hydrophilic, patient status such as volume status and end organ function and changes in pathophysiologic characteristics i.e., systemic inflammation and hemodynamics. Hydrophilic antibiotics have low volume of distribution, predominantly renal clearance and low intracellular penetration as compared to lipophilic antibiotics. Examples of hydrophilic antibiotics include beta-lactams, aminoglycosides, vancomycin, linezolid and colistin while lipophilic antibiotics are fluoroquinolones, macrolides, clindamycin and tigecycline.3

The antibiotics can be broadly classified into those with concentration dependent killing activity and those with time dependent killing activity. The examples of former include aminoglycosides, fluoroquinolones, metronidazole, colistin and clindamycin whereas that of latter include beta-lactams, linezolid and tetracyclines.

Sepsis affects the drug metabolism by various mechanisms. Being a hyperdynamic state it (pharmacologically or pathophysiologically enhanced) can increase creatinine clearance and hepatic perfusion thus increasing drug removal. At the same time, sepsis induced organ-dysfunction can reduce metabolism and elimination of active drug. Renal replacement therapies can increase clearance for some drugs like piperacillin-tazobactam and meropenem. Body has adaptive methods for increasing drug clearance during states of multiorgan failure. For example, gastrointestinal clearance of ciprofloxacin is increased in renal failure while biliary clearance of piperacillin increases in renal failure. Serum protein concentration also affects the antibiotic concentration. Significant changes in free fractions of drug are only relevant for highly protein bound drugs (>95%). Small changes in protein binding result in huge relative changes in free (unbound) drug. Changes in protein binding will affect both clearance as well as volume of distribution. Most antibiotics have low protein binding (<90%) except ceftriaxone (95% bound to albumin), ertapenem, teicoplanin, aztreonam and daptomycin.

An open-label RCT involving 140 patients with sepsis compared continuous infusion of beta-lactams with intermittent infusion and demonstrated higher clinical cure rates and higher ventilator-free days in continuous infusion group without any mortality difference between two groups.4 Similar results have been found in various other studies as well though a double-blind study by Dulhunty et al. did not find any difference in ICU-free days, 90-day survival and clinical cure between continuous infusion and intermittent infusion groups.5 An individual patient data meta-analysis found significantly lower hospital mortality rates with continuous infusion of beta-lactams as compared to intermittent infusion in patients with severe sepsis.6 Prolonged infusion (>3 hours) of antipseudomonal beta-lactams was associated with lower all-cause mortality than short-term infusion (<60 minutes) in a meta-analysis of 22 studies comprising 1876 patients with sepsis (Risk ratio, RR 0·70, 95% CI, 0·56-0·87).7 Regarding vancomycin, a meta-analysis including 11 studies comparing continuous versus intermittent infusion found that patients treated with continuous infusion had a significantly lower incidence of nephrotoxicity without any difference in treatment failure and mortality.8

Evidence Statement

Time-dependent antibiotics require drug concentrations greater than the minimum inhibitory concentration (MIC) for a certain time period between doses, which usually ranges from 40 to 50% of inter-dose interval for their best action. Continuous infusions are preferred over extended infusions for beta-lactam antibiotics and are associated with clinical benefits like decrease in hospital stay, cost of therapy and mortality. For vancomycin, continuous infusion is associated with reduced toxicity and cost of therapy but no mortality benefit.

Newer Diagnostics Including Multiplex PCR

Respiratory tract infections (RTIs) are amongst the most common infections in ICUs with high morbidity and mortality rates reported worldwide.9,10 A wide variety of agents, including bacteria, viruses, and fungi are responsible for causing RTIs, which are subclassified as upper respiratory infections (URTIs) and lower respiratory infections (LRTIs).11,12 Viruses followed by bacteria, are the most common cause of RTIs, although mycobacterial and fungal pathogens can cause them as well.11 Syndromic diagnosis is the most used strategy for clinical management because a careful evaluation by trained physician backed by radiological imaging and laboratory based biomarkers, is rapid, inexpensive, and easy to implement.13,14 However, syndromic approach fails to establish the definite etiological diagnosis. At present there is a great deficit in establishing the etiologic diagnosis of RTIs; in most studies almost 30-60% of cases remain without an etiologic diagnosis.14–17 Pathogen-specific microbiological diagnostic test can be categorized into direct diagnosis (microscopic examination, cultures, antigen detection and molecular detection) and indirect diagnosis (antibody detection by serological tests).14,16 Despite being the gold-standard, microbiological diagnosis cannot rely on conventional culture methods alone. These methods have low diagnostic yields due to various host factors, severity and extent of pneumoniae, use of empirical antimicrobials, and sampling method used (quality and site of specimens, transportation conditions, etc.). In addition, for pathogens such as Mycobacterium tuberculosis, atypical organisms like Legionella, Chlamydia pneumoniaee, Mycoplasma pneumoniaee, fungi, and viruses; culture has either a low sensitivity and/or is time-consuming.16,17

Recent times have seen a surge in rapid culture-independent novel assays and molecular diagnostics for common respiratory pathogens, as well as the availability of updated tests for newer strains of pathogens. These include antigen detection assays, reverse transcription–quantitative polymerase chain reaction (RT-qPCR) testing, multiplex PCR panels targeting multiple organisms, plasma cell-free DNA, next-generation sequencing (NGS), etc. on blood, and upper and lower respiratory tract specimens to detect viral, bacterial, fungal, and mycobacterial infections.11,18–21 These have enabled major advances in the speed and sensitivity of diagnostics for RTIs, although the clinical utility of these methods is still under evaluation. However, the clinical implementation of these techniques is challenging as mere detection of pathogens in respiratory specimens does not necessarily imply acute infection. 14,16 The increased sensitivity for detection of pathogens poses problem of distinctions between pathogens, colonizers, commensals, and contaminants. Other challenges include detection characteristics, bioinformatics requirements, and reimbursement issues. 16,20,21

The disease prevalence (i.e., the pretest probability of a given pathogen) is integral to diagnostic decision making since it affects the positive- and negative-predictive values of these assays. 14,16,20

Routine viral testing for influenza by molecular methods in general adult population with RTIs is not recommended, especially in periods of low prevalence. However, for more serious cases, such as those requiring hospitalization, ICU care or therapy, or pneumoniae in pediatric patients or immunocompromised hosts (ICHs), rapid diagnosis can be important.19,22–25

Rapid molecular diagnostics for viral, bacterial, and fungal pathogens should be considered in carefully selected cases symptomatic cases with worsening or new radiological infiltrates, having moderate/severe illness requiring hospitalization/ICU care; pediatric or ICH population, and/or in cases suspected to have polymicrobial/multidrug-resistant infections.14,16 NAATs (nucleic acid amplification tests) for the detection of respiratory pathogens have been available since early 2000s. These tests differ in complexity (i.e., PCR, nucleic acid sequence-based amplification (NASBA), transcription-mediated amplification (TMA), strand displacement amplification (SDA), loop-mediated isothermal amplification (LAMP), rolling circle amplification (RCA), and others) and, pathogen coverage.12,26,27 Moreover, the accuracy is not only dependent on their specific chemistry, but also critically affected by the type, quantity, and quality of specimens collected.26,28 There are a number of NAATs available commercially for the detection of respiratory pathogens, many of which are FDA approved. Simple to complex sample-to-answer molecular platforms and panels are available, which can be subclassified as low-plex integrated test systems (targeting 1-4 pathogens per assay, allow random access), moderate complexity multiplex integrated systems (moderate sample throughput i.e. 1-12 samples/run, with a fast turnaround time (TAT) of 1-2 hours, and allowing random/batched access), and high complexity multiplex panel assays (high sample throughput i.e. more than 20/run, usually batched access, with higher TAT). Syndromic multiplex panels require considerable knowledge, training, and experience. Despite the advantages, implementation of high throughput panels can be challenging because of demanding sample preparation, processing, and result interpretation procedures, and the turnaround time varies from approximately 5–16 h.26,28 NAAT based point-of-care (POC) testing is relatively new in the realm of RTI diagnosis, with contradicting opinions regarding their implementation and clinical utility. These have extremely short turnaround times (<30 min), minimal hands-on time (1–2 min), and can be easily operated by non-laboratory staff members, thereby making them suitable for near patient implementation and testing. However, these can be costly and more prone to incorrect results and contamination due to laboratory handling by inexperienced personnels.26,27,29 These have been summarized in Table 2.

Table 2 Types of FDA-approved commercially available molecular panels for bacterial and viral RTIs

Diagnostic assay	Type of respiratory specimen	Turn-around time	
Influenza A/B only
a) Waived POCT
b) Moderate to high complexity assays	Nasal/Nasopharyngeal swab
Nasal/Nasopharyngeal swab	15–30 minutes
30 minutes – 2 hours	
RSV only	Nasal/Nasopharyngeal swab	15–30 minutes	
Influenza A/B plus RSV
a) Waived POCT
b) Moderate to high complexity assays	Nasal/Nasopharyngeal swab
Nasal/Nasopharyngeal swab/Nasopharyngeal aspirates/Nasal washings	15–30 minutes
1–3 hours	
Parainfluenza viruses	Nasopharyngeal swab	2–4 hours	
Multiple viruses plus atypical bacteria
a) Waived POCT
b) Moderate to high complexity assays	Nasopharyngeal swab
Nasopharyngeal swab/Nasopharyngeal aspirates/Nasal washings	1–2 hours
1–5 hours	
Multiple viruses (Moderate to high complexity assays)	Nasopharyngeal swab/Nasopharyngeal aspirates/Nasal washings/Bronchoalveolar lavage (BAL)	2–5 hours	
Multiple bacteria with resistance genes (Moderate to high complexity assays)	Endotracheal aspirates/BAL	4–5 hours	
Multiple viruses and bacteria with resistance genes
a) Waived POCT
b) Moderate to high complexity assays	Sputum/Endotracheal aspirates/BAL
Sputum/Endotracheal aspirates/BAL	1–2 hours
>6 hours	
Adapted from: Murdoch DR, Werno AM, Jennings LC. Microbiological Diagnosis of Respiratory Illness: Recent Advances. In Kendig's Disorders of the Respiratory Tract in Children; Elsevier: Amsterdam, The Netherlands, 2019; pp. 396–405.e3. Hanson KE, Azar MM, Banerjee R, et al. Molecular Testing for Acute Respiratory Tract Infections: Clinical and Diagnostic Recommendations From the IDSA's Diagnostics Committee. Clin Infect Dis. 2020 Dec 17;71(10):2744-2751

There are upcoming technologies like untargeted next-generation sequencing-based metagenomics (mNGS) testing for accurate and unbiased detection of expected or unexpected pathogens that are either not targeted by the panel or missed due to highly divergent genome sequences. However, diagnostic implementation of NGS is currently limited by incomplete understanding of analytical performance, high cost of the system and complexity of sequence data analysis.

Currently, molecular diagnostics is the gold standard for the diagnosis of viral respiratory infections.15–17 Several types of specimens can be used for detection of respiratory viruses, including: bronchoalveolar lavage (BAL), throat/oropharyngeal (OP) swab, nasopharyngeal (NP) washes, NP aspirates, lung aspirates, and NP swabs, although the appropriate specimen type depends on the specific patient population.26,27,29 However, false-positive or false negative results can be a problem due to poor handling of specimen.12,15 In a recent meta-analysis, the pooled sensitivity and specificity of rapid viral NAAT were 90.9% and 96.1%, respectively, for the detection of either influenza virus, respiratory syncytial virus (RSV), influenza virus and RSV, or a viral panel including influenza virus and RSV.27 Upfront multiplex testing for multiple viruses may be most cost-effective in certain specific populations such as pediatric patients, ICH population, and critically ill patients with pneumoniae where it can reduce unnecessary antibiotics as well as chest radiographs.16,23 A recent meta-analysis compared the diagnostic accuracy of Luminex NxTAG respiratory pathogen panels (RPPs)™ (index) against other RPPs (comparator) for detection of RSV and influenza viruses.30 For RSV, predicted sensitivity was 99% and specificity 100%. For influenza A and B, predicted sensitivity was 97% and 98% respectively; specificity 100% and 100%, respectively. Multiplex vial panel can increase the detection of a number of infections that otherwise go undiagnosed because they are not suspected. A recent study demonstrated a 75% higher recovery rate of unexpected M. pneumoniaee infection using multiple PCR.28 NAAT based POC assays are currently limited to the detection of influenza A/B and RSV viruses, with the exception of the FilmArrayR RP EZ (BioFire) which detects 14 targets. The clinical performance of these assays is reported with a high sensitivity (87–100%) and specificity (>98%) for detecting influenza A/B and RSV in pediatric and adult patients. However, the clinical performance varies, and sensitivity is significantly low for influenza B (45.2–54.5%).26

NAAT based PCR assays have been developed for numerous bacterial pathogens, with greater accuracy and sensitivity of identification compared to conventional culture-based diagnostics.12,31,32 NAAT platforms may allow co-detection of multiple bacteria, viruses, or bacteria plus viruses in up to 30–40% of cases and have important implications for hospital infection control and treatment decisions.31,32 High analytic sensitivity of multiplex panels also translates to high negative predictive values (i.e., generally >97%, depending on prevalence), but there may be important differences among individual panel targets or across manufacturers.15–17,32,33 Due to the need for isolation of the microorganism for antibiotic susceptibility testing, molecular methods can theoretically replace cultures only in cases in which the pathogens are of predictable susceptibility or the genetics of resistance are well defined.34 Furthermore, there can be inconsistencies with resistance gene detection, especially in cases of co-infections or when the sample is obtained from an anatomical site with low prevalence of resistant pathogens.32–36 For example, the CTX-M type extended-spectrum beta-lactamases gene was reported for any member of the families Enterobacteriaceae, Acinetobacter spp., or P. aeruginosa, and for this reason, when a resistance phenomenon is common to different bacteria, the conventional culture and the phenotypic AST are required to confirm the indication of the resistance marker.32

Fungal diagnostics are rapidly evolving as conventional culture tests are faced by many challenges such as poor sensitivity, slow TATs, laborious process, and invasive nature of specimens required for testing. 19,37 Serological testing represents a quicker way of detecting the causal fungi, aiding in the diagnostic decision-making process.38 The major limitation of antibody-based testing is seen in ICH population, who are unable to elicit adequate levels of antibodies and may show false negative results.37,38 Galactomannan (GM) and β-1,3-D glucan (BDG) are fungal cellular wall constituents that can be detected in serum or bronchoalveolar lavage (BAL) fluid to aid in the diagnosis. GM is more specific to Aspergillus spp. than BDG. In a recent meta-analysis, serum GM in ICHs suspected of IPA had a pooled sensitivity and specificity of 71%, and 89% respectively.39 BAL GM, on the other hand, had a pooled sensitivity and specificity of 84%, and 88% respectively. BDG is pan-fungal antigen found in Candida spp., Aspergillus spp., Mucorales, and Pneumocystis jirovecii, etc. Antigen and antibody testing have made great strides with introduction of newer techniques like lateral flow assay (LFA) based tests to allow higher diagnostic accuracy; however, cross-reactivity with other fungi, and test availability remain considerable issues.38,39

Fungus-specific quantitative real-time PCR amplification has been available for diagnosis of invasive fungal infections.37 In the recent meta-analysis, the serum or whole-blood fungal PCR had pooled sensitivity and specificity of 81%, and 79% respectively. BAL fungal PCR in the same group had pooled sensitivity and specificity of 90%, and 96% respectively.39

Early and accurate diagnosis of causative pathogens in RTIs can help in administering appropriate antimicrobial therapy (time to initiation, duration, and discontinuation), initiate effective infection control measures, and reduce length of hospital/ICU stay.40–42 Rapid molecular testing for influenza can decrease unnecessary antibiotic use, improve antiviral prescribing, limit ancillary testing, shorten lengths of stay, and promote infection-control practices.22–25 Several studies evaluated the clinical and economic impacts of multiplex respiratory testing, and concluded that, despite their high cost, multiplex panels offering custom orders can limit unnecessary testing, improvement in the clinical outcomes of patients mainly by the early administration of a targeted antibiotic therapy, and in the rapid adjustment and de-escalation of empirical therapy resulting in a short duration of treatment, minimizing patient costs. Current evidence suggests that syndromic multiplex PCR testing, coupled with antimicrobial stewardship, increases the timeliness of antiviral prescription in influenza patients and the rapid appropriateness of antibiotic treatment.

Rapid pathogen identification tools for UTIs utilize existing molecular platforms such as mass spectrometry and multiplex PCR. MALDI-TOF (matrix-assisted laser desorption ionization time of flight) mass spectrometers are increasingly used for unambiguous species-level identification of bacteria and yeast.43,44 Multiplex PCR offers a cost-effective and rapid approach to pathogen identification. Many studies have examined PCR assays for specific UTI pathogens. All such studies have found that multiplex PCR compares favorably with a standard urine culture.45–47 A recent meta-analysis, concluded that multiplex PCR and RT-PCR are molecular techniques that might be comparable to standard urine culture for UTI diagnosis, with a pooled sensitivity at 80% and a specificity at 83% for multiplex-PCR.48 Upcoming molecular diagnostics include the Next-generation sequencing (NGS) studies. Next-generation sequencing (NGS) has been used to identify causative pathogens in various infectious diseases including UTI.49 A systematic review compared the diagnostic and therapeutic values of molecular diagnostic methods (NGS, and PCR) to urine culture in the management of UTI in adults.50

Nucleic acid purification directly from the fecal samples is a first and key step for rapid molecular diagnosis of enteric viruses.51,52 Multiplex RT-qPCR assay have been developed for the detection of different enteric viruses, namely Astrovirus, Adenovirus, Rotavirus A, C, Sapovirus, and Enterovirus from stool samples; many assays being able to detect up to 19 enteric pathogens with high sensitivity.53 A recent pragmatic, open label, randomized controlled trial (RCT)54 studied the clinical impact of syndromic molecular testing (mPOCT) for gastrointestinal pathogens in 128 adult patients presenting to hospital with suspected gastroenteritis. They found that 65% of patients received antibiotics in m-POCT group versus 47% in the control group (p = 0·0028). Another recent prospective, single‐center, RCT also found that use of multiplex GI PCR led to an increase in antibiotic use for bacterial and protozoal causes of infectious diarrhea compared to usual testing.55

Community-acquired Pneumoniae in the Intensive Care Unit

Community-acquired pneumoniae (CAP) refers to symptoms suggestive of acute lower respiratory tract illness (cough with or without expectoration, dyspnea, pleuritic chest pain) along with systemic manifestations (fever, chills, rigors or severe malaise), clinicoradiologic evidence (like crepitations or bronchial breath sounds; lobar or patchy consolidation or interstitial infiltrates) and no other explanation for the illness.56,57 CAP can simply be defined as pneumoniae which is not acquired in hospital or long-term care facility.58

What are the Common Organisms Causing Community-acquired Pneumoniae in Intensive Care Unit Worldwide and in India?

Most common etiology of community-acquired pneumoniae are viruses, ranging from 8.6% to 56.2%.59 Pooled proportion of viral pneumoniae was 25.5% (95% CI, 22–29%) amongst patients requiring admission, and 29% (95% CI, 14.5–43.4%) in patients requiring ICU admission. Most common viruses responsible for CAP were influenza (8%; 95% CI, 6.3–9.6%), rhinovirus (5.7%; 95% CI, 4.3–7.1%), respiratory syncytial virus (2.2%; 95% CI, 1.6–2.8%) and coronavirus (3.3%; 95% CI, 2.3–4.2%).59 Common organisms causing CAP requiring intensive care admission worldwide include streptococcus pneumoniaee (12–43%), Haemophilus influenzae (0–12%), Legionella pneumophila (0–30%), Staphylococcus aureus (0–19%), gram-negative enteric bacilli (0–27%), Mycoplasma pneumoniaee (0–7%), chlamydia species (0–2%) and Coxiella burnetti (0–2%).60 In a recent active population-based surveillance study, streptococcus pneumoniaee, Staphylococcus aureus and enterobacteriaceae were more commonly implicated in CAP requiring intensive care (p < 0.001).61 In secondary analysis of an international, multicenter, point-prevalence study on CAP in ICU, bacterial etiology could be identified in 35.3% patients. Streptococcus pneumoniaee (8.2%), Pseudomonas aeruginosa (4.1%), Klebsiella pneumoniaee (3.4%) and methicillin resistant Staphylococcus aureus, i.e., MRSA (3.0%) were the most common organisms isolated. MRSA and pseudomonas caused higher proportion of ICU admissions (p < 0.01).62 MRSA has been identified as important cause of CAP in intensive care unit (ICU) settings in earlier observational studies, case series and case reports.63–66 MRSA pneumoniae.

Literature on epidemiology of CAP in India comes from hospital based observational studies and surveillance data as the ICU specific studies are not available. Streptococcus pneumoniaee (2–35.8%), Mycoplasma pneumoniaee (3–24%), chlamydia pneumoniaee (6–18%), Legionella spp. (2–15%), Mycobacterium tuberculosis (0–5%), Haemophilus influenzae (0–15.4%), Staphylococcus aureus (2–13%), klebsiella pneumoniaee (3–25.5%), other gram-negative bacilli (0–19%) are the common organisms implicated in CAP requiring hospitalization in India.67–89 High prevalence of Staphylococcus aureus (26.7%) and MRSA causing CAP (60.9% of staphylococci) has been reported in one Indian study.68

Increasing age, active smoking, chronic obstructive pulmonary disease (COPD) and diabetes mellitus appear to be significant risk factors for development of severe CAP. Structural lung disease and COPD are risk factors for infection due to Pseudomonas aeruginosa.56,90–92

Streptococcus pneumoniaee largely remains sensitive to amoxycillin-clavulanic acid and azithromycin with only few studies reporting resistance to amoxycillin-clavulanic acid (20%), levofloxacin (20%) and azithromycin (13%).56,76,77,86 There is limited data on antibiotic sensitivity patterns of other microbes. H. influenzae also seems to be largely sensitive to amoxycillin clavulanic acid and azithromycin; in one study, 23% isolates were resistant to amoxycillin-clavulanic acid, 13% were resistant to azithromycin whereas only 6% were resistant to cefuroxime.86 gram-negative bacilli (GNB) are usually sensitive to beta-lactams and fluoroquinolones.84 However, in recent studies, prevalence of extended spectrum β-lactamase (ESBL) organisms appears to be increasing with resistance to carbapenems (16.6%), piperacillin-tazobactam (39.5%), and cefoperazone-sulbactam (42%) reported in a recent prospective study.86 Drugs effective against methicillin sensitive Staphylococcus aureus (MSSA) include penicillinase resistant penicillins (nafcillin, oxacillin) or penicillin-beta-lactamase combination (amoxycillin-clavulanate, ampicillin-sulbactam). Community-acquired methicillin resistant Staphylococcus aureus (CA-MRSA) has sensitivity to tetracycline, doxycycline, minocycline, -tigecycline, clindamycin and co-trimoxazole, whereas hospital-acquired MRSA (HA-MRSA) is sensitive to vancomycin, teicoplanin, daptomycin, linezolid and ceftaroline.93–97 Linezolid has shown better clinical success rate as compared to vancomycin in MRSA pneumoniae (57.6% vs 46.6%; 95% CI, for difference 0.5%-21.6%; p = 0.04) with lesser nephrotoxicity (8.4% vs 18.2%) and similar mortality in a prospective double blind RCT.98 In a recent meta- analysis, 7 RCTs (n = 1289) and 8 retrospective cohort/case control studies (n = 6125) of MRSA pneumoniae patients, linezolid was better than vancomycin in terms of microbiologic cure rates (RR = 0.81, 95% CI, 0.71-0.92), microbiological eradication (RR 0.71, 95% CI, 0.62-0.81) and clinical cure (0.35, 95% CI, 0.18-0.69), without any significant difference in adverse drug effects or mortality.99 Newer agents have been approved for treatment of CAP. These include omadacycline, delafloxacin and Lefamulin. Omadacycline, a tetracycline derivative, has activity against common CAP pathogens, MRSA, gram-negative bacilli, anaerobes but not against pseudomonas, and has been approved in hospitalized CAP patients is US Food and Drug Administration (FDA) approved for the treatment of hospitalized CAP.100,101 Lefamulin, a pleuromutilin, another antibiotic approved for CAP, is effective against H. influenzae, M. catarrhalis, S. Pneumoniaee, MRSA, anaerobes and atypical CAP pathogens, but not against GNBs and Pseudomonas.102,103 Delafloxacin, a quinolone, has activity against gram-positive and gram-negative bacteria, anaerobes, Neisseria gonorrhoeae, and atypical respiratory pathogens (Legionella, Chlamydia, Mycoplasma), MRSA and Pseudomonas and is efficacious for treatment of lower respiratory tract infections.104,105

Evidence Statement

Viruses (including influenza), streptococcus pneumoniaee, gram-negative bacilli (including klebsiella), Haemophilus influenzae and atypical organisms (Mycoplasma pneumoniaee) and are common causes of community-acquired pneumoniae (CAP) in intensive care unit (ICU). Staphylococcus aureus, Legionella and Mycobacterium tuberculosis are less common causes of CAP in ICU. Pseudomonas aeruginosa is an important pathogen causing CAP in patients with structural lung disease. Methicillin resistant Staphylococcus aureus (MRSA) and multidrug-resistant gram-negative organisms are relatively infrequent causes of CAP in India and are associated with risk factors such as structural lung disease and previous antimicrobial intake. Anaerobic organisms may cause CAP or co-infection in patients with risk factors for aspiration like elderly, altered sensorium, dysphagia, head and neck malignancy. S. pneumoniaee remains sensitive to beta-lactams and macrolides. Haemophilus influenzae has good sensitivity to beta-lactam with beta-lactamase inhibitors and fluoroquinolones. Recent studies show increasing prevalence of extended spectrum β-lactamase (ESBL) producing enterobacteriaceae. Newer agents like omadacycline, delafloxacin and Lefamulin have added advantages of being effective against MRSA and anaerobes. Omadacycline and delafloxacin are effective against GNBs, whereas only Delafloxacin has good sensitivity against pseudomonas. Nafcillin and oxacillin are preferred agents for MSSA whereas agents effective against MRSA pneumoniae include linezolid, vancomycin and teicoplanin.

What are the Risk Factors for Multidrug-resistant (MDR) Pathogens for CAP in ICU?

Age more than 65 years, chronic respiratory disease, prior antibiotic treatment, prior isolation of resistant organisms from respiratory secretions and presentation with acute renal failure were associated with increased risk of CAP due to multidrug-resistant (MDR) pathogens in prospective observational studies.106–112 Other factors associated with increased risk of MDR CAP include prior hospitalization for more than 48 hours in the last 3 months, home infusion therapy and patients on renal replacement therapy. Immunosuppression was also considered to be a risk factor for CAP due to MDR organisms.56

Evidence Statement

Risk factors for multidrug-resistant (MDR) organisms include age >65 years, antimicrobial therapy in the preceding 3 months, high frequency of antibiotic resistance in the community, hospitalization for ≥48 h in the preceding 3 months, home infusion therapy including antibiotics, home wound care, chronic dialysis within 1 month, family member with MDR pathogen and ongoing immunosuppressive treatment.

Recommendation

All patients admitted with CAP in ICU should be evaluated for risk factors for infection with MDR organisms (2A).

Antibiotic therapy should be individualized to cover the commonly implicated organisms according to risk factors, including Pseudomonas, ESBL producing enterobacteriaceae or MRSA (3A).

If antipseudomonal, MRSA specific or non-standard antibiotics are initiated emperically, early microbiologic diagnosis of respiratory secretions (Gram stain, PCR or multiplex PCR) and blood cultures should be sought for early de-escalation or narrowing down antimicrobial therapy (3A).

Should Serum Procalcitonin Levels be Done at Baseline in Patients Admitted with CAP in ICU?

Procalcitonin is a promising biomarker for antibiotic stewardship in lower respiratory tract infections (LRIs).113 Various trials evaluating use of procalcitonin in LRIs tested serum procalcitonin at baseline.114,115 Serum procalcitonin had an area under ROC curve 0.73 (95% CI, 0.69–0.77) in differentiating bacterial from viral etiology of CAP in a recent meta-analysis.116 Serum PCT had low sensitivity [0.55 (95% CI, 0.37–0.71) and specificity (0.76, 95% CI, 0.62–0.86) in differentiating bacterial from viral etiology in CAP.117 Though serum procalcitonin based strategies led to reduction in antibiotic exposure in a meta-analysis of 26 RCTs including 6706 patients, most benefit was attributed to early cessation, and not initiation.118 In the ProACT trial (n = 1656), PCT-based strategy did not show any significant difference in antibiotic expsoure for LRI patients (−0.05 day; 95% CI, −0.6–0.5; p = 0.87).114

Evidence Statement

Serum procalcitonin has moderate sensitivity and specificity in differentiating bacterial and viral etiology in CAP. Serial measurements of procalcitonin are useful in limiting antibiotic exposure in ICU patients with lower respiratory tract infections, predominantly by early cessation.

Recommendation

Serum Procalcitonin should not be used to differentiate bacterial and viral etiology in CAP in ICU (1A).

Serum procalcitonin levels should be measured at baseline and serially for use in antibiotic de-escalation for CAP in ICU (1A).

How Early should the Antibiotics be Initiated in Patients with CAP Who Require ICU Admission?

In retrospective studies on CAP, initiation of antibiotics within 4 hours of presentation has been associated with reduction in all-cause mortality, regardless of severity [relative risk (RR) 0.24; 95% confidence interval (CI) 0.08–0.71].119 Systematic review of prospective studies also favored early administration of antibiotics, however, confidence interval was wide (RR 0.82; 95% CI, 0.54–1.24).119 Recent meta-analysis of retrospective studies also showed decreased all-cause mortality with early administration of antibiotics before 4 hours of hospital admission, especially in severe CAP with pneumoniae severity index (PSI) IV to V (adjusted odds ratio, AOR 0.87; 95% CI, 78–97). However, no significant benefit was shown in clinical stability at 48 hours (AOR 1.04; 95% CI, 0.75–1.44), length of hospital stay (AOR 0.92; 95% CI, 84–1.01%) or readmission after discharge (AOR 0.99; 95% CI, 0.88–1.11%).58 However, all the included studies were retrospective or chart reviews, with low quality of evidence. There was no significant mortality benefit with administration of antibiotics before one hour of recognition of severe sepsis or septic shock (pooled odds ratio 1.46, 95% CI, 0.89–2.4) in a recent meta-analysis. Out of 18 eligible studies, 7 studies were excluded due to non-availability of data confounding the findings.120 In a recent retrospective study of 35,000 randomly selected inpatients with sepsis, each hour delay in administration of antibiotics was associated with increased odds of in-hospital mortality in patients with sepsis (Odds ratio, OR 1.09; 95% CI, 1.00–1.19; p = 0.046), severe sepsis (OR 1.07; 95% CI, 1.01–1.24; p = 0.014) and septic shock (OR 1.14; 95% CI, 1.06–1.23; p = 0.001).121

Evidence Statement

Early initiation of antibiotics has been associated with reduction in all-cause mortality in community-acquired pneumoniae, including severe pneumoniae with sepsis or septic shock.

Recommendation

Appropriate antimicrobial therapy should be initiated as early as possible in patients of CAP requiring ICU admission, preferably within the first hour after obtaining necessary microbiologic samples (3A).

Respiratory samples should be sent for Gram stain, bacterial culture, and other investigations as clinically indicated, as early as possible (3A).

Multiplex PCR may be used to obtain precise microbiologic diagnosis in patients with CAP admitted to ICU if feasible (2B).

Should CAP in ICU Receive Empirical Antimicrobials or Upfront Targeted Antimicrobial Therapy?

Targeted antibiotic therapy based on Legionella and pneumococcal urinary antigen testing was associated with higher relapse rate without any significant differences in clinical failure, length of hospital stay or clinical failure in a randomized controlled trial in patients with severe CAP. However, the study was inadequately powered for outcomes as less than 50% patients had PSI IV and V CAP and only one patient required ICU admission.122 In another randomized controlled trial, targeted antibiotic therapy based on respiratory secretions cultures, blood cultures, paired serum samples (for mycoplasma, chlamydia and coxiella) and urinary antigens (for pneumococcus and Legionella) was similar to empirical therapy in terms of clinical cure, length of hospital stay and late treatment failure or relapse. Study was inadequately powered for ICU patients, though it demonstrated significantly reduced mortality (45% vs 91%; p = 0.02) with targeted therapy as compared to empirical therapy.123 Similarly, in a large retrospective study, targeted antibiotic therapy has been associated with reduced 30-day mortality (AOR 0.64, 95% CI, 0.56–0.74) in CAP, severe CAP (AOR 0.70; 95% CI, 0.54–0.91)and very severe CAP (AOR 0.51,95% CI, 0.40 to 0.64).58,124 Other retrospective studies have demonstrated limited utility of diagnostic testing to influence prescription modification, clinical cure or failure though lower mortality is reported with targeted therapy (RR 0.37, 0.24 to 0.57).58,125 Obtaining blood cultures before initiating therapy was associated with mortality benefit in a large retrospective study in 14069 patients with CAP requiring hospitalization.126 In a multicentric randomized controlled trial of 208 hospitalized CAP patients at risk of GNB infections and indication for bronchoscopy, multiple PCR based therapy was associated with significantly shorter duration of inappropriate antibiotic treatment (38·6 h; 95% CI, 19·5–57·7; p < 0·0001) than conventional culture.127 In another RCT of 294 CAP inpatients, multiplex PCR based point of care (POC) strategy did not show any difference prescriptions of no or narrow-spectrum antibiotics at 4 hours after admission (OR 1.13; 95% CI, 0.96–1.34). However, POC strategy resulted in significant increase in targeted prescriptions at 4 hours (OR 5.68; 95% CI, 2.49–12.94; p < 0.001) and 48 hours (OR 4.20; 95% CI, 1.87–9.40; p < 0.001). Also, POC strategy was associated with more adequate prescriptions at 48-h (OR 2.11; 95% CI, 1.23–3.61; p = 0.006) and on day 5 (OR 1.40; (95% CI, [1.18, 1.66] p < 0.001).128 Multiplex PCR testing of respiratory specimens in 259 hospitalized pneumoniae patients showed 96.2% positive agreement and 98.1% negative agreement with routine bacterial culture, and a potential of modification of antibiotic therapy in 70.7% patients, including de-escalation or discontinuation in 48.2% patients.129

Evidence Statement

Early institution of targeted antibiotic therapy in severe CAP based on urinary antigen testing is associated with higher relapse rate without any mortality benefit in prospective randomized studies. Retrospective studies have shown mortality benefit with narrowing down of antibiotic therapy based on results from cultures of respiratory specimens, blood cultures as well as Legionella and pneumococcal urinary antigen testing. Multiplex PCR based diagnostic testing of respiratory specimens leads to more appropriate and focused antimicrobial therapy administration.

Recommendations

Empirical therapy covering common etiologic organisms should be initiated for severe CAP requiring ICU admission (2A).

Investigations including culture of respiratory secretions (sputum, endotracheal aspirate), blood cultures, urinary antigen testing for pneumococcus and Legionella may be performed to narrow down therapy. (UPP)

Multiplex polymerase chain reaction (PCR) testing of respiratory specimens, if available, should be performed for CAP in ICU for microbiologic diagnosis and subsequent antibiotic modification or de-escalation (3A).

PCR testing for viral etiology (e.g., influenza, SARS-Cov2) should be performed based on seasonality and local guidelines (3A).

Bronchoscopic BAL or protected specimen brush samples may be performed for microbiologic diagnosis on case by case basis (3A).

What is the Current Role of Radiologic Investigations in Guiding Antibiotic Therapy for CAP in ICU?

In a recent meta-analysis of 16 studies including 2040 suspected pneumoniae patients, pooled sensitivity of ultrasound (0.96) was higher than chest X-ray (0.65) for the diagnosis of pneumoniae. Pooled specificity was 0.85 for USG and 0.81 for CXR. The receiver operative characteristics areas under the curve for USG were 0.98 as compared to 0.77 for CXR.130 Similar results were reported by an earlier meta-analysis.131 Amongst 140 suspected CAP patients presenting to emergency department, LUS reduced diagnostic uncertainty in CAP from 73% to 14% and led to antibiotic prescription modifications in 32% cases.132 Claessen et al. prospectively evaluated the impact of Chest CT in 319 suspected CAP patients presenting to emergency department. Of these, 120 patients had no infiltrates on chest radiograph. CT scan revealed parenchymal infiltrates compatible with CAP in 33% (n = 40/120) in this group. CT chest also led to exclusion of CAP diagnosis in 29% (n = 56/188) patients with infiltrates on chest radiograph. CT chest led to modification in antimicrobial therapy and site of care in 194 (60.8%) patients. These included antibiotic initiation (n-51), antibiotic cessation (n = 29), anticoagulation (n = 3) and diuretics (n = 11).133 Low dose Chest CT (LDCT) in emergency department led to change in pneumoniae probability levels in 54 patients (27%) in another prospective study of 200 elderly patients with suspected CAP.134

Evidence Statement

Lung ultrasound has high sensitivity and specificity in diagnosis of pneumoniae, and better diagnostic accuracy as compared to chest X ray. Addition of lung ultrasound aids in improving confidence in diagnosis of CAP and leads to significant treatment modification. CT Chest leads to early diagnosis of CAP in ICU and modification of treatment in significant proportion of cases, though there is insufficient evidence in impact on short term outcomes.

Recommendations

Bedside chest ultrasound should be done for all suspected CAP patients in ICU at baseline, and at frequent intervals as indicated (1A).

CT Chest may be done for diagnosis of CAP in ICU in cases where diagnosis is in doubt, alternate causes (heart failure, pulmonary embolism) are suspected, to rule out rarer causes (e.g., tuberculosis, nocardia) or to decide on site of invasive sampling (bronchoscopy or image guided sampling) (3A).

For Empirical Therapy in Patients with CAP in ICU, should Combination Therapy be Preferred over Monotherapy?

In a recent meta-analysis of CAP patients including 28 observational studies, combination antimicrobial regimens including macrolides have been associated with significantly decreased mortality as compared to non-macrolides (RR 0.82; 95% CI, 0.70–0.97; p = 0.02), along with a trend towards mortality benefit favoring macrolides as compared to fluoroquinolones (RR 0.83; 95% CI, 0.67–1.03; p = 0.09).135 Combination therapy also resulted in better survival in patients with shock without any significant increase in microbial resistance.136 In a matched case-control study of prospectively studied cohorts, combination therapy including macrolides was independent predictor of survival (OR, 0.19; 95% CI, 0.07–0.51) in patients with pneumococcal CAP requiring ICU admission.137

Evidence Statement

Empirical combination therapy covering common organisms causing community-acquired pneumoniae improves survival without any significant increase in microbial resistance.

Recommendation

Patients with CAP requiring ICU admission should initially receive combination of empirical antimicrobial agents covering common causative organisms (2A).

What should be the Preferred Combination Therapy for CAP in ICU?

In a recent meta-analysis of 8 studies (1 randomized controlled trial and 7 observational studies), 2273 patients in beta-lactam macrolide arm were compared to 1600 patients in beta lactam-fluoroquinolone arm; beta lactam-macrolide combination was associated with a lower overall mortality as compared to that of beta lactam-fluoroquinolone combination (OR, 0.68; 95% CI, 0.49–0.94; p = 0.02) along with decreased length of hospital stay (mean difference, −3.05 days; 95% CI, −6.01 to −0.09; p = 0.04).138 In targeted maximum likelihood estimation and survival analysis of 3775 severe CAP patients, macrolide treatment was associated with significant mortality benefit at 6 months (HR 0.69; 95% CI, 0.60–0.78; p < 0.001) and 12 months (HR 0.72; 95% CI, 0.64–0.81; p < 0.001).139 Aztreonam and fluoroquinolones are effective alternatives to macrolides, however, with undue risk of masking and delaying diagnosis of tuberculosis.140 Aztreonam is effective alternative for patients with contraindication to beta lactams.

Evidence Statement

For patients with severe CAP requiring ICU admission without risk factors for pseudomonal infection, a combination of beta-lactams along with macrolides is better as compared to beta-lactam fluoroquinolone combination in terms of mortality benefit and length of hospital stay.

Recommendation

For patients with CAP requiring ICU admission, a non-pseudomonal beta-lactam (cefotaxime, ceftriaxone, or amoxicillin–clavulanic acid) plus a macrolide (azithromycin or clarithromycin) should be preferred if there are no risk factors for Pseudomonas aeruginosa infection (1A).

For penicillin-allergic patients, a respiratory fluoroquinolone (levofloxacin, moxifloxacin or ciprofloxacin) and aztreonam may be used (3A).

If macrolides cannot be used, a fluoroquinolone may be used if there is no clinical suspicion of tuberculosis, after sending sputum or endotracheal aspirate for AFB and Genexpert (3A).

When should Anti-pseudomonal Cover be Added for CAP in ICU? If Required, which are the Preferred Antimicrobials for Anti-pseudomonal Cover?

Age greater than 65 to 70 years, male sex, current smokers, chronic respiratory disease including chronic bronchitis, COPD, asthma or bronchiectasis, cerebrovascular disease, dementia, other chronic neurological disorders, cardiovascular diseases, cirrhosis, immunocompromised states, malignancy, current use of corticosteroids, enteral tube feeding, previous hospital admission, prior respiratory isolation of pseudomonas, prior antibiotic therapy and severe pneumoniae at presentation have been reported as risk factors for CAP due to Pseudomonas aeruginosa in various observational studies.77,110,111,141–145 In a recent multinational point prevalence study, only 2% of hospitalized CAP patients had drug-resistant pseudomonas.108 Prior antibiotic therapy has been associated with increased risk of multidrug-resistant pseudomonal infection.143 Use of bronchoscopic BAL and multiplex PCR in 208 hospitalized pneumoniae patients with risk factors for gram-negative infection led to 45% reduction in duration of inappropriate antibiotic treatment (difference 38.6 hours, 95% CI, 19.5–57.7) in a multicentric randomized controlled trial.127

Antipseudomonal antimicrobial agents include aminoglycosides (gentamicin, amikacin, tobramycin, plazomicin), quinolones (ciprofloxacin, levofloxacin), penicillins (carbenicillin, ticarcillin, piperacillin), carbapenems (meropenem, imipenem, doripenem), polymyxins (polymyxin B, colistin), monobactams (aztreonam), cephalosporins (ceftazidime, cefepime) and fosfomycin. Newer antibiotics (Ceftolozane-tazobactam, Ceftazidime-avibactam, Imipenem-cilastatin-relebactam, Cefiderocol) have proven to be efficacious in the treatment of multidrug-resistant pseudomonas.146

Evidence Statement

For patients with severe CAP requiring ICU admission, risk factors for infection with Pseudomonas aeruginosa include chronic pulmonary disease (chronic obstructive pulmonary disease, asthma, bronchiectasis), frequent systemic corticosteroid use, prior antibiotic therapy, old age, immunocompromised states, enteral tube feeding, cerebrovascular or cardiovascular disease. Prior antibiotic therapy is a risk factor for multidrug-resistant pseudomonal infection.

Recommendation

If P. aeruginosa is an etiological consideration, antipneumococcal, antipseudomonal antibiotic (like ceftazidime, cefoperazone, piperacillin–tazobactam, cefoperazone–sulbactam, imipenem, meropenem or cefepime) should be used (2A).

Combination therapy should be considered with addition of aminoglycosides or antipseudomonal fluoroquinolones (e.g., ciprofloxacin) (3A).

If empiric antipseudomonal treatment is started, a culture of respiratory specimens (sputum, miniBAL or BAL) should be obtained to confirm pseudomonal infection or subsequent de-escalation (3A).

When should MRSA Cover be Added to Empiric Regimen for CAP in ICU?

Evidence on CAP due to MRSA is limited, and mostly based on small prospective studies, case series or case reports.63–66 A systematic review (81 studies; 7 case series, 71 case reports, 3 observational studies) estimated incidence of MRSA CAP to be 0.51 to 0.64 cases per 100,000 population.63 MRSA CAP carries a high mortality (up to 60%). Close contact with a MRSA carrier or patient, preceding influenza infection, prisoners, professional athletes, army recruits, men having sex with men (MSM), intravenous drug abusers, regular sauna users, immunocompromised status (HIV, acute leukemia, ongoing systemic corticosteroid therapy) and those using antibacterial agents before infection have an increased risk of MRSA CAP.63,147 Multilobar consolidation, necrotizing consolidation and empyema were also observed in greater proportion of patients with MRSA CAP.65 Considering multiple risk factors, relatively low frequency but high morbidity and mortality associated with MRSA CAP, the expert group decided to emphasize on thorough assessment of risk factors for MRSA CAP in ICU, while balancing the recommendation to guard against blanket MRSA cover for all CAP cases getting admitted to ICU. The most effective antibiotics against MRSA are vancomycin and teicoplanin. Tigecycline is also effective against MRSA; linezolid has also been reported to be effective in MRSA and VRSA pneumoniae.58,148

Evidence Statement

Risk factors for MRSA in CAP in ICU include close contact with MRSA carrier or patient, influenza, prisoners, professional athletes, army recruits, men having sex with men (MSM), intravenous (IV) drug abusers, regular sauna users and those with recent antibiotic use. MRSA pneumoniae should be suspected after influenza or in previously healthy young patients, if there is cavitation or necrotizing pneumoniae, along with rapid increase of pleural effusion, massive hemoptysis, neutropenia or erythematous rashes. Vancomycin, teicoplanin, linezolid and tigecycline are effective antibiotics against MRSA.

Recommendation

All patients admitted with CAP in ICU should be evaluated for the presence of risk factors associated with MRSA (3A).

If MRSA is a consideration, empiric linezolid (1A), vancomycin (1A) or teicoplanin (2A) should be added to the regimen. Linezolid should be used for vancomycin intolerant patients, vancomycin-resistant Staphylococcus aureus (VRSA), or patients with renal failure (1A).

PCR and Gram stain of nasal swab, along with Gram stain and culture of respiratory specimens should be obtained for microbiologic diagnosis of MRSA if empiric MRSA treatment is initiated, for future de-escalation or targeted antimicrobial therapy (3A).

When should Anaerobic Cover be Added to Empiric Antibiotic Regimen for CAP in ICU?

Anaerobic organisms were reported to cause the majority of pulmonary infections associated with lung abscesses (26–100%), aspiration pneumoniae (62–100%) and empyema (9–76%) in observational studies.149–157 In a recent observational study of 64 patients with CAP, 15.6% of BAL samples had evidence of anaerobic infection on 16s RNA analysis.158 Witnessed aspiration, loss of consciousness due to drug or alcohol overdose, seizures with concomitant gingival disease and dysphagia have been considered as risk factors for anaerobic infection.159 In secondary analysis of a multicentric prospective study of 2606 CAP patients, anaerobic flora was similar in patients with aspiration pneumoniae as compared to overall CAP patients. Severe aspiration related CAP patients had higher prevalence of GNBs (p = 0.02) and lower prevalence of GPBs (p < 0.001). Also, more than 50% of patients received empiric anaerobic coverage irrespective of presence of risk factors or aspiration pneumoniae.160

Evidence Statement

Risk factors for aspiration pneumoniae in patients admitted with CAP in ICU include dysphagia, altered sensorium, coma, witnessed aspiration, putrid discharge, presence of lung abscess, empyema, or necrotizing pneumoniae. There is no significant difference in anaerobic flora of CAP patients with or without aspiration. Severe aspiration related CAP has increased prevalence of GNBs and decreased prevalence of GPCs.

Recommendation

Empirical antibiotics with anaerobic coverage should be considered for treatment of CAP in ICU in presence of witnessed aspiration, lung abscess, empyema, or necrotizing pneumoniae (2A).

Specific antibiotics with anaerobic coverage (such as clindamycin and metronidazole) should not be routinely prescribed in severe CAP (UPP).

Which Antibiotic should be Preferred for Anaerobic Coverage for CAP in ICU?

Clindamycin was associated with significantly higher cure rates as compared to penicillin in randomized controlled trials in anaerobic lung infections.154,161 In a randomized prospective study of 100 patients with anaerobic lung infections, ampicillin-sulbactam, clindamycin and panipenem-betamiprom had similar clinical efficacy (p = 0.62) and similar duration of treatment (p = 0.35) whereas non-clindamycin group had higher frequency of appearance of MRSA (22.7% vs 0%; p < 0.01).162 Ampicillin-sulbactam had similar clinical and bacteriologic response to clindamycin with or without cephalosporin in another prospective randomized multicenter study of 70 patients with anaerobic lung infections.163 Moxifloxacin demonstrated similar clinical response to ampicillin-sulbactam in a prospective open label randomized multicentric study involving 139 patients with aspiration pneumoniae and lung abscess, along with the added advantage of once daily dosing.164 Moxifloxacin was also shown to be superior to levofloxacin-metronidazole combination in terms of clinical cure at 7 weeks (76.7% vs 51.7%; p < 0.05) as well as similar bacteriologic cure (93.3% vs 96.4%, p > 0.05) without any significant difference in adverse drug reactions.165 Duration of treatment has been reported to be variable. Longer duration of treatment (3 to 6 weeks) is required in lung abscesses and empyema.154,163,164

Evidence Statement

Commonly prescribed empirical antibiotics for CAP in ICU such as ampicillin-sulbactam, amoxicillin-clavulanic acid, piperacillin-tazobactam and carbapenems have excellent anaerobic coverage. Clindamycin and moxifloxacin are effective against aspiration pneumoniae and lung abscess caused by anaerobic organisms. Lung abscess and necrotizing pneumoniae may require prolonged treatment up to 4 to 6 weeks.

Recommendation

Patients with CAP due to anaerobic infection should be initiated on antibiotics with anaerobic activity such as amoxicillin-clavulanate, clindamycin or moxifloxacin (1A).

Piperacillin-tazobactam or carbapenems can be used for empirical therapy in CAP due to anaerobes if otherwise indicated (3A).

Duration of treatment should be individualized according to response and severity of disease (3A).

What should be the Optimal Duration of Antibiotics for CAP in ICU?

On post-hoc analysis of a RCT comparing levofloxacin treatment for 5 days to 10 days, subgroup with moderate to high severity CAP had similar clinical cure rates (RR 1.07; 95% CI, 0.95 to 1.2).58,166 In another study on severe CAP, treatment for more than 7 days did not confer any mortality benefit.167 However, this study excluded ICU admission, complicated pneumoniae, non-responding pneumoniae or identification of organisms requiring prolonged treatment. Also, enterobacteriaceae, pseudomonas, Legionella and S. aureus was associated with requirement of prolonged treatment.

Evidence Statement

For CAP in ICU, there is limited evidence regarding duration of treatment, with no significant mortality benefit beyond 7 days of antimicrobial therapy in uncomplicated cases. However, CAP due to GNB, enterobacteriaceae, P. aeruginosa, S. aureus bacteremia and L. pneumophila requires prolonged treatment. Necrotizing pneumoniae, lung abscess, empyema or extrapulmonary infective complications like meningitis or infective endocarditis also require longer duration of treatment.

Recommendation

Patients with CAP requiring ICU admission should receive antibiotics for 7 to 10 days (2A).

Patients with CAP due to Pseudomonas or aspiration pneumoniae should be treated for 14 days (3A).

Necrotizing pneumoniae due to GNB, MRSA or anaerobes also require treatment for 14 to 21 days (3A).

Duration of treatment should be individualized according to causative organism, response, severity of disease and complications (3A).

What is the Role of Adjunctive Therapy, i.e., Systemic Corticosteroids and Inhaled Antibiotics for CAP in ICU?

Systemic corticosteroid administration for CAP has long been debated. Wan et al. performed a meta-analysis of nine RCTs (n = 1667) and six cohort studies (n = 4095) evaluating systemic steroids in CAP, and did not find any significant mortality benefit (RR, 0.72; 95% CI, 0.43–1.21) overall or in patients with severe CAP (RCTs: RR, 0.72; 95% CI, 0.43–1.21; cohort studies: RR, 1.00; 95% CI, 0.86–1.17). However, systemic steroids did reduce risk of ARDS (RR, 0.21; 95% CI, 0.08–0.59) and were not associated with significant adverse effects.168 Prolonged course (20 days) of tapering doses of methylprednisolone did not show any benefit in 60 day mortality (16% vs 18%; OR 0.90, 95% CI, 0.57–1.40) in a multicenter RCT. However, the study was well short of desired sample size, and could recruit only 584 patients against the planned sample size of 1420 patients.169 A recent meta-analysis of 16 studies involving 3,842 patients with hospitalized CAP patients demonstrated that systemic corticosteroids were associated with reduced need for mechanical ventilation (RR 0.51; 95% CI, 0.33–0.77; P = 0.001) and ICU admission (RR, 0.66 [95% CI, 0.45–0.97). However, there was no difference in all-cause mortality (RR, 0.85, 95% CI, 0.67–1.07), treatment failure (RR, 0.78; 95% CI, 0.37–1.67) or incidence of adverse events (RR 1.10; 95% CI, 0.97–1.25). Also, corticosteroid group had higher hospital readmission rates (RR 1.20; 95% CI, 1.05–1.38).Majority of trials gave corticosteroids for 7–10 days; hydrocortisone 200mg to 240 mg daily dose was the most commonly used regimen.170 In a subsequent multicenter RCT investigating role of hydrocortisone in severe CAP, 795 patients were analyzed. Hydrocortisone was given as an intravenous infusion of 200 mg over 24 hours for 4 days and continued till 8 or 14 days; intervention arm received hydrocortisone for a median of 5 (IQR3-8) days. Hydrocortisone infusion reduced 28 day mortality (5.6%; 95% CI, –9.6 to –1.7%), reduced incidence of endotracheal intubation (HR 0.59, 95% CI, 0.40–0.86) and need for inotrope initiation (HR 0.59; 95% CI, 0.43–0.82), without any significant increase in adverse events. However, the trial excluded patients with septic shock, pregnancy, immunodeficiency, viral infections (influenza, herpes, acute viral hepatitis), tuberculosis and invasive fungal infection.171

Inhaled antimicrobials have been studied as adjunctive therapy in ventilator and hospital-acquired pneumoniae and evidence has been summarized in subsequent section.

Evidence Statement

Short course of systemic corticosteroids has been associated with reduced risk of mortality, need for endotracheal intubation and inotrope initiation in severe CAP. Systemic corticosteroids are associated with reduced need for ICU admission and endotracheal intubation in patients hospitalized with CAP, albeit with higher risk of readmission rates. However, large trials have excluded patients with septic shock, pregnancy, immunodeficiency, viral infections (influenza, herpes, acute viral hepatitis), tuberculosis and invasive fungal infections. Hydrocortisone 200 mg to 240 mg daily infusion was most commonly used regimen in CAP trials for 7 to 10 days.

The evidence for inhaled antibiotics is predominantly from hospital-acquired and ventilator-associated pneumoniae, with better odds of clinical cure and microbiologic eradication in adjunct inhaled antibiotic therapy.

Recommendation

Short courses of systemic steroids should be given for patients with severe CAP after careful risk-benefit analysis (1A).

Hydrocortisone 200 mg infusion over 24 hours for 5 to 7 days should be used for systemic corticosteroid administration in severe CAP patients (2A).

Inhaled antibiotics may be used in severe CAP patients on a case-to-case basis. (UPP)

Should Procalcitonin be Used to Determine Duration of Antibiotic Administration for CAP in ICU?

In a recent Cochrane meta-analysis of 26 trials involving 6708 patients, procalcitonin utilization for antibiotic discontinuation was associated with reduced mortality (adjusted OR 0.83, 95% CI, 0.70 to 0.99, p = 0.037).118 In an observational cohort study of 352 hospitalized CAP patients, PCT-based therapy led to a 15% cost benefit (p = 0.005) and reduced duration of antibiotic therapy (8.6 days vs 12.6 days; p <0.001) without affecting clinical cure rates and mortality.172 In a randomized multicenter trial of 285 severe CAP patients procalcitonin guidance did not lead to a reduction in antibiotic duration compared to guideline-based clinical assessment (9 days vs 10 days; p > 0.05).173

Evidence Statement

Serial procalcitonin levels can be used to de-escalate antibiotics for CAP in the ICU without increasing mortality or recurrence rates.

Recommendation

Procalcitonin levels can be used along with clinical judgement for de-escalation of antibiotics in CAP in ICU in patients treated beyond 5-7 days (1A).

Hospital-acquired Pneumoniae and Ventilator-associated Pneumoniae

Pneumoniae is one of the commonest hospital-acquired infection. Hospital-acquired or nosocomial pneumoniae (HAP) is defined as pneumoniae that occurs 48 hours (or more) after admission and did not appear to be incubating at the time of admission. Ventilator-associated pneumoniae (VAP) is HAP that develops more than 48 to 72 hours after endotracheal intubation. The previously used term health care associated pneumoniae (HCAP) is currently not in use.174 To provide a more uniform and consistent reporting of cases of ventilator-associated complications, Centers for Disease Control (CDC) has proposed the term ventilator-associated events which includes ventilator-associated condition, infection-related ventilator-associated complication, probable VAP and possible VAP.175 The incidence of VAP varies among different ICUs and depends upon the definition used. In most ICUs, the incidence is around 10–20%.174 Endotracheal intubation compromises the natural barrier between oropharynx and trachea as well as facilitates entry of bacteria into lungs.176 Supine position also facilitates transfer of contaminated secretions leading to VAP.177 VAP is suspected in patients with new or progressive pulmonary infiltrates plus supportive clinical findings suggestive of infection. The diagnosis is made on clinicoradiologic findings and is supported by isolation of microorganism from lower respiratory tract sample. VAP is associated with overall attributable mortality of 13%, and higher risk of ICU mortality (RR 2.20, 95% CI, 1.91–2.54).178 VAP leads to significantly longer ICU length of stay and also incur additional hospital costs.179

What are the Common Organisms Causing HAP/VAP in ICU and What is their Antibiotic Susceptibility Pattern?

The microorganisms implicated in causation of VAP varies among ICUs. Studies conducted in Western countries demonstrated that majority of VAP episodes are caused by Staphylococcus aureus followed by Pseudomonas aeruginosa.180 In a retrospective review of 8474 cases of VAP reported to CDC, staphylococcus accounted for 24.1% of cases followed by pseudomonas (16.6%) and klebsiella (10.1%).181

Studies from Asia show preponderance of gram-negative organisms as etiologic agent of VAP. A prospective surveillance study from 73 hospitals in 10 Asian countries from 2008 to 2009 including 2554 cases with HAP or VAP found that pseudomonas (15.6%) was most common causative organism followed by Staphylococcus aureus (15.5%), Acinetobacter spp. (13.6%) and klebsiella pneumoniaee (12%). Imipenem resistance of Acinetobacter and P. aeruginosa was 67.3% and 27.2% respectively. A large proportion of Acinetobacter (82%) and P. aeruginosa (42.8%) were multidrug-resistant (MDR) while 51.1% and 4.9% were extensively drug resistant (XDR), respectively. The prevalence of MRSA among S. aureus isolates was 82.1%.182 Similarly, another retrospective study from Thailand also found A. baumannii (53.4%) as most common isolate followed by P. aeruginosa (35.2%) and MRSA (15.1%).183

Multiple studies from Indian ICUs have also shown predominance of gram-negative bacilli (Acinetobacter, pseudomonas and klebsiella) in VAP.184–186 These gram-negative bacilli are often multidrug-resistant. A prospective study from Pondicherry showed an incidence of VAP to be 18% where pseudomonas and Acinetobacter were common (21.3%) followed by staphylococcus (14.9%).187 Another study from Karnataka found A. baumannii to be the commonest organism in both early and late onset VAP followed by pseudomonas. All isolates of Acinetobacter were resistant to at least three antibiotics (i.e. MDR) and one isolate of Acinetobacter was pan resistant.188 There has been also a rise in carbapenem resistance of Acinetobacter. A study done by Gurjar et al. from SGPGI showed that 75% patients with VAP due to Acinetobacter were carbapenem resistant.189 Recent data from Indian Antimicrobial Resistance Surveillance Network also showed high prevalence of carbapenem resistant Enterobacteriaceae (96%), Acinetobacter (80%) and Pseudomonas (66.7%); colistin was the only drug with high sensitivity patterns (>90%).190

To ensure appropriate therapy and de-escalation, microbiologic diagnosis is important in HAP and VAP. A meta-analysis of five RCTs (n = 1367 VAP patients) did not show any mortality benefit of using quantitative or qualitative cultures (RR 0.91; 95% CI, 0.75 to 1.11), and invasive microbiologic sampling as compared to noninvasive sampling group (RR 0.93; 95% CI, 0.78 to 1.11). Also, there was no difference in mechanical ventilation duration, antibiotic modifications or length of ICU stay.191 Bronchoscopy is a safe procedure overall and in patients with HAP, COPD and acute respiratory failure.192–194 Use of bronchoscopic BAL led to significant reduction in antibiotic usage in intubated COVID19 patients.195,196 Bronchoscopic BAL has been the reference standard for the diagnosis of VAP in most studies.197 A meta-analysis included 25 studies (n = 1,639) which analyzed various diagnostic methods for VAP with histopathologic diagnosis as the reference standard. In this meta-analysis, endotracheal aspirate had sensitivity of 75.7% (95% CI, 51.5–90.1) and specificity of 67.9% (95% CI, 40.5–86.8); PSB and BAL were less sensitive (PSB 61.4%, 95% CI, 43.7–76.5; BAL 71.1%, 95% CI, 49.9–85.9) and more specific (PSB 76.5%; 95% CI, 64.2–85.6).198 Nonbronchoscopic BAL had sensitivity of 0.90 (95% CI, 0.78–1.00)) and specificity of 0.83 (95% CI, 0.72–0.94) when compared to bronchoscopic BAL for diagnosis of VAP in recent meta-analysis.199 In a prospective study of 652 lower respiratory tract samples with suspected nosocomial pneumoniae, multiplex PCR led to significantly higher rates pathogen identification (60.4% to 74.2%) as compared to routine microbiology.200 In a retrospective multicentric study of 159 pneumoniae episodes from France, which included 115 episodes of VAP and HAP, application of multiplex PCR would have led to empiric therapy modification in 77% episodes including de-escalation (40%) and escalation (22%). Application of multiplex PCR would have led to increased appropriate antibiotic therapy administration (87% vs 77%). As compared to routine care.201

Evidence Statement

Ventilator-associated pneumoniae (VAP) and hospital-acquired pneumoniae (HAP) are commonly caused by aerobic gram-negative bacilli, such as Acinetobacter baumannii, klebsiella pneumoniaee, Pseudomonas aeruginosa, or by gram-positive cocci (Staphylococcus aureus). In Indian ICUs, gram-negative organisms are most common etiologic agents (i.e., Acinetobacter, Klebsiella and Pseudomonas spp). Most of these pathogens have been found to be multidrug-resistant. Frequency of specific MDR pathogens causing HAP and VAP may vary by hospital, patient population, type of ICU patient, and change over time. Pan resistant organisms are increasingly being reported. Invasive sampling (including bronchoalveolar lavage) leads to better microbiologic diagnosis in HAP and VAP, but has not been associated with improved outcomes.

Should Baseline Serum Procalcitonin be Measured in Patients with Suspected VAP?

VAP has been associated with higher baseline serum procalcitonin (PCT) levels than controls in small observational studies.202 In a meta-analysis of 7 studies incorporating 373 patients, PCT had a pooled sensitivity of 76% (69–82), specificity of 79% (74–84), and positive and negative likelihood ratios of 4.35 (2.48–7.62), 0.26 (0.15–0.46) for VAP diagnosis.203 In a prospective multicenter database of 689 patients, serum PCT could not differentiate VAP from ventilator-associated tracheobronchitis.204 Use of baseline procalcitonin to decide antibiotic initiation has been discouraged by various international guidelines.113,174,205 Various trials and studies of antibiotic de-escalation have used a cut off of 80% drop from baseline along with clinical judgement, necessitating which a baseline PCT measurement.115,118,206–208

Evidence Statement

Baseline serum procalcitonin has moderate sensitivity and specificity for the diagnosis of ventilator and hospital-acquired pneumoniae, and cannot reliably differentiate between ventilator-associated tracheobronchitis and ventilator-associated pneumoniae. An 80% decline from baseline procalcitonin levels has been used along with absolute value of less than 0.5 mL to make decisions regarding antibiotic de-escalation.

Recommendation

Serum procalcitonin should not be used for diagnosis of Ventilator-associated or Hospital-acquired Pneumoniae or for decision making regarding antibiotic initiation (1A).

Baseline procalcitonin levels may be measured in VAP, for future use in antibiotic de-escalation (2B).

What are the Risk Factors for MDR Pathogens in VAP in ICU?

Incidence of VAP caused by MDR organisms has increased in last decade and has been associated with increased cost of care, morbidity and mortality. Data from the early 1980s show that about 50% of mechanically ventilated patient develop VAP within first 4 days after intubation and were due to non-MDR pathogens. However, several recent studies show no significant difference between causative organisms in both early and late VAP.209 Various factors like advanced age (>60 years) and prior use of antibiotics have been consistently associated with increased risk of MDR organisms.210,211 In a prospective study done by Trouillet et al. in 135 cases of VAP, the three variables identified as risk factors for MDR VAP were duration of mechanical ventilation (7 days or more) and prior use of broad-spectrum antibiotics (third generation cephalosporins, fluoroquinolones, or imipenem).212 Renal replacement therapy and septic shock at admission were also found to be risk factors for MDR VAP.213 Higher Acute Physiology And Chronic Health Evaluation II (APACHE II) score on admission, pleural effusion, prior antibiotic treatment, illicit drug use and tobacco are also found to be risk factors for MDR VAP due to MRSA.214,215 Similarly, vasopressor use, trauma and neurological emergency were identified as additional risk factors for MDR VAP.210 Two studies show that systemic corticosteroid therapy has also been implicated as risk factor for MDR VAP. However, both these studies do not mention the dose and duration for which corticosteroid therapy was used.210,216 In a recent meta-analysis of 10 studies comprising 4285 patients, Acute Physiology and Chronic Health Evaluation II score (APACHE-II, OR 1.01, 95% CI, 0.73–1.29), Simplified Acute Physiology Score II (SAPS-II, OR 2.81, 95% CI, 0.85–4.76), length of stay in hospital prior to VAP onset (OR 2.64, 95% CI, 0.39–4.89), ICU duration of stay (OR 3.95, 95% CI, 0.89–7.02), Charlson comorbidities index (OR 1.00, 95% CI, 0.89–1.11), overall hospital-stay [OR = 20.742, 95% CI, (18.894, 22.591)], quinolone administration (OR 2.02, 95% CI, 1.34–3.04), carbapenem (OR 3.53, 95% CI, (2.48–5.02), combination of >2 antibiotics (OR 3.18, 95% CI, 2.10–4.81) and prior antibiotic use (OR 2.97, 95% CI, 2.00–4.41) were independent risk factors of MDR bacterial VAP, whereas diabetes and duration of mechanical ventilation did not show any positive correlation with MDR VAP.217 Hospital settings with prevalence of MDR organisms more than 25% has also been identified as a risk factor for MDR VAP.205 Other approach has been to emperically use antibiotics against MDR GNBs and pseudomonas if their prevalence in local ICU or hospital setting is more than 15%, and to use empiric anti-MRSA antibiotics if local prevalence is >10%. If a patient has risk factors for GNBs and MRSA, empiric regimen covering both is initiated. Various guidelines suggest prescription of empiric antimicrobials based on risk factors for MDR organisms and to target threshold of 90% to 95% of prevalent MDR organisms while treating VAP.174,205 However, these risk factors have been criticized for having very low specificity.218 Therefore it is pertinent to obtain a early microbiologic diagnosis to narrow down antibiotic therapy in VAP and HAP.

Evidence Statement

The risk factors for VAP due to MDR organisms include age >60 years, duration of mechanical ventilation ≥7 days, prior antibiotic use within 3 months, presence of severe sepsis or septic shock at time of VAP, ARDS preceding VAP, renal replacement therapy prior to VAP, systemic corticosteroid therapy and high prevalence (>25%) of MDR organisms in the hospital setting.

What should be the Initial Combination of Empiric Antibiotic Therapy for VAP in ICU?

Inadequate or inappropriate therapy for VAP has been associated with higher mortality rates.219 A Cochrane review included four studies that compared monotherapy to combination antibiotic therapies for VAP. This analysis found no significant difference in primary end point of all-cause mortality and clinical cure rate in intention-to- treat population and clinically evaluable population between monotherapy and combination therapy. Similarly, comparison of combination therapy with optional adjunctive antibiotics (amikacin, vancomycin, linezolid, aztreonam, ceftazidime and tobramycin) did not find any difference in all-cause mortality, clinical cure rate in intention-to-treat population and clinical cure rate in clinically evaluable population. No difference in all-cause mortality or clinical cure rate in intention to treat population was found when carbapenems were compared with non-carbapenems; however, carbapenems had higher chance of clinical cure rate in clinically evaluable population. This meta-analysis supports the use of single antibiotic regimen with understanding that resistance patterns may vary depending upon the local factors.220 A similar meta-analysis by Infectious Disease Society of America (IDSA) also found no difference between combination therapy versus monotherapy, cephalosporins versus non-cephalosporin regimen, antipseudomonal penicillin versus non-antipseudomonal penicillin regimen and carbapenems versus non-carbapenem regimen. For infections with carbapenemase producing MDR or XDR gram-negative bacteria, a meta-analysis of 53 studies, including 10 studies with pneumoniae, reported no mortality benefit or improved clinical cure with combination as compared to monotherapy in RCTs, whereas case series did show mortality benefit (RR 0.83, CI 0.73–0.93).221 ESBL producing E. coli or Klebisella related bloodstream infections had significantly lower mortality with meropenem as compared to piperacillin tazobactam in a RCT of 391 patients.222 Empiric carbapenems were associated with mortality benefit (RR 0.84; 95% CI, 0.74–0.96; P = 0.01) in a meta-analysis of 20 trials including 5489 patients. However, there was a trend towards resistance emergence (RR, 1.40; 95% CI, 0.95–2.06; P = 0.09). Also, most quantum of benefit was seen in early VAP trials prior to 2010.223 In a recent meta-analysis including 9 RCTs, carbapenems were associated with better resolution of pneumoniae (OR 1.09; 95 % CI, 1.01–1.17) but had no mortality benefit (OR 0.83; 95% CI, 0.67–1.02) as compared to non-carbapenem regimen in VAP.224 Among aminoglycoside versus non-aminoglycoside regimen, use of aminoglycoside regimen was associated with less chance of clinical response compared to non-aminoglycoside regimen. When comparing quinolones versus non-quinolone regimen, adverse event rates were less with quinolone regimen [Risk Ratio 0.88 (0.78–0.99) with 95% CI,].174 A meta-analysis by Walkey et al.225 found that linezolid was not superior to glycopeptide antibiotics for the end points of clinical success, microbiological success and mortality for patients with MRSA nosocomial pneumoniae, without any significant difference in adverse events. However, another meta-analysis found more frequent gastrointestinal adverse effects with the use of linezolid.226 Colistin and polymyxin B usage has increased in recent years for use in VAP in view of increasing prevalence of multidrug-resistant gram-negative infections.227 A recent meta-analysis showed no significant difference in unadjusted mortality between colistin and polymyxin B (RR 0.71; 95% CI, 0.45–1.13), however, colistin has increased risk of nephrotoxicity (RR 1.55,95% CI, 1.36–1.78).228 A propensity score based single center cohort study (n = 102) evaluated outcomes for VAP due to carbapenem-resistant Klebsiella pneumoniaee and Acinetobacter baumannii, and did not find any benefit with tigecycline-polymyxin B combination as compared to high dose tigecycline in terms of 14-day mortality (OR, 0.72, 95% CI, 0.27–1.83), clinical cure (OR, 1.09, 95% CI, 0.48–2.54) microbiological cure (OR, 0.96, 95% CI, 0.39–2.53) and nephrotoxicity (OR 0.85, 95% CI, 0.36–1.99).229 There was no significant difference in 30 day all cause mortality between colistin monotherapy as compared to combination therapy in multidrug infections (OR OR 0.81, 95% CI, 0.65–1.01).230 In a multicenter cohort study of 445 patients with pneumoniae (CAP, n = 1; HCAP, n = 321), the authors used guideline-recommended risk factor assessment, and treated patients with >2 risk factors with empiric regimen covering MDR organisms, whereas patients with none or one risk factor were treated with antibiotics for CAP. Using this method, 53% patients required broad-spectrum empiric therapy for MDR organisms, and yet 92.9% patients received appropriate therapy for the identified pathogen.231

In a prospective study of 95 BAL and non-bronchoscopic BAL samples of HAP and VAP patients, multiplex PCR had a low turn-around time (4.6 hours), high sensitivity (80%, 95% CI, 73–88%), and specificity (99%, 95% CI, 99–100). Sensitivity for GNBs was better than that for GPBs (90% vs 62%; p < 0.005), with detection of extended spectrum beta-lactamases gene (CTX-M) and carbapenemase genes (NDM, oxa-48) in 75% (n = 9/12) cases. Multiplex PCR was simulated to have led to earlier identification of appropriate antibiotic (n = 20; 21%) and early de-escalation (n = 37;39%) in 37 patients (39%) including de-escalation of empiric carbapenem regimen in 10 cases.232 Multiplex PCR had a high sensitivity (100%) and specificity (87.2%) as compared to quantitative culture in a multicentric study of 842 prospectively collected respiratory specimens.233 However, with multiplex PCR, risk of overdiagnosis in terms of detecting resistance genes (15% to 45%) has been highlighted.234 In a multicentric randomized controlled trial of 206 VAP patients without septic shock, Gram stain based empiric antibiotic regimen was noninferior to guideline based therapy in terms of clinical cure (77% vs 72%; risk difference 0.05, 95% CI, -0.07 to 0.17), with reduced empiric anti-pseudomonal agents (70% vs 100%) and anti-MRSA antibiotics (61% vs 100%).235 However, the participating ICUs had low MDR GNB prevalence (<10%), and MRSA was the most common organism isolated (50%), thus limiting application in ICUs with high prevalence of NF-GNBs.

It is important to choose appropriate empiric antimicrobials for patients at high risk for MDR GNBs or in ICUs with high prevalence of MDR GNBs. However, in view of high prevalence of carbapenem resistant GNBs, it is important to plan empiric therapy to cover for these pathogens. Approaches to identify Options for empiric treatment for carbapenem resistant GNBs include addition of polymyxins to an antipseudomonal beta lactam, or treatment with newer antimicrobials or beta-lactamase combinations like ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-cilastatin-relebactam, and meropenem-vaborbactam. Other options include aztreonam, tigecycline, minocycline and respiratory fluoroquinolones.

Ceftazidime-avibactam is approved for treatment of HAP or VAP and is shown to have better clinical cure rates and survival benefit in VAP due to carbapenem resistant GNB infections. In a muiltinational phase 3 double blind non inferiority trial randomizing 879 VAP patients, ceftazidime-avibactam met the pre-specified criteria for non-inferiority for clinical cure (68% vs 73% (difference -4·2%, 95% CI, -10·8-2·5) as compared to meropenem (standard treatment group) without any significant difference in adverse events. Common isolated organisms in the study included Klebsiella pneumoniaee (37%) and Pseudomonas aeruginosa (30%); 28% were not susceptible to ceftazidime.236 Ceftazidime-avibactam salvage therapy was associated significantly lower 30 day mortality (36.5% vs 55.8%, p = 0,005) in a retrospective study of 138 bacteremic carbapenemase producing Klebsiella pneumoniaee infected patients.237 In a meta-analysis of prospective studies and case series (29 studies, 1620 patients), efficacy of ceftolozane-tazobactam, ceftazidime-avibactam and meropenem-vaborbactam was studied. Pneumoniae was the most common infection (49.8%); common organisms were MDR Pseudomonas (MDRPA, 65.3%) and Carbapenem resistant enterobacteriaceae (CRE, 24%). Resistance to the studied antibiotics was seen in 8.9%. Pooled success rate for these antibiotics was 73.3% (95% CI, 68.9%–77.5%).238

Ceftolozane-tazobactam was evaluated in a randomized controlled double blind non-inferiority trial in 726 patients with nosocomial pneumoniae. As compared to meropenem (control arm), treatment arm had similar 28 day mortality (24% vs 25,3%, weighted treatment difference 1.1%, 95% CI, –5.1 –7.4), clinical cure rates (54% vs 53%, weighted treatment difference 1.1%, 95% CI, –6.2–8.3).239 Ceftolozane-tazobactam had significantly higher clinical success rates than colistin (72.2% vs 30.3%) in a retrospective, observational study of 51 XDR Pseudomonas VAP patients, with higher odds for clinical success (OR 4.47, 95% CI, 1.17–17.08), and lesser nephrotoxicity (11.1% vs 48.5%, p =  0.01).240 In a retrospective study of 200 patients with hospital-acquired infections due to MDR pseudomonas, efficacy of ceftolozane-tazobactam was compared with polymyxins and aminoglycosides. 52% of the cases had VAP, 7% had bacteremia and 42% had severe sepsis or septic shock. The ceftolozane-tazobactam arm had significantly less combination therapy (72% vs 15%, p < 0.001), higher clinical cure rates (adjusted OR 2.63; 95% CI, 1.31–5.30) and less nephrotoxicity (aOR, 0.08; 95% CI, 0.03–0.22).241 Ceftolozane-tazobactam has been observed to have in vitro activity against 36.4% isolates of Pseudomonas with ceftazidime resistance.242

Imipenem-cilastatin-relebactam restores activity of imipenem against CRE and Pseudomonas, and was non-inferior in terms of 28-day all-cause mortality (15.9% vs 21.3%; difference –5.3%, 95% CI, –11.9%–1.2%) and clinical response (61.0% vs 55.8%; difference 5.0%, 95% CI, –3.2%–13.2%) when compared to piperacillin-tazobactam in a randomized controlled trial of 537 bacterial HAP and VAP. Common pathogens in the trial were Klebsiella pneumoniaee (25.6%) and Pseudomonas aeruginosa (18.9%).243 Imipenem-cilastatin-relebactam had higher clinical response (71.4 vs 40 %, difference 26.3% 90% CI, 1.3–51.5), lower mortality (9.5% vs 30%; difference –17.3%, 90% CI, –46.4–6.7), and nephrotoxicity (10.3 vs 56.3%; difference –45.9%, 90% CI, –69.1 to 18.4) as compared with imipenem plus colistin in a double blind RCT of 47 patients with imipenem resistant pathogens.244

Meropenem-vaborbactam, another carbapenem-beta-lactamase inhibitor, has activity against carbapenemase resistant enterobacteriaceae and had better clinical cure and 28 day all cause mortality when compared to best available therapy in a open label randomized controlled trial of 77 confirmed or suspected CRE infections.245 Meropenem-vaborbactam had similar mortality and adverse effects as compared to ceftazidime-avibactam in a retrospective study of 131 patients with CRE infections.246 However, this drug is not effective against carbapenem resistant pseudomonas or Acinetobacter.

Prolonged infusion of anti-pseudomonal beta-lactams showed mortality benefit (30% lower, RR 0.7, 95% CI, 0.56–0.87) in a meta-analysis of 22 RCTs (n = 1876) as compared to rapid infusion in patients with sepsis.7

Polymyxin B and colistin have similar microbiologic spectrum. They are highly efficacious against MDR Pseudomonas, Acinetobacter and enterobacteriaceae including Klebsiella pneumoniaee. However, colistin is a prodrug, and needs conversion to active drug for efficacy.247 Pharmacokinetics of polymyxin B ensure rapid achievement of therapeutic levels in plasma, whereas even after giving a loading dose, colistin plasma levels rise slowly and variably, and desired plasma levels of 2 mg/L are difficult to achieve.248 A multicenter prospective trial comparing combination of colistin and levofloxacin to meropenem levofloxacin combination had to be terminated early due to excessive nephrotoxicity (33% vs 18.8%; p = 0.012).249 Polymyxin B has lesser incidence of acute kidney injury than colistin. Also, colistin achieves high concentrations in the urine due to activation into active form in the urinary tract. For this reason, polymyxin B is preferred in most invasive infections including VAP, whereas colistin is preferred in patients with complicated urinary tract infections.250

Aztreonam is a monobactam and acts on bacterial cell wall, though the targets are different than beta-lactams. Also, aztreonam is not degraded by class B metallo-beta-lactamases (e.g., NDM). It is active against gram-negative bacteria including enterobacterieaceae and pseudomonas. However it lacks activity against gram-positive organisms, anaerobes, and majority of Acinetobacter or Stenotrophomonas maltophilia.251

Fosfomycin is bactericidal against a variety of gram-negative and gram-positive organisms like Escherichia coli, Proteus mirabilis, Klebsiella pneumoniaee, Enterobacter spp., Citrobacter spp., and Salmonella typhi.252 Intravenous fosfomycin use was reported in 209 ICU patients across 20 centers in Europe. Main indications were CNS infections (21.5%), CAP/VAP (15.3%), bone and joint infections (11%) abdominal infections (11%) and bacteremia (10.5%). MDR pathogens were isolated in 24.4% patients. Fosfomycin was nearly always used in combination with other antibiotics. Clinical success was 81.3% overall and 84.8% in cases with MDR pathogens.253

Tetracyclines like minocycline, tigecycline and eravacycline have been considered as potential alternatives to beta-lactams and polymyxins in CRE infections. They function independent of carbapenemases making them potentially useful in treating resistant infections. However, they have rapid distribution into tissue following administration, and thus attain low serum and urine concentrations making them ineffective for bloodstream infections and urinary tract infections. Also, due to bacteriostatic nature of tetracyclines, they need to be used as a part of combination regimen. Tetracyclines can be used for carbapenem resistant enterobacteriaceae and Acinetobacter, whereas pseudomonas are intrinsically resistant to tetracyclines.254 Minocycline, a tetracycline, has been studied for MDR VAP especially in ICUs with high prevalence of CRE Acinetobacter. A recent meta-analysis evaluated the efficacy of combination therapy with minocycline as compared to other combination regimens as controls. Out of 10 eligible studies, 9 were retrospective case series and one was a prospective single center study (n = 268). Most common comparators were colistin or carbapenems. Pneumoniae was the most common infection (80.6%) with VAP in 50.4% cases. Intravenous minocycline had good clinical success (72.6%) and microbiologic success rates (72.6%) with 20.9% mortality.255 Minocycline was effective in treating pneumoniae and bloodstream infections due to GNBs in a prospective study (n = 71) with clinical and microbiologic response in 80% patients. The most prevalent gram-negative pathogens in the study were Stenotrophomonas (52%), Acinetobacter (30%), and Burkholderia (10%).256 Tigecycline monotherapy was associated with higher mortality as empiric therapy in pneumoniae in a meta-analysis.257 Subsequently, a phase II trial of higher doses of tigecycline monotherapy were compared to imipenem-cilastin in HAP, and had similar efficacy outcomes, without any safety issues.258 High dose tigecycline demonstrated efficacy in a meta-analysis of 10 studies (n-543) in terms of all-cause mortality (OR 0.44, 95% CI, 0.30–0.66), clinical cure rates (OR 3.43, 95% CI, 2.09–5.63), p < 0.00001), and microbiological eradication (OR 2.25, 95% CI, 1.44–3.50) with mortality benefit in subgroup with CRE infections. However, most studies were retrospective, with only one observational study, and one phase II RCT. Also, most studies had given high dose tigecycline in combination with standard background therapy (i.e., beta-lactams, carbapenems, colistin or aminoglycosides).259 In CRE Acinetobacter pneumoniae, tigecycline had similar mortality and clinical cure rates as compared to other regimens, but had significantly lesser microbiologic eradication (OR = 0.43, 95% CI, = 0.27–0.66) highlighting potential concerns for resistance induction.260 Eravacycline and has been studied in intra-abdominal infections.261 In a retrospective study of 97 patients with Acinetobacter VAP, eravacycline arm had higher mortality and lesser clinical cure and microbiologic eradication rates.262 Omadacycline is another tetracycline with in vitro activity against CRE, but has not been recommended due to PK/PD issues and reduced potency.263,264

MDR VAP pathogens have increasing prevalence of resistance against antipseudomonal fluoroquinolones (ciprofloxacin and levofloxacin) and aminoglycosides and therefore, the merit of adding these as a part of combination therapy has been questioned.174

Adjunct inhaled antibiotics have been studied in VAP and HAP treatment. In a prospective, multicenter, double-blind, randomized, placebo-controlled, phase 3 study of 725 VAP patients with isolation of MDR GNB or presence or two risk factors for MDR GNB, inhaled amikacin did not demonstrate any mortality benefit (75% vs 77%, OR 0.84, 95% CI, 0.55–1.28; p = 0.43).265 In a recent meta-analysis of eleven RCTs (n = 1210), adjunctive inhaled antibiotics improved clinical cure rates (RR 1.13, 95% CI, 1.02–1.26) and microbiological eradication (RR 1.45, 95% CI, 1.19–1.76) in VAP patients without any mortality benefit (RR 1.00, 95% CI, 0.82–1.21).266 There was no increased risk of renal impairment, however, there was increased risk of bronchospasm (RR 2.74, 95% CI, 1.31–5.73) during treatment. In another meta-analysis evaluating efficacy of adjunct nebulized colistin in VAP treatment, 7 observational studies and three RCTs including 850 VAP patients were included. Nebulized colistin had higher microbiologic eradication (OR, 2.21; 95% CI, 1.25–3.92) without any increase in nephrotoxicity (OR, 0.86; 95% CI, 0.60–1.23). However, nebulized colistin did not improve clinical response (OR, 1.39; 95% CI, 0.87–2.20), mortality (OR, 0.74; 95% CI, 0.50–1.12), duration of mechanical ventilation (mean difference –2.5; 95% CI, −5.20–0.19), or length of ICU stay (MD,–1.91; 95% CI, −6.66–2.84) as compared to intravenous therapy group. In terms of adverse effects, nebulized colistin had higher risk of bronchospasm (OR, 5.19; 95% CI, 1.05–25.52).267 In a retrospective multicentric cohort study evaluating efficacy of adjunct polymyxin B in 132 VAP patients, there was no significant difference in clinical cure rates (43.2% vs 27.3%, p  =  0.06), bacterial eradication (36.4% vs 23.9%, p  =  0.132) and mortality (34.1% vs 42.0%, p  =  0.38).268

For MRSA coverage in VAP and HAP, Linezolid, vancomycin and teicoplanin are commonly used drugs. Linezolid showed better clinical success rates, microbiologic eradication and lesser nephrotoxicity than vancomycin in various trials and meta-analyses.98,99 Other antibiotics with activity against MRSA include daptomycin, ceftaroline, tedizolid, omadacycline, Lefamulin, Delafloxacin, telavancin and ceftobiprole. Off-label Ceftaroline had success rate of 75% in a retrospective study of 40 MRSA HAP and VAP patients.269 Tedizolid was compared to linezolid in a RCT of 726 patients with HAP or VAP with suspected gram-positive pathogen, and was found to be noninferior in terms of all-cause mortality (28.1% vs 26.4%, difference 1.8%; 95% CI, –8.2–4.7) but had inferior clinical cure rates (56.3% vs 63.9%; difference 7.6%, 97.5% CI, –15.7–0.5).270 Telavancin was noninferior to vancomycin in terms of cure rates (82.4% vs 80.7%; 95% CI, for difference, –4.3%–7.7%) in RCT of hospitalized patients with gram-positive HAP and VAP.271 However, telavancin had lower cure rates and lower survival rates in patients with moderate to severe renal impairment (CrCl <50 mL/minute).272 Ceftobiprole was evaluated in a RCT of 781 patients with HAP and VAP, and compared to ceftazidime-linezolid combination. Overall cure rates (50% vs 53%) and microbiologic eradication (63% vs 68%; 95% CI, –16.7 to 7.6) were similar. However, VAP patients had significantly lower cure rates (23% vs 37%) and microbiologic eradication (30% vs 50%; 95% CI, –38.8 to –0.4) in ceftobiprole group.273 Tigecycline has MRSA activity but has been associated with increased mortality when used for MRSA HAP and VAP.274

Evidence Statement

Use of combination therapy for VAP has better outcomes in patients who are at risk for MDR pathogens. Commonly used antimicrobial agents include piperacillin-tazobactam, cefepime, levofloxacin, imipenem and meropenem. Among antimicrobial agents, carbapenems have a higher chance of clinical cure than non-carbapenems. Patients with high risk of MDR HAP or VAP, i.e., those admitted in ICUs with high prevalence of MDR organisms, prior isolation of MDR GNBs from respiratory secretions have been treated with combination therapy of carbapenems or beta-lactams with colistin or polymyxin. Monotherapy with newer beta-lactam-beta-lactamase combinations (e.g., ceftazidime-avibactam) or carbapenem-beta-lactamase combination (e.g., Imipenem-cilastatin-relebactam, meropenem-vaborbactam) have better outcomes and less toxicity as compared to other available regimens or polymyxins. Polymyxin B and colistin have been found to be efficacious in treatment of carbapenem resistant Klebsiella and Acinetobacter, but colistin has a higher incidence of nephrotoxicity. Tigecycline and minocycline are alternative options for CRE infections when pseudomonas is not a consideration. Aztreonam as a part of combination therapy is an alternative when newer beta-lactam-beta lactamase combinations are not available, or in presence of metalloproteinases like NDM. For treatment of VAP due to MRSA, glycopeptides and linezolid have similar clinical success, however, linezolid may be associated with higher chance of thrombocytopenia and gastrointestinal adverse events. Adjunct nebulized antibiotics (colistin, aminoglycosides) have been found to increase microbiologic eradication without any mortality benefit in VAP and HAP.

Gram staining of respiratory secretions can lead to lesser prescription of anti-pseudomonal and anti-MRSA antibiotics without compromising clinical cure rates in ICUs with low MDR organism prevalence. Molecular techniques like multiplex PCR have a very less turnaround time and can be used to effectively modify empiric regimen for HAP and VAP.

Recommendation

Among patients with VAP who are at high risk of MDR pathogens or are in ICU with high prevalence of MRSA (>15%) and resistant gram-negative organisms (>10%), an agent active against MRSA and at least two agents active against gram-negative organisms including P. aeruginosa is recommended (3A).

Among patients with VAP who are not at high risk of MDR pathogens and are in ICU with high prevalence of resistant gram-negative organisms (>15%) but low prevalence of MRSA (<10%), two agents active against gram-negative organism including P. aeruginosa is recommended (3A).

Linezolid, vancomycin or teicoplanin should be used for empiric MRSA coverage in patients at high risk of MRSA (1A).

In patients with high risk for MDR GNBs and prior isolation of MDR or carbapenem resistant GNBs from respiratory secretions, monotherapy with newer agents (Ceftazidime-avibactam, Ceftolozane-tazobactam, Imipenem-cilastatin-relebactam or Meropenem-vaborbactam) should be preferred to combination therapy (2A).

Polymyxin B (preferred) or colistin as part of empiric combination regimen can be used in the ICUs with high prevalence of carbapenem-resistant enterobacteriaceae (>20%) in patients with risk factors for MDR or XDR gram-negative pathogens (2A).

In patients with high risk for MDR GNBs or prior isolation of MDR/carbapenem resistant GNBs from respiratory secretions, tetracyclines (tigecycline or minocycline) may be used as part of combination therapy if no alternate drugs can be given, in patients without bacteremia, and pseudomonas is not a consideration (3B).

In patients with high risk for MDR GNBs, aztreonam can be used as part of combination regimen if no alternate drugs are available or pseudomonal coverage is needed (3A).

In ICU where distribution of pathogen and antibiotic resistance pattern is known, empiric treatment should be designed accordingly, based upon patient risk factors for MDR pathogens (UPP).

Adjunct nebulized antibiotics (colistin, aminoglycosides) can be used in combination with systemic therapy for empiric treatment of VAP on case-to-case basis or microbiologic sensitivity (3A).

Invasive sampling (Nonbronchoscopic BAL or bronchoscopic BAL, protected specimen brushing) should be performed in VAP for microbiologic diagnosis and definitive antibiotic therapy (2A).

Multiplex PCR of respiratory specimens (non-bronchoscopic BAL, or bronchoscopic BAL) should be used for early identification of causative organisms and appropriate modification of antibiotic therapy (2A).

Gram stain of respiratory specimens can be used for early de-escalation of empiric anti-MRSA therapy (2A).

In our country or in areas with high endemicity of tuberculosis, use of linezolid may be restricted unless no suitable alternative is available (UPP).

Fluoroquinolones and aminoglycosides should be cautiously used as monotherapy in VAP in our country as well as in other areas with high endemicity of tuberculosis. (UPP)

When to Give Antipseudomonal Drugs for VAP in ICU?

Antipseudomonal drugs are often started empirically in VAP when the risk factors for pseudomonas infection are high. In a prospective surveillance study, it was found that the odds of developing P. aeruginosa VAP were 8 times higher in patients with prior pseudomonas colonization than uncolonized patients.275 In a multicenter study, the independent risk factors for the presence of P. aeruginosa were duration of hospital stay ≥48 hours before ICU admission, prolonged duration of ICU stay before enrollment >9 days (highest quartile) versus ICU stay ≤4.8 days (lowest quartile).276 Risk factors of MDR P. aeruginosa include COPD, patients on mechanical ventilation >8 days or patients with >3 previous hospitalizations, and previous use of antibiotics.277,278

Evidence Statement

Prior use of antibiotics (most consistent association), prolonged duration of mechanical ventilation, and chronic obstructive pulmonary disease (COPD) have been identified as risk factors for MDR P. aeruginosa infection.

Recommendation

Empiric treatment should be given to cover Pseudomonas if there are risk factors for MDR Pseudomonas infection (2A).

In ICUs where gram-negative isolate resistance rate is high (>10 % gram-negative isolate resistant to agent being considered for monotherapy or not known), two anti-pseudomonal antibiotics from different class to be given (3A).

What should be the Duration of Antibiotic Treatment for HAP/VAP?

Prompt initiation of appropriate antimicrobial therapy is the main stay of treatment of VAP. Selection of correct antimicrobial agent must be paired with appropriate duration of therapy in order to optimally treat VAP/HAP. Several studies have evaluated the role of short duration antibiotic treatment in VAP/HAP. A study comparing 8 days therapy to 15 days therapy found no difference in mortality, relapses, mechanical ventilator free days, organ failure free days and length of ICU stay while short course regimen was associated with more antibiotic free days. However, gram-negative bacilli (P. aeruginosa) with short course regimen were more likely to have a relapse (40.6% vs 25.4%).279 A randomized comparison of antibiotic discontinuation policy (discontinuation group) with treating physician teams policy (conventional group) found lower antibiotic duration in discontinuation group without any difference in secondary episode of VAP, hospital mortality or ICU length of stay.280

A recent meta-analysis by Dimpoulous et al. reviewed 4 RCTs comparing short (7-8 days) with long (10-15 days) regimens and found increased antibiotic free days with short course treatment with mean difference of 3.4 days(p < 0.001) and no difference in mortality, clinical and microbiological relapses, mechanical ventilation duration, mechanical ventilation free days and length of ICU stay.281 In another meta-analysis of 5 studies (n = 1069), short and long course antibiotic therapy had similar VAP recurrence (OR 1.48, 95% CI, 0.96, 2.28; p = 0.08) overall, and in patients with NF-GNB VAP (OR 1.90, 95% CI, 0.93, 3.33; p = 0.05), without any difference in duration of mechanical ventilation, length of ICU stay or mortality.282

Evidence Statement

Short-course regimens for VAP are associated with significantly more antibiotic-free days without any significant difference in duration of ICU or hospital stay, recurrence of VAP and mortality. Short-course regimens are associated with more recurrences in VAP due to non-fermenting gram-negative bacilli (NF-GNB).

Recommendation

Short course (7-8 days) of antibiotic therapy should be used, in case of VAP with good clinical response to therapy (1A).

Longer duration (14 days) of antibiotic therapy should be considered, in case of VAP caused by NF-GNBs or is associated with severe immunodeficiency, structural lung disease (COPD, bronchiectasis, and interstitial lung disease), empyema, lung abscess, necrotizing pneumoniae and inappropriate initial antimicrobial therapy (3A).

When should Anaerobic Cover be Added for VAP and Which is the Preferred Antimicrobial Agent?

Studies have reported variable incidence of anaerobic organism isolation in nosocomial pneumoniae occurring in mechanically ventilated patients as isolation of anaerobic bacteria requires adequate transport conditions and special growth media. In a retrospective study in 415 patients, factors associated with anaerobic infection were found to be altered level of consciousness and higher simplified acute physiology score (SAPS).283 Out of 163 isolates from VAP patients, only one was anaerobic (Veillonella) in a study done by PE Marik et al.284 Robert et al. evaluated the lower respiratory tract colonization by anaerobic bacteria in ICU patients on prolonged mechanical ventilation. Out of 26 patients, 22 were colonized by at least one bacterial strain and 5 patients developed VAP following colonization and two were attributable to anaerobic bacteria.285

Evidence Statement

Incidence of anaerobic bacteria as causative agent of VAP is 2 to 7%. Risk factors for VAP due to anaerobes are altered consciousness, aspiration pneumonitis and high simplified acute physiology score (SAPS).

Recommendation

Empirical antibiotic regimen for VAP should not include coverage for anaerobic organisms routinely (2A).

In the presence of risk factors for VAP due to anaerobic pathogens, anaerobic antimicrobial coverage should be added in empirical regimen (2B).

In patients with risk factors for anaerobic organisms, clindamycin or metronidazole should be added to empirical antibiotics regimen for VAP, if it does not include carbapenems (meropenem or imipenem) or piperacillin-tazobactam in the ongoing empirical regimen (UPP).

When to Give Atypical Cover for VAP and Which is the Preferred Agent?

Atypical bacteria have been implicated as etiologic agents for VAP, however, no sufficient literature exists to assess the size of their role as causative agent in VAP. Incidence of atypical bacteria is variable in various studies. A prospective study utilizing polymerase chain reaction (PCR) amplification method found 9 (15%) cases caused by atypical organisms (5 mycoplasma, 3 Legionella and 1 chlamydia).286 Another study reported 6 cases of VAP due to Legionella among 26 patients with definite VAP.287 M. pneumoniaee in 3 patients and C. pneumoniaee in 2 patients were diagnosed among 100 VAP cases in a study by Apfalter et al.288 The risk factors for Legionella infection include use of cytotoxic therapy and corticosteroids.289 If L. pneumophila is suspected organism for VAP, the combination antibiotic regimen should include a macrolide or a fluoroquinolone rather than an aminoglycoside.290

Evidence Statement

Incidence of atypical bacteria as causative agents of VAP is low (5 to 7.5%). Risk factors for VAP due to Legionella are Legionella colonization in hospital water supply, prolonged use of corticosteroids, cytotoxic chemotherapy, elderly, chronic renal failure, previous antibiotic use, granulocytopenia and poor Glasgow coma score.

Recommendation

Empirical antibiotic regimen for VAP should not include coverage for atypical organisms routinely (2A).

In the presence of risk factors for VAP due to atypical bacterial pathogens, atypical antimicrobial coverage should be added to empirical regimen (2B).

The preferred atypical coverage in combination antibiotics regimen is fluoroquinolones (levofloxacin or moxifloxacin) or macrolides (azithromycin or clarithromycin) (UPP).

Can Serum Procalcitonin be Used for De-escalation of Antibiotic Therapy in VAP?

Procalcitonin (PCT) is a polypeptide precursor to hormone calcitonin and is up-regulated from its normal low serum concentration in response to bacterial endotoxin or mediator of bacterial infection.291 Measurement of serum PCT has been investigated as biomarker for the presence and persistence of infection, in order to guide decisions for initiation, de-escalation and termination of antibiotic treatment. Delayed initiation of antibiotics in patients with sepsis contribute to increase mortality, while inappropriately prolonged use of antibiotics increases the risk of adverse events, including Clostridium difficile infection, and the development of antibiotic resistance. Various studies have evaluated the role of serum PCT in de-escalation of antibiotics. In a multicentric non-blinded RCT comparing guideline based antibiotic discontinuation with procalcitonin based antibiotic discontinuation, procalcitonin group had higher antibiotic free days and reduction in overall duration of antibiotic therapy though the ventilator free days alive, ICU free days alive, length of hospital stay and mortality on 28 days were similar.206 PRORATA trial found that PCT guided strategy to treat suspected bacterial infection in ICU could reduce antibiotic exposure by 2.7 days with no apparent adverse outcome.292 Two meta-analyses have also demonstrated increased antibiotic free days in PCT based strategies without negatively affecting the outcome.293,294 International guidelines differ on using procalcitonin for antibiotic de-escalation in VAP. American Thoracic Society guidelines suggest using PCT plus clinical criteria to guide the discontinuation of antibiotic therapy rather than clinical criteria alone.174 In contrast, European respiratory Society (ERS) guidelines do not recommend the routine measurement of serial serum PCT levels to reduce the duration of antibiotic course in patients with HAP or VAP when the anticipated duration is 7-8 days although panel mention that they believe in measurement of serial serum PCT levels together with clinical assessment in specific clinical circumstances (such as severely immunocompromised patients, drug resistant pathogens-NF-GNB, and initial inappropriate therapy).205

Evidence Statement

Use of procalcitonin to guide de-escalation of antibiotic treatment in patients with VAP is effective in reducing antibiotic exposure, without an increase in the risk of mortality or treatment failure.

Recommendation

Serum procalcitonin may be used to guide the de-escalation of antibiotics in VAP, when the anticipated duration of therapy is >7–8 days (1B).

Serum procalcitonin levels (together with clinical response) should be used for de-escalation of antibiotic therapy in VAP in specific clinical conditions (severely immunocompromised patients, drug resistant pathogens-NF-GNB, initial inappropriate therapy) (3A).

How to Approach a Patient of Non-responding VAP?

Non-responding VAP or treatment failure in VAP is defined as the lack of improvement in clinical parameters (48–72 hours) with or without persistence of the infecting microorganism from appropriate sample.295,296 Various clinical parameters such as the white blood cell count, measures of oxygenation and core temperature have been used in studies to define the normal pattern of resolution of HAP. In a prospective cohort study assessing the resolution of VAP, it was found that temperature normalizes within a median of 3 days and ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2 ratio) improves by 2 days.297 Another study evaluated bacteriological and clinical efficacy of microbiological treatment of VAP among 76 VAP cases and demonstrated that appropriate antimicrobial therapy for VAP results in the control of the initial infection in 88% of the patients, after day 3 of treatment.298 There are many implicated causes for non-resolution of VAP. These include wrong diagnosis (such as collapse, mass or pleural effusion), inappropriate initial treatment, delayed initiation of treatment, superinfection, concomitant focus of infection or associated complications in the form of lung abscess, empyema or drug fever.299,300

Evidence Statement

Re-evaluation at 48 to 72 hours after the initial diagnosis of VAP is the most suitable time. By then the results of the initial microbial investigation are usually available and treatment modification can be done. Evaluation of treatment response for VAP should be on the basis of clinical, laboratory, radiograph and microbiological results. Factors associated with treatment failure in VAP includes host factors (advanced age, immunosuppressed, chronic lung disease, ventilator dependence), bacterial factors (drug resistant pathogens, opportunistic pathogens), therapeutic factors (inappropriate antibiotics, delayed initiation of therapy, insufficient duration of therapy, suboptimal dosing, inadequate local concentration of drugs), complications of initial VAP episode (lung abscess, empyema), other non-pulmonary infections or non-infectious mimics of pneumoniae.

Recommendation

Non-responding VAP should be evaluated for non-infectious mimics of pneumoniae, unsuspected or drug-resistant pathogens, extrapulmonary sites of infection, and complications of pneumoniae or its therapy and diagnostic testing should be directed to whichever of these causes is likely (2A).

CT Chest and other indicated imaging modalities should be performed to clarify diagnosis in non-responding VAP and HAP (3A).

Microbiologic analysis of blood, respiratory specimen (non-bronchoscopic or bronchoscopic BAL) and other samples like pleural fluid should be performed using conventional culture and molecular methods for identification of pathogens in non-responding HAP and VAP (3A).

Catheter-related Bloodstream Infections (CRBSI)

Intravascular catheters are integral in the management of critically ill patients, especially those who require long-term medical care. They are most commonly used to access the vascular system for the delivery of medication, parenteral nutrition, collection of blood samples and hemodynamic monitoring.301 CRBSI is defined as the presence of bacteremia originating from an intravenous catheter is a common complication leading to morbidity, mortality and adds to the cost of ICU stay. It is also the most common cause of nosocomial bacteremia in ICUs.302

Definition and Diagnosis

Catheter-related Bloodstream Infections (CRBSI) is defined as bacteremia or fungemia in a patient who has an intravascular device and one positive blood culture result obtained from the peripheral vein, clinical manifestations of infection (e.g., fever, chills, and/or hypotension), and no apparent source for bloodstream infection (other than the catheter). One of the following should be present, i.e., a positive result of semi-quantitative [>15 colony forming units (CFU) per catheter segment] or quantitative (>102 CFUs per catheter segment) catheter culture, whereby the same organism is isolated from a catheter segment and a peripheral blood culture; simultaneous quantitative cultures of blood with a ratio 13:1 of CFU per milliliter of blood (catheter vs peripheral blood); differential time to positivity (growth in a culture of blood obtained through a catheter hub is detected by an automated blood culture system at least 2 hours earlier than a culture of simultaneously drawn peripheral blood of equal volume).303 Catheter tip colonization (CC) is defined as significant growth of a microorganism (>15 colony-forming units) from the catheter tip culture.303 CRBSI rates are expressed as CRBSI rate per 1000 central line days. However, the suspicion of CRBSI arises in a patient using any intravascular catheter especially central venous catheter (CVC) who develops new onset fever or chills, unexplained hypotension without any other localizing signs of infection.302

What is the Incidence of Catheter Colonization and CRBSI?

Based on United States (US) data from national nosocomial infections surveillance (NNIS) from 1990 to 1994, the CRBSI incidence (per 1000 catheter days) was 4.3 for respiratory intensive care units (RICU), 4.6 for medical-surgical ICUs, 7.3 for trauma ICUs and 12.2 for burn units.304 Data from NNIS from January 1992 through June 2004 showed that the median rate of CRBSI in ICUs of all types ranged from 1.8 to 5.2 per 1000 catheter days,305 whereas more recent survey in 2010 showed the mean incidence up to 1.76 per 1000 catheter days, suggesting a decreasing trend.306

Data from extended prevalence of infection in intensive care study (EPIC 2) showed an overall point prevalence of 4.7 per 1000 catheter days.307 In the EPIC III study, 1239 (15.2%) patients had CRBSI with a hospital mortality of 38.1%.308 A prospective observational study by Lorente et al. showed incidence of CC as 6.04 % and of CRBSI to be 2.79 per 1000 catheter days.309 Other studies have shown global incidence of CC to be 1.4-20 % while that of CRBSI to be 2.4–12.5 per 1000 catheter days. 310–313 Majority of these studies have shown CVCs as the commonest cause for CRBSIs. The data from India suggest higher incidence of CC and CRBSI. In a study by Mittal et al. CC was found in 59 % catheters with CRBSI rate of 9.5 per 1000 days.301 Others have shown incidence of CC as 18-42 % while of CRBSI is 1-16.1 per 1000 catheter days.314,315

Evidence Statement

The global incidence of CC ranges from 1.4 % to 19.4 % whereas CRBSI incidence ranges from 2.4 % to 12.5 %. The incidence of CC is higher in Indian ICUs ranging from 18 % to as high as 59 %, whereas incidence of CRBSI is up to 16.1 per 1000 catheter days.

What are the Risk Factors for CRBSI?

Incidence of CRBSI varies considerably according to various factors such as the type of catheter (single or multi lumen), duration of indwelling catheters, frequency of catheter manipulation, and patient-related factors such as age, underlying disease and severity of illness. In a retrospective study in 73 events of CRBSI, major risk factors found were advanced age, long-term indwelling catheter, parenteral nutrition, diabetes mellitus (DM), and APACHE II score >23, and more than three underlying diseases. Multivariate analysis showed that an APACHE II score >20 and more than three underlying diseases were independent factors associated with CRBSI occurring within 14 days of CVC insertion.316 Duration of catheter is an important parameter and catheter duration >14 days is an independent risk factor for CRBSI.310,313,317–320 Risk for CRBSI is higher when the interval time for dressing change is longer than 48 hours irrespective of the dressing material (permeable or semi-permeable).312 Use of transparent dressings, regular change of dressings, total parenteral nutrition, and use of three way cannulas have not been consistently associated with increased risk for CRBSIs.312,317 Regarding hemodialysis (HD) catheters, prospective data by Caylan et al. in 248 patients with HD catheters have shown acute renal disease, administration of antibiotics at the time of catheterization, insertion in the femoral vein, emergency situation for catheter insertion, high number of catheter manipulation, and inadequate hand hygiene prior to catheter manipulations as risk factors of CRBSI.321 Catheter-related candidemia should be suspected in patients with any of the following risk factors: total parenteral nutrition, prolonged use of broad-spectrum antibiotics, hematologic malignancies, and receipt of bone marrow or solid-organ transplant, femoral catheterization, or colonization due to Candida species at multiple sites.303

Evidence Statement

Longer indwelling catheter duration, immunosuppression, diabetes mellitus, sepsis at the time of insertion, multilumen catheters and APACHE >23 are important risk factors for CRBSI. APACHE at admission, renal failure, central venous catheterization and steroid therapy are important risk factors for fungal CRBSI.

What are the Common Organisms Causing CRBSI and their Antibiotic Susceptibility?

Apart from severity of the patient's clinical disease and risk factors for infection, initial choice of antibiotics will also depend on the likely pathogens and their susceptibility patterns. According to the available literature, certain organisms should always be considered, apart from taking the local epidemiology into account. National Nosocomial Infections Surveillance (NNIS) survey of nosocomial infections from 1990 to 1999 showed coagulase negative staphylococcus (CONS), Staphylococcus aureus and enterococcus as common organisms while Candida albicans accounted for 5% of the CRBSI. A large proportion of CONS isolates were methicillin resistant and the incidence of MRSA and vancomycin-resistant enterococcus (VRE) was 54.5 % and 25.9 % respectively.304 According to NNIS 2004 data, 87 % of CRBSI were monomicrobial, out of which 65 % were gram-positive organisms, 25 % were gram-negative organisms and 9.5 % were fungi, with CONS, Staphylococcus and Candida being the common organisms.322 During this period, there was 12 % increase in VRE and 11 % increase in MRSA. There was a marked increase in ESBL producing Klebsiella with 47 % increase in overall incidence. The proportion of CRBSI due to gram-negative organisms like Pseudomonas, Acinetobacter and Klebsiella is also on rising trends according to recent studies. In a recent observational study, CRBSIs due to Pseudomonas and Acinetobacter were 22.2% and 20% respectively.310 This rise in gram-negative organisms has been found in various studies from India as well.315,316,323,324 In a meta-analysis of 11 studies including 1205 patients with bloodstream infections, Ceftazidime-avibactam had significantly lower 30-day mortality than control groups overall (RR  =  0.55, 95% CI, 0.45 to 0.68), when compared to colistin (RR  =  0.48, 95% CI, 0.33–0.69), and in subgroup of CRE producing Klebsiella (RR = 0.59, 95% CI, 0.46–0.75).325

In Indian ICUs the MRSA incidence ranges from 30% to 87% and that of VRE is as high as 25 %.323,324 Incidence of ESBL producing organisms has also increased with some studies showing all isolates to be ESBL producing.326 The proportion of CRBSI caused by fungi varies among different studies and usually ranges from 4.4 % to 20 % and mostly were due to Candida albicans.324,327 However, a prospective observational study from 27 Indian ICUs found Candida tropicalis (41.6 %) as the most common cause of fungemia followed by Candida albicans (20.9%) and Candida parapsilosis (10.9 %). Majority of C. tropicalis isolates were sensitive to amphotericin B (99.0 %), azoles (90.1 %), fluconazole (97.4 %) and echinocandins (94.2 %).328

Evidence Statement

Coagulase-negative staphylococci (CONS), S. aureus, enterococcus and Candida species are the common organisms accounting for the majority of the CRBSIs. Large proportion of Staphylococcus aureus and CONS are methicillin resistant ranging from 11 % to 87 %. There is an increased incidence of CRBSI due to gram-negative organisms (most of which are ESBL producers) and Candida especially the non-albicans Candida.

What is/are the Empiric Antibiotic(s) of Choice for CRBSI in ICU?

Empiric treatment, when indicated, should provide coverage against the most frequent organisms causing CRBSI i.e. gram-positive as well as gram-negative organisms. Vancomycin, teicoplanin and linezolid are considered the initial drugs of choice for empiric treatment for gram-positive organisms as the incidence of methicillin resistance is high among CONS and S. aureus. A recent meta-analysis by J Li et al. included 7 RCTs comparing linezolid with vancomycin in 5376 patients with MRSA.329 The clinical cure rate of linezolid group was higher than that of vancomycin group after treatment (OR 1.85; 95% CI, 1.33–2.59, p < 0.001) and at follow-up (OR 1.49; 95% CI, 1.17–1.91, p = 0.001). However, linezolid monotherapy has not been recommended for empirical treatment of patients with suspected CRBSI.330 Teicoplanin is a safe and effective alternative to vancomycin considering the lesser toxicity and once daily schedule.331 Quinupristin-dalfopristin and daptomycin might be alternative drugs effective in MRSA bacteremia and enterococci showing comparable results with vancomycin in RCTs.332,333 Dalbavancin is another drug belonging to same class as vancomycin and when used in weekly doses, has been shown higher success rate than vancomycin for treatment of CRBSI.334 For treatment of VRE, a significantly lower mortality rate and trend towards better clinico-microbiologic response has been seen using linezolid as compared to quinupristin-dalfopristin.335 Apart from gram-positive, an antimicrobial agent with activity against aerobic gram-negative bacilli should be added to the empiric coverage of CRBSI. The appropriate options include aminoglycosides, aztreonam, third-generation cephalosporins with antipseudomonal activity, fourth-generation cephalosporins, piperacillin-tazobactam or quinolones.303 In patients with risk factors for candidemia empiric treatment against Candida is sometimes considered. Caspofungin and fluconazole have equal success cure rates in culture positive Candida infections with no difference in mortality as compared to amphotericin B.336,337 However, increasingly fluconazole resistant Candida albicans are being reported in bloodstream infections. Also, non-albicans species with fluconazole resistance, like Candida auris are also becoming common in nosocomial settings.338,339 Echinocandins are therefore being preferred for management of patients admitted in ICU with suspected bloodstream infections due to Candida or with Candida colonization.340 Biofire Blood culture identification 2 (BCID2) multiplex PCR panel had high diagnostic accuracy (91.7%) for on-panel pathogens, with overall concordance of 98%.341 In a multicenter evaluation of BCID2 multiplex PCR panel, the assay correctly classified 90% of gram-negative and 89% of gram-positive bacteria and had mean positive percent agreement of 97% (95% CI, 95-99%) with blood culture; agreement was 67% for Candida and 100% for the on-panel targets. However, performance in detection of ESBL encoding genes, or other resistance targets was discordant with blood cultures.342

Evidence Statement

Vancomycin, teicoplanin, linezolid and daptomycin are effective in treatment of CRBSI due to MRSA and MR-CONS. Fourth-generation cephalosporin, carbapenem or beta-lactam/beta-lactamase combination like piperacillin-tazobactam and aminoglycosides might be used for gram-negative organisms causing CRBSI. Caspofungin and fluconazole have been equally effective as amphotericin-B for treatment of candidemia. However, increasingly fluconazole resistant Candida are becoming more common, and echinocandins are preferred as initial therapy in suspected Catheter-related bloodstream infections due to Candida.

Recommendation

Empirical antibiotic regimen for CRBSI should include coverage for both gram-positive and gram-negative organisms (2A).

Vancomycin or teicoplanin is the recommended first line drug for the empiric treatment of CRBSI for MRSA and MR-CONS while linezolid and daptomycin are good alternative agents (2A).

Empiric coverage for gram-negative bacilli should include a fourth-generation cephalosporin, a carbapenem, or a β-lactam/β-lactamase inhibitor combination, newer agents (like ceftazidime-avibactam) or without an aminoglycoside (UPP).

An echinocandin should be used as empirical antifungal agent for treatment of suspected central line-associated candidemia (2A).

What should be the Duration of Antibiotic Treatment for CRBSI?

Optimum duration of antibiotic treatment to the bare minimum required to treat infections is a reasonable approach to reduce the prevalence of resistance to antibiotics. No significant differences in clinical cure, microbiologic cure and survival were detected among bacteremic patients receiving shorter (5 to 7 days) versus longer duration (7 to 21 days) of antibiotic therapy in a meta-analysis.343,344 There was 5-10% relapse rate after short course therapy for Staphylococcus aureus catheter-associated bacteremia suggesting that short course therapy is acceptable for uncomplicated infections. In case of complicated S. aureus infections like infective endocarditis, longer duration (4 to 6 weeks) of treatment is required. Studies have shown similar response irrespective of duration of therapy in gram-negative infections as well. A retrospective study comparing short-course (7 days), intermediate-course (8 to 14 days) and long-course (>14 days) treatment for gram-negative bacteremia has shown similar clinical response rates and microbiological cure. Regarding the duration of empirical antifungals for CRBSIs, there has been no comparative studies but based on the consensus, approximately14 days of empirical antifungals is recommended.

Evidence Statement

Short duration (<14 days) of antibiotics is as effective as longer duration (>14 days) for uncomplicated Staphylococcus aureus bacteremia. Complicated bacteremia due to S. aureus or those associated with endocarditis should receive longer duration. For gram-negative bacteremia, seven days of antibiotics is sufficient. In responding patient with uncomplicated CONS infection, 5–7 days therapy is considered optimum. Minimum 14 days treatment with antifungals is required for fungal CRBSI.

Recommendation

Minimum 2 weeks antibiotics should be given for uncomplicated and 4- 6 weeks for complicated Staphylococcus aureus CRBSI and infective endocarditis (2A).

Minimum 7 days of antibiotics should be given for gram-negative CRBSI (2A).

Five to seven days antibiotics are recommended for CONS bacteremia (3A).

For suspected fungal CRBSI, antifungal therapy for at least 14 days is recommended (UPP).

Empirical Antibiotics for Urinary and Urogenital Sepsis in ICU

Urogenital infections in patients in the ICU include urinary tract infection (UTI) and prostatitis in males. The clinical spectrum of UTI includes asymptomatic bacteriuria and funguria to pyelonephritis, and urosepsis with or without obstructive uropathy. Urinary tract infections are the fourth most common type of healthcare-associated infection.345 UTI additionally account for more than 12% of infections reported by acute care hospitals. About 12%-16% of hospitalized adults have indwelling urinary catheter at some time during their hospitalization. Each day the indwelling urinary catheter is in place, there is 3%–7% increased risk of acquiring a catheter-associated urinary tract infection.346 UTIs in ICU have different microbiology and higher resistance rates than UTI occurring outside ICU. Urinary tract infection is defined as significant bacteriuria in a patient with symptoms or signs attributable to the urinary tract and no alternate source. Significant bacteriuria in a patient without symptoms or signs attributable to the urinary tract is defined as asymptomatic bacteriuria.

Catheter associated urinary tract infection (CA-UTI) is defined as infection occurring in a person whose urinary tract is currently catheterized or has been catheterized within the previous 48 hours with urethral, suprapubic or intermittent catheterization. It is characterized by symptoms and signs suggestive of UTI with no other obvious source, urine sample (from urinary catheter, or midstream urine for catheter duration less than 48 hours) demonstrating more than 1000 CFU per mL. On the other hand, catheter associated asymptomatic bacteriuria refers to patients with urethral, suprapubic or intermittent catheterization with urine culture positivity (>100,000 CFU/mL) without any signs or symptoms attributable to UTI. According to CDC, CA-UTI is defined as a UTI in patients with an indwelling urinary catheter that had been in place for >2 days on the date of event (day of device placement = D1) and was either present for any portion of the calendar day on the date of event or removed the day before the date of event. Patient should have at least one of the following signs or symptoms: fever, supra-pubic tenderness, costovertebral angle pain or tenderness, urinary urgency, urinary frequency and dysuria along with urine culture with no more than two species of organisms identified at least one of which is a bacterium of ≥105 CFU /mL.347

What is the Incidence of UTI in ICU? What are the Common Organisms and Risk Factors for UTI in ICU?

The incidence of UTI ranges from 5 to 23 per 1000 catheter days as reported from various observational studies from the West.348–353 In a observational study, Tay MK et al. from Singapore reported the incidence of UTI from mixed ICU to be 13.7% in patients admitted for more than 48 hours, with the incidence of Candida being about 34%.354 The organisms causing UTI were Klebsiella (7%), E. coli (7%), polymicrobial (37%) and others (7 %). Female gender, prior antibiotic exposure, duration of ICU and urinary catheter were identified as risk factors for UTI. In a prospective observational study from China, Xie DS et al.355 reported the incidence of UTI to be 25.5 per 1000 catheter days. Fungi (21.3%) were the most common cause of UTI followed by infection with E. coli (17.02%) and pseudomonas (10.64%). The risk factors for CA-UTI were duration of catheter for >7 days, benign prostatic hypertrophy and >5 days antibiotic duration. Pseudomonas showed absolute resistance to ciprofloxacin, amikacin, ceftazidime, and meropenem. A prospective study by Leone et al. reported incidence of UTI to be 9.6%. The common organisms isolated were E. coli (39%), Pseudomonas (22%) and Enterobacter (15%).356 Duration of catheterization, length of ICU stay, advanced age, female gender and disease severity score were identified as risk factors for CA-UTI. Similar findings were reported by various studies from western world.357–360 In the ENVIN registry, gram-negative bacteria were responsible for more than half of the cases of UTI (56.7%) with E. coli being the commonest organism isolated (26.7%). Fungal infection was second most common (25.4%) with Candida albicans as most common fungus isolated.361 In a prospective study by Agarwal et al.314 from Northern India, the organisms causing UTI in ICU included Acinetobacter (34.8%), Pseudomonas (23.8%) and E. coli (15.2 %). Length of ICU stay, renal failure and total parenteral nutrition (TPN) were reported as risk factors for UTI. In a prospective observational study by Habibi et al.362 including patients with greater than 48 hours of ICU stay, most common causes of UTI were Candida spp. (90%) followed by pseudomonas (14%) and E. coli (10 %). Increased ICU stay and catheterization were identified as risk factors for UTI. Das Gupta et al.363 reported the incidence of UTI in patients admitted in ICU to be 28%. E. coli was the most common organism responsible for UTI (30.8%). Longer ICU stay, catheterization and prior antibiotics use were identified as risk factors for UTI. In a retrospective review by Sahu et al.,364 incidence of UTI reported was 6.9%. Identified risk factors included longer ICU stay and catheterization.

Evidence Statement

Incidence of CA-UTI ranges from 5-30% of all ICU admissions. The most common organism causing UTI in ICU are gram-negative bacteria (E. coli, Klebsiella) and fungi (especially Candida). Risk factors for UTI in ICU include duration of catheterization, length of ICU stay, prior antibiotic use, higher disease severity score, and female Gender.

What is the Empirical Antimicrobial Agent of Choice for Treating UTI in ICU?

A systemic review and meta-analysis by Vardakas et al.365 included 21 studies and 1584 patients with ESBL producing enterobacteriaceae bacteremia. He compared the mortality associated with carbapenems and alternative antibiotics (beta-lactams/beta-lactamase inhibitors) for the treatment of patients with ESBL-positive enterobacteriaceae bacteremia. No statistically significant differences in mortality was found between carbapenems and beta-lactams/beta-lactamase inhibitors administered as definitive or empirical treatment for UTI.

In an observational study on gram-negative UTI in hospitalized patients, all isolates were susceptible to carbapenems, with 70 to 80% susceptible to fluoroquinolones, aminoglycosides and cefepime. Organisms were resistant to amoxycillin, amoxycillin-clavulanic acid and co-trimoxazole. gram-negative enterobacteriaceae was also resistant to the second and third generation cephalosporins.366 Another prospective study reported increase in frequency of gram-negative enterobacteriaceae and S. aureus in catheter associated nosocomial UTI over 10 years, with high sensitivities to amikacin, imipenem, and piperacillin-tazobactam (72.0%, 77.5% and 76.1%, respectively). Lower susceptibility to third-generation cephalosporins and ciprofloxacin (55.2% and 45.0% respectively) were reported. Gram-positive organisms showed high susceptibility to teicoplanin and vancomycin (91.1% and 87.9%, respectively) and low susceptibility to ampicillin and ciprofloxacin (24.1% and 25.5%, respectively).367 Habibi et al.362 from northern India reported the antibiotics resistance pattern of gram-negative bacteria causing UTI. In this study, the bacteria were resistant to ceftazidime and netilmicin. Cefoperazone–sulbactam resistance was least common among gram-negative organisms. Sahu et al.364 reported least resistance to tigecycline, colistin and carbapenems among the gram-negative enterobacteriaceae. One study reported antibiotic susceptibility pattern in gram-negative enterobacteriaceae and most of the isolates were susceptible to carbapenems, amikacin and levofloxacin.368 In a RCT, three antibiotics piperacillin-tazobactam, cefepime and ertapenem were compared in terms of clinical and microbiological cure rate and 28 days mortality for treatment of ESBL producing E. coli. Both cure rates were high for piperacillin-tazobactam and ertapenem. Cefepime was found least effective in terms of both cure rate and prevention of mortality.369 In a prospective study, 89.2% of urinary culture isolates were sensitive to fosfomycin; 89.2% of gram-negative bacilli including enterobacteriaceae were also susceptible.370 Patel et al.371 evaluated in vitro activity of fosfomycin against urinary tract enterobacteriaceae; 79.16% of the isolates were susceptible to fosfomycin with 92% susceptibility in ESBL producing enterobacteriaceae and 72.34% in carbapenem resistant enterobacteriaceae (CRE). MDR enterobacteriaceae with diverse resistance mechanisms, including ESBL and CRE were found to be susceptible to fosfomycin.

Newer antimicrobial agents and combinations have been studied in MDR UTI infections. In a double blind RCT of complicated UTI patients with clinically suspected GNB infection, ceftriaxone-sulbactam-EDTA was non-inferior to meropenem for co-primary end points of symptomatic resolution (95.9% vs 89.9%, treatment difference 6%, 95% CI, –2.6% to 16%), symptomatic as well as microbiological eradication (94.6% vs 87%; treatment difference, 7.6%; 95% CI, −2.0% to 18.4%), and microbiologic eradication (94.6% vs 88.4%; treatment difference, 6.2%; 95% CI, −3.2% to 16.6%). Escherichia coli (n = 113, 80.7%) was the most common organism. ESBL producing pathogens were identified in 119 (83.2%) patients, whereas MDR pathogens were identified in 100 (69.9%) patients.372 However, ceftriaxone-sulbactam-EDTA did not meet pre-specified efficacy outcome in a RCT of 66 patients with complicated UTI due to Metallo-Beta Lactamase (MBL) producing enterobacteriaceae.373

Efficacy of Ceftolozane-tazobactam was evaluated in complicated UTI (cUTI) and complicated intra-abdominal infections (cIAI) due to ESBL producing enterobacteriaceae in a recent RCT. Most isolates were sensitive to ceftolozane-tazobactam (81.8%) and meropenem (98.3%) whereas sensitivity was low for levofloxacin (25.3%). Ceftolozane-tazobactam had higher cure rates (97.4%) as compared to meropenem (88.5%) or levofloxacin (82.6%).374 In a multicenter, open label phase 3 trial involving 333 patients with cUTI and cIAI due to ceftazidime resistant enterobacteriaceae or pseudomonas, ceftazidime-avibactam was noninferior to best available therapy in terms of clinical cure (91%; 95% CI, 85.6–94.7) with comparable adverse effects (31% vs 39%).375 Meropenem-vaborbactam was compared to piperacillin tazobactam in a phase 3 multinational RCT in 550 patients with cUTI, and was noninferior in terms of overall success (98.4% vs 94%; difference 4.5%, 95% CI, 0.7% –9.1%) and microbial eradication (66.7% vs 57.7%; difference 9.0%; 95% CI, –0.9%–18.7%).376 Plazomicin, an aminoglycoside with bactericidal activity against MDR Enterobacteriaceae, was evaluated in an RCT of cUTI 609 patients and was noninferior to meropenem with respect to composite cure at day 5 (88.0% vs 91.4%; difference, –3.4%; 95% CI, –10.0 to 3.1) and at test of cure visit (81.7% vs 70.1%; difference, 11.6%; 95% CI, 2.7–20.3).377 Fosfomycin was noninferior to piperacillin-tazobactam in a phase 2/3 RCT of 465 patients with cUTI and acute pyelonephritis, with comparable overall success rate (64.7% vs 54.5%; difference 10.2%; 95% CI, –0.4, 20.8).378

The choice of empirical antibiotic therapy is guided by estimates of the likelihood of a resistant organism (as estimated on the basis of epidemiologic data and individual patient risk factors for resistance) and by an assessment of whether the patient will have an adverse outcome if the treatment is inadequate (temporarily) because of a resistant organism. Clinical worsening or lack of any improvement after 1 to 2 days of antibiotic therapy mandates repeat urine culture and imaging to identify whether an obstruction or other anatomical complication is the reason for the lack of clinical improvement. Data is lacking on the optimal treatment duration in cases with severe disease, delayed treatment response, mechanical interventions (including those for hydroureter, stones, abscesses, or necrotizing infection), or other antimicrobial agents.379 In a descriptive study for the management of febrile UTI among the patients of spinal cord injury with neurogenic bladder, the cure rate was similar for single and dual therapy and duration of antibiotics 10 days as compared to more than 10 days.380 Among fungal UTI, Candida albicans was the most common organism. Both albicans and non-albicans Candida were susceptible to imidazoles and fluconazole is the drug of choice.381,382 IDSA recommends that the patients with CA-UTI who have prompt resolution of symptoms should be treated for 7 days. The patients with delayed response to treatment, regardless of whether the patient remains catheterized or not should be treated for 10-14 days. Levofloxacin should be considered in patients with CA-UTI who are not severely ill. The regimen of antibiotics for 3 days should be considered for women aged 65 years who develop CA-UTI without upper urinary tract symptoms after an indwelling catheter has been removed.345

Evidence Statement

There has been a trend towards increasing prevalence of extended spectrum beta-lactamase producing gram-negative bacteria in the urinary cultures of catheter associated UTI. Aminoglycosides, beta-lactams along with a beta-lactamase inhibitor as well as carbapenems and fosfomycin have good efficacy in catheter associated UTI. The susceptibility for fluoroquinolones is decreasing over time among organisms isolated from nosocomial UTI. Candida species isolated from the patients with UTI show sensitivity to fluconazole, but increasingly fluconazole resistance is being reported.

Recommendations

Initial choice of antibiotics should cover for ESBL producing gram-negative organisms and includes aminoglycosides, beta-lactam along with a beta-lactamase inhibitor or carbapenems (2A).

In initial empirical regimen for UTI, antibiotics against gram-positive organisms is not recommended (3A).

In appropriate clinical settings antifungals should be considered in the empirical regimen. Fluconazole is preferred, amphotericin deoxycholate is an alternative if fluconazole resistance is suspected (3B).

Catheter removal, if no longer indicated, or intermittent catheterization should be done in patients with catheter associated urinary tract infection (3A).

Acute Infective Diarrhea, Antibiotic-induced Diarrhea, and Clostridium difficile-associated Diarrhea in the ICU

Diarrhea is defined as the passage of more than three liquid stools in a day.386 Nosocomial diarrhea is defined as one which arises after 3 or more days of admission to the hospital.383 Up to 30% of patients in hospital develop nosocomial diarrhea and majority of which have non-infectious etiology. Among infectious causes, Clostridium difficile-associated diarrhea is the most common.384 Overall the incidence of diarrhea in intensive care unit varies between 15-40% in different studies where most cases have a non-infectious or multifactorial etiology.385

Etiology of Diarrhea in the ICU

Non-infectious etiologies of diarrhea are commoner in ICU, including enteral feeding, stool impaction and drugs (laxative, prokinetics, histamine antagonists, potassium supplements).386 Other factors such as sepsis, antibiotic therapy, and hypoalbuminemia increase the likelihood of diarrhea.387 Clostridium difficile is the most common infectious agent associated with diarrhea in the ICU.388 Infectious etiology is suspected if diarrhea is associated with fever, leukocytosis, vomiting, severe abdominal pain, mucus or blood in stool.389 Clinical presentation may range from mild infection to life threatening illness with pseudo-membrane formation, toxic megacolon, colonic perforation, sepsis or even death.388 The American College of Gastroenterology (ACG) have proposed a severity scoring system for Clostridium difficile infection.390

Diagnosis of Acute Infective Diarrhea in the ICU

Clostridium difficile accounts for the majority of infectious diarrhea in the ICU. Most commonly employed screening test is enzyme immunoassay (for Toxin A and B).391 Gold standard for diagnosis remains cytotoxin neutralization assay (CCNA) and toxigenic culture, with the latter being more sensitive.391 Other diagnostic tests include stool glutamate dehydrogenase and polymerase chain reaction techniques. As per clostridium difficile infection (CDI) severity index, CDI is defined as severe and complicated if it is associated with any of the following, i.e., hypotension, fever (≥38.5 °C), ileus or significant abdominal distension, mental status changes, leukocytosis (≥35,000 cells/mm3), leukopenia (<2,000 cells/mm3), lactic acidosis (>2.2 mmol/L) or end organ failure. Severe disease refers to CDI with hypoalbuminemia (<3 g/dL) along with either abdominal tenderness or leukocytosis (WBC ≥15,000 cells/mm3). Mild to moderate disease refers to CDAD not satisfying above criteria.390

What are the Common Organisms Causing Acute Infective Diarrhea in the ICU?

In a large prospective study, it was reported that infectious etiologies accounted for 9.2% cases of acute diarrhea in a mixed general intensive care unit.392 Clostridium difficile was the most common infective cause accounting for 97 out of the 112 patients in the above study.392 In Indian studies, incidence of CDI was around 16 – 17%.393,394 Other organisms include pseudomonas aeroginosa and staphylococcus which have been associated with sporadic outbreaks of diarrhea in the intensive care unit.395,396 Viruses are another important cause of infective diarrhea in ICU. Norovirus was isolated in 5.7% cases in one study.392 Outbreaks of viral diarrhea due to norovirus have also been reported in ICU settings.397

Evidence Statement

The incidence of diarrhea in the ICU ranges from 12.9 to 38%. Majority of the cases of diarrhea in ICU are non-infectious in etiology. Clostridium difficile is responsible for majority of infectious cases of diarrhea in ICU.

What are the Empirical Antibiotics of Choice for Treating Acute Infective Diarrhea in the ICU?

There is a lack of studies that evaluate the use of empirical antibiotics in patients with diarrhea in the ICU setting. In a prospective study evaluating utility of metronidazole in presumptive clostridium difficile diarrhea involving 70 patients, 18 (25%) were subsequently proven to have clostridium difficile-associated diarrhea (CDAD) whereas 49 (68%) patients had no identifiable cause. Patients who had CDAD had significant improvement in symptoms as compared to those without it.398 The American College of Gastroenterology guidelines assert that patients with diarrhea in the ICU who have a strong pre-test suspicion of CDI should receive empirical treatment pending the results of laboratory testing, and even in patients with negative testing, as the negative predictive value of existing tests for CDI are insufficiently high to rule out the infection.390

Evidence Statement

Empirical use of metronidazole in patients with diarrhea suspected due to Clostridium difficile in ICU setting results in significant symptomatic improvement.

Recommendation

We recommend that empiric metronidazole be used for therapy of patients with acute diarrhea in the ICU with suspected Clostridium difficile infection (3A).

What are the Risk Factors for the Development of CDI or CDAD?

Various factors associated with increased risk of CDI include prior antibiotic use, advanced age, prolonged ICU or hospital stay, immunosuppression, proton pump inhibitor use and enteral feeding. In a recent meta-analysis, prior antibiotic use of second-generation cephalosporins (OR 2.23, 95% CI, 1.47–3.37), third-generation cephalosporins (OR 3.20, 95% CI, 1.80–5.71), fourth-generation cephalosporins (OR 2.14, 95% CI, 1.30–3.52), carbapenems (OR 1.84, 95% CI, 1.26–2.68), clindamycin (OR 2.86, 95% CI, 2.04–4.02), co-trimoxazole (OR 1.78, 95% CI, 1.04–3.05), fluoroquinolones (OR 1.66, 95% CI, 1.17–2.35) and penicillin combinations (OR 1.45, 95% CI, 1.05–2.02) increased the risk of CDAD.399–409

Advanced age has been shown to be associated with increased incidence of CDI.394,410–412 Other risk factors for CDI/CDAD include longer ICU stay, enteral feeding, prolonged mechanical ventilation, and immunosuppression.388–390,393,400,411–416 Proton pump inhibitors (PPI) have been shown to be independent risk factor for CDAD, possibly due to elevated gastric pH accelerating conversion of C. difficile spores to vegetative forms.394,417–420

Evidence Statement

Risk factors for development of CDI include prior antibiotic therapy, advanced age, prolonged ICU/hospital stay, immunosuppression, proton pump inhibitors and enteral feeding. Cephalosporins, clindamycin, fluoroquinolones, carbapenems and penicillin derivatives are the commonly implicated antibiotics for CDAD/CDI.

What is the Recommended Treatment for CDI/CDAD: Which Antibiotics and Duration? Should Offending Antibiotics be Stopped? What is the Role of Probiotics in the Treatment of CDAD? How should Recurrent Clostridium difficile Infection be Treated?

While certain antibiotics have a propensity to cause CDI, antimicrobial therapy against C. difficile has been found to be successful in treating CDI in a clear majority of cases. In a Cochrane review that included 22 randomized controlled trials with 3,215 participants, four RCTs directly compared vancomycin and metronidazole for symptomatic cure of CDI.421–425 It was found that vancomycin was modestly superior to metronidazole for the treatment of CDI with a moderate quality of evidence. However, metronidazole has a much lower cost and an acceptable efficacy for this indication. Fidaxomicin (a newer oral antibiotic with minimal absorption) was non-inferior to vancomycin for treatment of CDI in a multicenter randomized trial.426 It was more effective than vancomycin in achieving clinical cure when patients were receiving concomitant antibiotics for concurrent infections.427 There are no direct comparisons between fidaxomicin and metronidazole, however, a network meta-analysis including studies that compared fidaxomicin with vancomycin and vancomycin with metronidazole concluded that fidaxomicin was superior to the other two agents for sustained cure of CDI.428 Clinical cure rate following oral teicoplanin for management of CDI was comparable with oral vancomycin for management of CDI (96.2% vs 100%, p = 0.56).429 Similar cure rates were reported on comparing teicoplanin with both metronidazole and vancomycin for management of CDI.425 A pertinent question is whether the offending antibiotic should be stopped during treatment of C. difficile infection. A retrospective review of 246 patients found that the use of implicated antibiotics after the completion of CDI treatment was significantly associated with recurrence of CDI compared to no antimicrobial use (odds ratio [OR] 3.02; 95% CI, 1.66–5.52). On the contrary, the use of the implicated antibiotic during the CDI therapy was not associated with recurrent CDI (OR 0.79; 95% CI, 0.40–1.52).430 This suggests that treatment of the primary infection may continue, if necessary, with appropriate antibiotic under the cover of CDI therapy.

Use of probiotics in addition to antibiotics for treatment of CDI showed that probiotics reduced the rate of recurrence in patients with recurrent CDI but not in patients with an initial episode.431 In a systematic review use of probiotics in treatment of CDI was not effective.432 Whilst probiotics are unsuccessful in treatment of CDI, they have been found to be beneficial for preventing CDI in patients receiving antibiotics. In a review of 26 RCTs, probiotics (including Lactobacillus, Saccharomyces, and combinations) significantly reduced the risk of developing CDAD by 60.5% (RR = 0.395; 95% CI, 0.294–0.531; p < 0.001).433

Recurrent CDI occurs in up to one-third of the patients and is associated with considerable morbidity and costs. A systemic review that included three studies comparing vancomycin with metronidazole, reported that vancomycin and metronidazole are equally effective in treatment of recurrent CDI.434–437 Addition of saccharomyces boulardii to vancomycin significantly decreased the recurrence rate (16.7% vs 50%, p = 0.05).437 Fidaxomicin was more effective as compared to vancomycin for recurrent CDI (RR 1.86, 95% CI, 1.04 – 3.31, p = 0.04).426,437 Fecal microbiota transplantation has also been compared to drug therapy for treatment of recurrent CDI. It was found that vancomycin therapy with duodenal infusion of donor feces had relapse free cure rate of 93.8% as compared to 30.8% and 23.1% in vancomycin with bowel lavage and vancomycin therapy alone respectively.438,439

Evidence Statement

Both metronidazole and oral vancomycin have similar efficacy in clinical and bacteriologic cure of CDI. Use of implicated antibiotic after completing the treatment of CDI is associated with increased risk of recurrence of CDI. There is insufficient evidence to justify the use of probiotics as an adjunct to antibiotics in the treatment of CDAD. In a single RCT, fecal microbiota transplantation was found to be highly efficacious for treatment of recurrent CDI.

Recommendations

We recommend metronidazole as the first line treatment of mild to moderate CDI/CDAD (1A).

We recommend oral vancomycin as the first line treatment of microbiologically proven severe CDI/CDAD (1A).

We recommend oral vancomycin as the treatment of recurrent CDI/CDAD infection (2A).

We recommend fecal microbiota transplantation as an alternate treatment of recurrent CDI/CDAD infection (2A).

We recommend that implicated antibiotics should be discontinued as soon as clinically feasible (2A).

We recommend against the use of probiotics as an adjunct for the treatment of CDI/CDAD (2A).

We recommend addition of vancomycin to a patient with microbiologically proven CDI/CDAD, if the patient is already on metronidazole or has no clinical response to metronidazole within 3-4 days (UPP).

Abdominal Infections in ICU

Acute Pancreatitis and Infected Pancreatic Necrosis

Acute pancreatitis (AP) is the inflammatory condition of the pancreas characterized clinically by abdominal pain and raised serum levels of pancreatic enzymes.440 Majority of the cases are caused by cholelithiasis and chronic alcohol consumption.441,442 Depending on the severity, AP is divided into mild, moderate and severe. Severity of pancreatitis is based upon the presence of organ failure and complications of acute pancreatitis either local or systemic.443 Local complications include peripancreatic fluid collections and pancreatic or peripancreatic necrosis (sterile or infected) whereas systemic complications include failure of an organ system (respiratory, cardiovascular, or renal) and exacerbation of a pre-existing disorder (e.g., chronic obstructive pulmonary disease, heart failure, or chronic liver disease).444 Patients with mild AP have no evidence of organ failure, local or systemic complications. Moderately severe AP is defined by presence of transient organ failure lasting less than 48 hours with or without local and systemic complications. Persistent organ failure for more than 48 hours associated with local and systemic complications defines severe AP (SAP).440,443 About 20% to 30% of patients with AP develop acute necrotizing pancreatitis.445,446 Pancreatic necrotic tissue may remain sterile (~70%) or may get infected (~30%). The severity of necrotizing pancreatitis is determined on the basis of the extent of parenchymal involvement by necrosis (i.e.,<30%, 30%-50% and >50%).447 Infected pancreatic necrosis is associated with higher mortality as compared to sterile necrosis.448,449 Thus, early recognition and institution of appropriate therapy is necessary. Treatment options include administration of antibiotics and surgical intervention if there is no response to antibiotics.450,451

What is the Incidence, Risk Factors and Microbiology of Pancreatic Infection Following Acute Pancreatitis?

Incidence and Risk Factors for Infected Pancreatic Necrosis

Incidence of infected pancreatic necrosis (IPN) in patients with acute pancreatitis varies from 12% to 37% depending upon the patients included (AP vs SAP) and diagnostic modality used for IPN.452–455 Patients with necrotizing pancreatitis are more prone to develop pancreatic infection and organ failure.448,449 Greater the extent of necrosis more likelihood of IPN. In a retrospective review of 300 patients of AP, pancreatic infection and organ failure were directly related to the extent of pancreatic necrosis.454 In a prospective single center study that included 204 patients of AP, pancreatic necrosis of more than 50% was significantly associated with the development of pancreatic infection and multiorgan failure.455 In a prospective observational study from India, similar findings were reported.452 Patients of AP can develop organ failure either during early phase (<1 week) known as primary organ failure or during later phase of AP (>1 week) known as secondary organ failure.456,457 In a prospective observational study in 805 patients of acute pancreatitis, presence of primary organ failure was associated with mortality of 15.8% and was a risk factor for development of infected pancreatic necrosis in 76% of patients.458

Evidence Statement

Incidence of pancreatic infection following acute pancreatitis ranges from 12-37%. Presence of pancreatic necrosis of >50% is a major risk factor for pancreatic infection following acute pancreatitis. Primary organ failure predicts development of infective pancreatic infection in patients with acute pancreatitis.

Microbiology of Pancreatic Infection Following Acute Pancreatitis

Enteric gram-negative bacteria including E. coli, Klebsiella, Pseudomonas and Enterobacteriaceae are the most common organisms isolated from IPN.452,459,460 It has been demonstrated that translocation of enteric bacteria (from the gut) is the main source of infection in necrotizing pancreatitis.461,462 A recent prospective observational study from India evaluated 209 patients with AP; 108 (52%) developed infected pancreatic necrosis (IPN). Polymicrobial infection was seen in 51% patients. Most common GNB isolated was E. coli (32%), E. faecium was the most common gram-positive organism (7%), whereas fungi were isolated in 13% cases. Importantly, 42% of isolates were MDR, whereas 25% were XDR.463 Gram-positive bacteria including Staphylococcus aureus, Streptococcus Fecalis, Enterococcus as well as anaerobes, and fungi have also been found.464,465 There are several studies that reported increase in the incidence of IPN caused by gram-positive organisms especially in patients who received prophylactic antibiotics for the prevention of development of IPN.455,466–468 Gram-negative organisms isolated from IPN show varying susceptibility to beta-lactam /beta- lactamase inhibitors, aminoglycosides, quinolones and carbapenems. Garg et al. reported that majority of the isolates from IPN were sensitive to third generation cephalosporins and quinolones. A more recent study from India observed that amikacin and imipenem were active against majority of the gram-negative organisms isolated from IPN.452,460 Resistance in gram-negative organisms to aminoglycosides, quinolones, beta-lactam /beta- lactamase inhibitors as well as to carbapenems has increased over last few decades. However, they remain sensitive to colistin and tigecycline. Gram-positive organisms remained sensitive to vancomycin, linezolid and teicoplanin.

Evidence Statement

Gram-negative organisms are the most common organisms isolated from infected pancreatic necrosis following acute pancreatitis in Indian patients. Prophylactic antibiotic use in patients of AP to prevent IPN has been associated with increased risk of infection with gram-positive organisms. Resistance to carbapenems, beta-lactam /beta- lactamase inhibitors and quinolones in gram-negative organisms isolated from IPN has increased, however, with maintain sensitivity to colistin and tigecycline.

What are the Empirical Antibiotics of Choice for Treatment of Pancreatic Infection Following Acute Pancreatitis?

Initial reports on use of prophylactic antibiotics in patients with AP to prevent IPN was associated with reduction in the incidence of IPN and mortality, however, well designed RCTs and meta-analysis failed to confirm the advantage of prophylactic antibiotics.469–471 Antibiotics should be prescribed in patients with evidence of IPN (positive image guided FNA or surgical specimen) or suggested by presence of air within the necrotic pancreatic tissue or persistent fever with leukocytosis and multiorgan failure.450,451 Empirical antibiotic regimen is selected based upon the local susceptibility pattern, pharmacokinetic properties of antibiotics and previous antibiotic exposure. Gram-negative organisms isolated from IPN show varying susceptibility to aminoglycosides, cephalosporins, quinolones, piperacillin-tazobactam and carbapenems. Over the past few decades there is an increase in the resistance among GNBs isolated from IPN to cephalosporins, quinolones, piperacillin-tazobactam and carbapenems with maintained sensitivity to colistin.472 Various pharmacokinetic studies have demonstrated the existence of blood pancreatic barrier and this barrier is responsible for the selective uptake of antibiotic drugs into the pancreas.473,474 These studies demonstrate that carbapenems have the highest while as aminoglycosides have least penetration to pancreatic tissue.474

Duration of antibiotic therapy in patients with IPN is not clear. However, Malaysian Society of Intensive Care suggests that duration should be guided by serial assessment of clinical and radiological response.475 There are multiple case series, observational studies and meta-analysis which suggest that conservative management with use of antibiotics in patients with IPN is associated with improved outcome and less mortality as compared to surgical debridement.476–480 Percutaneous drainage or endoscopic necrosectomy should be considered if the patient fails to improve or deteriorates clinically.450,451

Evidence Statement

Prophylactic use of antibiotics in patients with necrotizing pancreatitis has not been shown to reduce incidence of pancreatic infection and mortality. Presence of persistent fever, leukocytosis, multiorgan failure and presence of air within pancreatic necrosis suggest infected pancreatic necrosis. Cephalosporins, piperacillin-tazobactam, quinolones and carbapenems have the highest whereas aminoglycosides have the lowest penetration into necrotic pancreatic tissue. Response to antibiotic therapy is assessed by clinical and radiological parameters.

Recommendation

Routine use of prophylactic antibiotics to prevent pancreatic infection following acute pancreatitis of any severity is not recommended (1A).

Empirical antibiotic regimen in patients with infected pancreatic necrosis should be guided by local microbiological data, susceptibility pattern, pharmacokinetic property of antibiotics and previous antibiotic exposure (UPP).

In treatment-naïve patients with evidence of infected pancreatic necrosis, we recommend empirical treatment with either carbapenems, piperacillin-tazobactam or cefoperazone- sulbactam (2A).

In patients not responding or already exposed to the piperacillin-tazobactam, cefoperazone- sulbactam or carbapenems, colistin should be added to the empirical regime (3B).

Duration of antibiotic therapy should be guided by clinical, radiological and laboratory parameters (UPP).

Patients not responding to antibiotics should undergo necrosectomy and drainage (3B).

Biliary Sepsis

Acute Cholangitis

Acute cholangitis (AC) is a bacterial infection of the biliary tract that commonly occurs in an obstructed system and leads to systemic signs of infection. Choledocholithiasis is the most common cause of acute cholangitis.481 AC is classified as mild, moderate, and severe based on organ dysfunction and various biochemical abnormalities.482 Grade III AC is associated with organ dysfunction that includes any of the following: hypotension requiring either inotropic or vasopressors, confusion, PaO2:FiO2 ratio <300, serum creatinine levels>2 mg/dL, an international normalized ratio >1.5 or platelet counts <100 × 109/L. Grade II cholangitis is associated with any two of the following conditions: WBC count >12,000/mm3 or <4,000/mm3, high fever (≥39°C), age >75 years, hyperbilirubinemia (>5mg/dL) or hypoalbuminemia. Grade I do not meet any of the grade III or grade II criteria. Management of acute cholangitis depends on the severity of the illness and include administration of antibiotics and biliary drainage to relieve the obstruction. Drainage can be done electively in patients with mild cholangitis, within 24-48 hours in patients with moderate cholangitis and immediately in case of severe cholangitis.483

What are the Incidence, Risk Factors, and Microbiology of Biliary Infection in ICU?

Incidence and Risk Factors

The incidence of acute cholangitis varies with underlying etiology. In patients with cholelithiasis, symptomatic acute cholangitis develops in 0.2%-9% of cases.484,485 The incidence of acute cholangitis after endoscopic retrograde cholangiopancreatography (ERCP) ranges from 0.4% to 10%.486,487 Risk factors for acute cholangitis include obstruction of the biliary tree (choledocholithiasis, biliary stricture, cholangiocarcinoma, periampullary carcinoma, stent placement for biliary drainage or worm infestation) or biliary intervention (ERCP, post-surgical biliary stricture).488–492

Evidence Statement

Incidence of acute cholangitis varies with underlying etiology and ranges from 0.2 to 10%. Cholelithiasis, choledocholithiasis, benign and malignant common bile duct (CBD) strictures, CBD interventions, and stenting are the most common risk factors for cholangitis.

Microbiology of Acute Cholangitis

Various observational studies among patients with acute cholangitis from India and across the world have reported that gram-negative enteric organisms are the most common pathogens isolated from bile and/or blood.490,493–498 In patients with nosocomial acute cholangitis e.g., postoperative state, with indwelling biliary stents or those with malignant biliary obstruction, more resistant organisms such as MRSA, VRE, and pseudomonas are frequently detected as causative microorganisms. Risk factors for MDR organisms causing acute cholangitis include previous hospitalization and antibiotic use within 90 days.492 Although the bacteriological profile of acute cholangitis has remained stable over the last few decades, their antibiotic susceptibility pattern has changed. Most of the gram-negative isolates show varying sensitivity to carbapenems, piperacillin-tazobactam, cefoperazone-sulbactam, aminoglycosides, and quinolones, with increased resistance to cephalosporins and penicillins.490,492,494–497, 499

Evidence Statement

Gram-negative organisms are the most common organisms isolated from patients with acute cholangitis. Most of the pathogens isolated are susceptible to third-generation cephalosporins (such as cefoperazone-sulbactam), aminoglycosides, quinolones, ureidopenicillins, and carbapenems. Risk factors for multidrug drug resistance organisms causing acute cholangitis include an indwelling biliary stent, malignant biliary obstruction, previous hospitalization, and antibiotic use within 90 days.

What is the Empirical Antibiotic Rgimen for Acute Cholangitis?

Empirical antibiotic regimen in patients with acute cholangitis depends on the antimicrobial activity against causative bacteria, the severity of cholangitis, past history of antimicrobial administration to the patient, local susceptibility patterns (antibiogram) of the suspected causative organisms, and biliary penetration of the antimicrobial agents.500 Biliary obstruction reduces the antibiotic concentration within the bile and improves after biliary drainage, therefore should be considered in all patients of acute cholangitis.483 Tokyo guidelines for the management of acute cholangitis suggest monotherapy with beta-lactam/beta lactamase inhibitor (cefoperazone-sulbactam, piperacillin-tazobactam) or carbapenems or fluoroquinolone plus metronidazole to cover anaerobes.501 IDSA suggests combination of beta-lactam/beta-lactamase inhibitor (BL/BLI) or carbapenems or quinolones with metronidazole for moderate to severe community-acquired cholangitis. For nosocomial moderate to severe cholangitis combination of BL/BLIs or carbapenems or quinolones with metronidazole plus vancomycin is advised.502 IDSA suggests that antimicrobial therapy of established infection should be limited to 4–7 days, unless it is difficult to achieve adequate source control.502 Previous Tokyo guidelines recommended antibiotics for 2-3 days in case of mild and 5-7 days in case of moderate to severe cholangitis.501 However, latest revised Tokyo guidelines for management of acute cholangitis suggest duration of antibiotic to be 4-7 days once the source of infection iscontrolled.500 Duration of antibiotics may be guided by clinical response. Empiric antifungal therapy is usually not warranted.

Evidence Statement

The empirical antibiotic regime in patients with acute cholangitis is guided by the severity of the disease, local antibiotic susceptibility pattern, and biliary penetration of the antibiotics. The duration of antibiotics depends on the severity of cholangitis and adequacy of source control. Biliary drainage (percutaneous or endoscopic) is required in addition to antibiotic use in the management of acute cholangitis.

Recommendation

Empirical antibiotic therapy should be guided by the severity of the cholangitis, local microbiological susceptibility patterns, biliary penetration of antibiotics, and previous antibiotic exposure (UPP).

We recommend either beta-lactam/beta-lactamase inhibitor (such as cefoperazone-sulbactam or piperacillin/tazobactam) or carbapenems (imipenem/meropenem) as monotherapy in patients with moderate to severe cholangitis (3B).

We recommend antibiotic duration for 4-7 days in patients with acute cholangitis after adequate source control (2B).

Biliary drainage should be considered in all patients with cholangitis in addition to empirical antibiotic therapy (1A).

Anti-anaerobic therapy (such as metronidazole, tinidazole, or clindamycin) is required if a biliary-enteric anastomosis is present and the primary antibiotic therapy does not include carbapenems, piperacillin/tazobactam, or cefoperazone/sulbactam as these drugs have sufficient anti-anaerobic activity (3A).

Liver Abscess

A liver abscess is an infectious, space-occupying lesion in the liver. Pyogenic and amoebic liver abscesses are the two most common causes of liver abscess. Appropriate initiation of antibiotics will help to prevent potentially lethal complications like bacteremia and the spread of abscesses to other organs.

Incidence and Risk Factors

The incidence of pyogenic liver abscess varies from as low as 2.3 per lac population to as high as 446 per lac depending upon the presence of risk factors that predispose the person to liver abscess.503,504 The various risk factors for pyogenic liver abscess include male gender, older age, diabetes mellitus, biliary diseases, endobiliary procedures, alcoholism, hepatobiliary malignancies, and infected cystic liver lesions.504–508

What are the Most Common Organisms Causing Liver Abscess in ICU?

Microorganisms causing liver abscess have shown varying trends over the years. The earlier studies had shown predominantly gram-positive organisms like streptococcus as common cause of pyogenic liver abscess.509 However, recent studies have reported gram-negative organisms (including Klebsiella pneumoniaee, E. coli, and P. aeruginosa) to be responsible for the majority of cases of pyogenic liver abscess.505,506,510–514 Rarely pyogenic liver abscess is caused by organisms like Burkholderia, Prevotella and anaerobic bacteria including Eikenella and Peptostreptococcus.515–517 In Indian setting, amoebic liver abscess is the most common cause of liver abscess caused by infection with Entamoeba histolytica.514 The Streptococcus milleri group (including Streptococcus anginosus, Streptococcus constellatus, and Streptococcus intermedius) is also an important cause of liver abscess in western world and usually suggests a disseminated infection.

Evidence Statement

Amoebic liver abscess is the most common cause of liver abscess in Indian setup. The incidence of pyogenic liver abscess varies from 2.3 to 446 per 100,000 hospital admissions per year. Gram-negative organisms (E. coli and Klebsiella) are the most common organisms causing pyogenic liver abscess. Risk factors for pyogenic liver abscess include diabetes mellitus, older age, male gender, biliary diseases, biliary procedures, alcoholism, malignancy, intra-abdominal infection, and cystic lesions in the liver.

What are the Empirical Antibiotics of Choice for Treating Liver Abscess in ICU?

Amoebic Liver Abscess

Empirical treatment of amoebic liver abscess consists of a combination of a tissue agent and a luminal agent. Metronidazole is the drug of choice for the management of amoebic liver abscess. Metronidazole given for a period of 10 days has been shown to be effective.517 Alternatives to metronidazole include tinidazole, ornidazole, and nitazoxanide.518,519 The luminal agents used to remove any intraluminal cysts include paromomycin, diiodohydroxyquin or diloxanide furoate, even if the stool microscopy is negative. Routine use of drainage of amoebic liver abscess is not indicated in uncomplicated cases.517 However, the addition of needle aspiration to metronidazole has shown to hasten clinical improvement, especially in a large abscess (5 cm to 10 cm).514 Surgical intervention is required if there is no response to medical management.517,520

Evidence Statement

Metronidazole is the drug of choice for the treatment of amoebic liver abscess. The optimum duration of treatment in patients with amoebic liver abscess is 7-10 days. Routine needle aspiration of amoebic liver abscess is controversial. Addition of aspiration to drug therapy in patients with amoebic liver abscess of >5 cm in size hastens clinical improvement.

Recommendation

We recommend metronidazole as an initial antibiotic of choice in patients with amoebic liver abscess (2A).

We recommend antibiotic treatment for a period of 7-10 days in patients with amoebic liver abscess (3B).

Needle aspiration of amoebic liver abscess is recommended in patients with a lack of clinical improvement in 48-72 hours, left lobe abscess, abscess more than 5-10 cm or thin rim of liver tissue around the abscess (<10 mm) (UPP).

The luminal agents used to remove any intraluminal cysts (paromomycin, diiodohydroxyquin or diloxanide furoate) should be used even if the stool microscopy is negative (UPP).

Pyogenic Liver Abscess

Antibiotics that are effective in the treatment of pyogenic liver abscess include third and fourth-generation cephalosporins (such as ceftriaxone, and cefepime), aminoglycosides, fluoroquinolones, beta-lactam/beta-lactamase inhibitor (piperacillin-tazobactam), carbapenems, and metronidazole.511,521–523 Carbapenems are effective for the treatment of liver abscess caused by melioidosis or infection with ESBL producing organism.524,525

The empirical regimen should include a broad-spectrum parenteral antibiotic pending microbiologic analysis of the abscess contents. It should cover enteric gram-negative bacilli, streptococci, and anaerobes. Antibiotic therapy should generally be continued for four to six weeks.512 However, the optimal duration of therapy is unclear and is guided by the clinical and radiological response. Studies have reported that shorter courses of antibiotics for 2-4 weeks are effective as well.512,521,526 In case of abscess cavity with a size less than 5 cm, a needle aspiration is preferred and in case of abscesses more than 5 cm in size, percutaneous catheter drainage is preferred.527–529 Surgical drainage is required in cases of abscesses with viscous contents obstructing the catheter, an underlying disease requiring primary surgical management and inadequate response to percutaneous drainage within 7 days.530

Evidence Statement

Beta-lactam/beta-lactamase inhibitors, metronidazole, and carbapenems are effective antibiotics for management of pyogenic liver abscess. Carbapenems are effective in case of suspected infection with ESBL producing organisms or melioidosis. Antibiotics are required for prolonged periods ranging from 4-6 weeks. Clinical and radiological assessment is required to guide the adequate treatment duration. Initial 2-4 weeks therapy may be parenteral while oral therapy may be given for rest of the duration.

Recommendation

We recommend beta lactam/beta lactamase inhibitors with metronidazole in patients with pyogenic liver abscess for a duration of 4-6 weeks (2A).

We recommend carbapenems in case of infection with ESBL-producing organisms or melioidosis (2B).

The empiric regimen should also cover E. histolytica until the causative pathogen is found or amebic abscess is excluded (UPP).

Peritonitis

Peritonitis is defined as an inflammation of the peritoneum from any cause. Peritonitis occurs due to a variety of etiologies, of which the most common is infections. It is broadly classified as primary, secondary, and tertiary. Primary peritonitis, also known as spontaneous bacterial peritonitis (SBP), has no identifiable anatomical dehiscence. It is usually managed non-surgically. The risk factors for the development of primary peritonitis include advanced cirrhosis, nephrotic syndrome, and peritoneal dialysis.531,532 Secondary peritonitis is the infection of peritoneum that occurs in critical ill patients secondary to organ perforation, anastomotic leak or trauma to the gastrointestinal tract. Tertiary peritonitis may be defined as a severe recurrent or persistent intra-abdominal infection after apparently successful and adequate surgical source control of secondary peritonitis.533 It leads to prolonged systemic inflammation and is usually associated with high mortality (30-64%).Longer ICU stay, emergency abdominal surgery and total parenteral nutrition are risk factors associated with the development of tertiary peritonitis.534–539

What are the Most Common Organisms Causing Peritonitis in ICU?

Enteric gram-negative organisms including E. coli, klebsiella and enterobacteriaceae are the most common causative agents for primary and secondary peritonitis.540,541 Other organisms include gram-positive bacteria(such as enterococcus)as well as anaerobes (i.e. bacteroides).541 Tertiary peritonitis is usually due to opportunistic and nosocomial drug resistant bacteria and fungi. Various organisms reported are enterococcus, Candida, staphylococcus and enterobacter.539,542

Evidence Statement

The risk factors for development of primary peritonitis are decompensated cirrhosis, nephrotic syndrome and peritoneal dialysis. The risk factors for development of secondary peritonitis include intra-abdominal organ perforation, post intra-abdominal surgery, and trauma. Longer ICU stay, urgent operation on hospital admission, total parenteral nutrition, and stomach-duodenum as primary infection site are associated with the development of tertiary peritonitis. Gram-negative enteric organisms (such as E. coli, and Klebsiella pneumoniae) are the common causes of primary and secondary peritonitis. Other organisms include gram-positive as well as anaerobic bacteria. The organisms commonly isolated in tertiary peritonitis are Candida, Enterococcus faecium and Staphylococcus epidermidis.

What are the Empirical Antibiotics of Choice for Treating Peritonitis in ICU?

Primary Peritonitis

Cephalosporins and fluoroquinolones are effective against the majority of the cases of primary peritonitis.540,543–546 Antibiotics for a period of 5–7 days are effective in SBP.540,543,547,548 In difficult to treat SBP, cefepime and imipenem are reported to be effective.549

Secondary Peritonitis

The antibiotics effective in secondary peritonitis are beta-lactam/beta-lactamase inhibitors (piperacillin-tazobactam), quinolones, carbapenems (Imipenem with Cilastin), aminoglycosides, and metronidazole.541,550,551 When enterococci are considered, the addition of vancomycin or linezolid is required for a spectrum adequacy rate of more than 95%.552 Community-acquired infections of mild to moderate severity can be treated with Cefoxitin, Cefotetan, Cefmetazole, Ticarcillin-clavulanic acid.553

The average duration of antibiotic therapy is 10 to 14 days. However, recently the emphasis is on a shorter course of antibiotics after adequate source control. The recent STOP –IT trial has found that in patients after an adequate source control, outcomes after fixed-duration antibiotics (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days).554

Evidence Statement

Third-generation cephalosporins are the most effective antibiotic therapy for primary peritonitis. Antibiotics are usually required for 7-10 days for adequate treatment. Most of the organisms isolated in secondary peritonitis are sensitive to beta-lactam/beta-lactamase inhibitors or carbapenems. For gram-positive organisms, vancomycin and linezolid are effective treatment options. Short duration of antibiotic treatment (4 days) is as effective as a longer duration after adequate source control.

Recommendation

We recommend third generation cephalosporins (such as cefotaxime and ceftriaxone) for a duration of 7-10 days in patients with primary peritonitis (2A).

We recommend either beta-lactam/beta-lactamase inhibitor or carbapenems with an anaerobic cover (using metronidazole) for the treatment of secondary peritonitis (2A).

For secondary peritonitis, antibiotic treatment is required for at least 4 days after an adequate source control; however, longer treatment is required if adequate source control is not achieved (2A).

CNS Infections in ICU

Infections of the central nervous system (CNS), either community or hospital-acquired, are frequent causes of admission to the ICU. Bacterial meningitis and brain abscesses are one of the most common CNS infections and can result in significant morbidity and mortality. CNS infections are markedly different from systemic infections because of closed anatomic space and immunologic isolation of CNS from the rest of the body. They often have nonspecific clinical manifestations posing a diagnostic challenge to the clinician. Early suspicion, rapid diagnosis, and aggressive management are essential for better outcomes and to prevent various complications and neurological sequelae.

What are the Most Common Organisms Causing Acute Bacterial Meningitis in ICU?

Bacterial meningitis, an infection of the meninges and subarachnoid space, is a complex disorder in which injury is caused partly by the causative organism and partly by the host inflammatory response. Bacterial meningitis is a medical emergency, given the associated mortality and neurological sequelae requiring prompt recognition, rapid diagnostic evaluation, and emergent antimicrobial therapy. Hence accurate information regarding the incidence, risk factors, and microbiological profile of bacterial meningitis is necessary to ensure appropriate empirical antibiotic management. Meningitis can be community-acquired or associated with a variety of neurosurgical procedures (e.g., craniotomy, placement of invasive neuro-monitoring techniques, external ventricular drain catheters, or cerebrospinal fluid shunts) and penetrating head injury. The latter group is classified as nosocomial meningitis or healthcare-associated meningitis and ventriculitis. Both groups differ in their pathogenic mechanisms, risk factors, etiological agents microbial susceptibility patterns and hence are discussed separately.

Community-acquired Meningitis

The incidence of bacterial meningitis in the USA was 2 cases per 100,000 population in 1998–1999 that decreased to 1.38 cases per 100,000 population in 2006–2007; the most common organisms were Streptococcus pneumoniaee (56.8%), Neisseria meningitidis (17.2%), group B streptococci (16.7%), Haemophilus influenzae (5.8%) and Listeria monocytogenes (3.2%).555,556 In a retrospective study of 195 culture positive acute bacterial meningitis patients, the most common organism was streptococcus pneumoniaee followed by Staphylococcus aureus and klebsiella pneumoniaee.557 Various large studies have found S. pneumoniaee as the most common etiological agent followed by N. meningitidis, L. monocytogenes, H. influenzae and group B Streptococcus.558–562 Though S. aureus has also been reported as one of the common etiological agents in some studies.559–560 Otitis media, immunocompromised status, elderly population, and prior use of antibiotics have been described as risk factors for bacterial meningitis.558,563,564 Various Indian studies have yielded similar results.565–568 The prevalence of meningitis in hospitalized and critically ill patients of all age groups (0–75 years) varies from 8.68% and 78.85% in India. Streptococcus pneumoniaee is the predominant pathogen causing meningitis across different regions of India, with a frequency ranging from 4% to 61.8%.569,570

Evidence Statement

The incidence of community-acquired pyogenic meningitis ranges from 2 to 7.40 per lakh population and data suggest higher incidence in children. The common causative organisms include streptococcus pneumoniaee, Neisseria meningitidis, other streptococci, Haemophilus influenzae and Listeria monocytogenes. Other causative organisms are staphylococcus species, gram-negative bacilli, and Pseudomonas. Common risk factors for community-acquired bacterial meningitis are otitis media, elderly population, depressed immune status and prior use of antibiotics.

Nosocomial Meningitis

Nosocomial meningitis may result from various invasive procedures including craniotomy, placement of internal or external ventricular catheters, lumbar puncture, intrathecal infusions of medications, spinal anesthesia or complicated head trauma or rarely from metastatic infection in patients with hospital-acquired bacteremia.

Incidence of post-ventricular drain or catheter-related infections have been studied in many retrospective and prospective studies and ranges from 5.6% to 14.2% and 5.5% to 19% respectively.571–576 A systematic review from January 1990 through March 2008 reporting on ventriculostomy and extraventricular drain (EVD) related CNS infections described an incidence of 2–27%.577 Staphylococcus epidermidis (70%) is the most common microbiological agent followed by gram-negative bacilli (15%) and Staphylococcus aureus (10%). Risk factors described included EVD duration greater than 11 days, frequency of cerebrospinal fluid (CSF) sampling, intraventricular hemorrhage, and surgical technique (subcutaneously tunneled EVD, Rickham reservoir with percutaneous CSF drainage). Post craniotomy or neurosurgery incidence of meningitis ranges from 0.02% to 9.5%.573,578–584 Most of the studies have reported staphylococcus to be the most common causative organism.573,578,580,582,583 Few studies have also reported Acinetobacter and Enterobacteriaceae as the most common organisms.579,581 Postoperative CSF leak has been consistently shown to be a risk factor.573,578–580,582,583,585 Other risk factors are placement of external shunts, longer duration of drainage, multiple intracranial operations, emergency or prolonged surgery, diabetes, and elderly population.573,578–583 The role of prophylactic antibiotics for post-neurosurgery and craniotomy meningitis has been debatable, however, a recent meta-analysis of 7 RCTs including 2365 post-craniotomy patients found that prophylactic antibiotic use reduced the rate of post neurosurgical meningitis.586 The incidence of post-spinal blockade meningitis is very low with a large retrospective analysis of 12,60,000 spinal blockades and 450,000 epidural blockades showing incidence to be 1 in 53,000 with alpha-hemolytic streptococci as the most common causative organism.587 Exogenous inoculation is a risk factor and various measures such as hand disinfection, sterile gloves, face masks and operating caps decrease the risk of development of meningitis.588 The incidence of meningitis or ventriculitis in patients with post-traumatic head injury is 1.39%-2%.589,590 Common organisms include CONS, gram-negative bacilli, and Acinetobacter. Lumbar and ventricular drains are described as the risk factors. A recent Cochrane systematic review has not shown benefit of using prophylactic antibiotics in patients with basilar skull fracture, independent of CSF leakage.591 Post-internal ventricular drain infections incidence has been reported between 5.9% to 15.2% in various prospective and retrospective studies. Most common causative organisms included Staphylococcus aureus and CONS.592,593 Postoperative CSF leak, use of single gloves and number of times shunt system exposed to breached surgical gloves were described as risk factors.594,595 Indian studies suggest a 0.7–8.9% incidence of meningitis in post-neurosurgical patients.596 There have been reports of such infections with MDR organisms and newer antibiotics such as Ceftazidime-avibactum have been used for the same.597

Evidence Statement

Incidence of post-ventricular drain or catheter meningitis ranges from 2% to 27%. Commonly implicated organisms are CONS (especially staphylococcus epidermidis), Staphylococcus aureus, Acinetobacter, pseudomonas, and Enterobacteriaceae. Risk factors are repeated catheterization, higher catheter duration, CSF sampling, presence of concomitant systemic infection, and surgical technique i.e., subcutaneously tunneled extraventricular drain (EVD), Rickham reservoir with percutaneous CSF drainage. The incidence of post craniotomy or post neurosurgery meningitis is 0.02% to 9.5%. Most commonly implicated organisms are Staphylococcus aureus, coagulase-negative staphylococci (especially S. epidermidis), Enterobacteriaceae, Acinetobacter, and pseudomonas. Risk factors include CSF leak, EVD, longer duration of drainage, multiple operations, lack of antibiotic prophylaxis, and emergency surgery. The incidence of post-neuroaxial blockade meningitis is 0.2 per 10000 with Viridans streptococci and Staphylococcus aureus being common organisms. Exogenous inoculation is the main risk factor. Post-head trauma meningitis incidence ranges from 1.39% to 2% with CONS, Acinetobacter, and Enterobacteriaceae as common microbes and prolonged hospitalization, and insertion of a lumbar and ventricular drain as common risk factors. Post-internal ventricular drain infection incidence ranges from 5.9% to 15.2%. The most common causative organisms are CONS, Staphylococcus aureus, gram-negative bacilli, group D streptococci, and Propionibacterium acnes. CSF leak, single gloves use, and number of times shunt exposed to breached surgical gloves are the risk factors.

What are the Empirical Antibiotics of Choice for Treating Acute Bacterial Meningitis in ICU? What should be the Duration of Antibiotic Treatment?

Early diagnosis and urgent appropriate antimicrobial therapy along with other adjunctive therapy is necessary to reduce morbidity and mortality associated with bacterial meningitis. As isolation of microorganisms takes time and sometimes it may not be isolated at all, empirical antimicrobial therapy needs to be based on the most likely involved organism as determined by the presence of risk factors for various organisms and local antibiotic susceptibility patterns.

Community-acquired Meningitis

The evidence regarding empirical antibiotic choice in acute bacterial meningitis (ABM) is limited.598 A retrospective study found reduced penicillin susceptibility in 23% of patients with meningitis, including 16% in community-acquired meningitis. Ceftriaxone combined with penicillin was found adequate in 97% cases.599 Retrospective study by Hakam Erdem et al. reported the inadequacy of ceftriaxone alone in the treatment of pneumococcal meningitis in view of increasing penicillin resistance in pneumococci worldwide.600 A Cochrane review in 2007 comparing third-generation cephalosporins (ceftriaxone or cefotaxime) with conventional antibiotics (ampicillin-chloramphenicol combination, or chloramphenicol alone) as empirical therapy for ABM in adults and children found no statistically significant difference between the groups in the risk of death, risk of deafness or risk of treatment failure although significantly decreased chances of culture positivity of CSF after 10 to 48 hours with the third generation cephalosporins at the cost of increased risk of diarrhea.601 A recent Indian study including 266 culture-positive ABM patients (including 142 CAM patients) found that gram-positive pathogens exhibited maximum sensitivity to vancomycin and linezolid whereas most gram-negative pathogens were sensitive to carbapenems.602 Seven days antibiotic therapy has been recommended for N. meningitidis and H. influenzae, 10-14 days for S. pneumoniaee, 14–21 days for S. agalactiae, 21 days for aerobic GNB and 21days or more for L. monocytogenes.603

Evidence Statement

Choice of antibiotics depends on the most likely causative microorganisms, local antibiotics sensitivity patterns, mechanism of infection, and patient's predisposing condition. Most commonly recommended empirical antibiotic regimens include third-generation cephalosporin plus vancomycin, third-generation cephalosporin monotherapy and penicillin monotherapy. Addition of amoxicillin, ampicillin or benzyl-penicillin has been recommended in patients older than 50 years. However, antibiotic therapy should be modified according to the isolated organisms since MDR organisms are being reported from community as well.

Recommendation

We recommend third-generation cephalosporin (preferably ceftriaxone) plus vancomycin as empirical antibiotics of choice for community-acquired meningitis (3A).

We recommend adding ampicillin or amoxicillin if the age >50 years (3A).

If beta-lactams are contraindicated, we recommend chloramphenicol plus vancomycin as the antibiotic of choice, and to add cotrimoxazole if age >50 years (3A).

We recommend ciprofloxacin or aztreonam plus vancomycin as an alternative regimen and to add cotrimoxazole, if age greater than 50 years (UPP).

We recommend the duration of antibiotics based on suspected or isolated organisms i.e., 10 to 14 days for streptococcus pneumoniaee, 14 to 21 days for Streptococcus agalactiae, 7 days for Neisseria meningitidis or Haemophilus influenzae, 21 days for aerobic gram-negative bacilli, and 21 days or more for Listeria monocytogenes (3A).

If no microorganism is identified, antibiotics should be given for at least 10 to 14 days (3A).

Nosocomial Meningitis

Treatment recommendations for nosocomial meningitis are largely based upon expert opinion. IDSA guidelines for the management of bacterial meningitis recommend vancomycin plus third generation cephalosporin for post-basilar skull fracture meningitis; vancomycin plus cefepime, ceftazidime or merepenem has been recommended for post neurosurgery nosocomial meningitis or meningitis occurring after CSF shunt or penetrating trauma.603 Meropenem is the preferred option in a setting of infections by extended-spectrum beta-lactamase-producing Enterobacterales.604

A systematic review of intraventricular or intrathecal use of polymyxins in patients with gram-negative meningitis including 31 case reports and case series found limited available evidence to suggest the addition of intraventricular or intrathecal antimicrobials to systemic therapy in gram-negative meningitis. Toxicity was dose-dependent and reversible.605 Another review for use of intraventricular use of vancomycin found its use safe and effective.606 IDSA guidelines recommend vancomycin plus an anti-pseudomonal beta-lactam (such as cefepime, ceftazidime, or meropenem) as empiric antimicrobial of choice for suspected healthcare-associated ventriculitis and meningitis.607 The current IDSA guidelines suggest using adjunct intraventricular or intrathecal antimicrobial administration if the patient did not clinically improve on solely systemic treatment or the disease is caused by a difficult-to-treat resistant microorganisms. The common drugs include amikacin, colistin and gentamicin. Regarding optimum duration of antibiotic therapy, IDSA recommends therapy for 10 days if coagulase-negative staphylococcus or P. acnes with no or minimal CSF pleocytosis, normal CSF glucose, and few clinical symptoms or systemic features; 10 to 14 day treatment is recommended in case of significant CSF pleocytosis, CSF hypoglycorrhachia, clinical symptoms or systemic features. Treatment for 21 days is recommended for gram-negative bacilli and Staphylococcus aureus. In patients with repeatedly positive CSF cultures on appropriate antimicrobial therapy, IDSA recommends treatment to be continued for 10 to 14 days after the last positive culture.607 Currently, a single-dose of an antibiotic as per local susceptibility patterns is recommended for prophylaxis.608,609

Evidence Statement

Vancomycin in combination with cefepime, ceftazidime or meropenem is a commonly recommended empirical antibiotic regimen for nosocomial meningitis. Alternative regimens include third-generation cephalosporin or meropenem monotherapy or ceftriaxone plus flucloxacillin or cloxacillin combination therapy. Limited available evidence shows the efficacy of intraventricular or intrathecal antibiotics in the management of nosocomial meningitis poorly responsive to systemic antibiotics.

Recommendation

We recommend vancomycin plus cefepime or ceftazidime or meropenem as empirical antibiotics of choice for nosocomial meningitis (3A).

Colistin may be given if the incidence of CRE or drug-resistant Acinetobacter is high in the specific unit (UPP).

If beta-lactams are contraindicated, we recommend replacing beta-lactam with aztreonam or ciprofloxacin (3A).

Intraventricular or intrathecal antibiotics should be considered if infection responds poorly to appropriate systemic antibiotics clinically or microbiologically (3A).

What are the Most Common Organisms Causing Brain Abscess in ICU?

Brain abscess is a serious life-threatening emergency with high morbidity and mortality. The management of brain abscess is challenging and needs good clinical and surgical skills for better outcomes. The choice of pharmacological therapy should be based on the most likely organism, patient's predisposing condition or risk factors, mechanisms of infection, antimicrobial susceptibility patterns, and on the ability of the antimicrobial agent to penetrate the abscess.

In a recent single center retrospective study over 62 years including 620 patients of brain abscess, the incidence of brain abscess (per lakhs population) was 2.5 between 1952–1972, 2.6 in 1980–1991 and 2.2 in 2002–2014.610 Staphylococcus aureus is one of the commonest organism followed by Proteus sp. and Streptococcus. Chronic ear infection is a common predisposing factor (65% cases).611 Streptococcus (34%), followed by staphylococcus (18%), gram-negative enteric bacilli (15%), pseudomonas and haemophilus (2% each) were found to be the commonly isolated organisms in a recent meta-analysis. Peptostreptococcus, bacteroides and Fusobacterium were isolated in 3%, 6% and 2% respectively and polymicrobial etiology was found in 23% cases.612 Most common predisposing condition was otitis media followed by sinusitis, heart disease, post traumatic, hematogenous, pulmonary disease, postoperative, odontogenic, immunocompromised and meningitis. Two retrospective studies found Staphylococcus aureus to be the most common causative organism followed by Streptococcus.613,614 Otitis media was the most common risk factor followed by congenital heart disease, paranasal sinus infections, dental causes, trauma and postoperative state.613–616 Various prospective Indian studies found streptococci to be most common microbe.615,616 A recent Indian retrospective study reported that 47.14% samples from brain abscess were culture positive in which 50% had single aerobic/facultative anaerobic bacteria, 30.3% had a mixture of more than one aerobic/facultative anaerobic bacteria, 18.18% had single obligate anaerobic bacteria and 1.5% sample had Mycobacterium tuberculosis isolated. Among the total isolates, Pseudomonas aeruginosa and Staphylococcus aureus predominated.617

Evidence Statement

Incidence of brain abscess ranges from 1.3 to 2.6 cases per lakh population. Most commonly involved micro-organisms include streptococcus (especially S. viridans), staphylococcus (especially S. aureus), gram-negative bacilli, anaerobes (bacteroides, Peptostreptococcus, Fusobacterium), pseudomonas and H. influenzae. Polymicrobial etiology accounts for 23-26% cases. Risk factors include otitis media, sinusitis, head trauma, congenital heart diseases, hematogenous spread, surgery, immunocompromised status, pulmonary disease, meningitis and odontogenic infections.

What are the Empirical Antibiotics of Choice for Treating Brain Abscess in ICU? What should be the Duration of Antibiotic Treatment?

The data regarding the efficacy of various empirical antibiotic regimens in the management of brain abscess is limited to observational studies and expert opinion. In a systematic review and meta-analysis of clinical characteristics and outcomes of brain abscess, 17 studies described how many patients received which regimen.628The most common empiric treatment consisted of a third-generation cephalosporin combined with metronidazole, which was given in 53% of cases while vancomycin was added in additional 15% cases. Other regimens had combinations of chloramphenicol, metronidazole with penicillin (9%), ampicillin, gentamicin with metronidazole (9%), and imipenem monotherapy (4%).612 There is insufficient evidence to make specific recommendations but on the basis of limited clinical data, recommendations include cefotaxime plus metronidazole with or without rifampicin for post-trauma abscess, linezolid or vancomycin plus rifampicin plus meropenem or piperacillin/tazobactam for post-surgical abscess, cefotaxime or piperacillin-tazobactam plus metronidazole for post middle ear, paranasal sinuses, dental causes and cefotaxime with or without metronidazole or ampicillin-sulbactam for cryptogenic or metastatic abscess.618 Four to six weeks of antibiotic therapy is required for surgically treated abscesses and 6-8 weeks for solely medically treated or multiple surgical abscesses with the largest one treated surgically.619

Evidence Statement

The most common empiric treatment consists of a third-generation cephalosporin combined with metronidazole. Antibiotic duration ranges from 4 to 8 weeks.

Recommendation

We recommend third-generation cephalosporins plus metronidazole as the empirical antibiotic of choice for brain abscess (3A).

We recommend adding vancomycin if there is a high likelihood of MRSA (3A).

We recommend vancomycin plus ciprofloxacin if beta-lactams are contraindicated (3A).

We recommend aztreonam if ciprofloxacin cannot be given or contraindicated (UPP).

We recommend a minimum 4 weeks of therapy; however, duration may be extended according to clinic-radiological response irrespective of aspiration or excision of abscess (3A).

Skin and Soft Tissue Infections in ICU

An inflammatory microbial invasion of the epidermis, dermis and subcutaneous tissues is defined as skin and soft tissue infection (SSTI). In ICU, 4.3% to 10.5% of septic episodes may be caused by SSTIs,620 with attributable mortality of 11.7%.621 Spectrum of SSTI includes abscess, carbuncle, cellulitis, surgical site infection, diabetic foot and necrotizing fasciitis. SSTI has been classified based on signs of sepsis and comorbidities. SSTI without any signs or symptoms of systemic toxicity or comorbidities is termed Class 1. SSTI in patients with significant comorbidities (diabetes or obesity), but without any evidence of sepsis is termed class 2. Class 3 SSTI refers to SSTI with fever, tachycardia and tachypnea with or without hypotension. Class 4 SSTI refers to life threatening infections like necrotizing fasciitis along with sepsis.622 For treatment decision, it is important to classify SSTIs into purulent (carbuncle, furuncle and abscess) and non-purulent (necrotizing fasciitis, cellulitis and erysipela). Non-purulent SSTIs are classified into mild (no focus of purulence), moderate (presence of systemic inflammatory response syndrome, i.e., SIRS) and severe (failed oral antibiotics, SIRS, immunocompromised, deeper infection or organ dysfunction). Purulent SSTIs are classified into mild (no systemic signs of infection), moderate (SIRS present) and severe (SIRS along with treatment failure, or organ dysfunction).623

What are the Most Common Organisms and Risk Factors for SSTI in ICU?

Staphylococcus aureus (20.9%–38.1%) and gram-negative bacilli (29.1%–57.4%) have been commonly implicated in SSTIs in India.624–626 Pseudomonas (11.8%–57.4%) and E. coli (17.3%) are most common GNBs.625,626 High proportion of Staphylococcus aureus (40%–74%) have been reported to be methicillin resistant,625,627 whereas majority of (66.7%–74%) GNBs have been reported to be ESBL producing.625 Necrotizing fasciitis is caused mostly by Streptococcus pyogenes in monomicrobial form. Clostridial species are also responsible for monomicrobial necrotizing fasciitis.628 In polymicrobial necrotizing fasciitis, the most commonly implicated pathogens are coliforms, anaerobic bacteria and staphylococcus.629,630 Old age, obesity, diabetes mellitus, malignancy, higher APACHE score, longer ICU stay, end stage renal disease, cirrhosis of liver, intravenous drug abuse and neutropenia are risk factors for SSTI.622,631,632

Evidence Statement

Older age, diabetes mellitus, obesity, malignancy, cirrhosis and longer ICU stay are risk factors for SSTIs. Gram-positive organisms (Staphylococcus aureus) are the most common organism responsible for the SSTIs. E. coli and pseudomonas are common pathogens among gram-negative organisms. MRSA and ESBL producing gram-negative organisms are the most common causative agents for SSTIs in ICU. Monomicrobial necrotizing fasciitis is commonly caused by Streptococcus pyogenes; mixed coliforms, anaerobes and staphylococci are common causes of polymicrobial necrotizing fasciitis.

What are the Empirical Antibiotics of Choice for Treating SSTI in ICU ? For Empirical Therapy, should Combination Therapy be Preferred over Monotherapy?

Studies on SSTIs specific to ICU settings are not available. Meta-analysis performed by Rebecca J et al.633 showed clear superiority of linezolid and vancomycin in treating skin and soft tissue infection caused by S. aureus. Teicoplanin is also a good choice for treating severe SSTI caused by MRSA, with similar efficacy and fewer adverse effects as compared to vancomycin.634–636 Daptomycin has been shown to have more rapid clinical cure, reduced length of hospital stay and lower cost as compared to vancomycin in a prospective study of SSTIs in ICU.637 Other RCTs have demonstrated non-inferiority of daptomycin to vancomycin.638 MRSA remains sensitive to vancomycin and linezolid, and majority remain sensitive to clindamycin also (79%).627 For gram-negative pathogens, piperacillin-tazobactam and imipenem have been reported to be most effective antibiotics.620

Evidence Statement

Vancomycin, teicoplanin, daptomycin and linezolid are effective in SSTIs caused by MRSA. Piperacillin-tazobactam and carbapenems are the most effective antibiotics for ESBL producing gram-negative organisms. Penicillin plus clindamycin are most effective antibiotics in monomicrobial necrotizing fasciitis, whereas a combination of piperacillin-tazobactam, fluoroquinolone and clindamycin is effective for polymicrobial necrotizing fasciitis.

Recommendation

For moderate non-purulent SSTI, we recommend intravenous penicillin or clindamycin as first choice of antibiotics (2A).

Severe non-purulent SSTI should be treated with a combination of piperacillin-tazobactam along with coverage for MRSA (vancomycin, teicoplanin, daptomycin or linezolid) (2A).

Concomitant surgical inspection or debridement should be considered for severe non-purulent SSTIs (2A).

For severe purulent SSTI, incision and drainage followed by empiric antibiotics including piperacillin tazobactam, along with MRSA coverage (vancomycin, teicoplanin, daptomycin or linezolid) is recommended (3A).

Penicillin plus clindamycin is recommended for monomicrobial necrotizing infection caused by Streptococcus pyogenes or clostridial species. For polymicrobial necrotizing fasciitis, a combination of piperacillin-tazobactam, fluoroquinolone and clindamycin is recommended (3A).

What should be the Duration of Antibiotic Treatment for SSTI?

There is limited literature to guide treatment of severe or complicated SSTIs. In uncomplicated SSTI, antimicrobial administration for 5 days was equally effective to 10 day treatment.639 Complicated SSTIs may require longer treatment.

Evidence Statement

Shorter course of antibiotic therapy is adequate for uncomplicated SSTIs while complicated SSTIs require longer duration of antibiotic therapy.

Recommendation

Severe nonpurulent SSTIs should be treated with at least 5 days of antibiotics (3A).

Severe SSTIs with organ dysfunction should be treated with a prolonged course of antibiotics of 2-3 weeks duration (3A).

Sepsis of Unknown Cause in ICU

Mortality from severe sepsis and septic shock remains consistently high.640,641 Delay in antimicrobial therapy is associated with increased in-hospital and overall mortality in severe sepsis and septic shock.642,643 In view of this data, empiric antimicrobial therapy should be started immediately (preferably within 1 hour) after presumptive clinical diagnosis of septic shock. While every effort should be made to secure site-specific cultures to guide microorganism-specific therapy, this should never delay the administration of empiric antimicrobials.644 Intensive efforts, including imaging, should be undertaken in an attempt to evaluate the source of infection. Two sets of blood cultures and other appropriate microbiological specimens should preferably be taken before empirical therapy. Urgent empirical broad-spectrum coverage to include all common pathogens should be administered.644

What is the Empirical Treatment for Sepsis of Unknown Cause in ICU?

There is paucity of data on empirical antimicrobial therapy in sepsis of unknown cause in ICU. Combination antimicrobial therapy (using two drugs from different class) improves survival and clinical outcomes in patients with sepsis who are critically ill and in septic shock as compared to monotherapy.645 Beta-lactams with aminoglycosides or fluoroquinolones gives a broad empirical coverage. If the patient has risk factors for MRSA, vancomycin should be added to the regimen.646 Accordingly if risk factors for MDR pathogens are present in an individual patient, beta-lactam of choice is a carbapenem. In India, empirical therapy should cover for various tropical infections till a definite diagnosis is reached. Third-generation cephalosporins with doxycycline is an appropriate option keeping this fact in mind.

Evidence Statement

Empirical therapy with dual class (with different mechanisms of action) combination antimicrobial therapy for sepsis of unknown cause in ICU is associated with have better clinical outcomes. Empirical therapy with either piperacillin-tazobactam or carbapenems in combination with aminoglycoside or fluoroquinolone has been shown to give appropriate broad coverage leading to better clinical outcomes as compared to monotherapy.

Recommendation

We recommend empirical antimicrobial therapy with combination of ceftriaxone and doxycycline or macrolide for community-acquired sepsis of unknown origin in ICU (UPP).

We recommend empirical antimicrobial therapy with combination of beta-lactam/beta-lactamase inhibitor and fluoroquinolone or aminoglycoside for nosocomial sepsis of unknown origin in ICU (UPP).

Empiric therapy should attempt to provide antimicrobial activity against the most likely pathogens based upon clinical features along with local patterns of infection and resistance (UPP).

Duration of therapy is 7 to 10 days, though longer courses may be appropriate in patients with slow response (3B).

Empirical Antifungals for Non-neutropenic Patients in ICU

Invasive fungal infection (IFI) is an important cause of morbidity and mortality among critically ill patients. Early institution of antifungal therapy is pivotal for mortality reduction. Starting targeted antifungal therapy after culture positivity or identification of pathogen requires a long time. Therefore, alternative strategies (defined as untargeted antifungal treatment) for antifungal therapy institution in patients without proven microbiological evidence of fungal infections have been considered.647 Untargeted antifungal strategies include prophylactic antifungals, pre-emptive antifungals and empirical antifungals. Prophylaxis refers to use of antifungals without proven or suspected fungal infection but with risk factors for its development. Pre-emptive (diagnosis driven) approach means evidence of fungal infection, without definitive microbiological proof on the basis of surrogate biomarkers like 1-3 ß-D-glucan, mannan or anti-mannan antibodies, whereas empirical(fever-driven) approach refers to using antifungals in patients at risk for IFI, with signs and symptoms of infection, in absence of microbiological evidence of infection.647

Among fungal pathogens, Candida spp. are the most commonly isolated microorganisms, currently being the fourth most commonly identified pathogens in nosocomial BSIs and the third most common pathogens isolated in ICU patients.307 Despite advances in antifungal therapy, the mortality associated with invasive candidiasis remains as high as 40%.647 In India, incidence of C. albicans ranges from 34% to 45.6 % with an attributable mortality of 20% to 35.6%. Incidence of non-albicans Candida is on the rise with attributable mortality ranging from 23% to 52%, with higher mortality associated with Candida krusei.648 An observational study from Indian ICUs revealed an incidence of 6.5 cases per 1000 ICU admissions. There was a high prevalence of C. tropicalis (41.6%) and 46.6% isolates were susceptible to all antifungals. Fluconazole resistance was 5.2% for C. albicans while it was 2.6% for Candida tropicalis. Risk factors for invasive candidemia were found to be surgery especially abdominal surgery, central venous catheters, invasive mechanical ventilation, urinary catheterization, hemodialysis and total parenteral nutrition.328

What are the Risk Factors for Invasive Fungal Infections in ICU?

Risk factors for invasive fungal infections (IFIs) in ICU have been studied extensively. A large retrospective study in 301 surgical ICU patients found the risk factors for IFI to be peripheral and central intravenous catheters, bladder catheters, mechanical ventilation, lack of enteral nutrition and TPN.649 In a prospective study of 150 cardiothoracic ICU patients, risk factors for IFIs were prolonged mechanical ventilation (>10 days), hospital-acquired bacterial infection, cardiopulmonary bypass duration greater than 120 min, diabetes mellitus and high APACHE II score (>30).650 A systematic review demonstrated that major surgery (OR-7.3), TPN (OR-3.8), fungal colonization with colonization index >0.5 (OR-19.1), hemodialysis (OR-3.8), acute renal failure (OR-4.2), severe sepsis, mechanical ventilation >3 days, diabetes (OR-2.8), APACHE 2 score >16 (OR-1.03), cardiopulmonary bypass >120 min (OR-8.1), use of broad-spectrum antibiotics (OR-3), red cell transfusion and central or peripheral venous catheters were significantly associated with IFIs.651

Evidence Statement

Risk factors for invasive fungal infections in non-neutropenic patients in ICU are surgery, total parenteral nutrition, renal replacement therapy, cardiopulmonary bypass >120 minutes, diabetes mellitus, central venous catheters, urinary catheters, Candida colonization with colonization index >0.5, use of broad-spectrum antibiotics, acute renal failure, mechanical ventilation >3 days and APACHE II score >16.

What is the Role of Empirical Antifungals in Non-neutropenic Patients in ICU?

The advantage of empirical antifungal treatment has already been established in high-risk patients such as cancer patients and solid organ transplant recipients in various studies.652–654 However, in non-neutropenic critically ill patients, the definitive evidence for efficacy of untargeted treatment in terms of prevention of IFIs or mortality benefit has been equivocal. Moreover, studies have shown potential detrimental effects of the injudicious use of antifungal agents in the form of emergence of drug resistance, side effects and financial costs.655–657 Several randomized controlled trials have compared empirical antifungals to placebo in non- neutropenic critically ill patients.658–663 In a RCT including post-surgery patients, fluconazole reduced the occurrence of candidemia (5.8% in fluconazole vs 16% in placebo) though the mortality rates were similar.658 Similarly, use of caspofungin was also associated with trend towards decreased IFI without any difference in mortality or length of hospital stay.660 A systematic review demonstrated that although empirical antifungals in non-neutropenic patients in ICU reduced the incidence of subsequent IFI, it had no impact on mortality.663 In a randomized controlled trial involving 260 mechanically ventilated patients with Candida colonization, empirical micafungin administration reduced the rate of subsequent proven IFI (12% vs 3%; p = 0.008) without any significant mortality benefit.662

Evidence Statement

Empirical antifungals for non-neutropenic patients in ICU routinely has not been associated with decrease in mortality or hospital length of stay. Empirical antifungals in patients at high risk for invasive fungal infections in ICU has been shown to reduce incidence of subsequent proven invasive fungal infections.

Recommendation

We do not recommend the routine use of empirical antifungals in non-neutropenic patients in ICU (1A).

Empirical antifungals may be considered in critically ill patients with high risk of invasive fungal infections to reduce the incidence of subsequent invasive fungal infections (1B).

What is the Antifungal Agent of Choice and Duration of Empirical Therapy in Non-neutropenic Patients in ICU?

The options for antifungal therapy include fluconazole, amphotericin-B and echinocandins. In a systematic review, empirical use of fluconazole and caspofungin reduced rates of subsequent IFI while micafungin, nystatin and amphotericin-B did not.663 No direct comparative data of efficacy of different antifungals for empirical therapy in non- neutropenic patients in ICU is available. Indian studies have shown increasing prevalence of non-albicans Candida with high rates of fluconazole resistance in the range of 5% to 7%.664 Regarding duration of empirical antifungal therapy, there are no studies directly comparing different duration of empirical antifungal therapy. Most of the studies have used at least 2 weeks therapy.663

Evidence Statement

Fluconazole and caspofungin are useful as empirical antifungal therapy in non-neutropenic ICU patients at high risk of Invasive fungal infection. In India, rate of fluconazole resistance is up to 7%, especially in non-albicans Candida species.

Recommendation

We recommend fluconazole or caspofungin as preferred empirical antifungal agents in non- neutropenic ICU patients at risk for invasive fungal infection (1A).

Caspofungin may be preferred in areas with high prevalence of fluconazole resistance (1B).

Micafungin or anidulafungin may be used as alternative agents (3A).

Recommended duration of empirical antifungal therapy is 2 weeks (3A).

Antibiotic Stewardship

Antibiotic stewardship program is defined as “coordinated interventions designed to improve and measure the appropriate use of antibiotic agents by promoting the selection of the optimal drug regimen including dosing, duration of therapy, and route of administration.”665 An efficient antibiotic stewardship program results in optimum clinical outcomes while reducing adverse effects of unnecessary antibiotic use. Every additional 10 days of antibiotic therapy conferred a 3% increased risk of an adverse drug event. These adverse effects include emergence of antibiotic resistance, clostridium difficile infections and drug toxicity and occurs in 20% of patients.666 A structured antibiotic stewardship program requires a multidisciplinary approach. Core elements of antibiotic stewardship program includes committed leadership, accountability, expertise in drugs, action, tracking drug resistance patterns, regular reporting and education to clinicians about optimal prescribing.667

Does Antibiotic Stewardship Improve Patient Outcome in ICU?

Antibiotic stewardship programs reduced duration of antibiotic treatment (1.95 days; 95% CI, 2.22 to 1.67) and duration of hospital stay (1.12 days, 95% CI, 0.7- 1.54) without any significant difference in mortality in a recent systematic review.667 In a recent meta- analysis, there was reduced mortality with guideline directed empirical therapy (RR 0.65, 95% CI, 0.54- 0.80, p < 0.0001) and antibiotic de-escalation (RR 0.44, 0.30- 0.66).668 Mortality benefit has also been reported in another systematic review (RR 0.68, 95% CI, 0.52- 0.88).669 However, a single non blinded randomized study showed significantly higher rate of superinfection with de-escalation of antibiotics as compared to continuation of empirical therapy (27% vs 11%; p = 0.03).670

Evidence Statement

Antibiotic stewardship programs in hospitalized patients are associated with reduction in number of antibiotic days, duration of hospital stay and all-cause mortality.

Recommendation

All hospitals should have an antibiotic stewardship program including the intensive care units (1A).

What are the Essential Strategies of Antibiotic Stewardship in an ICU Setting?

Prospective audit-feedback and Preauthorization are commonly used strategies of antibiotic stewardship.671–673 In prospective audit and feedback, treating clinicians are provided recommendations regarding appropriateness of antibiotics used. Advantages of this strategy include avoidance of delay in antibiotic administration (as physician is engaged after prescription of antibiotics). Limitations of this strategy include partial compliance (due to voluntary participation of physicians), resource intensive nature, and longer lag period for visible benefits to become apparent. Prospective audit and feedback strategy resulted in reduction in utilisation of antibiotics and significant cost reduction.674–675 In a systematic review, enabling strategies including feedback resulted in greater efficacy of stewardship interventions.671 Preauthorization, another strategy of antibiotic stewardship, requires approval by concerned authority before starting antibiotics.672 This affects use of restricted antibiotics only and may result in potential delay in antibiotic initiation. Without feedback, this may also result in increased use of other antibiotics and hence lead to selection of different resistance patterns. However, it provides immediate results in terms of recued antibiotic usage. Other potential drawbacks include development of negative professional culture because of breakdown in communication between infectious disease specialists and clinical teams.671 Enabling and restrictive strategies have been compared in a quasi-experimental crossover trial using days of antibiotic therapy in both strategies.676 In this study involving 2,686 patients in pre-prescription authorization (PPA) group and 2,693 patients in post prescription review with feedback (PPRF) group, initially antibiotic days of treatment (DOT) remained relatively unchanged in the PPA arm. When changed to the PPRF arm, antibiotic use decreased (-2.45 DOT per 1000 patient-days [PD]) hence concluding that PPRF may have more impact on decreasing days of antibiotic therapy.

In another quasi-experimental study comparing both strategies in 55336 patients, after the introduction of prospective audit with feedback, both total antimicrobial use (+9.65 DOT/1,000-PD per month; p < 0.001) and broad-spectrum anti-gram-negative antimicrobial use (+4.80 DOT/1,000-PD per month; p < 0.001) increased significantly as compared to preauthorization in the pre intervention period.677 Use of cefepime and piperacillin-tazobactam both significantly increased after the intervention (p = 0.03). Hospital LOS and LOS after first antimicrobial dose also significantly increased after the intervention (p = 0.016 and 0.004, respectively).

Evidence Statement

Antibiotic stewardship requires a multidisciplinary approach with integration of infectious disease physician, microbiologist with logistic and financial support from hospital administration. Both enablement and restrictive strategies are useful in improving adherence to antibiotic stewardship programs. Restrictive strategies give immediate results. Enablement practices are more resource intensive. Most studies have used a combination of both the methods and have shown additive effects. Providing feedback to the treating team improves adherence. A single RCT has shown that restrictive strategy alone may cause delay in initiation of antibiotics.

Recommendation

Prospective audit of antibiotic use and/or preauthorization (if feasible) along with feedback to the treating team is recommended as part of antibiotic stewardship program (1A).

What is the Role of Antibiotic Cycling, Intravenous to Oral Switch and De-escalation in the ICU?

Antibiotic cycling refers to withdrawing a specific antibiotic or an antibiotic class from use for a definite period of time and substituting with another antibiotic or antibiotic class having a similar spectrum of activity.672 This is postulated to induce different resistance mechanisms in the microorganisms and hence prevent or reverse the development of antibiotic resistance. There is no compelling evidence on the benefit of antibiotic cycling in terms of clinical end points. Several prospective before and after studies without control groups have demonstrated reduction in incidence of ventilator-associated pneumoniae (6.7% with antibiotic cycling as against 11.6% before the intervention)678 as well as reduction in colonization.678–680 A newer prospective cohort study681 comparing antibiotic mixing and antibiotic cycling found no significant differences in infection rates (16.6% and 14.5%, OR 0.9), infection due to target microorganisms (5.9% and 5.2%, OR 0.9), hospital length of stay (median 5 days for both groups) or in hospital mortality (13.9% and 14.3%, OR 1.03).

Evidence Statement

Antibiotic cycling in the intensive care unit has not been adequately studied in randomized controlled trials. Non-randomized studies show significant heterogeneity in terms of site of study, method of cycling and confounders like simultaneous infection control measures being employed. Evidence of benefit of antibiotic cycling is lacking, with few studies demonstrating reduction in colonization though mortality and length of hospital stay remain unchanged.

Recommendation

Antibiotic cycling should not be used as a method of antibiotic stewardship program (2A).

Scheduled Intravenous to Oral Switch

Timely switch from intravenous to oral antibiotics has been shown to reduce cost of health care and length of hospital stay.682–687 In case of antibiotics with availability of equivalent oral formulations, the scheduled switch is easier than in case of broad-spectrum antibiotics without oral formulations or precise like piperacillin tazobactam or meropenem. A multicenter randomized controlled trial done in CAP which evaluated scheduled switch to oral antibiotics after 2 days of intravenous antibiotics found similar cure rates, survival or resolution of chest radiology with significantly lower total cost of care (2953$ and 5002$, p < 0.05).686 Oosterheert et al.685 also found similar results when comparing scheduled switch on day 3 and day 7 with similar cure rates and mortality rates in both groups but with significantly reduced duration of intravenous antibiotics and hospital stay, with differences of 3.4 days and 1.9 days respectively.

Evidence Statement

Early intravenous to oral transition of antibiotics reduce hospital length of stay and cost of care. There is no increase in mortality or other adverse events when this is done after assessing as to which patients can be safely transitioned to oral therapy.

Recommendation

Antibiotic stewardship programs should implement strategies to improve timely transition from parenteral to oral antibiotic therapy (2A).

De-escalation in Intensive Care Unit

Antibiotic de-escalation refers to a strategy of switching from broad-spectrum antimicrobials to a narrower spectrum of antimicrobials. It is recommended to reduce emergence of multidrug-resistant bacteria as well as costs of health care. In a multicenter randomized controlled trial, de-escalation was associated with longer ICU stay but similar in hospital mortality in severe sepsis.670 In a recent meta-analysis of 9 studies involving 1,873 patients with septic shock, de-escalation of antibiotics was associated with trend towards reduced mortality (RR 0.74, 95% CI, 0.54- 1.03).688 In another systematic review, de-escalation was associated with lower mortality (RR 0.68; 95% CI, 0.52–0.88).669

Evidence Statement

Pooled results from observational studies in an ICU setting do not show any increase in mortality with antibiotic de-escalation while significantly reducing antibiotic exposure days and ICU length of stay.

Recommendation

Antibiotic de-escalation in the ICU is recommended as part of antibiotic stewardship program (2A).

What is the Role of Procalcitonin in Antibiotic De-escalation in ICU?

Procalcitonin is a 116 amino acid precursor to calcitonin. Normal serum or plasma levels of procalcitonin in healthy adults are <0.05 ng/mL. It can be produced by a variety of cell types in response to inflammatory stimuli, especially of bacterial origin. It does not usually rise significantly in response to viral or non- infectious inflammation and so has the potential to be used as a marker of bacterial infection. The levels in serum is quantified using immunoassay.284 Procalcitonin use to guide antibiotic therapy in sepsis in intensive care unit resulted in reduction in antibiotic days (MD –3.19 days, 95% CI, –5.44 to –0.95) duration of hospital stay (MD –3.85 days, 95% CI, –6.78 –0.92) as well as a trend towards reduction in duration of ICU stay (MD –2.03 days, 95% CI, –4.19 to 0.13 days).689 Procalcitonin guided algorithm for antibiotic discontinuation (decrease by >80% of peak value, or <0.5 ng/mL) led to reduced antibiotic administration (between-group absolute difference 1.22, 0.65–1.78, p < 0.0001), with significant mortality benefit (20 vs 25%; between-group absolute difference 5.4%, 95% CI, 1.2–9.5, p = 0.0122).115 In a recent Cochrane meta-analysis involving 26 trials, procalcitonin utilisation for antibiotic discontinuation was associated with reduced mortality (adjusted OR 0.83, 95% CI, 0.70 to 0.99, p = 0.037).118

Evidence Statement

Implementation of antibiotic de-escalation algorithm based on serial procalcitonin measurements has been shown to reduce mortality, length of ICU stay, total duration of antibiotic days and health care costs.

Recommendation

Procalcitonin based algorithms may be used for antibiotic de-escalation (1A).

Antimicrobial Prescription in Critically Ill Immunocompromised Patients

Advances in ICU care of immunocompromised patients have resulted in improved and meaningful survival rates.690 Early intensive care can be used to treat reversible causes of acute worsening in patients with advanced malignancy.691 Patients with primary immunodeficiencies are increasingly being recognised. However, more often, patients without a prior diagnosis present with severe sepsis and septic shock in the intensive care unit where careful clinical assessment and high index of suspicion can lead to diagnosis of the underlying immunodeficiency.692 This separate yet heterogenous group of immunocompromised patients present different challenges to the intensive care physician due to febrile neutropenia, increased risk of bloodstream infections, invasive fungal infections and other complex issues which have led to separate guidelines for this group.693–695

The Febrile Neutropenic Patient

Febrile neutropenia (FN) is defined as an oral temperature of >38.3°C or two consecutive readings of >38.0°C for 2 h and an absolute neutrophil count (ANC) of <0.5 × 109/L or expected to fall below 0.5 × 109/L.693 These guidelines are applicable in a critically ill febrile neutropenic patient presenting to the ICU with any of the following clinical or laboratory parameters of organ failure but not limited to

Hypotension.

Tachypnea requiring oxygen therapy more than 4 liters/min to maintain saturation >90%.

Altered mental status (without focal neurological deficit).

Oliguria or rising serum creatinine.

What should be the Empiric Antibiotic Therapy in Critically Ill Febrile Neutropenic Patients with Suspected Bloodstream Infection?

In India, in febrile neutropenic patients, gram-negative bacteremia is much more common than gram-positive bacteremia (Table 3); in contrast to the western data, where gram-positive isolates are more common.694,695 The spectrum of bacterial isolates from number of studies in India suggest Enterobacteriaceae (E. coli and Klebsiella species) and Pseudomonas aeruginosa to be the most common among gram-negative organisms. Among gram-positive isolates, Staphylococcus aureus and Coagulase negative staphylococcus are most common isolates (Table 3).696–703

Table 3 Isolates from blood of febrile neutropenic patients in India

Author, year	No. of isolates	Gram-negative isolates (%)	Common organisms (%)	Gram-positive isolates (%)	Common organisms (%)	
Prabhash K et al.696 2010	484	68.1	Pseudomonas 30.37, Acinetobacter 11.57
E. coli 10.9
Klebsiella 7.23
Enterococcal spp. 4.13	31.9	Staph Aureus- 12.6(MRSA- 2)
Cons-10.5
Streptococcus spp. 4.55
Burkholderia spp. 2.89
Enterobacter spp. 2.27	
Karanwal et al.697 2013	23	78	E. coli 43, Pseudomonas 17.47	22	Staph aureus 22
CONS- 4	
Singh et al.698 2014	693	74.6	E. coli 23.5, Pseudomonas 6.7	25.4	Staph Aureus- 34(MRSA 13)
Enterococcus 29	
Rajendranath R et al.699 2014	40	58.3	E. coli 36.7, Pseudomonas 9.2	41.7	Staph aureus- 25
(MRSA- 2.5)	
Sengar M et al.700 2014	739	66	E. coli 19, Pseudomonas 18.7
Acinetobacter 7.1
Enterobacter 4.8	34	Cons-2
Staph aureus- 5.5
Streptococcus 3.9
Enterococcus 3.6	
Lakshmaiah KC et al.701 2014	92 (11 positive)	61.7	E. coli 36	38.3	Staph Aureus- 36(MRSA 9)	
Vivek B et al.702 2016	285	63	Pseudomonas 22
E. coli 21.4	37	CONS 12.9
Staph Aureus 8	
Sevitha Bhat et al.703 2021	306 (blood –46 patients)	69.9	Klebsiella spp-18.3
Pseudomonas spp -17.6
E. coli -14.7%	30.1	Staph aureus -13.7	

There is scarce data regarding the choice of empirical antibiotic regimens in critically ill febrile neutropenic presenting to the Indian ICUs. Most of the studies have heterogeneous patient population—leukemia, lymphoma, solid tumors etc. Choice of antibiotics depends on most likely causative microorganism as per the local isolate patterns, clinical focus of infection, host and disease characteristics, local antimicrobial sensitivity patterns, and mechanism of action of antimicrobials (bacteriostatic/bactericidal). Recent data shows increased prevalence of MDR organisms. Several studies in India have shown that majority of gram-negative bacteria isolated on initial blood cultures from patients were resistant to the non-carbapenem first-line antibiotics.704–707 Hence, initial antibiotic choice in a febrile neutropenic patient who is critically ill presenting to the ICU will be carbapenems like Meropenem or Imipenem. The prevalence of carbapenem resistant gram-negative organisms is alarming at present. According to ICMR data on non-neutropenic population, carbapenem resistance among Enterobacteriaceae is 35-50 %, Pseudomonas spp 47% and Acinetobacter spp 62%.707 Based on the epidemiology, current evidence and clinical experience the committee has identified risk factors for carbapenem resistance. Particular subgroups of patients, such as acute leukemia patients presenting to the ICU, patient already on carbapenem shifted to ICU from ward, previous multidrug-resistant infections in the last 1 month and patients on vasopressors are at risk of harboring carbapenem resistant organisms.708 Hence in these groups of patients, initial empiric antibiotic regimen should include colistin/polymyxin B along with meropenem.707

Vancomycin is not a standard part of empirical antibiotic therapy for febrile neutropenic patient. In the western countries with predominant gram-positive bacteremia and high incidence of MRSA, studies have failed to show any benefit with empiric vancomycin in terms of fever or mortality.709 In India, with predominant gram-negative sepsis and low incidence of MRSA-35%.707 Vancomycin or Teicoplanin is recommended as part of initial antibiotic regimen only in patients with suspected indwelling catheter infection (rigors following infusion, cellulitis at exit site), skin and soft tissue infection, severe mucositis, culture growing gram-positive cocci pending identification, previous MRSA colonization/infection and hemodynamic instability admitted from home/OPD.696

Evidence Statement

Gram-positive and gram-negative organisms are common causes of febrile neutropenia, with gram-negative organisms predominating in India. The commonly isolated GNBs include Enterobacteriaceae (E. coli and Klebsiella species) and Pseudomonas aeruginosa to be the most common among gram-negative organisms. Staphylococcus aureus and Coagulase negative staphylococcus are most common gram-positive isolates. Recent studies have reported increasing prevalence of MDR organisms. Choice of antibiotics depends local epidemiology, focus of infection and host and disease characteristics. Current evidence shows carbapenem resistance among Enterobacteriaceae is 35–50%, Pseudomonas spp. 47% and Acinetobacter spp. 62%. Acute leukemia patients presenting to the ICU, patient already on carbapenem shifted to ICU from ward, previous multidrug-resistant infections in the last 1 month and patients on vasopressors are at risk of harboring carbapenem resistant organisms. Empiric upfront vancomycin has not been shown to improve clinical outcomes or mortality in febrile neutropenia. Patients at risk of MRSA infections include suspected indwelling catheter infection (rigors following infusion, cellulitis at exit site), skin and soft tissue infection, severe mucositis, culture growing gram-positive cocci pending identification, previous MRSA colonization/infection and hemodynamic instability at admission.

Recommendation

In a critically ill febrile neutropenic patient presenting to the ICU with organ failure, empiric antibiotic therapy should be initiated with or escalated to a broad-spectrum carbapenem like imipenem or meropenem (UPP).

Empiric combination of Meropenem and Colistin/Polymyxin B should be considered in patients having high risk of infection with resistant gram-negative organisms (3A). Following risk factors should be assessed:

– Critically Ill patients with underlying acute leukemia (on induction or consolidation therapy) presenting to the ICU.

– Patients of acute leukemia/lymphomas on beta-lactam/beta lactamase inhibitor± aminoglycosides, shifted to ICU from ward.

– Previous history of infection with multidrug-resistant organism in last 1 month.

– Hypotensive patients requiring vasopressor infusions (refractory septic shock).

– Patient shifted to the ICU on carbapenem therapy.

We strongly caution against the use of empiric combination of Meropenem and Colistin/Polymyxin B or Colistin/Polymyxin B alone in patients who are not high risk of infection with carbapenem resistant gram-negative organisms as defined above (3A).

We caution against use of other carbapenems like Doripenem and Ertapenem due to lack of positive evidence and inadequate spectrum respectively (2A).

Vancomycin/Teicoplanin should be added as empiric therapy in critically ill febrile neutropenic patient with risk factors for MRSA infection (3A). These include:

– Suspected indwelling vascular catheter infection.

– Skin and soft-tissue infection.

– Previous colonization/infection with methicillin-resistant Staphylococcus aureus.

– Blood Culture growing gram-positive cocci awaiting identification.

– Severe mucositis.

– Hemodynamic instability(hypotension) at admission from home or outpatient department (UPP).

Empiric MRSA coverage should be avoided in absence of risk factors for MRSA and in ICUs with low prevalence of MRSA (UPP).

After the initiation of empiric therapy based on the factors listed above, the subsequent therapy should be based on the organisms isolated and sensitivity patterns. In patients with no isolates, the treatment should be continued as per the response to ongoing antibiotics and appearance of any new focus of infection (UPP).

What Methods should be Used for Early Identification of Causative Organisms in Febrile Neutropenia Patients?

Blood cultures are an important investigation in all patients with sepsis requiring ICU admission.710 However, the method of sample collection is associated with improved yield. With the advent of modern point of care tests like multiplex PCR, early isolation of causative organism can lead to early institution of appropriate antimicrobial therapy. Volume of blood is an important variable for detection of bloodstream infection volume of blood. Each mL of blood increased the yield (detection of positive culture) of blood cultures in adults by approximately 3%. Collection of two blood culture sets prior to antibiotic administration provide 30% yield of bloodstream pathogens in critically ill patients.711 In pediatric population, smaller volumes of blood are suggested due to lesser total blood volume. Consensus is not to exceed 1% of a patient's total blood volume. Use of BioFire Blood Culture Identification 2 panel for pathogen identification has shown pooled specificity of >97% and pooled sensitivity was 92.3–98.2% for the common organisms as compared to the culture-based methods. This could guide early treatment for multidrug-resistant organisms.341 Their utility in Indian scenario has not been proven with high quality studies.

Evidence Statement

Two sets of blood cultures drawn prior to antibiotic administration yields microbiologic diagnosis in 30% cases. Addition of multiplex PCR techniques can aid in early diagnosis and has high sensitivity and specificity as compared to culture-based methods.

Recommendation

We recommend collection of at least 2 sets of blood cultures, with a set collected simultaneously from peripheral site and one central. In case of multi lumen catheter, one set per lumen should be collected (1A).

Two blood culture sets from separate veneipunctures should be sent if no central venous catheter is present (1A).

One set includes one aerobic and one anaerobic culture bottle. Blood culture volume should be at least 10 mL/bottle (1A).

The use of molecular methods for identification of multidrug-resistant organisms and their antibiotic sensitivity pattern can be considered in critically ill patients, however, the availability and cost may be a concern along with risk of false negativity and false positivity (2B).

What should be the Approach to Empiric Antifungal Therapy in Febrile Neutropenia in Critically Ill Immunocompromised Patients?

Invasive Candida or Aspergillus infections have been demonstrated in the autopsy of patients who died of neutropenic fever with no clinical evidence of invasive fungal infection (IFI) except for a continuous fever.712 It is estimated that approximately 15–45% of patients with prolonged neutropenia have invasive fungal infection (IFI). IFI is difficult to diagnose both in critically ill patients and in patients with febrile neutropenia. Invasive fungal infection is associated with high mortality in both these groups especially if treatment is delayed.713–716 Invasive aspergillosis should be suspected in patients with persistent febrile neutropenia with the development of signs of pneumoniae including lung infiltrate.695 There is limited evidence for antifungal prophylaxis in febrile neutropenia to prevent Candida infections.714,717–719 High-risk patients who have received intensive cytotoxic chemotherapy are at risk for invasive fungal infection. Yeast (primarily Candida species) and molds typically cause infections, which are manifested by persistent or recurrent fever in patients with prolonged neutropenia, rather than causing initial fever in the course of neutropenia. Empirical antifungal therapy is instituted for the treatment of “occult” fungal infection presenting as persistent neutropenic fever despite 4–7 days of empirical antibiotic therapy, however, early initiation may be needed in critically ill patients with risk factors for the invasive fungal infections.719 Poor sensitivity of chest radiograph compared to CT scan for detection of pneumoniae in this population should be kept in mind.34 The galactomannan assay is highly specific for Aspergillus species with some cross-reactivity with Histoplasma capsulatum and Penicillium species. False-positive reaction can occur with concomitant use of b-lactam/b-lactamase combinations, such as piperacillin/tazobactam, however, false positivity rates are considerably lower with newer generation assays.720,721 Bronchoalveolar lavage (BAL) galactomannan had sensitivity of 0.88 and a specificity of 0.81 in immunocompromised patients if standard cut-off of 0.5 optical density (OD) was used, in a recent meta-analysis. Increasing the limit to OD> 1 led to sensitivity of 0.78 and a specificity of 0.93.722 Use of Beta-D Glucan (BDG) alone has limited sensitivity for the diagnosis of invasive candidiasis.723 However, BDG had good sensitivity 76.8% (95% CI, 67.1–84.3%), and specificity (85.3, 95% CI, 79.6–89.7%) for differentiating probable or proven IFI from no IFI.734 Pre-emptive antifungal therapy for invasive fungal infections is a strategy which involves serial screening of high risk patients for fungal colonization using biomarkers like beta-D-glucan, galactomannan and imaging (CT Chest) and initiation of treatment if either imaging or serology shows any evidence of an invasive fungal infection.695,725 This approach is useful in patients who develop febrile neutropenia on antifungal prophylaxis with suspicion is for an invasive mould infection. Pre-emptive antifungal therapy was similar in terms of all-cause mortality in febrile patients with mixed population of cancer and post-transplant (HSCT) patients.726 A RCT of 549 AML and MDS patients undergoing induction chemotherapy or allogeneic HCT had similar survival with empiric and pre-emptive caspofungin.727

Amphotericin B has been most commonly prescribed as empiric antifungal therapy in febrile neutropenia, Due to similar efficacy and lesser toxicity, liposomal formulations are preferred over deoxycholate.728 Caspofungin was found to have similar overall success rates when compared to liposomal amphotericin B in an RCT of 1,095 patients with febrile neutropenia.729 It is generally agreed upon that individual echinocandins namely caspofungin, micafungin and anidulafungin have similar efficacy and are interchangeable.730 Other echinocandins (micafungin, anidulafungin, and rezafungin) have limited data for febrile neutropenia. The echinocandins have demonstrated significant fungicidal activity and treatment success against most of the Candida species in randomized clinical trials. Availability of intravenous formulation, limited drug interactions, favorable safety and efficacy profile make them the first choice of empirical antifungal in critically ill patients including patients with febrile neutropenia. Caspofungin (loading dose 70 mg followed by 50 mg daily) needs dose adjustment for moderate to severe hepatic dysfunction whereas micafungin and anidulafungin do not need dose adjustments in liver or renal failure. Echinocandins do not provide coverage against cryptococcus, trichosporon and non-aspergillus filamentous molds like fusarium, endemic fungi.731 As echinocandins have poor penetration in eye, CNS, and urine, they should not be used for treatment of fungal meningitis, endophthalmitis and urinary tract infection. Echinocandins have shown to be effective in salvage therapy however they are not recommended as monotherapy for the primary treatment of IA due to lack of evidence.719

Voriconazole could not achieve its primary endpoint of noninferiority when compared to liposomal amphotericin in 837 patients with febrile neutropenia and persistent fever, though voriconazole group had fewer breakthrough fungal infection (2% vs 5%), and had lesser adverse events.732 Voriconazole remains an option in febrile neutropenia due to spectrum of activity against Candida and aspergillus species.695 Posaconazole has not been studied for febrile neutropenia. Posaconazole is noninferior for treatment of invasive aspergillosis,733 whereas Isavuconazole is efficacious in treatment of invasive aspergillosis and mucormycosis.734 Isavuconazole was inferior in treatment of invasive candidiasis and candidemiasis.735 Though itraconazole has been studied in febrile neutropenia, it is not preferred due to lack of common availability of intravenous preparations, variable bioavailability of oral preparations, negative inotropic properties and safety concerns in patients with renal or hepatic dysfunction.736

Lipid formulations of amphotericin B should be used as first-line treatment if Mucormycosis (Zygomycosis) is suspected. Recommended dose is 3–5 mg/kg daily.728 Amphotericin B deoxycholate should be avoided in patients with underlying renal impairment, patients on other nephrotoxic drugs such as cyclosporine or tacrolimus after allogeneic HSCT, or antibiotics, such as aminoglycosides and in patients with previous history of toxicity. Voriconazole can be used for suspected or proven cases of invasive pulmonary aspergillosis. Dose of Voriconazole is 400 mg (6 mg/kg) twice daily for 2 doses, then 4 mg/kg) twice daily. As mentioned above, Echinocandins are recommended for salvage therapy of aspergillosis.719

Recommended minimum duration of therapy for candidemia without metastatic complications is 2 weeks after documented clearance of Candida from the bloodstream, provided neutropenia and symptoms attributable to candidemia have resolved.695 Recommended duration of invasive pulmonary aspergillosis is 6–12 weeks based on the resolution of symptoms and neutropenia.725

Combination antifungal treatments are used with the rationale to maximize treatment by targeting multiple sites or metabolic pathways or different steps in the same pathway hence leading to an additive or synergistic effect. While in vitro studies on combination antifungals showed additive or synergistic effect; in vivo studies have given mixed results. Marr et al. demonstrated 8.2% absolute reduction in mortality rates with the combination of voriconazole and anidulafungin in adult patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT) having probable or proven Invasive aspergillosis. However, this difference was not statistically significant.737

Evidence Summary

Patients with febrile neutropenia are at risk of developing invasive fungal infections. IFIs have high mortality in patients with febrile neutropenia. Persistent or recurrent febrile neutropenia and development of lung infiltrates may be clues to fungal etiology of febrile neutropenia. Yeast (primarily Candida species) and molds are common etiologic agents. In patients with persisting fever without any localization, empiric antifungals targeting Candida species are initiated. Chest radiograph has poor sensitivity for pneumoniae detection in patients with febrile neutropenia, and CT Chest is preferred. Galactomannan assay is highly specific for Aspergillus species with some cross-reactivity with Histoplasma capsulatum and Penicillium species. False-positive reaction can occur with concomitant use of b-lactam/b-lactamase combinations, such as piperacillin/tazobactam. Use of Beta-D Glucan alone has limited sensitivity for the diagnosis of invasive candidiasis. Invasive aspergillosis should be suspected in patients with persistent febrile neutropenia with the development of signs of pneumoniae including lung infiltrate.

The echinocandins have demonstrated significant fungicidal activity and treatment success against most of the Candida species in randomized clinical trials. Individual echinocandins namely caspofungin, micafungin and anidulafungin have similar efficacy and are interchangeable. Echinocandins have poor penetration in eye, CNS, and urine. Echinocandins are not active against Zygomycosis. Voriconazole is the preferred agent for invasive aspergillosis, whereas liposomal amphotericin B is preferred for zygomycosis. Echinocandins have been useful in salvage therapy of aspergillosis. Guidelines advise to continue treatment for candidemia for at least two weeks after 2 weeks after documented clearance of Candida from the bloodstream, and resolution of neutropenia and symptoms attributable to candidemia. Recommended duration of invasive pulmonary aspergillosis is 6–12 weeks based on the resolution of symptoms and neutropenia. Combination antifungal treatments have limited evidence for added efficacy.

Recommendation

Following patients should be considered for initiation of antifungal therapy when they present to ICU with shock or respiratory distress especially when they have persistent or recurrent fever or clinical deterioration after >3 days of broad-spectrum antibiotics (2A).

– Allogenic HSCT.

– Severe mucositis with diarrhea.

– Prolonged/anticipated duration of neutropenia >10 days.

– Worsening on broad-spectrum antibiotics like BL/BLI and Carbapenems.

– More than 2 weeks of high-dose steroids (more than 15–20 mg of prednisolone or equivalent).

– History of invasive fungal infection.

– New onset lung infiltrate. (Since chest x ray has low sensitivity, HRCT should be done in these patients).

We recommend the use of caspofungin (echinocandin group) as initial antifungal therapy. Caspofungin should be avoided in patients with chronic liver disease (Child-Pugh C) (2A).

Anidulafungin and Micafungin can be considered if there are contraindications to use of caspofungin (3A).

Voriconazole is the drug of choice for proven, probable or possible aspergillosis. Due to its variable bioavailability voriconazole should be administered IV. In patients with renal dysfunction caspofungin can be given instead of IV voriconazole (1A).

Liposomal Amphotericin B is the drug of choice for suspected or confirmed Mucormycosis (1A).

All efforts should be made to confirm presence of invasive fungal infection with the use of tests including CT Chest/suspected site (abdomen for hepatosplenic candidiasis or mucormycosis/paranasal sinus for mucormycosis), β–D-glucan, serum and BAL Galactomannan, fungal culture. Tissue (lung/other clinically involved sites) biopsy should be performed if required, whenever feasible and safe (1A).

We do not recommend routine use of combination antifungal therapy for probable or proven Invasive aspergillosis (IA) due to lack of strong evidence (3A).

Which Patients Empiric Treatment Against Pneumocystis jirovecii Pneumoniae?

Patients considered high risk for PCP infection are allogeneic HSCT recipients, autologous HSCT, high-dose corticosteroid therapy and patients receiving T-cell-depleting agents such as fludarabine, purine analogues and rituximab.738–740 Hypoxemia is the most characteristic abnormality in PCP pneumoniae. Chest radiograph might be normal in early disease. Though most patients with hematologic malignancies and chemotherapy receive prophylaxis for pneumocystis jirovecii infection,741 acute onset hypoxemic respiratory failure, or characteristic radiologic infiltrates should prompt empiric initiation of sulfamethoxazole/trimethoprim.

Evidence Statement

HSCT, high dose corticosteroids, T-cell depleting agents and rituximab predispose to PCP infection. Hypoxemia and characteristic radiologic abnormalities indicate PCP pneumoniae, though chest radiograph might be normal in early disease. Empiric treatment with trimethoprim-sulfamethoxazole is indicated in suspected PCP pneumoniae.

Recommendations

Treatment with sulfamethoxazole/trimethoprim should be considered in high risk patients such as allogenic HSCT, high-dose corticosteroid therapy administration of T-cell-depleting agents such as fludarabine/purine analogues and rituximab when such patients present with hypoxemic respiratory failure with or without radiological evidence of Pneumocystis carinii pneumoniae especially if they are not on PCP prophylaxis (3A).

Every attempt should be made to confirm PCP infection (3A).

What is the Role of Empiric Antiviral Therapy in Immunocompromised Patients with Febrile Neutropenia?

Respiratory syncytial virus and parainfluenza are important co-pathogens causing upper and lower respiratory tract infections, especially in post hematopoietic stem cell transplantation. These infections lead to increased risk of mortality. Although aerosolized and oral administration of ribavirin has been used, there is no antiviral agent proven to be effective against parainfluenza virus. There is no clear evidence from randomized trials that aerosolized or oral ribavirin or any other antiviral is effective against RSV pneumoniae.742–745

Evidence Statement

Antiviral therapy in febrile neutropenia is given according to treatment guidelines of the etiologic agent. There are no effective agents for treatment of parainfluenza and respiratory syncytial virus infection at present.

Recommendations

There is no role of empirical antiviral therapy with febrile neutropenia. Active HSV or VZV infections in neutropenic patients indicated by clinical or laboratory evidence should be treated with Acyclovir (3A).

Immunoglobulin tests should not be used to diagnose VZV or HSV infection (3A).

Ganciclovir is recommended for the empiric therapy for CMV in patients with high risk of CMV reactivation (3A):

– Administration of T-cell-depleting agents such as fludarabine/purine analogues, rituximab.

– Patients on high dose steroids who develop diarrhea.

– Pneumoniae not responding to antibiotics & antifungals.

No specific treatment for infections with RSV and parainfluenza viruses due to lack of specific evidence (3A).

What is the Role for Empiric Antimicrobial Therapy for Tropical Infections like Malaria, Leptospirosis in Patients with Febrile Neutropenia?

There are occasional reports of malaria in patients on chemotherapy with solid tumor and hematolymphoid malignancies with febrile neutropenia. In a series of 99 patients of acute leukemia on chemotherapy with febrile neutropenia, malaria was responsible for fever in only 4% of patients.746

Febrile Neutropenia patient presenting to ICU often have thrombocytopenia due to disease itself, chemotherapy or sepsis. Presence of fever and thrombocytopenia itself should not warrant empirical anti-malarial therapy even in malaria endemic country like India.

A high-index of suspicion is warranted in a resident or traveler of malaria endemic area who presents with the classic triad of symptoms (fever, chills and sweating). If malaria is suspected, peripheral smear for malaria parasite and rapid malaria antigen (histidine-rich protein II (HRP-II) antigen of Plasmodium falciparum and common Plasmodium lactate dehydrogenase (pLDH) of Plasmodium species should be performed early and antimalarial therapy should be initiated in positive cases. With rapidity (diagnosis in less than an hour) and good negative predictive value of (98.2 %) malaria antigen test, antimalarial therapy is restricted only to positive cases.747

There is lack of enough evidence documenting etiological role of other tropical infections like Leptospirosis in subset of patients with febrile neutropenia; hence we believe that until enough evidence is available, suspected or documented tropical infections in neutropenic patients in ICU should be treated similar as they are treated in non-neutropenic patients.

Evidence Statement

There is insufficient evidence regarding tropical infections in patients with hematologic or solid organ malignancies and febrile neutropenia.

Recommendation

There is no role for empirical antimicrobial therapy against tropical infections like malaria, leptospirosis in febrile neutropenia patients (3A).

Documented tropical infections in neutropenic patients in ICU should be treated similar as they are treated in non-neutropenic patients (UPP).

What is the Role of Surveillance Cultures in Guiding Therapy in Febrile Neutropenia Patients?

As most of the infections in neutropenic patients occur due to organisms in respiratory or gastrointestinal tract, therefore surveillance culture seems to be a reasonable strategy in deciding the empiric antibiotic therapy in febrile neutropenia. The studies published in 1980's and 90's supported the practice of surveillance culture. However there has been a very poor correlation between blood and fecal isolates in most of the studies.748,749

Widespread antimicrobial treatment may inhibit the growth or distort the proportion of different species found in Fecal cultures. A recent study conducted in pediatric allogeneic HSCT patients has demonstrated a positive predictive value of 0.9% to bacterial surveillance cultures, with a sensitivity of 33.3% and a specificity of 47.4%. Surveillance cultures were not cost effective. The sampling and analyses require lots of laboratory and nursing resources.750 Another study in adults who got admitted for HSCT concluded that surveillance blood cultures in patients who have undergone HSCT do not identify bloodstream infections. The number of positive blood cultures was not helpful in determining which patients had infection.751

Evidence Statement

Surveillance cultures have not been shown to correlate with subsequent causative organisms in immunocompromised patients.

Recommendation

We strongly recommend against repeated surveillance cultures as these do not help to guide antibiotic therapy (3A).

What is the Role of Source Control in the Treatment of a Febrile Neutropenic Patient?

Control of source in the form of drainage of an abscess, debridement of infected necrotic tissue and removal of a potentially infected device is of paramount importance. Foci of infection readily amenable to source control include but not limited to intra-abdominal abscesses, gastrointestinal perforation, ischemic bowel or volvulus, cholangitis, cholecystitis, pyelonephritis associated with obstruction or abscess, necrotizing soft tissue infection, empyema, septic arthritis and implanted device infections. There is general agreement that source control should be done at the earliest to reduce microbiological burden and mere antibiotics and resuscitation would not achieve cure unless adequate source control is done. If Vascular catheters are suspected, its prompt removal should be considered. It is important to note that the classical clinical signs of infection (rubor, calor, dolor etc.) be absent due to low neutrophil counts.710

Evidence Statement

Source control at the earliest possible time reduces microbiologic burden and improves outcomes. Source control includes debridement, drainage of collections, removal of incriminated indwelling catheters and implanted devices.

Recommendations

We recommend that in patients with febrile neutropenia with clinically documented source of infection (as defined below), immediate intervention should be undertaken for source control (3A).

What Should be the Approach to Antibiotic De-escalation in Patients with Febrile Neutropenia?

Data on de-escalation strategies in neutropenic patients after identification of a clinically relevant pathogen is scant but there is no data on de-escalation when no pathogen has been identified. Although antibiotics are required to treat an occult infection during neutropenia, marrow recovery is necessary to protect the patient.18Shorter duration of antibiotics have been shown to have equal efficacy to longer courses (7–14 days) in various ICU infections including CAP and VAP.167,174 However, most stewardship trials have excluded immunocompromised patients. In leukemia, discontinuation of empiric antibiotics have been advised in hemodynamically stable patients who remain afebrile for 72 hours.708 Early discontinuation (72 hours) of antibiotics was noninferior to extended antibiotic therapy (afebrile for 5 days, of till recovery of neutrophils) in an open label RCT of 281 patients with febrile neutropenia after chemotherapy of hematopoietic stem cell transplantation. However, there was higher adverse events (16% vs 10%) and greater mortality (3% vs 1%), which was due to patients who continued to remain febrile.752

Evidence Statement

Antibiotic de-escalation to definitive therapy is feasible after identification of causative organism or in patients who remain afebrile for >48 hours with evidence of marrow recovery.

Recommendations

Antibiotic de-escalation should be considered in the following situations (3A):

Once and if a pathogen is identified, we recommend de-escalation to an antibiotic that the organism is susceptible to.

Treat with appropriate agents based on the site and pathogen until the patient is afebrile for at least 48 hours and there is evidence of marrow recovery (neutrophil count ≥500 cells/mm3).

In patients without microbiologically documented infection continue empirical antimicrobials until the patient is afebrile for at least 48 hours and there is evidence of marrow recovery (neutrophil count ≥500 cells/mm3).

Which Antibiotics Should be Used for Febrile Neutropenia due to Multidrug-resistant Bacteria?

If MRSA is suspected or isolated, Vancomycin, teicoplanin, linezolid and daptomycin are the available options. Linezolid and daptomycin are effective against vancomycin-resistant enterococci. However, daptomycin cannot be used in cases with pneumoniae. For ESBL producing GNBs carbapenems are efficacious. However, carbapenemase producing Klebsiella need to be treated with colistin or tigecycline.695 Combination therapy of piperacillin tazobactam with tigecycline had high success rate (68% vs 44%) in an open-label trial of 390 high-risk patients with hematologic malignancies. More than 30% of GNB isolates were piperacillin-tazobactam resistant.753 Other antibiotics with efficacy against MDR GNBs include fosfomycin, but have limited evidence.754

Evidence Statement

Antibiotics like fosfomycin, tigecycline and minocycline have activity against variety of MDR gram-negative organisms. For MRSA, vancomycin, teicoplanin and linezolid have most evidence. Linezolid is effective against vancomycin-resistant enterococci. However, good quality RCTs for MDR infections are lacking in immunocompromised patients.

Recommendation

Antibiotics like Fosfomycin, tigecycline and minocycline may be considered in infection with multidrug-resistant bacteria in presence of in vitro susceptibility after considering the in vivo penetration at source of sepsis, and if alternate agents with proven efficacy are not available or contraindicated (3A).

Vancomycin or linezolid can be used in cases of MRSA (1A).

Antimicrobial Guidelines in Solid Organ Transplant Recipients

Infectious complications in solid organ transplant (SOT) recipients admitted to intensive care unit (ICU) pose a challenge with respect to both diagnosis and treatment. The epidemiological exposures of the recipient as well as the donor and the net immunological state of the recipients determine the risk of infection in them.755,756 The latter incorporates an assessment of several important contributing factors like755,757

Pretransplant diagnosis or treatment.

Specific organ transplanted (e.g., lung/kidney vs liver transplant).

Intraoperative events like cold ischemia time, severity of shock or need for blood/blood product transfusion, duration of surgery.

Choice of induction and maintenance immunosuppression.

Comorbidities (e.g., viral co-infection [hepatitis C virus (HCV), cytomegalovirus (CMV)], malnutrition, end-organ failure [cirrhosis, chronic kidney disease]).

Breach of the mucocutaneous barrier: Indwelling devices, mucositis.

Need for extracorporeal therapies.

These patients may not mount typical symptoms and signs of infection like fever or any localizing signs, so a high index of suspicion for infection and detailed assessment is required. The infections in SOT patients can be categorized as follows:

C–Community-acquired

R–Reactivation

E–Epidemiologic exposure

D–Donor-derived

I–Iatrogenic

T–Travel related

It is advisable to have a syndrome-based approach (e.g., Nonspecific febrile illness, pneumoniae, urinary tract, central nervous system) at first and then narrow the differential diagnoses of possible organisms that could cause the clinical presentation(s).

Microbiological diagnosis is crucial in this patient group. In the context of extensive differential diagnoses, the value of early and specific diagnostics with the use of invasive procedures if necessary (bronchoscopy, tissue biopsy, or aspiration of collections) to obtain specimens cannot be underestimated. After transplantation, serologic techniques are of limited use because transplant recipients may not mount timely serologic responses. Thus, antigen detection or molecular nucleic acid detection assays are preferred over serologic testing.

What are the Common Infections in Post Solid Organ Transplant Patients? What Should be the Preferred Approach to Empiric Therapy and Diagnostic Evaluation?

The timeline of post-transplant infections can be used to establish a differential diagnosis for infectious syndromes at various stages after transplantation (Table 4).755–757 Infections occurring outside the usual period or of unusual severity suggest excessive immunosuppression or epidemiologic hazard. Most centers use a variation of standard ‘triple immunosuppression’ (prednisone, calcineurin inhibitor, antimetabolite such as mycophenolate mofetil).

Table 4 Timeline of infections post solid organ transplant (SOT)

	0–1 month post SOT	1–6 months post SOT	>6 months post SOT	
Infection characteristics	• Nosocomial infection- pneumonia/UTI/bloodstream infection
• MDRO infection
• Post-surgical/surgical site infection
• Indwelling device related infection- CRBSI/CAUTI
• Donor derived infection
• Recipient colonization related infection (e.g., Aspergillus, Pseudomonas)	Opportunistic infection
• Re-activation of latent infection	Community-acquired infection (usually): pneumonia/UTI
• Chronic or recurrent infection with stereotypical organisms in specific subsets
• Re-activation of latent infection in presence prolonged immunosuppression	
Common responsible organisms	
Bacteria	• MDR organisms
MRSA
VRE
MDR GNB
• Clostridium difficile associated infection
• Pseudomonas/Burkholderia spp. in Cystic fibrosis: lung tr	• Mycobacterium tuberculosis
• Listeria
• Legionella
• Nocardia
• Clostridium difficil colitis
• Gram-negative enteric bacilli in Small bowel transplant
• Pseudomonas/Burkholderia spp. in Cystic fibrosis-lung transplant	Ongoing risk of M. tuberculosis, Listeria, Legionella, Nocardia if immunosuppression continued
• Nontuberculous mycobacteria
• Community-acquired pathogens: S pneumoniae, H influenzae, M catarrhalis, S aureus, Mycoplasma pneumoniae, Chlamydia pneumoniae	
Viruses	• HSV (in absence of anti-HSV prophylaxis)
• HIV
• West Nile virus	• CMV, EBV, HSV, VZV (if not on prophylaxis)
• HCV reactivation
• RSV, Adenovirus
• BK polyoma virus	• Recurrent HSV, VZV
• Adenovirus
• RSV
• HCV Reactivation
• Late-onset CMV (colitis, retinitis),
• EBV related PTLD	
Fungi	• Candida (likely to be Fluconazole resistant)
• Early Aspergillosis (Uncommon, possible due to recipient colonization)	• Aspergillus
• Cryptococcus
• neoformans
• Pneumocystis jiroveci i (if not on prophylaxis)	During intense immunosuppression:
• Aspergillus (more so in Lung transplants with chronic rejection)
• Cryptococcus
• Mucor, atypical molds
• Pneumocystis jirovecii	
Parasites	Rare	• Toxoplasma gondii
• Strongyloides
• Leishmania
• Trypanosoma cruzi	Ongoing risk of Toxoplasma, Strongyloides, Leishmania, Trypanosoma, if immunosuppression intensified	
MDRO, multidrug-resistant organism; UTI, urinary tract infection; CRBSI, catheter related blood stream infection; CAUTI, catheter associated urinary tract infection; MRSA, methicillin resistant Staphylococcus aureus; VRE, vancomycin resistant enterococcus; GNB, gram negative bacteria; HSV, herpes simplex virus; VZV, varicella zoster virus; CMV, cytomegalovirus; EBV, Epstein Barr virus; HIV, human immunodeficiency virus; RSV, respiratory syncytial virus; HCV, hepatitis C virus; PTLD, Post-transplant lymphoproliferative disorder

Incidence of sepsis in SOT recipients ranges between 20% to 60% and is associated with in-hospital mortality ranging between 5% to 40%.758 The infections in the first month posttransplant are usually of nosocomial origin, opportunistic infections predominantly till around 6 months and after that community-acquired infections are the predominant ones. During the first month after SOT, opportunistic infections are generally absent as the full effect of immunosuppression has not yet been established. The common infections in this period are of nosocomial origin, donor or recipient derived, related to surgical/technical issues and indwelling catheters.755,756 Most of these infections are of bacterial followed by fungal etiology. In a study by Ram et al. in post renal transplant patients, urinary tract infection (UTI) followed by line related infections were the most common in the first moth after transplant. Ram et al. reported that 23.6% of the SOT recipients develop UTI during first 4 weeks and E. coli was the most common causative agent (12.6%). CMV was the most common (prevalence of CMV 21.8%) between 4 weeks to 3 months after renal transplantation and could cause allograft loss. Tuberculosis reactivation was more common between 3 months to 1-year post-transplant (prevalence of tuberculosis being 10.6%). Pneumocystis carinii and Aspergillus infection usually occurred after 1 year.759

Kumar et al.760 and Sriperumbuduri et al.761 also found UTI to be the most common infection in the post renal transplant patients. Neelima et al. studied the microbiological profile of transplant (SOT and hematopoetic stem cell transplant - HSCT) recipients in a south Indian center and found UTI to be the most common infection (53.3%) followed by bloodstream infection (BSI) (21.6%). Of all the bacterial isolates, 81.6% were gram-negative, 18.4% gram-positive, E. coli being the predominant one (52.5%). In 38.77% drug resistance was observed and of them 68.4% were multidrug-resistant (MDR).762 Al-Hasan et al. found that the incidence of gram-negative BSI was highest in the first month post SOT (210.3/1000 person-years) which sharply declined to 25.7 per 1000 person-years between 2 and 12 months. Most of GNB BSI was nosocomial (27.4%) or healthcare associated (49.8%), remaining being community-acquired. For 55.2% of gram-negative BSI, urinary tract was the primary source follows by gastro-intestinal tract, respiratory tract, intravascular catheters, skin-soft tissue in that order.763 Escherichia coli accounted for 36.8% of gram-negative BSI followed by Klebsiella pneumoniaee (14.3%), Pseudomonas aeruginosa (13.0%), Enterobacter cloacae and Citrobacter freundii in that order. Pseudomonas aeruginosa was the most common isolate in the first month post SOT, while E. coli and K. pneumoniaee were more common 12 months post SOT.

In a prospective Swiss Transplant Cohort Study (STCS) studying the burden and timeline of post SOT infections in the first year postoperatively in 3,541 patients, the authors reported that 1,520 patients (55%) suffered 3,520 infections. 63% of the infections were caused by bacteria, Enterobacteriaceae being the predominant ones (54%) as urinary pathogens in heart, lung, and renal transplant recipients, and as digestive tract pathogens in liver transplant recipients. Enterococcus was found to be responsible for 20% of infections (as urinary tract pathogens in renal transplant recipients and as digestive tract pathogens in liver transplant recipients) and Pseudomonas aeruginosa was the isolated pathogen (9%) in lung transplant recipients. Herpes virus was the predominant viral pathogen among the 1,039 viral infections in post renal, cardiac and liver transplant patients. Candida species accounted for 60% of the 263 fungal infections. Opportunistic infections including Aspergillus and CMV were rare (1.4% and 6% respectively), spread throughout the year.764

In a systematic review and meta-analysis conducted by Green et al.,765 they reported that 25 to 45% of kidney transplant recipients develop UTI in immediate postoperative period, out of which around 50% were related to urinary catheters. The incidence of UTI increased to up to 70% in first 6 months post-transplant. Enteric gram-negative bacteria and Enterococci were the most common pathogens, with the resistant strains (e.g., extended spectrum beta-lactamase-positive Escherichia coli, carbapenem-resistant Klebsiella pneumoniaee) becoming more frequent. They reported that the risk for developing sepsis with bacteremia was lowered by 87%, and the risk for developing bacteriuria (symptomatic or asymptomatic) by 60% by initiating prophylaxis in these patients. However they couldn't find any difference in incidence of all cause mortality or graft survival with or without prophylaxis. This study was limited by the small number of trials evaluating the efficacy and outcome related to prophylaxis.

Depending upon the organ transplanted, the local epidemiological factors, and the local antibiogram, the anti-infective surgical prophylaxis should be prescribed. Antimicrobial coverage for skin flora, enterobacteriaceae, biliary enterococcus species, anaerobes is usually prescribed for liver transplant patients. Similarly for lung transplant patients, the prophylaxis is usually targeted against molds, gram-negative bacteria or usual colonizer patterns.755 For example, the patients undergoing lung transplant for cystic fibrosis often are colonized with MDR bacteria (Pseudomonas aeruginosa most commonly, in up to 52% pre-transplant; Burkholderia, Stenotrophomonas maltophilia and Achromobacter being the less frequent ones in that order) in the pre-transplant period. Early postoperative prophylaxis should be initiated/modified depending on donor and recipient bronchial cultures.766

TMP-SMX as primary prophylaxis for UTI in post-renal transplant patients (given for PJP prophylaxis) has been found to decrease UTI and bacteremia. If TMP-SMX cannot be used as primary prophylaxis, other agents like nitrofurantoin, cephalexin or fluoroquinolone (ciprofloxacin/ofloxacin) may be used in high risk patients or those having recurrent UTI in the preoperative period, and in this case limited to first month after transplant.767 Fluoroquinolones should only be used with special caution.768 Their use for primary prophylaxis has been linked to increase in fluoroquinolone resistant Pseudomonas aeruginosa.767

The incidence of opportunistic infections have decreased owing to anti-infective prophylaxis.756,757 The patterns of opportunistic infections also have altered because of anti-CMV strategies and TMP-SMX prophylaxis. TMP-SMX prophylaxis provides protection not just against Pneumocystis jirovecii pneumoniae, but also against Toxoplasma gondii infection and has been proven to decrease incidence of UTI, Listeria monocytogenes meningitis, and Nocardia infections.755

As the immunosuppression is progressively reduced after 6 months, the prophylaxis against the opportunistic infections should also be withdrawn. However, it can be re-introduced in case of intensified immunosuppression, wherever indicated.757

Evidence Statement

Incidence of sepsis in solid organ recipients ranges from 20% to 60% and is associated with in-hospital mortality of 5% to 40%. Nosocomial infections predominate in the first month, opportunistic infections till six months posttransplant and subsequently community-acquired infections become most common. Most of these infections are of bacterial followed by fungal etiology. Most common site remains urinary tract infection, followed by line related infections, and E. coli the most common etiology. CMV is most common infection from 1 month up to 3 months, whereas tuberculosis reactivation is more common from 3 months to 1 year posttransplantation. Pneumocystis and aspergillus infections are common after 1 year. MDR GNB isolates are increasing in prevalence, especially in nosocomial infections. Risk for developing sepsis with bacteremia can be lowered significantly by antibiotic prophylaxis. Prophylaxis is governed by type of transplant and risk of specific infections. Liver transplant patients often receive antibiotics covering skin flora, enterobacteriaceae, enterococci and anaerobes whereas post-lung transplant, prophylaxis is against molds, gram-negative bacteria or colonizers. Post-kidney transplantation trimethoprim-sulfamethoxazole given for PJP prophylaxis reduces UTI and bacteremia. Alternatives include nitrofurantoin and cephalexin. Fluoroquinolone increase risk of resistant infections like pseudomonas, and should be used with caution. Opportunistic infections have decreased due to anti-infective prophylaxis for CMV and PJP. TMP-SMX provides protection against toxoplasma, and protects against UTI, Listeria meningitis and nocardial infections.

Recommendation

Anti-infective Prophylaxis

Prophylaxis in first month posttransplant should depend upon the nosocomial infections, colonization of donor and recipient, and the organ transplanted (1A).

Trimethoprim-sulfamethoxazole (TMP-SMX) for primary prophylaxis for urinary tract infection (UTI) in renal transplant patients is recommended; TMP-SMX usually given for 6 months for PJP prophylaxis decreases UTI and bacteremia in renal transplant recipients (1A).

Primary prophylaxis for UTI with agents other than TMP-SMX may be limited to the first month after transplant (3B).

Approach to Diagnosis and Treatment of Infection

Infections in the first month (0–30 days) of post SOT period should be investigated and treated similarly to those of non-immunocompromised postoperative patient (1A).

Infections in the first month (0–30 days) of post SOT period should be investigated and treated on the lines of nosocomial infections/donor derived infections (1A).

Complete blood count with differential, liver and renal function tests, serum electrolytes should be obtained in all patients with suspected infection (3A).

We recommend obtaining blood cultures at presentation and preferably prior to initiation of antibiotics in all patients presenting with features suggestive of infection (3A).

Antimicrobials should be administered considering prior cultures, local antibiogram and susceptibility patterns (1A).

Asymptomatic bacteriuria (AB) should not be treated (1A) unless same pathogen has been isolated twice consecutively >105 CFU/mL in first 2 months post SOT (2B) or AB is found in Post-kidney transplant recipients (1B).

Multidrug-resistant (MDR) urinary tract infection (UTI) with gram-negative bacteria such as Pseudomonas spp and Klebsiella spp, newer agents like ceftazidime-avibactam can be considered as alternatives to colistin or aminoglycosides (1B).

Approach to Diagnosis and Treatment of Respiratory Infection

Acute respiratory failure (ARF) following SOT could be of infectious or non-infectious etiologies such as pneumoniae, pulmonary edema, alveolar hemorrhage, primary graft dysfunction (PGD)/rejection, acute respiratory distress syndrome (ARDS), pleural effusion.757,768 Chest radiograph should be obtained in all patents with ARF as it may help in narrowing down the differential diagnosis.769 Consolidation may be observed in bacterial infection or pulmonary hemorrhage, diffuse interstitial infiltrates are usually suggestive of pneumoniae (due to CMV, Pneumocystis jirovecii, respiratory viruses, EBV, mycoplasma, Legionella etc.) or other non-infectious etiologies like alveolar hemorrhage, pulmonary edema, graft rejection, ARDS.757,769,770 Ground glass pattern or ground glassing along with micro nodular infiltrates could suggest PJP or CMV pneumoniae.769,771

Bronchopneumoniae or peribronchial opacities maybe observed in infection due to Chlamydia, Mycoplasma, Haemophilus, Neisseria, respiratory viruses. Nodular infiltrates (single/multiple) may suggest invasive mold (aspergillosis), Nocardia, TB, non-tuberculous mycobacteria infections or possibility of malignancy/PTLD.769,771

Obtaining appropriate routine microbiologic cultures before starting antimicrobial therapy in patients suspected of having sepsis or septic shock, without causing a delay in start of treatment, was recommended as a best practice statement in Surviving Sepsis Guidelines (SSC) 2016 and remained valid in SSC 2021 guidelines.772,773

In a prospective multi center study, incidence of pneumoniae was found to be 10.1 episodes/1000 recipients/year and in 70.4% of cases it was classified as late-onset pneumoniae (>6 months post SOT). In 94.4% of patients, an attempt to obtain a microbiological diagnosis was made and diagnostic yield was reported to be 60.7%.774

In an active population-based surveillance for community-acquired pneumoniae requiring hospitalization among adults, the authors found that among 2,259 patients who had radiographic evidence of pneumoniae and specimens available for both bacterial and viral testing, a pathogen was detected in 853 (38%): one or more viruses in 530 (23%), bacteria in 247 (11%), bacterial and viral pathogens in 59 (3%), and a fungal or mycobacterial pathogen in 17 (1%). They concluded that despite current diagnostic tests, no pathogen was detected in the majority of patients.61 In another prospective study of 610 kidney transplant recipients, of the 60 episodes of pneumoniae in 54 patients (8.8%), 23 (38%) were of nosocomial origin and rest were community-acquired infections. Bacterial infection was the most common, followed by fungal and viral (44%, 7%, and 3.5% respectively). P. aeruginosa was the most common microorganism isolated in nosocomial pneumoniae (26%), among which 50% were multidrug-resistant). No microorganism was isolated in 34% episodes. Among community-acquired pneumoniaes S. pneumoniaee (11%) was the most common pathogen. No microbiologic confirmation of disease was made in 54% of cases. The overall accuracy of bronchoalveolar lavage (BAL) was found to be 72%. The authors concluded that nosocomial pulmonary infections were associated with considerable morbidity and mortality in kidney transplant recipients and that carrying out invasive procedures for the diagnosis of pneumoniae is useful.775

Performance of BAL in SOT recipients with pneumoniae provides a moderate chance to come to a microbiological diagnosis, performed with or without transbronchial biopsy, the microbiological yield of BAL ranging from 39% to 77% in various studies (highest yield reported in nosocomial pneumoniae).769 Different studies have studied performance of lung biopsy for diagnosis of lung infiltrates in SOT patients. The diagnostic yield of open lung biopsy was reported to be 85.1% in a single center study on renal transplant patients with resultant change in therapeutic management in 53% of patients. However, complications were reported in 28.7%.776 The diagnostic yield of percutaneous CT guided lung biopsy in a series of 45 biopsies in SOT patients with parenchymal lung nodules was reported to be 53%, with complications in 13% of patients.777 The decision for performance of lung biopsy should be left to clinician's discretion and be individualized per patient depending on the risk -benefit ratio.769

Empiric antimicrobial therapy for pneumoniae in SOT patients would depend upon the net state of immunosuppression, the epidemiological exposures, the clinical and radiological profile of the patient, and the local antibiogram. The usual empiric coverage doesn't include antifungals, or coverage for invasive and opportunistic infections; this gap in antimicrobial coverage should always be borne in mind.

Evidence Statement

Acute respiratory failure (ARF) following SOT can be due to variety of infective and noninfective causes. Patterns of involvement on chest radiograph or CT scan can help to narrow down diagnosis. Ground glass opacities and micronodular infiltrates can suggest PJP or CMV, whereas lobar consolidation suggests bacterial etiology. Nodular infiltrates suggest fungal, tubercular or malignant etiology. Majority of cases of community-acquired pneumoniae have been seen after 6 months posttransplantation. Early initiation of antibiotics after sending blood cultures in patients with septic shock leads to better outcomes. Organisms responsible for CAP include viruses, bacteria, fungal and mycobacteria. Streptococcus pneumoniaee has been reported to be most common bacteria causing CAP, whereas P. aeruginosa was the most common microorganism isolated in nosocomial pneumoniae. Bronchoscopic BAL leads to microbiologic diagnosis in up to 77% cases. CT Guided biopsy has been used for diagnosis of patients with lung nodules. Open lung biopsy has been reported to have high yield (85%) but with increased risk of complications. Empiric antimicrobial therapy for pneumoniae in SOT patients would depend upon the net state of immunosuppression, the epidemiological exposures, the clinical and radiological profile of the patient, and the local antibiogram.

Recommendation

We recommend obtaining chest radiograph in all patients with suspected pneumoniae (2A).

We recommend performing a chest computerized tomography (CT) scan in all SOT patients with pneumoniae (I, A) and high resolution CT (HRCT) scan in patients with nodular infiltrates with suspected invasive aspergillosis (1A).

We recommend obtaining nasopharyngeal swab for influenza virus testing by PCR if seasonally appropriate and high suspicion for viral pneumoniae(1A).

Early BAL should be considered in SOT patients with suspected pneumoniae admitting to ICU (1A).

We recommend BAL in patients with pulmonary infiltrates not improving on empiric antimicrobial therapy or in whom there is diagnostic uncertainty on non-invasive testing (1A).

– BAL fluid should be tested for:

- Stains and immunohistochemistry: Gram stain, KOH/Calcofluor white, Auramine-rhodamine, Auramine-O, or Ziehl-Neelsen, Modified acid-fast stain, Silver methenamine stain, Galactomannan assay (<0.5 Negative predictive value, >3 positive predictive value)

- Polymerase chain reaction (PCR): Mycobacterium tuberculosis (Cartridge Based Nucleic Acid Amplification Test (CB-NAAT or GeneXpert), Multiplex PCR assay [(Including Respiratory viruses, CMV)(Quantitative or semiquantitative detection-particularly bacterial)].

- Culture: Aerobic culture for bacteria, mycobacterial growth indicator tube (MGIT) for Mycobacterium tuberculosis, fungal culture.

Following organisms are diagnostic of infections. If identified, they are less likely to be the contaminants/colonizers and should be treated: Pneumocystis carinii, Toxoplasma gondii, Strongyloides stercoralis, Legionella pneumophila, Cryptococcus neoformans, Histoplasma capsulatum, Mycobacterium tuberculosis, Mycoplasma pneumoniaee, Influenza a and b viruses, Respiratory syncytial virus. (2A)

Open/Video-assisted thoracoscopy (VATS)/CT guided/transbronchial biopsy should be done in patients with lung infiltrates where the non-invasive testing/BAL haven't been able to provide the diagnosis and who have failed to respond to therapy, after risk-benefit assessment on case to case basis (2A).

Any prior microbial colonization or antimicrobial resistance pattern of particular organisms should be considered while deciding empiric treatment for pneumoniae in SOT patients, particularly so in case of colonization of airway in lung transplant patients (3A).

Empiric antibiotic therapy with carbapenem based on local susceptibility patterns for suspected community-acquired bacterial pneumoniae along with coverage of atypical/intracellular pathogens like Mycoplasma pneumoniaee, Chlamydia pneumoniae, and Legionella spp. is recommended (2A). For the coverage of latter, among macrolides, consider using azithromycin instead of clarithromycin or erythromycin because of its relatively less likelihood to interact with immunosuppressants.

For suspected viral pneumoniae, adding antiviral for influenza should be considered (2A).

We recommend empiric treatment of recipients requiring hospitalization for pneumoniae with broad-spectrum antibiotics (carbapenem ± antipseudomonal ± anti MRSA) depending on local flora and resistance patterns, along with coverage for atypical organisms (2A).

Antipseudomonal agent/polymyxin should be added if the patient is admitted in the hospital for ≥48 hours before symptoms (nosocomial pneumoniae) (2A), visited medical care (hemodialysis, wound care, immunosuppressants) within the previous 30 days, or hospitalized in an acute care hospital ≥2 days within the prior 90 days (UPP).

Empiric antifungal therapy may be initiated where there is strong suspicion based on the clinical and radiological profile of the patient (3B).

Empiric therapy should be initiated/modified as per clinical, radiological and microbiological findings and response (2A).

CMV Management

It has been recommended to use the standardized definitions of CMV infection and disease in transplant patients.778,779

CMV Infection

Presence of CMV replication in tissue, blood, or other bodily fluids regardless of symptomatology detected by (a) nucleic acid testing (NAT), (b) antigen testing, and (c) viral culture.780

Asymptomatic CMV Infection

CMV replication without clinical signs and symptoms of disease.781

CMV Disease

CMV infection that is accompanied by clinical signs and symptoms. (a) CMV syndrome, (b) end‐organ CMV disease. CMV has a predilection to invade the transplanted allograft; hence, CMV more commonly causes hepatitis in liver recipients, nephritis in kidney recipients, or pneumonitis in lung recipients.

Refractory CMV Infection

CMV DNAemia or antigenemia increases (i.e., >1 log10 increase in CMV DNA levels in blood between peak viral load within the first week and the peak viral load at 2 wk or more) after at least 2 wk of appropriately dosed antiviral therapy.

Refractory CMV Disease

Worsening in signs and symptoms or progression into end‐organ disease after at least 2 wk of appropriately dosed antiviral therapy. Resistant CMV—Presence of viral genetic alteration that confer reduced susceptibility to one or more antiviral drugs.781

It is strongly recommended that CMV-IgG serology be done for all organ donors and transplant recipients in the preoperative period to evaluate their baseline immune status and both be interpreted together to assess the risk of posttransplant CMV risk in the recipient and thus guide the prophylaxis accordingly.778 Recipients who are CMV seronegative (R–) and receive organ from a seropositive donor (D+), (that is D+/R–) have the maximum risk of developing CMV disease in the post-transplant period.782,783 Severe lymphopenia (decreased number of lymphocytes) or lymphocyte anergy (decreased function of lymphocytes) due to drug induced immunosuppression is associated with higher risk of CMV after SOT.800,801

CMV IgM and IgG serology should not be used for the diagnosis of CMV disease after SOT as these patients might not mount a robust antibody response. The detection of CMV in the post-transplant period may be done by molecular assays (CMV QNAT-quantitative nucleic acid amplification test), pp65 antigenemia, histopathology and viral culture, CMV DNA by QNAT being the preferred one.778 A positive correlation between higher viral load and end organ disease has been observed.786,787 Detection of CMV by QNAT in BAL fluid and cerebrospinal fluid (CSF) can also be done. High viral load in BAL fluid has been found to be associated with CMV pneumoniae, however there isn't any standard threshold to define the same.788 Positive CMV QNAT in CSF might be indicative of possible CNS CMV disease.796 For end organ CMV disease, histopathologic diagnosis remains the gold standard modality, except for CMV retinitis, which is diagnosed based on ophthalmologic examination.778,780 In a retrospective study, the response to therapy was assessed using RT-PCR (2262 samples) and antigenemia using pp65 assay (1285 specimens). Both methods had >90% specificity, but RT-PCR had better sensitivity. The authors concluded that RT-PCR was a more reliable tool to monitor the response to therapy.789

For the prevention of CMV disease in SOT recipients, either the antiviral prophylaxis or the pre-emptive therapy may be used, but in lung transplant recipients where only the prophylaxis is recommended. Valganciclovir and intravenous ganciclovir are the antivirals recommended for CMV prophylaxis and CMV disease.788,790 Oral ganciclovir should not be used due to poor bioavailability. Limaye et al. compared letermovir (a novel viral terminase inhibitor) versus valganciclovir for prophylaxis in high risk kidney transplant recipients (D+/R–) in a randomized control trial and found it to be noninferior to valganciclovir.791 Asberg et al. in a randomized controlled trial compared the outcome of CMV disease after treatment with IV Ganciclovir and oral valganciclovir. Three hundred twenty-one SOT recipients were enrolled and randomized to receive either twice daily intravenous ganciclovir or oral valganciclovir for 21 days followed by once daily valganciclovir until day 49 in all the patients. All patients were followed up for 1 year. The success rate was the same in both the groups with a similar rate of clinical and viral eradication. The clinical recurrence rate was also not statistically different in both the groups.792 Valacyclovir in high doses may be used for prophylaxis only in renal transplant patients as an alternative.793 The duration of antiviral prophylaxis has been summarized in Table 5.778

Table 5 Recommendations for antiviral prophylaxis in SOT recipients

Duration of antiviral prophylaxis	
Organ transplanted	Heart	Lung	Kidney	Liver	Pancreas	Intestinal	
CMV serostatus							
CMV D+/R–	3–6 months	6–12 months	6 months	3–6 months	3–6 months	6 months	
CMV R+	3 months	6–12 months	3 months	3 months	3 months	3 months	
CMV D-/R–	Not recommended	
CMV, cytomegalovirus; D+, D, donor seropositive and seronegative respectively; R+, R–, recipient seropositive and seronegative respectively

Due to the prescription of antiviral prophylaxis initially after transplant, CMV disease tends to occur in CMV D+/R− SOT recipients during 3–6 months after completion of antiviral prophylaxis and is termed as “post-prophylaxis delayed‐onset CMV disease” compared from truly late‐onset CMV diseases that occur many years after transplantation.778 Pre-emptive therapy with oral valganciclovir (900 mg twice daily) or intravenous ganciclovir (5 mg/kg twice daily), which is another way of prevention of CMV disease, is initiated when the viral load reaches the predefined threshold and continued until virologic clearance (undetectable or level below predefined threshold).794,795 Various studies have demonstrated the efficacy of intravenous ganciclovir for treatment of CMV disease and also shown comparable efficacy of valganciclovi and intravenous ganciclovir and have suggested that duration of therapy should be individualised as per the clinical response and the viral clearance.792,796,797 There is a direct association between viral suppression below the lower limit of quantified test and disease resolution. Rapid resolution of CMV disease is seen with lower pre-treatment viral load (lower than 18,200 IU/mL).798 The dose of antivirals should not be reduced for neutropenia.755 For patients with suspected resistant CMV disease, high dose ganciclovir (10 mg/kg every 12 hours, renally adjusted) or foscarnet as empiric therapy can be initiated, pending the results of genotype testing according to which the therapy should be modified. In patients with resistant or refractory disease, cautious reduction in immunosuppression is recommended and immunoglobulins may be used as adjunct to antiviral therapy.778

Evidence Statement

CMV reactivation risk is increased in post SOT patients due to immunosuppression induced lymphopenia and lymphocyte anergy. Preoperative CMV-IgG serology of donor and recipient can be used to assess risk and guide prophylaxis. In posttransplant period, CMV DNA using quantitative nucleic acid amplification is the diagnostic modality of choice. Detection of CMV by QNAT in BAL fluid and cerebrospinal fluid (CSF) is feasible. For end organ CMV disease, histopathologic diagnosis is the gold standard. CMV retinitis is diagnosed based on ophthalmologic examination. RT-PCR was a more reliable tool to monitor the response to therapy. Pre-emptive therapy is used for most SOT recipients, however, lung transplant patients should receive prophylaxis. Valganciclovir and intravenous ganciclovir have good efficacy and are used for prophylaxis and disease respectively. Letermovir has been shown to be noninferior to valganciclovir for prophylaxis in post renal transplant patients. Post prophylaxis delayed onset CMV disease occurs in donor positive recipient negative SOT recipients three to six months after completion of antiviral prophylaxis and should be treated with pre-emptive therapy. High dose ganciclovir or foscarnet are effective in empiric reatment of refractory disease, along with cautious reduction in immunosuppression. Immunoglobulins as adjunct therapy have been used in refractory disease.

Recommendation

Antiviral Prophylaxis

Antiviral prophylaxis should be initiated within 10 days post SOT in all at-risk recipients for prevention of CMV infection/disease (1A).

Valganciclovir (oral 900 mg once daily) or intravenous ganciclovir (5 mg/kg IV once daily) should be used for prophylaxis in all SOT recipients. Only in Post-kidney transplant patients, high dose oral valacyclovir (2 Gram qid) may be used as an alternative agent (1A).

The duration of prophylactic therapy depends upon the CMV serostatus of the donor (D) and recipient (R) pre-transplant and the specific organ transplanted (Table 5).

For patients receiving lymphocyte‐depleting anti‐lymphocyte antibodies (e.g., anti-thymocyte globulin ATG) for rejection, antiviral prophylaxis with valganciclovir or intravenous ganciclovir should be initiated (1A).

Pre-emptive Therapy

Pre-emptive therapy for prevention of CMV disease in asymptomatic CMV infection in SOT patients (tested weekly post-transplant for up to 12 weeks or longer) with valganciclovir 900mg twice daily or intravenous ganciclovir (5 mg/kg twice daily) should be initiated once the predefined viral load threshold has been achieved, and duration be guided by viral load monitoring (i.e., CMV DNAemia or antigenemia below the predefined threshold or not detected) (1A).

Antiviral prophylaxis is preferred over pre-emptive therapy for prevention of CMV disease heart transplant patients (1A).

Preemptive therapy is not recommended for prevention of CMV disease in lung transplant patients (1A).

Therapy for CMV Disease

We recommend CMV DNA by QNAT as the laboratory method of choice for rapid diagnosis of CMV infection in blood after SOT (1A).

We recommend treatment of CMV disease with intravenous ganciclovir (5 mg/kg 12th hourly) or oral valganciclovir (900 mg twice daily) (in renally adjusted dosages) (1A).

For severe or life‐threatening CMV disease, very high viral load, and doubtful gastrointestinal absorption, use of intravenous ganciclovir is recommended (1A).

Oral valganciclovir is an effective initial therapy for mild to moderate CMV disease (I, A), or as a step down to intravenous ganciclovir after clinical improvement (2B).

Foscarnet and cidofovir can be used only as second‐line agents for SOT recipients (due to high risk of nephrotoxicity associated) who are unable to tolerate intravenous ganciclovir or valganciclovir (2A).

We recommend against use of acyclovir, valacyclovir, and oral ganciclovir for treatment of CMV disease (1A).

We recommend a duration of treatment with antiviral for a minimum of two weeks and till there is resolution of clinical signs along with viral clearance as tested by weekly CMV quantitative NAT (QNAT: polymerase chain reaction- PCR) (1A).

After completion of full-dose antiviral treatment, a 1 to 3 months course of secondary prophylaxis may be considered depending on the clinical situation (2B).

We recommend monitoring complete blood count with differential and serum creatinine weekly for assessment of potential hematologic and renal toxicity (1A).

The drug dosage of antiviral should be adjusted as per the renal function test (1A).

The drug dosage of antiviral should not be decreased due to neutropenia or pancytopenia (1A). Hemopoietic growth factors may be used to counter the myelosuppressive effect of the drugs.

Cautious reduction in immunosuppression should be considered in SOT patients presenting with CMV disease, especially if the disease is moderate to severe, or with severe lymphopenia or with refractory/resistant CMV disease (2B).

Empiric treatment of suspected resistant CMV disease include high‐dose intravenous ganciclovir (up to 10 mg/kg q12 hours, renally adjusted) or foscarnet. Definitive antiviral treatment should be guided by results of genotypic testing (2B).

CMV immunoglobulin or IVIg may be used as an adjunct to antiviral drugs in transplant recipients with life-threatening disease, CMV pneumonitis or resistant CMV disease (2B).

Tuberculosis (TB) in SOT Recipient

Given that tuberculosis is an immunological disease and with the high prevalence of TB in India, the incidence of active tuberculosis infection is higher among SOT recipients as compared to the general population. The diagnosis of TB in SOT recipients presents challenges that may lead to treatment delay. These include atypical clinical presentations, increased likelihood of negative tuberculin skin tests and/or IGRA, and negative sputum smear results despite active disease makes TB diagnosis in SOT recipients a challenge.799–805 Radiological investigations like CT scan and the invasive modalities like BAL with or without biopsy should be performed early in case of suspicion of TB. One-third to one-half of cases of tuberculosis after transplant are disseminated or extrapulmonary. Lung transplant recipients are most likely to develop pulmonary manifestations of TB. Drug-drug interactions between immunosuppressive and AKT, allograft-related drug toxicities, and inadequate immune responses to TB makes treatment of TB in transplant recipients also very challenging.801,805 The standard 4 drug regimen should be used wherever possible803 and if necessary, rifampicin can be replaced by levofloxacin. In the latter case, 4 drugs, that is, isoniazid (INH), ethambutol, pyrazinamide and levofloxacin are given for 2 to 3 months for initiation and then 3 drugs (INH, ethambutol and either pyrazinamide or levofloxacin) continued to complete the therapy duration of 12 months.805 Using rifamycin as one of the drugs for the treatment of post-transplant TB would increase the cost significantly because of the high doses of CNIs/mammalian target of rapamycin inhibitors needed to maintain the levels and the requirement for frequent drug monitoring. So, the South Asian Transplant Infectious Disease Guidelines for solid organ transplant Candidates, recipients, and donors recommends a rifamycin-free regimen as the standard approach to treating posttransplant TB in this region except in special situations.805

Evidence Summary

Incidence of tuberculosis is higher as compared to general population. Up to 50% cases of tuberculosis can be disseminated or extrapulmonary in post SOT patients. Atypical clinical presentations, less sputum positivity and false negative tuberculin and IGRA tests lead to delays in diagnosis. Radiological investigations like CT scan along with bronchoscopy, BAL or histopathologic evaluation from involved site are needed for prompt diagnosis. Rifampin containing regimens reduce serum concentrations of tacrolimus, cyclosporine, sirolimus and everolimus, whereas rifampin free regimens increase the duration of antitubercular therapy.

Recommendation

The diagnosis of active TB in transplant recipients requires a high index of suspicion. Although the diagnostic modalities and treatment of TB in SOT patients remains the same as that in immunocompetent hosts, these individuals often require an invasive procedure, such as bronchoscopy with BAL or lung biopsy (1A).

Rifamycins, particularly rifampin, reduce serum concentrations of tacrolimus, cyclosporine, rapamycin (sirolimus), and everolimus via induction of the cytochrome p450 isoenzyme CYP3A4, necessary dose adjustments, and therapeutic drug monitoring are warranted to avoid development of rejection (II, A). When rifampin is not used, a longer than usual duration of treatment is required (2B).

Infective Diarrhea in SOT Recipient

Diarrhea of varied etiology is a common occurrence in post-transplant patients, incidence ranging between 17 to 50%. It can be attributed to infectious and non-infectious causes, which have been summarized in Table 6.806 As per the DIDACT study from Belgium on etiology of diarrhea in renal transplant recipients, drug-induced diarrhea was most common (70%) followed by infectious etiology (bacterial infection 20% and CMV 7%).807 In a study analysing the etiological profile of diarrhea in SOT recipients at a tertiary care center in Southern India, they found that of the 58 episodes of diarrhea in 55 recipients, 70% were reported in renal transplant recipients. 79%of the patients were >6 months post-transplant. Infective diarrhea was the etiology in 46%, drug-related diarrhea in 29.3% and no specific etiology was identified in 22.4% of patients. Of the cases with infective diarrhea, parasites were responsible for 69%. Stool analysis included wet mount examination for ova, trophozoites, and cysts, modified acid-fast staining for Cryptosporidium spp, Isospora belli, Cyclospora cayetanensis, and modified trichrome stain for Microsporidia spp., C difficile toxin assay using ELISA method for detection of glutamate dehydrogenase antigen and toxin A and B; stool culture in selected patients.808 In another Indian study on etiological spectrum of infective diarrhea in renal transplant patients by stool PCR, they found that 86% of the stool samples were positive for infection and 68% had more than one organism identified. The most common pathogen isolated was Norovirus and Giardia lamblia with Norovirus was the most common coinfection.809 Due to frequent exposure to antibiotics and repeated hospitalizations SOT patients are a risk of developing intra-abdominal infections (IAI). It is recommended for all SOT patients with diarrhea to undergo stool testing for C. Difficile, CMV, and bacterial pathogens, also considering multiplex PCR testing, testing for parasites and Norovirus (stool PCR).806 The medications that the patient is on should be reviewed and any possibly responsible ones should be withheld. Those not responding to therapy, or negative infectious screening or having chronic diarrhea should be evaluated using colonoscopy with or without biopsy. The initial management of C difficile infection (CDI) remains similar to non-transplant patients.806 The American Society of Transplantation Infectious Diseases Community of Practice have recently published updated guidelines to address the prevention and management of CDI in SOT recipients.810 Vancomycin 125 mg PO QID or fidaxomicin 200mg PO BID 10–14 days is the preferred treatment for initial mild to moderate CDI. FMT should be considered for second further recurrences. For fulminant disease, vancomycin PO 500 mg q.i.d. and vancomycin via rectal administration and metronidazole 500 mg intravenously Q6–Q8 h should be prescribed and surgical consultation should be sought.810,811 A series of cases (75 adults and 5 pediatric patients) treated with FMT for recurrent, refractory, and severe and/or overlap of recurrent/refractory and severe CDI had 78% cure rate after first FMT. There were no related infectious complications or adverse events in these high-risk patients.812

Table 6 Causes of diarrhea in solid organ transplant recipients

Infectious	Non-infectious	
Bacterial	Viral	Parasitic	Immunosuppressant drugs	Other drugs and etiologies	
Clostridium difficile	Cytomegalovirus	Giardia	Mycophenolate (most common)	Antibiotics, oral hypoglycemic agents	
Small bowel bacterial growth (SBBO):
Escherichia coli,
Campylobacter,
Shigella,
Salmonella	Norovirus	Cryptosporidium	Tacrolimus	Proton pump inhibitors, laxatives	
Adenovirus	Entamoeba	Cyclosporine	GVHD, PTLD	
Rotavirus,
Sapovirus, Enterovirus,
Human herpes virus 6	Isospora belli
Microsporidium	Sirolimus	Colon cancer
Inflammatory bowel disease	
GVHD, graft versus host disease; PTLD, Post-transplant lympho-proliferative disorder

Evidence Statement

Diarrhea in posttransplant patients can be due to infectious and non-infectious causes. Drug induced diarrhea and infections are most common reported causes. Bacterial infections, parasitic infections (giardiasis) and viral infections (CMV, norovirus) are common infectious causes. Due to frequent exposure to antibiotics and frequent hospitalization, clostridium difficile-associated diarrhea is also common. Stool investigations should be performed for all suspected organisms. The initial management of C difficile infection (CDI) remains similar to non-transplant patients.

Recommendation

We recommend empiric management of gastrointestinal infections/diarrhea with ceftriaxone IV + ganciclovir 5mg/kg BD IV and vancomycin 125mg PO QID (if the patient is already on antibiotics to cover CDI) till definitive diagnosis is made (1A).

If the patient is in septic shock, based on local resistance pattern, and previous drug history of patient consider carbapenems (UPP).

We recommend cessation of the inciting antimicrobial agent whenever possible (2A).

We recommend using a NAAT alone or a multistep algorithm for testing (i.e., GDH plus toxin; or NAAT plus toxin) rather than a toxin test alone for the diagnosis in stool specimens likely to be having Clostridium difficile infection CDI (2A).

For treatment of CDI in adults, either vancomycin (125 mg given 4 times daily orally for adults; 40 to 50 mg/kg/day divided QID for pediatric patients, not to exceed adult dosing; for 10–14 days) or fidaxomicin (200 mg given twice daily orally for 10 days) is recommended over metronidazole (1A). If these agents aren't available, metronidazole 500 mg 3 times daily by mouth can be used as an alternative.

We recommend oral vancomycin up to 500 mg orally QID in adults for the treatment of severe/fulminant CDI (I, A). If ileus, consider adding rectal instillation of vancomycin 500 mg in 100 mL normal saline as retention enema 4 times a day (2B).

Intravenous metronidazole 500 mg intravenously every 8 hours may be administered together with oral or rectal vancomycin (1B).

In cases of multiple recurrences of CDI, we recommend prolonged courses of oral vancomycin, either in a tapering or pulse dose schedule (2A). Fidaxomicin can be used if available (2B).

Fecal microbiota transplant (FMT) may be considered in recurrent or relapsing CDI (2B).

We suggest consideration for surgical intervention in cases of complicated CDI (2B).

Invasive Fungal Infection in SOT Recipients

The epidemiology of fungal infections in posttransplant patients depends upon certain host and environmental factors.813 The highest risk of first invasive fungal infection (IFI) among SOT recipients as reported by TRANSNET network (2010) has been found in small bowel transplant followed by lung, liver, heart, pancreas and kidney transplant in that order (the one year cumulative incidences being 11.6%, 8.6%, 4.7%, 4%, 3.4%, and 1.3%, respectively). Invasive candidiasis (IC) was the most common IFI (53%) followed by invasive aspergillosis (IA) (19%), cryptococcosis (8%), non aspergillus molds (8%), endemic fungi (5%) and zygomycosis (2%). Median time to onset of IC was 103 days, 184 days for IA and 575 days for cryptococcosis. They observed an increase in cumulative incidence of IFIs during the surveillance period.814 Emerging Candida strains that are drug resistant are a cause for concern and pose challenge in the management. Indian data regarding epidemiology of IFI in SOT is scarce.815 In a review by Sharma et al., the maximum available data was from renal transplant patients and they found mucormycosis to be the predominant. They reported an increase in IFIs and more renal transplant patients acquiring mucormycosis during the COVID-19 outbreak.816

As per a review, IC is the most common the IFI in India, followed by mucormycosis, IA, and cryptococcosis; and prevalence of azole and multidrug resistance among Candida infections in South Asia is increasing. They reported that the most common endemic mycoses in Asia-Pacific region are histoplasmosis, talaromycosis and sporotrichosis.817 Another recent publication showed 67 (9.2%) of 725 renal transplant recipients had IFIs. Invasive candidiasis was the most common IFI followed by mucormycosis, IA, and cryptococcosis.818 As per TRANSNET 2016 on Candida infections, among IFI in SOT patients IC constituted 50–60%. Most of them are bloodstream infections (44%), followed by intra-abdominal (14%), and they occurred mostly in liver (41%) and kidney (35%) transplant. Mortality is higher in liver transplant.819 Blood cultures are the mainstay of diagnosis. Non‐culture based methods such as 1,3 beta‐D glucan or T2 Candida assay maybe used in patients suspected of having IC, if culture and/or histopathology of tissue are not available or negative.820

IA infections incidence was higher in lung and heart transplant recipients.69 CT scan is able to give diagnosis of IPA in only half of the patients, direct examination of respiratory secretions in 49% and culture in 70%, BAL galctomannan in 39% and serum galactomannan (GM) in 35%.821 Serum GM is not recommended for diagnosing IA. A retrospective study involving 362 lung transplant recipients found that 105/335 (31%) patients had evidence of aspergillus infection (colonization or invasion), 83 (25%) patients had colonization and 22 (6%) patients had radiographic or histological evidence of invasive disease. Most of the infections occurred within the first 3 months after transplantation. Invasive aspergillosis (IA) was associated with 58% mortality after 2 years, while colonization was associated with increased mortality after 5 years compared non-colonised patients (p < 0.05).822

Voriconazole remains the drug of choice for treatment of IA, isavuconazole and lipid formulations AmpB being the alternative agents. Infectious Diseases Society of America (IDSA),725 the European Society for Clinical Microbiology and Infectious Diseases823 and American Society of Transplantation Infectious Diseases Community of Practice (AST‐IDCOP)821 endorse this recommendation. Echinocandins should be used alone or in combination only as salvage therapy.725 Herbrecht et al.824 compared voriconazole with amphotericin B in a large randomized trial for the treatment of IA in immunocompromised patients. In their study they found that at week 12, there were more successful outcomes 52.8% patients in the voriconazole group (complete response 20.8% and partial response in 31.9%) compared to 31.6% in the amphotericin B group (complete response 16.5% partial response in 15%). The survival rate was better at 12 weeks in voriconazole compared to amphotericin B group. (71 vs 58%) (HR –0.59; 95% CI, –0.40 to 0.88). Denning et al. in their study showed good response in IA treated with voriconazole; 56 out of 60 patients in voriconazole group were treated successfully.825 Voriconazole was successfully used in heart transplant recipients as first-line and salvage therapy for IA.826,827

Isavuconazole was found to be non‐inferior to voriconazole for the primary treatment of invasive mold disease caused by Aspergillus and other filamentous fungi, in a trial conducted in hematological patients (SECURE RCT). All cause mortality through day 42 was the primary endpoint and was found to be 19% and 20% in isavuconazole and voriconazole group respectively. The former has been found to be associated with lesser visual, skin/subcutaneous tissue, and hepatobiliary side-effects.734

Therapeutic drug monitoring (TDM) for azole antifungals (especially voriconazole and posaconazole) should be done and all current guidelines recommend the same.725,821,823 Plasma drug level monitoring is important when voriconazole is used as the plasma levels achieved are variable and very often do not reach therapeutic levels in the plasma, requiring dose adjustments.828 The fact that clinical efficacy is dependent on the achievement of therapeutic drug levels has been well established.829

For IC or candidemia, echinocandins remain the drug of choice and in a clinically stable patient it can be switched to fluconazole if the Candida isolate is susceptible to fluconazole. Antifungal should be continued for minimum 2 weeks after first negative fungal blood culture and till the resolution of features of IC.725,820 Antifungal prophylaxis for IFI depending upon the host factors and the organ transplanted has been recommended.817,820,821

Evidence Statement

SOT recipients are at increased risk of fungal infections, highest risk in small bowel transplant, followed by lung, liver, heart, pancreas and kidney transplant. Invasive candidiasis is most common fungal infection, followed by aspergillosis, cryptococcosis, non-aspergillus molds, endemic fungi and zygomycosis. Emerging Candida strains that are drug resistant are a cause for concern and pose challenge in the management. India data is limited, and mucormycosis is the commonest infection. Candida infections are most commonly bloodstream infections followed by intraabdominal infections. Aspergillus colonization and infection is associated with increased mortality in lung transplant recipients. Various diagnostic modalities including serum markers such as beta-D glucan, galactomannan, imaging (CT scan), bronchoscopic evaluation or histologic evaluation of involved site lead to early diagnosis.

Voriconazole remains the drug of choice for treatment of IA, isavuconazole and lipid formulations AmpB being the alternative agents. Echinocandins can be used as salvage therapy. Isavuconazole is non‐inferior to voriconazole for the primary treatment of invasive mold disease caused by Aspergillus and other filamentous fungi. Therapeutic drug monitoring (TDM) for azole antifungals (especially voriconazole and posaconazole) improves clinical efficacy and is preferred. For IC or candidemia, echinocandins remain the drug of choice and in a clinically stable patient it can be switched to fluconazole if the Candida isolate is susceptible to fluconazole. Duration is dependent on culture negativity and resolution of features of invasive candidiasis.

Recommendation

Antifungal Prophylaxis

Recommendations for antifungal prophylaxis in different solid organ transplant recipients are enumerated in Table 7 and Table 8.

Table 7 Anti fungal prophylaxis (for Candida) in Solid organ transplant recipients

Candida	
Organ transplanted	Universal prophylaxis	Targeted prophylaxis	Drug	Duration	
Liver	May be given (UPP)	Should be given in patients at high risk of invasive candidiasis (1A) e.g.:
• Re‐transplantation
• Renal replacement therapy at the time of or within 7 days of transplantation.
• Choledochojejunostomy.
• Perioperative Candida colonization
• Transfusion of ≥40 units of cellular blood products.
• MELD score ≥30
• Fulminant hepatic failure
• Biliary leak	• Azoles or echinocandins preferred over amphotericin B lipid formulation (1A).
• Fluconazole is the drug of choice (1B).	2 to 4 weeks (2B)	
Small bowel	Recommended (1B)	In high risk patients: graft rejection or dysfunction, enhanced immunosuppression, anastomotic disruption, abdominal reoperation, or multivisceral transplantation	Fluconazole
Others if higher prevalence of Candida non albicans or prior azole exposure	4 weeks or until the anastomosis has healed, and no rejection (1A, 1B)	
Pancreas	Not recommended	When at least one risk factor associated with candidiasis is present: (2B)
Enteric drainage,
Vascular thrombosis
Post‐perfusion pancreatitis	Fluconazole
(Others if higher prevalence of Candida non albicans)	Depend on reduction in risk factors	
Heart	Not recommended (1B)	
Kidney	Not recommended (1B)	

Table 8 Anti fungal prophylaxis (for Aspergillus) in Solid organ transplant recipients

Aspergillus	
Organ transplanted	Universal prophylaxis	Targeted prophylaxis	Drug	Duration	
Liver	Not recommended (1A)	In high risk cases: Re-transplantation Renal replacement therapy Reoperation involving thoracic or intra-abdominal cavity	Echinocandin or voriconazole (1A). Lipid formulation of amphotericin B 3‐5 mg/kg may be considered (2B)	14 to 21 days (1A)	
Lung	Recommended (1A)	Recommended in:
• Pre‐transplant Aspergillus colonization
• Post‐transplant Aspergillus colonization within a year of transplant
• Single‐lung transplant
• Positive intraoperative Aspergillus culture in patient with cystic fibrosis	Systemic antifungal for prophylaxis or preemptive therapy:
Voriconazole (6 mg/kg for two doses followed by 4 mg/kg every 12 h), itraconazole or posaconazole.
Nebulized L-AmB or ABLC for prophylaxis (II, B)	4 to 6 months (1A)	
Heart	Not recommended	• Recommended in: Isolation of Aspergillus species in respiratory tract cultures without radiological abnormality.
• Presence of airborne Aspergillus spores in the ICU
• Re‐operation(thoracic) Presence of CMV disease
• Post‐transplant hemodialysis	Itraconazole or voriconazole
OR
Echinocandins (1B)	Up to 150 days	
Other SOTs	No recommendation	

Invasive Aspergillosis (IA) Treatment

It is recommended not to use serum galactomannan (GM) to diagnose IA in SOT patients (1A)

Serum or BAL beta-D-Glucan should not be used to screen or diagnose SOT patients for IA (1B).

BAL GM is the preferred parameter for diagnosis of invasive pulmonary aspergillosis and a value of ≥1.0 in combination with other fungal diagnostic methods is used to diagnose IA in SOT recipients (1A).

For IA or positive BAL galactomannan, we recommend voriconazole in the dose of 6mg/kg bd for 1 day f/b 3mg/kg bd (1A).

Isavuconazole and lipid formulations of Amphotericin B (AmB) can be used as alternative agents (1A).

As a salvage therapy, posaconazole can be used where patients fail to respond or are intolerant to first line agents (1B).

Echinocandins are not recommended as a primary therapy (1B) and can be used only as a salvage therapy or as a second agent where combination therapy is being considered (3B).

We recommend therapeutic drug level monitoring (TDM) for voriconazole when using it for the treatment of IA (1A).

We recommend that treatment be continued for minimum 12 weeks, if tolerated, and guided by clinical and radiological response (1A).

Other Emerging Fungal Infections

For infection by mucormycetes, lipid formulations of AmB is the drug of choice for induction therapy (1A).

Posaconazole or isavuconazole can be used as alternative agents for induction and for maintenance therapy (2B).

Surgical excision or debridement is recommended for all wherever feasible, particularly for mucormycetes infection outside of lungs (2A).

For trichosporon, azoles are the recommended first line agents (3A), subject to the susceptibility.

Pneumocystis Jirovecii Infection Management

The incidence of PCP in SOT recipients is variable. In a retrospective study of 1192 renal transplant patients, it was reported to be 0.6 to 9%. Authors observed that the incidence of PCP with a moderate cyclosporine based immunosuppressive regimen is low and seems to occur only in cases of additional immunosuppressive cofactors.830 In another retrospective study of 601 renal transplant recipients, PCP incidence was 2.2%.831 In liver transplant recipients (154 adult patients) PCP occurred in 5.2% and the authors observed that patients who developed PCP had more episodes of rejection (p < 0.05), received more OKT3 (p < 0.05), a prednisone (p < 0.05) than controls.832 Another retrospective study of 43 adult OLT recipients showed that the incidence of PCP was 0.9%. Most of the patients developed PCP at around 1 year of post-OLT, and the risk of PCP was closely related to strong immunosuppressive regimen. Thus they advised that routine PCP prophylaxis for 12 months be continued for 12 months, among patients receiving antirejection treatment.833

TMP-SMX acts by interfering with folate metabolism and remains the drug of choice for treatment of PCP in SOT patients, HIV patients, and non-HIV patients. TMP-SMX has high efficacy and availability in both oral and IV preparation with good oral bioavailability too.834 Intravenous pentamidine has been found to be equally effective in HIV-infected patients and remains the second line of choice for treatment of PCP in SOT patients.835–839 However, the use of pentamidine has been largely limited in view of its numerous toxicities in 71% patients leading to withdrawal in around 18% patients.836 The optimal duration of therapy is usually 14 days which can be extended to 21 days in severe cases with slow clinical improvement.840 Adjunctive glucocorticoids are recommended for HIV- positive patients with moderate to severe PCP, defined as PaO2 <70 mmHg while breathing ambient room air.841 The benefit in survival from corticosteroids begins during the first 72 hours of treatment.842

With the provision of PJP prophylaxis, the incidence of PJP is less in the initial 6to 12 months posttransplant. However, in the absence of prophylaxis, risk of PJP is maximum in the first 6 months after SOT. TMP-SMX is the drug of choice for prophylaxis as well as treatment PJP.843

Evidence Statement

Incidence of PJP infections in SOT recipients ranges from 0.6% to 9% in various studies. Risk depends on degree of immunosuppression. PJP infection, in turn, leads to more episodes of rejection and increased need for steroids and immunosuppression. TMP-SMX has high efficacy and availability in both oral and IV preparation with good oral bioavailability. The optimal duration of therapy is usually 14 days which can be extended to 21 days in severe cases with slow clinical improvement. Adjunctive glucocorticoids are recommended for moderate to severe PCP. PJP prophylaxis reduces incidence of PJP in the first year after transplant.

Recommendation

Anti-pneumocystis Prophylaxis

We recommend anti-pneumocystis prophylaxis to all SOT recipients for 6 to 12 months posttransplant, particularly for centers with incidence ≥3–5% among transplant recipients (1A).

Longer duration of prophylaxis may be considered in patients with prior history of PJP (Pneumocystis jirovecii pneumoniae) infection, chronic CMV infection, higher intensity of immunosuppression, lung and small bowel transplant recipients, prolonged neutropenia (1A).

Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for prophylaxis of PJP, in a (adult) dose of either 80 mg TMP/400 mg SMX (single strength) daily or 160 mg TMP/800 mg SMX (double strength) orally three times weekly (1A).

PJP treatment

We recommend TMP-SMX as the first-line agent and drug of choice with the Trimethoprim component being 15–20 mg/kg/day in 3 to 4 divided doses (1A).

In severe infections, if available, intravenous pentamidine probably remains the second-line agent after TMP-SMX (2A). Its usage should be avoided in pancreas transplant recipients (1B).

Primaquine and clindamycin in combination may be used as alternative in mild to moderate infection. However, primaquine should be avoided in G6PD deficient patients, and association of clostridium difficile-associated diarrhea (CDAD) with long term usage of clindamycin should be considered (2B).

In patients with hypoxemia (PaO2 <70 mmHg on room air), adjunctive corticosteroids should be administered with antimicrobial therapy, ideally within 72 hours of initiating antimicrobial therapy for maximum benefit (2A). The dose of steroids should be 1 mg/kg/day prednisone (or equivalent) given in two divided doses daily for 5 to 7 days (2A). Steroids should be tapered over a period of 7 to 14 days (2B).

Duration of antimicrobial therapy should be for at least 14 days (1B).

CNS infections in SOT recipients

SOT patients with altered sensorium should be evaluated with detailed workup. Multifactorial etiologies coexist which are often obscured in these group of patients.844 Although each imaging modality has unique insight to diagnose pathophysiology, but magnetic resonance imaging (MRI) is the preferred modality. It can diagnose infectious as well as non-infectious etiologies like drug toxicities, metabolic disorders as well as the progression of the disease and response to the therapy.845,846 Empiric broad-spectrum antimicrobial therapy including viral and fungal infections are preferred. It is preferred to use empirical bactericidal or fungicidal agents having CNS penetration until a diagnosis is achieved.844 There has been always a risk of donor-derived infections in SOT recipients thus donors should be screened with standard screening tests.847,848

Common pathogens causing CNS infections in SOT recipients are mentioned in Table 9.757,849,850 In a Swiss Transplant Cohort Study (STCS), the incidence rate of CNS infection was 2.06 per 1000 patient-years and was similar across all types of transplantations. Time to CNS infection onset ranged from 0.6 to 97 months after transplant. Of the 4762 patients, 42 episodes of CNS infections were observed and 22/42 (52.4%) cases were viral infections, 11/42 (26.2%) fungal, 5/42 (11.9%) bacterial and 4/42 (9.5%) were of probable viral/bacterial etiology. Viral meningoencephalitis was the most common disease, and fungal infections were associated with a high mortality.850

Table 9 Common organisms causing central nervous system infection in solid organ transplant recipients

Intracerebral abscess	Meningoencephalitis	
• Bacterial: Embolic or contiguous disease from the local site
• Nocardia
• Listeria monocytogenes
• Fungal: Aspergillus; Zygomycetes;
• Cryptococcus
• EBV associated post-transplant lymphoproliferative disorder (PTLD)
• Mycobacterium tuberculosis
• Toxoplasmosis	Bacterial: S. pneumoniaee, Neisseria meningitides, Listeria, Gram-negative bacilli
• Viral: CMV, EBV, HSV, VZV, HHV, Enterovirus, JC virus
• Fungal: Cryptococcus, Coccidioides,
• Histoplasma capsulatum
• Mycobacterium tuberculosis
• Treponema pallidum
• Borrelia burgdorferi	

Lipid amphotericin B plus 5‐flucytosine is used as initial treatment of meningitis, disseminated infection, and moderate‐to‐severe pulmonary infection, followed by fluconazole as consolidation therapy.851 Cryptococcosis is a significant opportunistic infection in SOT recipients following aspergillosis and candidiasis. CSF analysis is highly recommended to diagnose underlying CNS disease in suspected cases.852 Cryptococcus can colonize the airways of lung transplant recipients and can cause endobronchial fungal infection. It can present with skin manifestations and Immune reconstitution syndrome (IRIS) as well.853,854

They main components in management of cryptococcosis in SOT recipients include (a) performing lumbar puncture (for diagnostic purpose and for therapeutic purpose, that is, manage meant of intracranial pressure, which is often high in cryptococcal meningitis); (b) antifungal therapy (as described above); and (c) a gradual immunosuppression reduction (a rapid reduction can lead to development of IRIS).851

Evidence Statement

SOT patients with altered sensorium have multifactorial causes and need extensive work up, with MRI being the initial preferred imaging modality. Empirical regimens with bactericidal or fungicidal agents having CNS penetration are initiated at admission, until definitive diagnosis. Common pathogens causing CNS infections in SOT are viral followed by fungal and bacterial agents. Viral meningoencephalitis is most common CNS disease in large prospective studies. Thus, antibiotics covering both gram-positive and gram-negative pathogens along with Acyclovir is part of initial empiric regimen. Amphotericin B plus 5‐flucytosine is used as initial treatment of cryptococcal meningitis.

Recommendation

We recommend initial workup for suspected CNS infections should include (1A).

– MRI over CT scan.

– CSF analysis including India ink preparation.

– Rapid multiplex PCR on CSF.

– Serum cryptococcal antigen.

We recommend empiric treatment to be started with Ceftriaxone + Vancomycin + Acyclovir (1A).

We recommend liposomal Amphotericin B or AmB lipid complex (ABLC) plus flucytosine as the initial treatment for Cryptococcus for minimum 2 weeks for CNS disease, disseminated disease, or moderate‐to‐severe pulmonary disease (1A). Alternatively, liposomal AmB or ABLC can be used for minimum duration of 4 to 6 weeks (1B).

Nocardia in SOT Recipients

SOT recipients are at risk of developing nocardia infection which is an opportunistic event.855,856 The risk of developing nocardiosis after SOT varies with the type of organ transplanted, e.g., the highest incidence in recipients of a lung transplant. A review of 5126 organ transplant recipients has demonstrated that highest nocardial infection rate among lung transplant recipients (3.5%).855,857 TMP-SMX is the treatment of choice for nocardial infections as it has demonstrated clinical efficacy and achieves high tissue concentrations in lung, brain, skin, and bone. Combination therapy is recommended in critically ill patients with pulmonary nocardia, cerebral nocardia, and disseminated nocardia.858 Linezolid has shown good activity against all species of nocardia.859

Evidence Statement

Nocardia infection can occur post solid organ transplants. Lung transplant patients seem to be at highest risk. TMP-SMX, carbapenems and linezolid have efficacy against Nocardia. Combination therapy is recommended in critically ill patients with pulmonary, cerebral and disseminated nocardial infection.

Recommendation

We recommend the following regimens for treatment of post-transplant nocardia infections

Pulmonary: TMP-SMX (1A) (TMP‐SMX 15 mg/kg in 3‐4 divided doses, for 6 to 12 months)

Disseminated or CNS, Critically Ill: Imipenem plus TMP-SMX or Amikacin (2A)

Alternative: Linezolid, Meropenem (1A)

Multidrug-resistant (MDR) Infections in SOT Recipients

MDR gram-negative bacteria (GNB) infections- these recommendations have been adapted from AST-IDCOP860 guidelines and the more recently published IDSA guidelines861 for MDR-GNB infections.

For ESBL‐producing Enterobacteriaceae, carbapenems are the drug of choice. For Carbapenem‐resistant Enterobacteriaceae (CRE), ceftazidime/avibactam is preferred, and ceftazidime/avibactam plus aztreonam or cefiderocol as monotherapy for metallo‐β‐lactamase producing CRE is recommended for systemic infections. Tigecycline may be used as an alternative agent in non-urinary tract infections. For infections due to MDR Pseudomonas aeruginosa, high‐dose continuous or extended‐infusion antipseudomonal β‐lactam or Ceftolozane/tazobactam or Ceftazidime/avibactam is recommended. For treatment of Carbapenem‐resistant Acinetobacter baumannii infections, combination therapy with at least two agents, at least until clinical improvement is seen. High-dose ampicillin-sulbactam (total daily dose of 6-9 grams of the sulbactam component) is suggested as a component of combination therapy for CRAB, regardless of whether susceptibility has been demonstrated. Possible options to combine with it include: tetracycline derivatives (minocycline/tigecycline), polymyxin B, or cefiderocol.

For management of MDR Stenotrophomonas maltophilia, either of the 2 approaches is recommended: 1) the use of two of the following agents: TMP- SMX, minocycline/tigecycline, cefiderocol, or levofloxacin. 2) ceftazidime-avibactam plus aztreonam (when critical illness is evident or intolerance or inactivity of other agents is observed). Nadales et al. in their narrative review also focused on the contribution provided by INCREMENT-SOT project which is a large international retrospective cohort that includes nearly 800 consecutive SOT recipients diagnosed with bloodstream infection (BSI) due to ESBL-E and CRE between 2004 and 2016.862

For methicillin resistant Staphylococcus aureus (MRSA) bacteremia and pneumoniae, vancomycin remains the preferred initial drug of choice and the dose should be adjusted as per the serum trough levels or AUC/MIC ratio. For bacteremia, infective endocarditis, pneumoniae, and osteomyelitis target trough should be between 15 and 20 μg/mL or AUC/MIC >400. Teicoplanin has been found be as effective as vancomycin. Daptomycin can be used as an alternative agent where there is vancomycin intolerance or persistent bacteremia. It shouldn't be used for pneumoniae as it is degraded by surfactant. Linezolid may be used for skin and soft tissue infection (SSTI) and nosocomial pneumoniae. Ceftaroline, a fifth generation cephalosporin, has been approved for SSTIs, pneumoniae (community-acquired, nosocomial), but not particularly due to MRSA and is not approved for bacteremia. A lipoglycopeptide, dalbavancin has bactericidal activity against MRSA but is currently not approved for treatment of MRSA bacteremia.863

Evidence Statement

Carbapenems are effective for treatment of ESBL‐producing Enterobacteriaceae. For Carbapenem‐resistant Enterobacteriaceae (CRE), preferred antibiotics are ceftazidime/avibactam is preferred, whereas and ceftazidime/avibactam plus aztreonam or cefiderocol monotherapy are useful in metallo‐β‐lactamase producing CRE. Tigecycline is useful in treatment of CRE infections outside the urinary tract, and in absence of bacteremia, as combination therapy. For MDR pseudomonas, effective drugs are antipseudomonal β‐lactam or Ceftolozane/tazobactam or Ceftazidime/avibactam. For carbapenem resistant acinetobcacter, high dose ampicillin-sulbactam, tetracycline derivatives (minocycline/tigecycline), polymyxin B, or cefiderocol are options for combination therapy. For MDR Stenotrophomonas maltophilia, combination therapy with two agents (TMP- SMX, minocycline/tigecycline, cefiderocol, or levofloxacin) is effective. However, critically ill patients can be treated with ceftazidime-avibactam plus aztreonam. For MRSA, vancomycin with therapeutic drug monitoring has most evidence. Linezolid can be used for skin and soft tissue infection (SSTI) and nosocomial pneumoniae. Teicoplanin is another efficacious alternative.

Recommendation

Empiric antibiotics for MDR pathogens should be chosen to cover the suspected pathogen spectrum and local microbiology (2A)

The Human Immunodeficiency Virus (HIV) Positive Patient in the Intensive Care Unit

AIDS in adults is defined by Polymerase chain reaction (PCR)-confirmed HIV-positivity plus World Health Organization (WHO) stage IV disease (i.e., esophageal or bronchial candidiasis, wasting syndrome, central nervous system toxoplasmosis, Pneumocystis jirovecii pneumoniae (PCP), recurrent severe bacterial pneumoniae, chronic herpes simplex infection, Kaposi's sarcoma, Cytomegalovirus (CMV) infection, chronic cryptosporidiosis or isosporiasis, extrapulmonary cryptococcosis, disseminated endemic mycosis [coccidiomycosis or histoplasmosis] or non-tuberculous mycobacterial infection, extrapulmonary tuberculosis (TB), HIV encephalopathy, cerebral B-Non-Hodgkin-Lymphoma, progressive multifocal leukoencephalopathy (PML), symptomatic HIV-associated nephropathy, or cardiomyopathy) or immunological diagnosis with HIV-infection or first documented CD4+ cell count <200/μL.864 Since the first case report of HIV in 1981, we have come a long way. The HIV infected patients now have a normal life expectancy when treated with combination ART (cART). Successful HIV treatment can result in full suppression of the virus. cART is now started within 2 weeks of diagnosis as opposed to previous practice of delaying till the CD4 counts fell. Low CD4 cell counts predisposes patients to certain infections but in critical illness, the circulating CD4 count may be even lower as they are redistributed to the activated tissue.865–869

There is an increased risk of chronic conditions in HIV patients such as atherosclerosis, ischemic heart disease, chronic obstructive pulmonary disease, malignancy, renal and hepatic failure.870–872 Improved Survival of this cohort in ICU has resulted from better treatment of HIV and better critical care practices. Fewer than 30% of the admissions to ICU are due to opportunistic infections.865 Acute respiratory failure, reduced conscious level and bacterial sepsis are the most common causes of admission to ICU, be it HIV infected or non-infected patient. Risk factors for increased mortality in critically ill HIV patients include cART naivety, CD4 lymphocyte counts < 200 mm3, viral loads ≥ 50 mm3, HIV-unrelated comorbid disease, malignancies, chronic liver disease and hepatitis C virus infection; high critical illness severity indexes; admission for medical rather than surgical reasons; and a need for invasive mechanical ventilation, vasopressor infusion, renal replacement therapy, thrombocytopenia, length of ICU stay, and severity of illness (high APACHE II or SOFA scores).873–876

The HIV Patient in ICU with Acute Respiratory Failure

Respiratory failure is the most important cause of ICU admission among HIV patients.

Recurrent pneumoniae in a HIV patient is an AIDS defining condition. The incidence rate of serious bacterial infections was 0.87 per 100 person-years In the Strategic Timing of Anti Retroviral Treatment (START) study, and two-thirds of these infections were due to bacterial pneumoniae.877 The causes of community-acquired pneumoniae are like non- HIV patients. The most common pathogens are viral infections, Pneumocystis jirovecii, Streptococcus pneumoniaee, H. Influenzae, M. tuberculosis, Staphylococcus aureus, Klebsiella pneumoniaee, Pseudomonas aeruginosa, and Escherichia coli (Table 10).878–881

Table 10 Etiology of acute respiratory failure in patients with HIV

Author/Country	Design	Study Population	Microbiology	
Pecego et al., Brazil 2020878	Prospective observational study	49 patients
People living with HIV
With without SARI	Respiratory virus (9 SARI vs 13 non-SARI), bacteria (5 SARI vs 4 non-SARI), Mycobacterium tuberculosis (6 SARI group vs 7 non-SARI group), Pneumocystis jirovecii (4 SARI vs 1 non-SARI), Cryptococcus neoformans (1 SARI vs 3 non-SARI), and influenza A (1 SARI vs 2 non-SARI)	
Maartens et al., South Africa, 2020879	Prospective cohort study	284 HIV-infected inpatients with World Health Organization danger signs and cough	148 culture-positive tuberculosis, 100 had community-acquired pneumoniae (CAP), 26 had PCP Haemophilus influenzae and Streptococcus pneumoniaee were the commonest bacterial pathogens	
Elabbadi et al., France, 2020880	Bicenter retrospective study	123 episodes of HIV infection in ICU	Rhinovirus was predominant, followed by Influenza and Respiratory Syncytial Viruses. Non-viral copathogen in two-thirds of cases.	
Hao et al., China 2023881	Retrospective study	231 AIDS adult patients with respiratory failure who were admitted to the ICU	Pneumocystis jirovecii pneumoniae (80.1%)	

The viral infections such as influenza and covid-19 are associated with higher mortality in HIV patients than non-HIV patients.882 Antibiotics need to be given for a minimum of 5 days of treatment and may be stopped in case patients remain afebrile for 48 to 72 hours and are clinically stable. TB and PCP are the most common cause of respiratory failure in HIV patients, both accounting for 20% each as causes of respiratory failure in HIV patients. Individuals with HIV remain at higher risk for tuberculosis even with high CD4 counts. Table 11 enumerates risk factors for pseudomonas and staphylococcal infections in HIV infected patients.

Table 11 Risk factors for Pseudomonas and Methicillin resistant Staphylococcal infections

Risk factors for P. aeruginosa	Risk factors for methicillin-resistant S. aureus	
Advanced immunosuppression/full blown AIDS (CD4 count ≤50 cells/mm3)
underlying structural lung disease such as bronchiectasis
Profound neutropenia
Treatment with long term corticosteroids
Severely malnourished patients
Those residing in nursing homes/health care facilities or who had recent hospitalizations in the last 3 months.
Patients on chronic hemodialysis	Recent influenza infection;
IV drug abusers
Severe, bilateral, necrotizing pneumoniae
Recent head injury
Patients on chronic hemodialysis	

Pneumocystis jirovecii pneumoniae sets in slowly over weeks with increasing dyspnoea, dry cough and fever. It is treated with 3 weeks of cotrimoxazole (TMP (15–20 mg/kg/day) plus SMX (75–100 mg/kg/day) IV). Alternative treatment is Pentamidine IV 4 mg/kg/day. Moderate to severe cases (PaO2 9.3 kPa [70 mmHg] or SpO2 92%) should be given steroids within 72 hours for mortality benefit and reduction of duration of mechanical ventilation i.e. Prednisone PO 40 mg bid (D1–D5), 40 mg daily (D6–D10) then 20 mg daily (D11–D21), or methylprednisolone IV (75% of prednisone dose). Radiological findings include patchy or diffuse ground-glass opacities and alveolar consolidation with peripheral sparing, reticular infiltrates, intra-parenchymal cysts, without pleural effusion or mediastinal lymphadenopathy.871,883 Other rare pulmonary opportunistic infections include Kaposi sarcoma (HHV-8 human herpes virus-8), cytomegalovirus, toxoplasmosis, Mycobacterium avium complex, nocardiosis, aspergillosis, rhodococcosis, histoplasmosis, cryptococcosis, Legionella, mycoplasma, chlamydophila, etc. These are AIDS defining illness which occur when CD4 count falls below 200. Pulmonary TB presents typically as cavitary lesions but in immunocompromised patients may also present as diffuse miliary patterns or in extrapulmonary sites. The treatment remains standard antitubercular drug therapy for 6-12 months i.e., Intensive phase (2 months): isoniazid + rifampin or rifabutin + pyrazinamide + ethambutol and Continuation phase: isoniazid + rifampin or rifabutin.871 Disseminated Mycobacterium avium complex (MAC) disease may present as respiratory failure with diffuse reticulonodular pulmonary infiltrates. This should be treated with clarithromycin (500 mg PO two times daily) or azithromycin (500–600 mg) + ethambutol (15 mg/kg PO daily) for 12 months. Cytomegalovirus (CMV) reactivation is seen in severely immunocompromised patients with HIV (CD4 count <50 cells mm3) It is characterized by diffuse interstitial pulmonary infiltrates. It is treated with Ganciclovir 5 mg/kg IV q12h. The incidence of bacteremia accompanying pneumoniae is greater than in individuals without HIV, especially when infection is due to S. pneumoniaee. Predictors of mortality include CD4 count <100 cells/mm3, radiographic progression of disease, and presence of shock.871

Evidence Statement

Respiratory failure is the most important cause of ICU admission among HIV patients. Causes of community-acquired pneumoniae are similar to non-HIV patients. However, tuberculosis, and opportunistic infections (like Pneumocystis Jirovecii, cryptococcus, CMV) are also common, and can present with respiratory failure. Viral infections like influenza and covid-19 are other important causes. Increasing age, comorbidities, severity of illness, extent of organ dysfunction and cART naivety are predictors of increased mortality.

Recommendation

Patients with severe pneumoniae who require intensive care and without risk of Pseudomonas aeruginosa should be empirically treated with an IV β-lactam plus IV macrolide (2A). Preferred β-lactams are ceftriaxone, cefotaxime, or amoxicillin-clavulanic acid. In patients who are allergic to penicillin, aztreonam plus azithromycin should be used (3A).

If patients with HIV/AIDS develop acute respiratory failure and they have any of the risk factors (Table 1) for Pseudomonas infection we recommend dual antipseudomonal coverage such as anti-pseudomonal β-lactam plus aminoglycoside (examples of anti-pseudomonal β-lactams include ceftazidime, cefoperazone, cefoperazone-sulbactam, piperacillin-tazobactam, imipenem-cilastatin, or meropenem (3A).

In patients who are allergic to penicillin, aztreonam can be used in place of the β-lactam. Combination therapy may be considered with the addition of aminoglycosides or antipseudomonal fluoroquinolones (e.g., levofloxacin, ciprofloxacin) (3A).

We recommend continuing Azithromycin along with anti-pseudomonal therapy for coverage of atypical pathogens (2B).

We recommend against using fluoroquinolones empirically to avoid development of drug-resistant TB. Patients should also undergo sputum testing for acid-fast bacilli simultaneously if fluoroquinolones are being used (3A).

In patients who have risk factors for methicillin-resistant Staphylococcus aureus (MRSA) infection–empiric treatment should include vancomycin or linezolid (3A).

Empiric therapy should cover P. aeruginosa or MRSA if previously isolated from sputum cultures (3A).

Steroids are not indicated except in cases of refractory shock (2A).

We suggest the addition of clindamycin (to vancomycin, but not to linezolid) in cases of severe necrotizing pneumoniae to minimize bacterial toxin production (3B).

Those with CD4 counts <200/mm3 and without signs of focal consolidation may be suspected to have PCP (2A).

All diagnosed cases of HIV should receive cART and trimethoprim-sulfamethoxazole (TMP-SMX) for PCP prophylaxis to reduce the risk of pneumoniae (1A).

A switch to oral therapy should be considered in patients with community-acquired pneumoniae (CAP) on IV antibiotic therapy who have improved clinically, can swallow, and tolerate oral medications, and have intact gastrointestinal function (2A).

cART should be initiated promptly within 2 weeks of initiating therapy for the pneumoniae if not started (2A).

Diagnostic work up of acute respiratory failure in HIV patient should consist of: (3A)

– Complete blood count with CD4 cell count.

– Sputum microscopy and culture especially for acid fast bacilli (AFB), Nucleic acid amplification tests (NAATs) for TB.

– Chest imaging, lung ultrasound.

– Bronchoalveolar lavage (BAL) for culture, staining with Gomori-Grocott or Giemsa or direct fluorescence antibody for PCP, PCR.

– Blood culture.

– BAL 1, 3 beta-D-glucan (BDG).

– Urine antigen for L. pneumophila and S. pneumoniaee.

– Serum LDH, BDG.

Rule out non-infectious causes of respiratory failure- COPD, Bronchiectasis, lung cancer, heart failure, lung fibrosis, interstitial pneumonitis, drug toxicity, asthma, pulmonary embolism (3A).

HIV-positive Patient Presenting with Signs of CNS Infection in ICU

Low CD4 counts predispose these patients to infections and development of tumors. The most common focal lesion is toxoplasmosis. In severely immunosuppressed patients with CD4 cell counts <200/mm3, CNS mass lesions are most common. Common CNS opportunistic infections (OI) are toxoplasmosis, tuberculosis, cryptococcosis Rare CNS OI are CMV, nocardiosis, aspergillosis, PML, HIV encephalitis, NHL, neurosyphilis.

In addition, multiple etiologies can coexist in an immunosuppressed individual.884–886

TB meningitis typically presents with fever, focal neurological deficits, progressive cognitive decline and new-onset seizures. CSF suggests lymphocytosis, low glucose and increased protein. NAATs are highly specific. Treatment is as per national guidelines with four or more CNS penetrating drugs along with adjuvant steroid therapy (dexamethasone (0.3–0.4 mg/kg/day for 2–4 weeks, then tapering over 8–10 weeks).876

Cerebral toxoplasmosis presents as motor deficit, altered cognition and seizures. It is seen as ring enhancing lesions in brain, mostly in basal ganglia. Evaluation includes PCR for T. gondii on CSF sampling and a positive IgG test. Treatment is with a combination of pyrimethamine and sulfadiazine for 6 weeks or longer, with regular clinical and radiological review to monitor treatment response. Pyrimethamine 200 mg PO once then pyrimethamine 50–75 mg PO daily + sulfadiazine 1000–1500 mg PO q6h + leucovorin 10–25 mg PO daily. Corticosteroids are added to alleviate mass effect. Initial therapy is followed by chronic maintenance therapy by Pyrimethamine 25–50 mg PO daily plus sulfadiazine 2,000–4,000 mg PO daily (in 2–4 divided doses) plus leucovorin 10–25 mg PO daily.

Cryptococcal meningitis usually presents with low-grade fever, worsening headache, seizures, visual symptoms and a progressive cognitive deficit. Diagnosis includes India ink staining for cryptococcus and a positive CSF cryptococcal antigen test. MRI of the brain may reveal characteristic encephalitis, hydrocephalus and/or signs of raised intracranial pressure. Treatment includes Induction therapy (> 2 weeks): AmB-L 3–4 mg/kg IV daily plus flucytosine 25 mg/kg qid followed by Consolidation therapy ( 8 weeks from negative CSF): fluconazole 400 mg daily. For clinically stable patients with negative CSF cultures, dose can be reduced to 400 mg PO once daily and if CSF remains positive after 2 weeks, fluconazole increased to 1200 mg daily. Steroids are not indicated and are associated with worse outcomes. Maintenance therapy is with Fluconazole 200mg PO daily for ≥1 year from initiation of antifungal therapy.

Immune reconstitution inflammatory syndrome (IRIS) is a concern when cART is started in undiagnosed or partially treated opportunistic infection and its incidence is 13%. Paradoxical worsening of treated OIs is called paradoxical IRIS and unmasking of previously subclinical untreated infections is called unmasking IRIS. IRIS is diagnosed when there is a temporal association between starting of cART and development of symptoms within 3 months, evidence of an inflammatory process through clinical signs and symptoms and evidence of immune restoration (virologic and immunologic response). In CNS infections, there may be neurological deterioration after starting cART because of IRIS. Except for the life threatening conditions, cART provides mortality benefit in setting of IRIS and should be continued.876,883,887

Steroids should be given in patients with tuberculosis and Mycobacterium avium complex IRIS, but not in IRIS associated with Kaposi sarcoma.888 Progressive multifocal encephalopathy (PML) is caused by JC virus confirmed with Positive JCV PCR on CSF and presents with demyelinating white matter lesions. The treatment is to initiate or optimize cART. By all means, cART should be continued in the intensive care. Hurdles to implementation of the same are availability of only enteral medicines, disturbances in gastric pH, renal hepatic dose modifications, drug interactions, etc.889,890

Evidence Statement

Patients with HIV and low CD4 counts are prone to opportunistic CNS infections like toxoplasmosis, tuberculosis, cryptococcosis. Less common opportunistic CNS infections are CMV, nocardiosis, aspergillosis, and neurosyphilis. CNS mass lesions and lymphoma are also common with low CD4 counts, Multiple etiologies can often co-exist. Clinical and laboratory evaluation and prompt management is associated with improved outcomes.

Immune reconstitution inflammatory syndrome (IRIS) is another differential if cART is started in undiagnosed or partially treated opportunistic infections.

cART should be continued in the HIV patients admitted to intensive care unit as much as possible.

Recommendation

For a patient coming to ICU with altered CNS function and suspicion of meningitis, we recommend a third-generation cephalosporin- known to penetrate the blood-brain barrier - at higher doses, e.g., Ceftriaxone 2 gm BD intravenously (1A).

We suggest the addition of vancomycin empirically to the initial treatment regime (1B).

We recommend de-escalating antibiotics after culture reports are available (1A).

In patients above 50 years of age, we suggest the use of additional ampicillin at high doses of 2 gm every 6th hourly (1B).

In very young infants of age <1 month, we suggest Ampicillin plus cefotaxime or ampicillin plus an aminoglycoside as the initial management (1B).

Diagnostic work up for CNS infection in HIV patient should consist of (3A):

– Complete blood count with CD4 cell count.

– Lumbar puncture, CSF (Cerebrospinal fluid) for cell count, glucose, protein, ADA (Adenosine deaminase), lactate, culture, PCR.

– For immunocompromised host-Toxoplasma gondi IgG antigen and antibodies, cryptococcal antigen (serum and CSF).

– Brain imaging preferably MRI (Magnetic resonance Imaging).

HIV-positive Patients Presenting with Suspected Bloodstream Infections or Sepsis of Unknown Origin

Lack of cART, low CD4 count, alcohol abuse, smoking, and comorbidities such as liver disease are risk factors associated with bacteremia.891 The common organisms seem to be non-typhoid Salmonellae, Streptococcus pneumoniaee, Escherichia coli, Staphylococcus aureus, and coagulase-negative Staphylococci (Table 12).889,892–897 Undifferentiated fever in patients with low CD4 counts may be due to viral syndromes such as CMV, Disseminated mycobacterial disease, disseminated fungal disease (cryptococcal disease, etc. Non-infectious etiologies should also be kept in mind such as drug reactions, malignancy, hemophagocytic lymphohistiocytosis (HLH) or IRIS, etc. Septic shock and multiorgan failure may occur during the course of disseminated OIs like toxoplasmosis, tuberculosis, and histoplasmosis. These infections commonly trigger hemophagocytic lymphohistiocytosis. Drug-resistant organisms are also seen more commonly in HIV patients. In the absence of any localizing symptoms, the diagnostic work up should include bacterial blood cultures, a serum cryptococcal antigen, fungal markers, such as a BDG, serum or urine Histoplasma antigen, Coccidioides-specific antigen testing, CMV viral load, mycobacterial isolator blood cultures.868 HIV patient with high CD4 count, undetectable viral load and adherence to cART, the differential diagnosis of any critical illness will be similar to non-HIV patient as both are immunologically similar. There is evidence that in-hospital mortality in HIV patients depends on age, underlying comorbidities and extent of organ dysfunctions and not HIV related parameters such as viral load, CD4 cell count, admission for AIDS-related diagnoses, and prior cART use.871

Table 12 Common organisms isolated from the bloodstream in patients with HIV

Author/Country	Design	Study Population	Microbiology	
Michaëla et al., Netherland 2014892	Systematic literature review.	Hospitalized patients	Nontyphoid salmonellae (NTS), Streptococcus pneumoniaee, Escherichia coli, and Staphylococcus aureus	
Nadjm et al., Rural Tanzania 2012893	Prospective observational study and cohort study	Fever and 1 severity criterion	NTS 3 (25), S. pneumoniaee 3 (25), Streptococcus pyogenes 2 (17)	
Kiertiburanakul et al., Thailand 2012894	Retrospective observational study	BSI in HIV patients	Salmonella spp. 21 (26), E. coli 14 (18), S. aureus 12 (15)	
Phe et al., Cambodia 2013895	Retrospective study using prospectively collected data	435 patients community-acquired BSI	E. coli 27 (31), S. aureus 17 (19), NTS 16 (18)	
Barr et al., 2020896	Meta-analysis, 23 datasets	5751 seriously ill patients	M. tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality (adjusted hazard ratio 2.48)	
Qi et al., China 2016897	Retrospective cross-sectional study	2442 Chinese HIV-seropositive inpatients, 229 (9.38 %) experienced BSIs	Cryptococcus neoformans (22.7%), Penicillium marneffei (18.8%), Mycobacterium tuberculosis (15.3%), and non-tuberculous mycobacterium (14.8%)	

Evidence Statement

Lack of cART, low CD4 count, alcohol abuse, smoking, and comorbidities such as liver disease are risk factors associated with bacteremia in HIV patients, Common organisms seem to be non-typhoid Salmonellae, Streptococcus pneumoniaee, Escherichia coli, Staphylococcus aureus, and coagulase-negative Staphylococci. Undifferentiated fever in patients with low CD4 counts may be due to viral syndromes such as CMV, Disseminated mycobacterial disease, disseminated fungal disease or noninfectious etiology. Disseminated opportunistic infections may trigger hemophagocytic lymphohistiocytosis. Drug-resistant organisms are also seen more commonly in HIV patients. Extensive diagnostic work up is needed in HIV patients with sepsis of unknown origin. In-hospital mortality in HIV patients depends on age, underlying comorbidities and extent of organ dysfunctions and not HIV related parameters such as viral load, CD4 cell count, admission for AIDS-related diagnoses, and prior cART use.

Recommendation

In the presence of sepsis or septic shock, we recommend following the surviving sepsis guidelines like the management of other patients with sepsis (UPP).

In the absence of septic shock or absence of risk factors for Pseudomonas a monotherapy with a third-generation cephalosporin or a cephalosporin, the b-lactamase inhibitor is sufficient (2A).

In more severe disease states, such as in the presence of organ dysfunction or septic shock–a combination of broad-spectrum antibiotics may be used for initial empiric therapy (3A).

Empiric gram-positive coverage is suggested for those who have risk factors for MRSA (UPP).

Anti-fungal agents may be considered only if there is no clinical improvement or there is clinical deterioration even after 72 hours of appropriate empirical antibiotics therapy and CD4 counts <200/mm3 (2A).

We recommend against the use of routine empirical antifungal therapy (2A).

Congenital and Acquired Hyposplenism and Asplenia

Spleen is secondary lymphoid organ which filters organisms from the blood and also regulates immune response. Patients with congenital and acquired hyposplenism/asplenia are prone for specific infections, particularly by encapsulated bacteria (namely, Neisseria meningitidis, Streptococcus pneumoniaee, Haemophilus influenzae type b). These patients are at increased risk of severe sepsis. Asplenia is predominantly due to splenectomy for either traumatic events or onco-hematological conditions. Although the incidence of sepsis remains low, the risk for overwhelming post-splenectomy infection (OPSI) is higher than in the general population.898 Even if most post-splenectomy infections (OPSI) are caused by encapsulated bacteria, other infections can also occur.899,900 The infection starts as a minor flu-like illness and rapidly evolves into a fulminant course of hypoglycemia, metabolic acidosis, dyselectrolytemia, disseminated intravascular coagulation (DIC), shock, coma and death within 24 to 48h.901 OPSI usually occurs within the first two years after splenectomy but may also occur later and has a mortality rate of 50%-70% despite aggressive therapy.899 In view of the severe progression and high mortality of OPSI, stress has been given for early aggressive treatment as well as immunization of patients with splenectomy and thereby preventing OPSI.

What Should be the Approach to Empiric Therapy in Patients with Hyposplenism or Asplenia who Develop Sepsis?

Splenectomy is often performed in patients with an underlying malignant or nonmalignant hematologic disease or in patients with splenic rupture after trauma or infection. Rarely there may be congenital absence of spleen. Other causes of hyposplenia include auto infarction in subjects with sickle cell anemia and chronic graft-versus-host disease after stem-cell transplantation, severe celiac disease, and untreated human immunodeficiency virus infection.902

Overwhelming post-splenectomy infection (OPSI) is defined as an infection, occurring more commonly after splenectomy (or in hyposplenic host) which evolves over a short time and produces severe symptoms, often with hypotension and a high mortality rate.903

Patients with hyposplenism due to splenectomy or hyposplenia are at an increased risk for invasive infections with encapsulated bacteria as Streptococcus pneumoniaee, Haemophilus influenzae type b, Neisseria meningitidis.899,904 Some splenic function may be preserved in post-splenectomy patients due to seeding of the peritoneum due to rupture or intentional implantation of splenic tissue performed during elective surgery. These infections progress rapidly from a mild flu-like illness to fulminant sepsis and are associated with a high mortality rate of up to 50% despite maximal treatment. The lifetime risk of OPSI is assumed to be 5%, and the highest frequency of these OPSI is during the first 2 years after splenectomy.903,905,906 Patients with sickle cell anemia, thalassemia major or malignancies such as Hodgkin's lymhomas and non-Hodgkin's lymphomas have a higher risk for OPSI. Asplenic patients have a higher incidence of parasitemia, a delayed clearance of parasites after treatment or a severe or even fatal infection due to malaria. These patients are also at high risk for Babesiosis and this might be confused with Plasmodium falciparum.899 These patients are at an increased risk of OPSI with Capnocytophaga canimorsus, if bitten by dogs and other animals and should receive adequate antibiotic coverage following such bites.907 Otherwise rare, Ehrlichiosis is also more severe in patients with asplenia/hyposplenia.899

OPSI should be considered as a medical emergency and mandates early recognition and aggressive management. These patients should be managed aggressively including immediate cultures and administration of a combination of antibiotics to cover all possible etiological agents. In areas where penicillin-resistant pneumococci are prevalent, other agents such as vancomycin, teicoplanin or rifampicin should be added to ceftriaxone as the initial empiric therapy. Gram stain of the peripheral blood or buffy coat will give an idea regarding the presence or absence of intraleukocytic bacteria. Anti-pseudomonal coverage should be added in case of high risk for pseudomonas infection or peripheral blood growing GNB. The presence of intracellular bacteria within leukocytes should alert the clinician towards ehrlichiosis while the presence of parasites in RBC should alert for malaria or babesiosis. Once the blood cultures are positive antibiotics can be modified accordingly.

Evidence Statement

Patients with congenital and acquired hyposplenism/asplenia are at high risk for encapsulated bacterial infections like Neisseria meningitidis, Streptococcus pneumoniaee and Haemophilus influenzae type b. These patients are more likely to have severe sepsis, and overwhelming post-splenectomy infection (OPSI). OPSI can present with flu-like illness at onset, and rapidly progress to septic shock and death, and therefore needs prompt institution of antibiotics covering for both gram-positive and gram-negative organisms under close observation in high dependency or intensive care units.

Recommendation

If an asplenic or hyposplenic patient is suspected to have sepsis we recommend administration of IV ceftriaxone before transferring the patient to a higher center (2A).

We recommend that all patients with Overwhelming Post-Splenectomy Infection (OPSI) be treated in the ICU (UPP).

We recommend empiric antibiotic therapy for asplenic patients with a combination of ceftriaxone and vancomycin (1A).

In case of allergy to β-lactams, we recommend vancomycin with aztreonam or fluoroquinolones in adults. Do not delay administration of antibiotics, be prepared to treat reaction (UPP).

We recommend to add clarithromycin or erythromycin in case of respiratory symptoms (3A).

We recommend empiric therapy with IV Cefotaxime + vancomycin+ ampicillin, if the patient age <2 months (3A).

All febrile asplenic patients should be screened for malaria with peripheral smears. Start artesunate based antimalarial therapy, if the history is suggestive of Malaria (UPP).

If gram staining of peripheral blood smear shows gram-negative bacilli, we recommend addition of antipseudomonal coverage to the therapy (3A).

We recommend that urine be checked for urinary antigen for streptococcus pneumoniae (2A).

We suggest RT-PCR test for simultaneous identification of 3 main encapsulated bacteria (Str pneumoniae, H. influenzae type B and N. meningitidis) (3B).

We recommend that all asplenic patients should receive immunization against encapsulated bacteria (S. pneumoniaee, H. influenzae, and N. meningitidis) (1A).

Immunization against seasonal flu is recommended for patients over 6 months of age (1A).

Vaccination programs should be started no sooner than 14 days after splenectomy (1A).

If the patient is discharged before 15 days after splenectomy or angioembolization, where the risk to miss vaccination is deemed high, we suggest that patient be vaccinate before discharge (1B).

Antibiotic prophylaxis is indicated in patients for 1–2 years after splenectomy and lifelong for patient had an episode of overwhelming infection or immunocompromised (2B).

We recommend self-administration of one dose of, in stock “pill in pocket”, prescribed antibiotics in the event of any sudden onset of unexplained fever, malaise, chills or other constitutional symptoms, when medical consultation not readily accessible within 2 hours (2A).

We suggest that any patient with sepsis having risk factor for hyposplenia, the peripheral smear should be checked for Howell-Jolly bodies (2B).

We recommend formulation of Spleen registry (UPP).

Patients with Primary Immune Deficiency in the ICU

Primary immunodeficiencies is group of disorders that affect the development, function or both of the immune system. There are more than 300 disorders defined till date. The prevalence is approximately 1 in 10,000 live births.692,908,909 Any patient admitted to ICU could be a potential PID patient.

Diagnosis of PID

Diagnosis is often delayed since signs and symptoms such as bronchitis, pneumoniae, sinusitis, diarrhea are considered infection related without suspecting immunological process.

The absence of adenoid tissue in the nasopharynx or absence of the thymus should prompt suspicion of primary immunodeficiency (antibody or cellular/combined).

The presence of lymphocytopenia on complete blood count suggests a T-cell disorder, whereas a finding of neutropenia suggests a phagocytic disorder. Abnormal serum immunoglobulin levels suggest a B-cell disorder. Abnormalities on assay of the classic or alternative complement pathways suggest a complement disorder.910 Abnormal values of lymphocyte count should also raise suspicion of PID (Table 13).

Table 13 Absolute Lymphocyte count (ALC) nomoGram

Age	Lymphocytes (per mm3)	Range (per mm3)	
Neonatal	4.8	0.7–7.3	
1 month– 2 month	6.7	3.5–13.1	
2–5 months	5.9	3.7–9.6	
5–9 months	6.0	3.8–9.9	
9–15 months	5.5	2.6–10.4	
15–24 months	5.6	2.7–11.9	
2–5 years	3.3	1.7–6.9	
5–10 years	2.8	1.1–5.9	
10–16 years	2.2	1.0–5.3	
>16 years	1.8	1.0–2.8	
Any value below the reference range should raise suspicion of PID

Patients with PID commonly present with recurrent infections and invasive infections, atypical pathogens, partial response to antibiotics, failure to thrive, chronic diarrhea, fungal infections, unexplained skin rash and a family history. Infections such as Pneumoniae and bronchiolitis, acute gastroenteritis, otitis media, and bacteremia in patients with antibody, combined, and cellular deficiencies. Whereas viral infections meningitis, osteomyelitis, gastroenteritis is commonly seen in CVID. Children tend to have bacterial or fungal infections with unusual organisms, or unusually severe and recurrent infections with common organisms. A family history of primary immunodeficiency disease is the strongest predictor of a person having this type of disease.911

The typical presentations of various PIDs by age of presentation and spectrum of infections.

Combined T-cell and B-cell immunodeficiency (Presents early in life)

a) Bacteria: Campylobacter Listeria, Pyogenic bacteria, Mycobacteria

b) Viruses: RSV, EBV, Parainfluenza Virus

c) Fungi: Candida, Aspergillus

d) Protozoa: Pneumocystis jirovecii, Toxoplasma Gondi, Cryptosporidium parvum

B cell immunodeficiency (Presents when weaning is started and breast feeding stops)

Bacteria: S. pneumoniae, H. influenza, M. catarrhalis, P. aeruginosa, S. aureus, N. meningitidis, M. pneumoniae

Viruses: Enteroviruses

Protozoa: Giardia lamblia

Congenital defects of phagocyte number and function (Can present at any age based on severity of the defect)

Bacteria: S. aureus, P. aeruginosa, Nocardia, S. typhi

Fungi: Candida, Aspergillus

Mycobacteria: Nontuberculous including BCG

Complement deficiencies (Can present as early as within 6 months of life)

Bacteria: Streptococci, H. influenza, Neisseria,

Viruses: CMV, HSV

The European Society for Immunodeficiency (ESID) clinical guidelines912 proposed the grouping of immunodeficiency, syndromes and likely infections as follows (Table 14).

Table 14 The types of clinical patterns of presentation and infections in PIDs

Immunodeficiency	Infections	Example	
Antibody deficiency
Phagocyte deficiency
Complement deficiency	Bronchiectasis, rhino sinusitis	HIV, Wiskott-Aldrich Syndrome	
T-lymphocyte deficiency	Chronic diarrhea, Candida/PCP, Mycobacteria	SCID/HIV	
Neutrophil defects	Recurrent pyogenic infections, Invasive Aspergillus, Burkholderia	Chronic granulomatous disease (CGD)	
Defects of innate immunity(TLR3)
T-lymphocyte deficiency	Invasive pneumococcal disease
Herpes Simplex
Encephalitis	SCID/HIV
Wiskott-Aldrich Syndrome	
T-lymphocyte/macrophage deficiency	Meningococci, encapsulated bacteria or Candida/Mycobacteria		
Common variable
immunodeficiency (CVID)	Autoimmune or chronic
inflammatory disease	Hemophagocytic
lymphohistiocytosis (HLH)	
In ICU setting in patients with PID; following organisms are likely to cause infections

B cell deficiency

a) Pneumococcus

b) H. influenza

c) Staph Aureus

d) Giardia Lamblia

e) Viruses Enterovirus/echovirus

T cell deficiency

a) Mycobacteria

b) Viruses- CMV/EBV/HSV/RSV/VZ/Parainfluenza

c) Fungi- P. carini, Histoplasma, cryptosporidium, Toxoplasma

Phagocytic disorder

a) Gram-negative: E. coli/Klebsiella/B. cepacia/Pseudomonas/Serratia

b) Gram-positive: Staph/Nocardia/Listeria

c) Fungus: Aspergillus and Candida

Defects in the complement system: Streptococcus pneumoniae and Neisseria

Mendelian susceptibility to mycobacterium (MSMD): Mycobacteria, salmonella typhi and nontyphii, Listeria, viral and other intracellular pathogens (e.g., Histoplasma, leishmania)913–918

The data regarding the use of Antibiotics in Immunodeficiency states is scarce. The experts recommend using antibiotic as per organism isolated or expected. Generally the management depends upon the type of PID.

Therapy includes:

IV Immunoglobulin (IVIG) infusion mainly for B cell deficiency919–921

Antibiotics as per suspected source of infection and suspected organism

Rituximab in PID with Epstein Barr virus reactivation

Stem cell transplant is the most curative option for majority of the PID. Paradoxically Rituximab treatment has known to aggravate primary immunodeficiency or hypogammaglobulinemia in certain group of patients and appropriate care has to be taken in these patients. In PID such as X-linked Lymphoproliferative disorder, Rituximab can be given once in 4 weeks to decrease the EBV Viral load.692,908,910

Evidence Statement

A diagnosis of primary immunodeficiency should be considered in patients with serious infections. Significant family history, hematologic abnormalities like neutropenia, lymphopenia, recurrent infections, or infections with uncommon organisms can lead to evaluation for primary immunodeficiency. Recurrent sinopulmonary infections are seen with humoral immunodeficiencies. Recurrent infections with organisms like tuberculosis or endemic fungi should lead to evaluation for cell mediated immunodeficiency. Microbiologic diagnosis is important in patients with suspected immunodeficiency due to higher incidence of co-infections and drug resistant infections. In patients with primary immunodeficiency with serious infections, empiric coverage for causative organisms, including viruses and invasive fungal infections is practiced. Treatment for underlying immunodeficiency (e.g., intravenous immunoglobulin therapy) and comorbid autoimmune conditions improves outcomes.

Recommendations

PID should be suspected when the following history/symptoms or signs are present (UPP):

– Family history of sibling death.

– Four or more ear infections within 1 year.

– Two or more serious sinus infections or pneumoniaes within 1 year.

– Two or more months on antibiotics with little effect.

– Two or more deep seated infections including septicemia.

– Persistent thrush in mouth or fungal infection on skin.

– Infections in multiple anatomic locations.

– Increasing frequency and severity of infections with age.

– Recurrent serious infections with common pathogens.

– Serious infections with unusual pathogens.

We recommend that when PID is suspected, HIV infection should also be considered, and testing should be performed for HIV (UPP).

We recommend that patient should be investigated for PID when: (3A)

– In neonates, Absolute Lymphocyte count (ALC) of <2000/mm3 in cord blood or in an infant an ALC of <4000/mm3.

– Severe hypogammaglobulinemia with IgG <1 50mg/dL.

– Absolute Lymphocyte count <4000/mm3 (In non-chemotherapy setting).

– Unusual organism picked up on microbiology.

– Unexplained neutropenia.

We recommend that Initial laboratory screening should include a complete blood count with differential counts (including Absolute Lymphocyte Count, Absolute Neutrophil Count, Absolute Monocyte Count) and measurement of serum immunoglobulin and complement levels (UPP).

We recommend Severe Combined Immune deficiency (SCID) be considered as a pediatric emergency and attention be paid to Absolute Lymphocyte Count, at all time in ICU. If the Absolute Lymphocyte Count is less than normal for the age, we recommend to take immunology reference, use irradiated blood products, and avoid live vaccines till diagnosis is confirmed or ruled out (UPP).

We recommend that patient be investigated for Combined Variable Immuno-deficiency (CVID) when patient has any of the following (UPP):

– Recurrent bacterial infections.

– Serum IgG, IgM, IgA levels (at least two of the three) with a marked decrease (at least 2 SD below the mean for age).

– Onset of immunodeficiency at more than 2 years of age.

– Absence of isohemagglutinins and or poor response to vaccines.

We recommend that immunology consult be obtained for these patients and the patient be investigated to diagnose specific form of immunodeficiency (UPP)

– Lymphocyte subpopulations by Flow cytometry (CD3, CD4, CD8, CD19, CD20, CD16 & CD56).

– Naive T cells, Memory B cells, Memory T cells

– T-cell response to mitogens.

– Nitroblue Tetrazolium-NBT test

– Complement levels

– Bone Marrow and Genetic tests

We recommend for all critically ill patients with suspicion of PID the empirical antimicrobial treatment with IV Carbapenems with IV Vancomycin/Teicoplanin for broad-spectrum coverage.(UPP, A). Voriconazole is the preferred antifungal in case of proven, possible or probable invasive fungal infection with aspergillus (IA).

In critically ill patients diagnosed with Combined B and T cell deficiency the antimicrobial drug of choice is IV Carbapenems with Vancomycin/Teicoplanin and Trimethoprim-Sulfamethoxazole (UPP).

In critically ill patients diagnosed with Combined B and T cell deficiency with suspicion of viral infections, we recommend (UPP):

– IV Acyclovir if herpes group of infection is suspected

– Oral oseltamivir if influenza virus is suspected

– IV Ganciclovir if CMV is suspected radiologically or by laboratory tests

In critically ill patients diagnosed with B cell deficiency, based on the organisms expected (Capsulated), we recommend IV ceftriaxone with IV Vancomycin/Teicoplanin (UPP).

We recommend IV Immunoglobulin (IVIg) at dose of 1 gm/kg weekly in cases of severe infections especially ECHO/Enterovirus / Polio virus induced encephalitis (UPP).

In critically ill patients diagnosed with Phagocyte disorder we recommend.

antimicrobial drug of choice to be IV Carbapenems with IV Vancomycin/Teicoplanin and Voriconazole (UPP).

We Recommend the use of Granulocyte colony stimulating factor (GCSF) in patients of congenital Neutropenia (UPP).

In critically ill patients diagnosed with complement deficiency the antimicrobial drug of choice is IV Cephalosporin (UPP).

We recommend appropriate cultures, and PCRs; for organisms likely to cause infections pertinent to the conditions they are suffering from (UPP).

Attempt should be made to identify the microorganisms directly or on PCRs as serological tests in infectious diseases could give false-negative results if there is an antibody defect (UPP).

We recommend the use of Multiplex PCR to help diagnose infections (UPP).

We recommend intravenous Immunoglobulin for treatment of all antibody deficiency diseases, at doses of 400 mg/kg/doses every 4 weekly. We recommend 2 gm/kg single dose (Severe Infections) or 1 gm/kg weekly till infection subsides (UPP).

We recommend to maintain serum IgG trough levels above 500mg/dl and above 700 mg/dL in bronchiectasis (3A).

We recommend thoracic computed axial tomography, lung function tests with spirometry and DLCO every 6 months after discharge (UPP).

We recommend hematopoietic stem cell transplantation in cellular and macrophage immunodeficiency (UPP).

We recommend monoclonal antibodies such as rituximab only in autoimmune complications related to CVID (UPP).

We recommend Rituximab be given in PID complicated with EBV viremia (UPP).

What Should be the Approach to Vaccinations and Antimicrobial Prophylaxis at Discharge for Patients with Primary Immunodeficiency Requiring Intensive Care?

Vaccine recommendations should be earmarked only for patients certain PID. Live vaccines are avoided in patients with severe B- and T-cell dysfunction due to the risk of dissemination and the futility of immune response. All vaccines are safe and effective in the patients with complement deficiency(susceptibility to encapsulated organisms).922–924

Evidence Statement

Live vaccines are contraindicated in SCID whereas all vaccines are safe and effective in complement deficiency. Antifungal prophylaxis and PCP prophylaxis are important to prevent invasive life-threatening infections in patients with PID.

Recommendations

All forms of live vaccines, viral and bacterial, are contraindicated in patients with SCID (UPP).

We recommend vaccination for diagnosed patients with complement deficiency at time of discharge (UPP).

We recommend avoiding BCG vaccination in Chronic Granulomatous Disease /MSMD patient (UPP).

We recommend antifungal and anti PCP prophylaxis for all patients diagnosed with PID shifted from ICU (UPP).

PID patients with chronic granulomatous disease should be treated with Itraconazole (IA) and Trimethoprim-Sulfamethoxazole (2A).

PCP prophylaxis should be given to all patients with Combined B and T or T cell deficiency with drug of choice being Trimethoprim-Sulfamethoxazole (1A).

We recommend antifungal prophylaxis in all patients with T cell defects (3A).

Orcid

Gopi C Khilnani https://orcid.org/0000-0003-0820-0624

Pawan Tiwari https://orcid.org/0000-0002-5136-4221

Saurabh Mittal https://orcid.org/0000-0002-7979-6405

Atul P Kulkarni https://orcid.org/0000-0002-5172-7619

Dhruva Chaudhry https://orcid.org/0000-0001-5138-2908

Kapil G Zirpe https://orcid.org/0000-0002-8140-727X

Subhash K Todi https://orcid.org/0000-0003-2306-6080

Anant Mohan https://orcid.org/0000-0002-2383-9437

Ashit Hegde https://orcid.org/0000-0003-4342-122X

Bharat G Jagiasi https://orcid.org/0000-0002-3068-1201

Bhuvana Krishna https://orcid.org/0000-0002-0003-6797

Camila Rodrigues https://orcid.org/0000-0002-6105-6660

Deepak Govil https://orcid.org/0000-0002-4624-1614

Divya Pal https://orcid.org/0000-0002-1607-3816

Jigeeshu V Divatia https://orcid.org/0000-0001-7384-4886

Manju Sengar https://orcid.org/0000-0002-3509-5682

Mansi Gupta https://orcid.org/0000-0001-9506-1911

Mukesh Desai https://orcid.org/0000-0002-9253-7934

Narendra Rungta https://orcid.org/0009-0009-9836-9466

Parikshit S Prayag https://orcid.org/0000-0003-2102-7627

Pradip k bhattacharya https://orcid.org/0000-0002-0219-385X

Srinivas Samavedam https://orcid.org/0000-0001-6737-8663

Subhal B Dixit https://orcid.org/0000-0002-1441-0807

Sudivya Sharma https://orcid.org/0000-0003-0608-8819

Susruta Bandopadhyay https://orcid.org/0000-0001-5732-5461

Venkat Raman Kola https://orcid.org/0000-0002-6971-1236

Vikas Deswal https://orcid.org/0000-0002-5758-2262

Yatin Mehta https://orcid.org/0000-0002-0888-4774

Yogendra P Singh https://orcid.org/0000-0002-5026-9978

Sheila N Myatra https://orcid.org/0000-0001-6761-163X

Source of support: Nil

Conflict of interest: None
==== Refs
References

1. Khilnani G Zirpe K Hadda V Mehta Y Madan K Kulkarni A et al. Guidelines for antibiotic prescription in intensive care unit Indian J Crit Care Med Peer-Rev Off Publ Indian Soc Crit Care Med 2019 23 Suppl 1 S1 S63 10.5005/jp-journals-10071-23101
2. Kulkarni AP Chinnaswamy G Desai M Indian antimicrobial prescription guidelines in critically ill immunocompromised patients Indian J Crit Care Med 2018 23 S1 64 96 10.5005/jp-journals-10071-23102
3. Álvarez-Lerma F Grau S Management of antimicrobial use in the intensive care unit Drugs 2012 72 4 447 470 10.2165/11599520-000000000-00000 22303918
4. Abdul-Aziz MH Sulaiman H Mat-Nor MB Rai V Wong KK Hasan MS et al. Beta-lactam infusion in severe sepsis (BLISS): A prospective, two-center, open-labelled randomized controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis Intensive Care Med 2016 42 10 1535 1545 10.1007/s00134-015-4188-0 26754759
5. Dulhunty JM Roberts JA Davis JS Webb SAR Bellomo R Gomersall C et al. A multicenter randomized trial of continuous versus intermittent β-lactam infusion in severe sepsis Am J Respir Crit Care Med 2015 192 11 1298 1305 10.1164/rccm.201505-0857OC 26200166
6. Roberts JA Abdul-Aziz MH Davis JS Dulhunty JM Cotta MO Myburgh J et al. Continuous versus intermittent β-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials Am J Respir Crit Care Med 2016 194 6 681 691 10.1164/rccm.201601-0024OC 26974879
7. Vardakas KZ Voulgaris GL Maliaros A Samonis G Falagas ME Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: A systematic review and meta-analysis of randomized trials Lancet Infect Dis 2018 18 1 108 120 10.1016/S1473-3099(17)30615-1 29102324
8. Hao JJ Chen H Zhou JX Continuous versus intermittent infusion of vancomycin in adult patients: A systematic review and meta-analysis Int J Antimicrob Agents 2016 47 1 28 35 10.1016/j.ijantimicag.2015.10.019 26655032
9. [Internet] Severe acute respiratory infections treatment center [cited 2024 Feb 12]. Available from: https://www.who.int/publications-detail-redirect/10665-331603
10. Huang G Guo F Loss of life expectancy due to respiratory infectious diseases: Findings from the global burden of disease study in 195 countries and territories 1990–2017 J Popul Res Canberra ACT 2022 39 1 1 43 10.1007/s12546-021-09271-3
11. Metlay JP Waterer GW Long AC Anzueto A Brozek J Crothers K et al. Diagnosis and treatment of adults with community-acquired pneumoniae. An official clinical practice guideline of the american thoracic society and infectious diseases society of america Am J Respir Crit Care Med American Thoracic Society – AJRCCM 2019 200 7 e45 e67 10.1164/rccm.201908-1581ST
12. Calderaro A Buttrini M Farina B Montecchini S De Conto F Chezzi C Respiratory tract infections and laboratory diagnostic methods: A review with a focus on syndromic panel-based assays Microorganisms 2022 10 9 1856 10.3390/microorganisms10091856 36144458
13. Bartlow AW Stromberg ZR Gleasner CD Hu B Davenport KW Jakhar S et al. Comparing variability in diagnosis of upper respiratory tract infections in patients using syndromic, next generation sequencing, and PCR-based methods PLOS Glob Public Health. Public Library of Science 2022 2 7 e0000811 10.1371/journal.pgph.0000811
14. Stojanovic Z Gonçalves-Carvalho F Marín A Abad Capa J Domínguez J Latorre I et al. Advances in diagnostic tools for respiratory tract infections: From tuberculosis to COVID-19 – changing paradigms? ERJ Open Res 2022 8 3 00113 2022 10.1183/23120541.00113-2022 36101788
15. Murdoch DR Werno AM Jennings LC Microbiological diagnosis of respiratory illness KendigsDisord Respir Tract Child 2019 396 405.e3 10.1016/B978-0-323-44887-1.00022-5
16. Hanson KE Azar MM Banerjee R Chou A Colgrove RC Ginocchio CC et al. Molecular testing for acute respiratory tract infections: Clinical and diagnostic recommendations from the IDSA's diagnostics committee Clin Infect Dis Off Publ Infect Dis Soc Am 2020 71 10 2744 2751 10.1093/cid/ciaa508
17. Nelson PP Rath BA Fragkou PC Antalis E Tsiodras S Skevaki C Current and future point-of-care tests for emerging and new respiratory viruses and future perspectives Front Cell Infect Microbiol 2020 10 181 10.3389/fcimb.2020.00181 32411619
18. Cheng GS Crothers K Aliberti S Bergeron A Boeckh M Chien JW et al. Immunocompromised host pneumoniae: Definitions and diagnostic criteria: an official american thoracic society workshop report Ann Am Thorac Soc 20 3 341 353 10.1513/AnnalsATS.202212-1019ST
19. Fang W Wu J Cheng M Zhu X Du M Chen C et al. Diagnosis of invasive fungal infections: Challenges and recent developments J Biomed Sci 2023 30 1 42 10.1186/s12929-023-00926-2 37337179
20. Stellrecht KA Molecular testing for respiratory viruses Diagn Mol Pathol 2017 123 137 10.1016/B978-0-12-800886-7.00011-X
21. Greninger AL The challenge of diagnostic metagenomics Expert Rev Mol Diagn 2018 18 7 605 615 10.1080/14737159.2018.1487292 29898605
22. Wabe N Li L Lindeman R Yimsung R Dahm MR McLennan S et al. Impact of rapid molecular diagnostic testing of respiratory viruses on outcomes of adults hospitalized with respiratory illness: A multicenter quasi-experimental study J Clin Microbiol 2019 57 4 e01727 18 10.1128/JCM.01727-18 30541934
23. Campbell AP Guthrie KA Englund JA Farney RM Minerich EL Kuypers J et al. Clinical outcomes associated with respiratory virus detection before allogeneic hematopoietic stem cell transplant Clin Infect Dis Off Publ Infect Dis Soc Am 2015 61 2 192 202 10.1093/cid/civ272
24. Dignan FL Clark A Aitken C Gilleece M Jayakar V Krishnamurthy P et al. BCSH/BSBMT/UK clinical virology network guideline: Diagnosis and management of common respiratory viral infections in patients undergoing treatment for hematological malignancies or stem cell transplantation Br J Haematol 2016 173 3 380 393 10.1111/bjh.14027 27060988
25. Manuel O Estabrook M American Society of Transplantation Infectious Diseases Community of Practice. RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice Clin Transplant 2019 33 9 e13511 10.1111/ctr.13511 30817023
26. Das S Dunbar S Tang YW Laboratory diagnosis of respiratory tract infections in children - The state of the art Front Microbiol 2018 9 2478 10.3389/fmicb.2018.02478 30405553
27. Vos LM Bruning AHL Reitsma JB Schuurman R Riezebos-Brilman A Hoepelman AIM et al. Rapid molecular tests for influenza, respiratory syncytial virus, and other respiratory viruses: A systematic review of diagnostic accuracy and clinical impact studies Clin Infect Dis Off Publ Infect Dis Soc Am 2019 69 7 1243 1253 10.1093/cid/ciz056
28. Ramanan P Bryson AL Binnicker MJ Pritt BS Patel R Syndromic panel-based testing in clinical microbiology Clin Microbiol Rev 2017 31 1 e00024 17 10.1128/CMR.00024-17 29142077
29. Azar MM Landry ML Detection of influenza A and B viruses and respiratory syncytial virus by use of clinical laboratory improvement amendments of 1988 (CLIA)-Waived point-of-care assays: A paradigm shift to molecular tests J Clin Microbiol 2018 56 7 e00367 18 10.1128/JCM.00367-18 29695519
30. Jullien S Fitzgerald F Keddie S Baerenbold O Bassat Q Bradley J et al. Diagnostic accuracy of multiplex respiratory pathogen panels for influenza or respiratory syncytial virus infections: Systematic review and meta-analysis BMC Infect Dis 2022 22 1 785 10.1186/s12879-022-07766-9 36229786
31. Gadsby NJ Russell CD McHugh MP Mark H Conway Morris A Laurenson IF et al. Comprehensive molecular testing for respiratory pathogens in community-acquired pneumoniae Clin Infect Dis Off Publ Infect Dis Soc Am 2016 62 7 817 823 10.1093/cid/civ1214
32. Lee SH Ruan SY Pan SC Lee TF Chien JY Hsueh PR Performance of a multiplex PCR pneumoniae panel for the identification of respiratory pathogens and the main determinants of resistance from the lower respiratory tract specimens of adult patients in intensive care units J Microbiol Immunol Infect Wei Mian Yu Gan Ran Za Zhi 2019 52 6 920 928 10.1016/j.jmii.2019.10.009 31806539
33. BioFire Diagnostics [Internet] The BioFire® FilmArray® Pneumoniae Panel [cited 2024 Feb 12]. Available from: https://www.biofiredx.com/products/the-filmarray-panels/filmarray-pneumoniae/
34. Skevaki CL Papadopoulos NG Tsakris A Johnston SL Microbiologic diagnosis of respiratory illness Kendig ChernicksDisord Respir Tract Child 2012 399 423 10.1016/B978-1-4377-1984-0.00024-3
35. Cassidy H Van Genne M Lizarazo-Forero E Gard L Niesters HGM A discussion of syndromic molecular testing for clinical care J Antimicrob Chemother 2021 76 Supplement_3 iii58 66 10.1093/jac/dkab243 34555161
36. Dien Bard J McElvania E Panels and syndromic testing in clinical microbiology Clin Lab Med 2020 40 4 393 420 10.1016/j.cll.2020.08.001 33121611
37. Kelly BT Pennington KM Limper AH Advances in the diagnosis of fungal pneumoniaes Expert Rev Respir Med 2020 14 7 703 714 10.1080/17476348.2020.1753506 32290725
38. Richardson M Page I Role of serological tests in the diagnosis of mold infections Curr Fungal Infect Rep 2018 12 3 127 136 10.1007/s12281-018-0321-1 30294405
39. Haydour Q Hage CA Carmona EM Epelbaum O Evans SE Gabe LM et al. Diagnosis of fungal infections. A systematic review and meta-analysis supporting American Thoracic Society Practice Guideline Ann Am Thorac Soc 2019 16 9 1179 1188 10.1513/AnnalsATS.201811-766OC 31219341
40. Brendish NJ Malachira AK Armstrong L Houghton R Aitken S Nyimbili E et al. Routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (ResPOC): A pragmatic, open-label, randomized controlled trial Lancet Respir Med 2017 5 5 401 411 10.1016/S2213-2600(17)30120-0 28392237
41. Rappo U Schuetz AN Jenkins SG Calfee DP Walsh TJ Wells MT et al. Impact of early detection of respiratory viruses by multiplex pcr assay on clinical outcomes in adult patients J Clin Microbiol 2016 54 8 2096 2103 10.1128/JCM.00549-16 27225406
42. Green DA Hitoaliaj L Kotansky B Campbell SM Peaper DR Clinical utility of on-demand multiplex respiratory pathogen testing among adult outpatients J Clin Microbiol 2016 54 12 2950 2955 10.1128/JCM.01579-16 27654334
43. Kitagawa K Shigemura K Onuma K Nishida M Fujiwara M Kobayashi S et al. Improved bacterial identification directly from urine samples with matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry J Clin Lab Anal 2017 32 3 e22301 10.1002/jcla.22301 28737838
44. Huang B Zhang L Zhang W Liao K Zhang S Zhang Z et al. Direct detection and identification of bacterial pathogens from urine with optimized specimen processing and enhanced testing algorithm J Clin Microbiol 2017 55 5 1488 1495 10.1128/JCM.02549-16 28249997
45. Lehmann LE Hauser S Malinka T Klaschik S Weber SU Schewe JC et al. Rapid qualitative urinary tract infection pathogen identification by SeptiFast® Real-Time PCR PLOS ONE. Public Library of Science 2011 6 2 e17146 10.1371/journal.pone.0017146
46. van der Zee A Roorda L Bosman G Ossewaarde JM Molecular Diagnosis of urinary tract infections by semi-quantitative detection of uropathogens in a routine clinical hospital setting PloS One 2016 11 3 e0150755 10.1371/journal.pone.0150755 26954694
47. Wojno KJ Baunoch D Luke N Opel M Korman H Kelly C et al. Multiplex PCR based urinary tract infection (UTI) analysis compared to traditional urine culture in identifying significant pathogens in symptomatic patients Urology 2020 136 119 126 10.1016/j.urology.2019.10.018 31715272
48. Robledo XG Arcila KVO Riascos SHM García-Perdomo HA Accuracy of molecular diagnostic techniques in patients with a confirmed urine culture: A systematic review and meta-analysis Can Urol Assoc J J Assoc Urol Can 2022 16 9 E484 E489 10.5489/cuaj.7677
49. Sabat AJ van Zanten E Akkerboom V Wisselink G van Slochteren K de Boer RF et al. Targeted next-generation sequencing of the 16S-23S rRNA region for culture-independent bacterial identification - increased discrimination of closely related species Sci Rep Nature Publishing Group 2017 7 1 3434 10.1038/s41598-017-03458-6
50. Szlachta-McGinn A Douglass KM Chung UYR Jackson NJ Nickel JC Ackerman AL Molecular diagnostic methods versus conventional urine culture for diagnosis and treatment of urinary tract infection: A systematic review and meta-analysis EurUrol Open Sci 2022 44 113 124 10.1016/j.euros.2022.08.009
51. Malik YS Verma AK Kumar N Touil N Karthik K Tiwari R et al. Advances in diagnostic approaches for viral etiologies of diarrhea: From the lab to the field Front Microbiol 2019 10 1957 10.3389/fmicb.2019.01957 31608017
52. Iker BC Bright KR Pepper IL Gerba CP Kitajima M Evaluation of commercial kits for the extraction and purification of viral nucleic acids from environmental and fecal samples J Virol Methods 2013 191 1 24 30 10.1016/j.jviromet.2013.03.011 23578704
53. Wongboot W Okada K Chantaroj S Kamjumphol W Hamada S Simultaneous detection and quantification of 19 diarrhea-related pathogens with a quantitative real-time PCR panel assay J Microbiol Methods 2018 151 76 82 10.1016/j.mimet.2018.06.006 29928913
54. Brendish NJ Beard KR Malachira AK Tanner AR Sanga-Nyirongo L Gwiggner M et al. Clinical impact of syndromic molecular point-of-care testing for gastrointestinal pathogens in adults hospitalized with suspected gastroenteritis (GastroPOC): A pragmatic, open-label, randomized controlled trial Lancet Infect Dis Elsevier 2023 23 8 945 55 10.1016/S1473-3099(23)00066-X
55. Meltzer AC Newton S Lange J Hall NC Vargas NM Huang Y et al. A randomized control trial of a multiplex gastrointestinal PCR panel versus usual testing to assess antibiotics use for patients with infectious diarrhea in the emergency department J Am Coll Emerg Physicians Open 2022 3 1 e12616 10.1002/emp2.12616 35072157
56. Gupta D Agarwal R Aggarwal AN Singh N Mishra N Khilnani GC et al. Guidelines for diagnosis and management of community-and hospital-acquired pneumoniae in adults: Joint ICS/NCCP(I) recommendations Lung India 2012 29 6 27 10.4103/0970-2113.99248
57. Lim WS Baudouin SV George RC Hill AT Jamieson C Jeune IL et al. BTS guidelines for the management of community-acquired pneumoniae in adults: update 2009 Thorax 2009 64 Suppl 3 iii1 iii55 10.1136/thx.2009.121434 19783532
58. Eccles S Pincus C Higgins B Woodhead M; Guideline Development Group Diagnosis and management of community and hospital-acquired pneumoniae in adults: Summary of NICE guidance BMJ 2014 349 g6722 10.1136/bmj.g6722 25471702
59. Burk M El-Kersh K Saad M Wiemken T Ramirez J Cavallazzi R Viral infection in community-acquired pneumoniae: A systematic review and meta-analysis Eur Respir Rev European Respiratory Society 2016 25 140 178 188 10.1183/16000617.0076-2015
60. Woodhead M Blasi F Ewig S Garau J Huchon G Ieven M et al. Guidelines for the management of adult lower respiratory tract infections - Full version Clin Microbiol Infect 2011 17 E1 E59 10.1111/j.1469-0691.2011.03672.x
61. Jain S Self WH Wunderink RG Fakhran S Balk R Bramley AM et al. Community-acquired pneumoniae requiring hospitalization among U.S. adults N Engl J Med 2015 373 5 415 427 10.1056/NEJMoa1500245 26172429
62. Carugati M Aliberti S Sotgiu G Blasi F Gori A Menendez R et al. Bacterial etiology of community-acquired pneumoniae in immunocompetent hospitalized patients and appropriateness of empirical treatment recommendations: An international point-prevalence study Eur J Clin Microbiol Infect Dis Nature Publishing Group 2020 39 8 1513 10.1007/s10096-020-03870-3
63. Vardakas KZ Matthaiou DK Falagas ME Incidence, characteristics and outcomes of patients with severe community-acquired-MRSA pneumoniae Eur Respir J 2009 34 5 1148 1158 10.1183/09031936.00041009 19541719
64. Gillet Y Issartel B Vanhems P Fournet JC Lina G Bes M et al. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotizing pneumoniae in young immunocompetent patients Lancet Lond Engl 2002 359 9308 753 759 10.1016/S0140-6736(02)07877-7
65. Lobo LJ Reed KD Wunderink RG Expanded clinical presentation of community-acquired methicillin-resistant staphylococcus aureus pneumoniae CHEST 2010 138 1 130 136 10.1378/chest.09-1562 20173050
66. Self WH Wunderink RG Williams DJ Zhu Y Anderson EJ Balk RA et al. Staphylococcus aureus community-acquired pneumoniae: Prevalence, clinical characteristics, and outcomes Clin Infect Dis Off Publ Infect Dis Soc Am 2016 63 3 300 309 10.1093/cid/ciw300
67. Peto L Nadjm B Horby P Ngan TTD van Doorn R VanKinh N et al. The bacterial etiology of adult community-acquired pneumoniae in Asia: A systematic review Trans R Soc Trop Med Hyg 2014 108 6 326 337 10.1093/trstmh/tru058 24781376
68. Vanlalruati RSC Mamta Devi KSH Singh NB Singh NT A study of bacteriological profile (aerobic) and antimicrobial susceptibility of community-acquired pneumoniae cases in the RIMS hospital J Commun Dis 2012 44 1 47 49 24455915 24455915
69. Peto L Nadjm B Horby P Ngan TTD van Doorn R Kinh NV et al. The bacterial etiology of adult community-acquired pneumoniae in Asia: A systematic review Trans R Soc Trop Med Hyg 2014 108 6 326 337 10.1093/trstmh/tru058 24781376
70. Chawla R Kansal S Jain A Jibhkate B Chauhan M Predictors of mortality and length of stay in hospitalized cases of 2009 influenza A (H1N1): Experiences of a tertiary care center Indian J Crit Care Med 2013 17 5 275 10.4103/0972-5229.120318 24339638
71. Krishnappa L Marie M John J Dabwan K Shashidhar P Serological and molecular capsular typing, antibiotic susceptibility of Streptococcus pneumoniaee isolates from invasive and non-invasive infections Acta Microbiol Immunol Hung 2014 61 2 173 179 10.1556/AMicr.61.2014.2.7 24939685
72. Suryam V Bhatti VK Kulkarni A Mahen A Nair V Outbreak control of community-acquired pneumoniae in a large military training institution Med J Armed Forces India 2015 71 1 33 37 10.1016/j.mjafi.2014.09.015 25609861
73. Thomas K Prospective multicenter hospital surveillance of Streptococcus pneumoniaee disease in India The Lancet 1999 353 9160 1216 1221 10.1016/S0140-6736(98)07228-6
74. Thomas K Mukkai Kesavan L Veeraraghavan B Jasmine S Jude J Shubankar M et al. Invasive pneumococcal disease associated with high case fatality in India J Clin Epidemiol 2013 66 1 36 43 10.1016/j.jclinepi.2012.04.006 23177893
75. Chudasama R Patel U Verma P Amin C Savaria D Ninama R et al. Clinico-epidemiological features of the hospitalized patients with 2009 pandemic influenza A (H1N1) virus infection in Saurashtra region, India (September, 2009 to February, 2010) Lung India 2011 28 1 11 10.4103/0970-2113.76294 21654979
76. Menon R Menon U George A Etiology and antimicrobial sensitivity of organisms causing community-acquired pneumoniae: A single hospital study J Fam Med Prim Care 2013 2 3 244 10.4103/2249-4863.120728
77. Song JH Oh WS Kang CI Chung DR Peck KR Ko KS et al. Epidemiology and clinical outcomes of community-acquired pneumoniae in adult patients in Asian countries: A prospective study by the Asian network for surveillance of resistant pathogens Int J Antimicrob Agents 2008 31 2 107 14 10.1016/j.ijantimicag.2007.09.014 18162378
78. Hageman JC Uyeki TM Francis JS Jernigan DB Wheeler JG Bridges CB et al. Severe community-acquired pneumoniae due to Staphylococcus aureus, 2003–2004 influenza season Emerg Infect Dis 2006 12 6 894 899 10.3201/eid1206.051141 16707043
79. Tong SY Kearns AM Community-associated MRSA from the Indian subcontinent Lancet Infect Dis 2013 13 9 734 735 10.1016/S1473-3099(13)70231-7 23969208
80. Khadanga S Thatoi P Behera S Karuna T Changing bacteriological profile and mortality trends in community-acquired pneumoniae J Glob Infect Dis 2014 6 4 186 10.4103/0974-777X.145251 25538458
81. Bansal S Kashyap S Pal LS Goel A Clinical and bacteriological profile of community-acquired pneumoniae in Shimla, Himachal Pradesh Indian J Chest Dis Allied Sci 2004 46 1 17 22 14870864 14870864
82. Naik M Dhobi G Shah B Singh G Bacteriological and clinical profile of Community-acquired pneumoniae in hospitalized patients Lung India 2010 27 2 54 10.4103/0970-2113.63606 20616935
83. Madan R Kairo AK Sharma A Roy S Singh S Singh L et al. Aspiration pneumoniae related deaths in head and neck cancer patients: A retrospective analysis of risk factors from a tertiary care center in North India J Laryngol Otol 2015 129 07 710 714 10.1017/S0022215115001450 26077504
84. Lakshmaiah KC Sirsath NT Subramanyam JR Govind BK Lokanatha D Shenoy AM Aspiration in head and neck cancer patients: A single center experience of clinical profile, bacterial isolates and antibiotic sensitivity pattern Indian J Otolaryngol Head Neck Surg 2013 65 S1 144 149 10.1007/s12070-013-0645-7 24427632
85. Mathai AS Oberoi A Madhavan S Kaur P Acinetobacter infections in a tertiary level intensive care unit in northern India: Epidemiology, clinical profiles and outcomes J Infect Public Health 2012 5 2 145 152 10.1016/j.jiph.2011.12.002 22541261
86. Prasad P Bhat S Clinicomicrobiological study of community-acquired pneumoniae Lung India 2017 34 5 491 492 10.4103/lungindia.lungindia_89_17 28869245
87. Deva A Prasad SR Madappa BP Junjegowda K Bachu RPN Pneumococcal infections at a rural tertiary care hospital: A seven year study on isolation rate, clinical spectrum and antibiogram J Clin Diagn Res JCDR 2014 8 2 50 52 10.7860/JCDR/2014/7243.4005
88. Molander V Elisson C Balaji V Backhaus E John J Vargheese R et al. Invasive pneumococcal infections in Vellore, India: Clinical characteristics and distribution of serotypes BMC Infect Dis 2013 13 1 532 10.1186/1471-2334-13-532 24206667
89. Bharadwaj R Bal AM Joshi SA Kagal A Pol SS Garad G et al. An urban outbreak of leptospirosis in Mumbai, India Jpn J Infect Dis 2002 55 6 194 12606828
90. Yende S van der Poll T Lee M Huang DT Newman AB Kong L et al. The influence of pre-existing diabetes mellitus on the host immune response and outcome of pneumoniae: Analysis of two multicenter cohort studies Thorax 2010 65 10 870 877 10.1136/thx.2010.136317 20861291
91. Para RA Fomda BA Jan RA Shah S Koul PA Microbial etiology in hospitalized North Indian adults with community-acquired pneumoniae Lung India Off Organ Indian Chest Soc 2018 35 2 108 115 10.4103/lungindia.lungindia_288_17
92. Montull B Menéndez R Torres A Reyes S Méndez R Zalacaín R et al. Predictors of severe sepsis among patients hospitalized for community-acquired pneumoniae PLOS ONE Public Library of Science 2016 11 1 e0145929 10.1371/journal.pone.0145929
93. Liu C Bayer A Cosgrove SE Daum RS Fridkin SK Gorwitz RJ et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children Clin Infect Dis Off Publ Infect Dis Soc Am 2011 52 3 e18 e55 10.1093/cid/ciq146
94. Bassetti M Labate L Melchio M Robba C Battaglini D Ball L et al. Current pharmacotherapy for methicillin-resistant Staphylococcus aureus (MRSA) pneumoniae Expert Opin Pharmacother 2022 23 3 361 375 10.1080/14656566.2021.2010706 34882041
95. Brown NM Goodman AL Horner C Jenkins A Brown EM Treatment of methicillin-resistant Staphylococcus aureus (MRSA): Updated guidelines from the UK JAC-Antimicrob Resist 2021 3 1 dlaa114 10.1093/jacamr/dlaa114 34223066
96. Mahjabeen F Saha U Mostafa MN Siddique F Ahsan E Fathma S et al. An update on treatment options for methicillin-resistant staphylococcus aureus (MRSA) bacteremia: A systematic review Cureus 14 11 e31486 10.7759/cureus.31486
97. Timbrook TT McKay L Sutton JD Spivak ES Disproportionality analysis of safety with nafcillin and oxacillin with the fda adverse event reporting system (FAERS) Antimicrob Agents Chemother 2020 64 3 e01818 19 10.1128/AAC.01818-19 31844017
98. Wunderink RG Niederman MS Kollef MH Shorr AF Kunkel MJ Baruch A et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumoniae: A randomized, controlled study Clin Infect Dis Off Publ Infect Dis Soc Am 2012 54 5 621 629 10.1093/cid/cir895
99. Kato H Hagihara M Asai N Shibata Y Koizumi Y Yamagishi Y et al. Meta-analysis of vancomycin versus linezolid in pneumoniae with proven methicillin-resistant Staphylococcus aureus J Glob Antimicrob Resist 2021 24 98 105 10.1016/j.jgar.2020.12.009 33401013
100. Stets R Popescu M Gonong JR Mitha I Nseir W Madej A et al. Omadacycline for community-acquired bacterial pneumoniae N Engl J Med 2019 380 6 517 527 10.1056/NEJMoa1800201 30726692
101. Ramirez JA Tzanis E Curran M Noble R Chitra S Manley A et al. Early clinical response in community-acquired bacterial pneumoniae: From clinical endpoint to clinical practice Clin Infect Dis Off Publ Infect Dis Soc Am 2019 69 Suppl 1 S33 S39 10.1093/cid/ciz397
102. Alexander E Goldberg L Das AF Moran GJ Sandrock C Gasink LB et al. Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumoniae: The leap 2 randomized clinical trial JAMA 2019 322 17 1661 1671 10.1001/jama.2019.15468 31560372
103. File TM Goldberg L Das A Sweeney C Saviski J Gelone SP et al. Efficacy and safety of intravenous-to-oral lefamulin, a pleuromutilin antibiotic, for the treatment of community-acquired bacterial pneumoniae: The phase iii lefamulin evaluation against pneumoniae (leap 1) trial Clin Infect Dis Off Publ Infect Dis Soc Am 2019 69 11 1856 1867 10.1093/cid/ciz090
104. Horcajada JP Salata RA Álvarez-Sala R Nitu FM Lawrence L Quintas M et al. A phase 3 study to compare delafloxacin with moxifloxacin for the treatment of adults with community-acquired bacterial pneumoniae (DEFINE-CABP) Open Forum Infect Dis 2020 7 1 ofz514 10.1093/ofid/ofz514 31988972
105. Saravolatz LD Stein GE Delafloxacin: A New anti-methicillin-resistant staphylococcus aureus fluoroquinolone Clin Infect Dis Off Publ Infect Dis Soc Am 2019 68 6 1058 1062 10.1093/cid/ciy600
106. Webb BJ Dascomb K Stenehjem E Dean N Predicting risk of drug-resistant organisms in pneumoniae: Moving beyond the HCAP model Respir Med 2015 109 1 1 10 10.1016/j.rmed.2014.10.017 25468412
107. Aliberti S Reyes LF Faverio P Sotgiu G Dore S Rodriguez AH et al. Global initiative for meticillin-resistant Staphylococcus aureus pneumoniae (GLIMP): An international, observational cohort study Lancet Infect Dis 2016 16 12 1364 1376 10.1016/S1473-3099(16)30267-5 27593581
108. Restrepo MI Babu BL Reyes LF Chalmers JD Soni NJ Sibila O et al. Burden and risk factors for Pseudomonas aeruginosa community-acquired pneumoniae: A multinational point prevalence study of hospitalized patients Eur Respir J 2018 52 2 1701190 10.1183/13993003.01190-2017 29976651
109. Prina E Ranzani OT Polverino E Cillóniz C Ferrer M Fernandez L et al. Risk factors associated with potentially antibiotic-resistant pathogens in community-acquired pneumoniae Ann Am Thorac Soc 2015 12 2 153 160 10.1513/AnnalsATS.201407-305OC 25521229
110. Sibila O Laserna E Maselli DJ Fernandez JF Mortensen EM Anzueto A et al. Risk factors and antibiotic therapy in P aeruginosa community-acquired pneumoniae. Respirol Carlton Vic 2015 20 4 660 666 10.1111/resp.12506
111. Falguera M Carratalà J Ruiz-Gonzalez A Garcia-Vidal C Gazquez I Dorca J et al. Risk factors and outcome of community-acquired pneumoniae due to gram-negative bacilli Respirol Carlton Vic 2009 14 1 105 111 10.1111/j.1440-1843.2008.01371.x
112. Cilloniz C Martin-Loeches I Garcia-Vidal C San Jose A Torres A Microbial etiology of pneumoniae: Epidemiology, diagnosis and resistance patterns Int J Mol Sci 2016 17 12 10.3390/ijms17122120
113. Khilnani GC Tiwari P Zirpe KG Chaudhry D Govil D Dixit S et al. Guidelines for the use of procalcitonin for rational use of antibiotics Indian J Crit Care Med Peer-Rev Off Publ Indian Soc Crit Care Med 2022 26 Suppl 2 S77 S94 10.5005/jp-journals-10071-24326
114. Huang DT Yealy DM Filbin MR Brown AM Chang C-CH Doi Y et al. Procalcitonin-guided use of antibiotics for lower respiratory tract infection N Engl J Med. Massachusetts Medical Society 2018 379 3 236 249 10.1056/NEJMoa1802670
115. de Jong E van Oers JA Beishuizen A Vos P Vermeijden WJ Haas LE et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: A randomized, controlled, open-label trial Lancet Infect Dis 2016 16 7 819 827 10.1016/S1473-3099(16)00053-0 26947523
116. Self WH Balk RA Grijalva CG Williams DJ Zhu Y Anderson EJ et al. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumoniae Clin Infect Dis Off Publ Infect Dis Soc Am 2017 65 2 183 190 10.1093/cid/cix317
117. Kamat IS Ramachandran V Eswaran H Guffey D Musher DM Procalcitonin to distinguish viral from bacterial pneumoniae: A systematic review and meta-analysis Clin Infect Dis Off Publ Infect Dis Soc Am 2020 70 3 538 542 10.1093/cid/ciz545
118. Schuetz P Wirz Y Sager R Christ-Crain M Stolz D Tamm M et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections Cochrane Database Syst Rev 2017 10 CD007498 10.1002/14651858.CD007498.pub3 29025194
119. Yu KT Wyer PC Evidence behind the 4-hour rule for initiation of antibiotic therapy in community-acquired pneumoniae Ann Emerg Med 2008 51 5 651 662.e2 10.1016/j.annemergmed.2007.10.022 18272253
120. Sterling SA Miller WR Pryor J Puskarich MA Jones AE The impact of timing of antibiotics on outcomes in severe sepsis and septic shock: A systematic review and meta-analysis Crit Care Med 2015 43 9 1907 1915 10.1097/CCM.0000000000001142 26121073
121. Liu VX Fielding-Singh V Greene JD Baker JM Iwashyna TJ Bhattacharya J et al. The timing of early antibiotics and hospital mortality in sepsis Am J Respir Crit Care Med 2017 196 7 856 863 10.1164/rccm.201609-1848OC 28345952
122. Falguera M Ruiz-González A Schoenenberger JA Touzón C Gázquez I Galindo C et al. Prospective, randomized study to compare empirical treatment versus targeted treatment on the basis of the urine antigen results in hospitalized patients with community-acquired pneumoniae Thorax 2010 65 2 101 106 10.1136/thx.2009.118588 19703825
123. Eerden MM van der Vlaspolder F Graaff CS de Groot T Bronsveld W Jansen HM et al. Comparison between pathogen directed antibiotic treatment and empirical broad-spectrum antibiotic treatment in patients with community-acquired pneumoniae: A prospective randomized study Thorax 2005 60 8 672 678 10.1136/thx.2004.030411 16061709
124. Uematsu H Hashimoto H Iwamoto T Horiguchi H Yasunaga H Impact of guideline-concordant microbiological testing on outcomes of pneumoniae Int J Qual Health Care 2014 26 1 100 107 10.1093/intqhc/mzt078
125. Lidman C Burman LG Lagergren Å Örtqvist Å Limited value of routine microbiological diagnostics in patients hospitalized for community-acquired pneumoniae Scand J Infect Dis 2002 34 873 879 10.1080/0036554021000026967 12587618
126. Meehan TP Fine MJ Krumholz HM Scinto JD Galusha DH Mockalis JT et al. Quality of care, process, and outcomes in elderly patients with pneumoniae JAMA 1997 278 23 2080 2084 9403422 9403422
127. Darie AM Khanna N Jahn K Osthoff M Bassetti S Osthoff M et al. Fast multiplex bacterial PCR of bronchoalveolar lavage for antibiotic stewardship in hospitalized patients with pneumoniae at risk of gram-negative bacterial infection (Flagship II): A multicenter, randomized controlled trial Lancet Respir Med. Elsevier 2022 10 9 877 887 10.1016/S2213-2600(22)00086-8
128. Cartuliares MB Rosenvinge FS Mogensen CB Skovsted TA Andersen SL Østergaard C et al. Evaluation of point-of-care multiplex polymerase chain reaction in guiding antibiotic treatment of patients acutely admitted with suspected community-acquired pneumoniae in Denmark: A multicenter randomized controlled trial PLOS Med Public Library of Science 2023 20 11 e1004314 10.1371/journal.pmed.1004314
129. Buchan BW Windham S Balada-Llasat JM Leber A Harrington A Relich R et al. Practical comparison of the biofirefilmarray pneumoniae panel to routine diagnostic methods and potential impact on antimicrobial stewardship in adult hospitalized patients with lower respiratory tract infections J Clin Microbiol American Society for Microbiology 2020 58 7 e00135 20 10.1128/jcm.00135-20
130. Sistani SS Parooie F Diagnostic performance of ultrasonography in patients with pneumoniae: An updated comparative systematic review and meta-analysis J Diagn Med Sonogr SAGE Publications Inc STM 2021 37 4 371 381 10.1177/8756479321992348
131. Alzahrani SA Al-Salamah MA Al-Madani WH Elbarbary MA Systematic review and meta-analysis for the use of ultrasound versus radiology in diagnosing of pneumoniae Crit Ultrasound J 2017 9 6 10.1186/s13089-017-0059-y 28244009
132. Javaudin F Marjanovic N de Carvalho H Gaborit B Le Bastard Q Boucher E et al. Contribution of lung ultrasound in diagnosis of community-acquired pneumoniae in the emergency department: A prospective multicenter study BMJ Open 2021 11 9 e046849 10.1136/bmjopen-2020-046849
133. Claessens YE Debray MP Tubach F Brun AL Rammaert B Hausfater P et al. Early chest computed tomography scan to assist diagnosis and guide treatment decision for suspected community-acquired pneumoniae Am J Respir Crit Care Med 2015 192 8 974 982 10.1164/rccm.201501-0017OC 26168322
134. Prendki V Scheffler M Huttner B Garin N Herrmann F Janssens JP et al. Low-dose computed tomography for the diagnosis of pneumoniae in elderly patients: A prospective, interventional cohort study Eur Respir J 2018 51 5 1702375 10.1183/13993003.02375-2017 29650558
135. Sligl WI Asadi L Eurich DT Tjosvold L Marrie TJ Majumdar SR Macrolides and mortality in critically ill patients with community-acquired pneumoniae: A systematic review and meta-analysis Crit Care Med 2014 42 2 420 432 10.1097/CCM.0b013e3182a66b9b 24158175
136. Adrie C Schwebel C Garrouste-Orgeas M Vignoud L Planquette B Azoulay E et al. Initial use of one or two antibiotics for critically ill patients with community-acquired pneumoniae: Impact on survival and bacterial resistance Crit Care 2013 17 R265 10.1186/cc13095 24200097
137. Gattarello S Borgatta B Solé-Violán J Vallés J Vidaur L Zaragoza R et al. Decrease in mortality in severe community-acquired pneumococcal pneumoniae Chest 2014 146 1 22 31 10.1378/chest.13-1531 24371840
138. Lee JH Kim HJ Kim YH Is β-lactam plus macrolide more effective than β-lactam plus fluoroquinolone among patients with severe community-acquired pneumoniae? A systemic review and meta-analysis J Korean Med Sci 2017 32 1 77 84 10.3346/jkms.2017.32.1.77 27914135
139. Reyes LF Garcia E Ibáñez-Prada ED Serrano-Mayorga CC Fuentes YV Rodríguez A et al. Impact of macrolide treatment on long-term mortality in patients admitted to the ICU due to CAP: A targeted maximum likelihood estimation and survival analysis Crit Care Lond Engl 2023 27 1 212 10.1186/s13054-023-04466-x
140. Chang KC Leung CC Yew WW Lau TY Leung WM Tam CM et al. Newer fluoroquinolones for treating respiratory infection: Do they mask tuberculosis? Eur Respir J 2010 35 3 606 613 10.1183/09031936.00104209 19717477
141. von Baum H Welte T Marre R Suttorp N Ewig S, CAPNETZ study group Community-acquired pneumoniae through Enterobacteriaceae and Pseudomonas aeruginosa: Diagnosis, incidence and predictors Eur Respir J 2010 35 3 598 605 10.1183/09031936.00091809 19679601
142. Arancibia F Bauer TT Ewig S Mensa J Gonzalez J Niederman MS et al. Community-acquired pneumoniae due to gram-negative bacteria and Pseudomonas aeruginosa: Incidence, risk, and prognosis Arch Intern Med 2002 162 16 1849 1858 10.1001/archinte.162.16.1849 12196083
143. Cillóniz C Gabarrús A Ferrer M Puig de la Bellacasa J Rinaudo M Mensa J et al. Community-acquired pneumoniae due to multidrug- and non-multidrug-resistant Pseudomonas aeruginosa Chest 2016 150 2 415 425 10.1016/j.chest.2016.03.042 27060725
144. Rello J Rodriguez A Torres A Roig J Sole-Violan J Garnacho-Montero J et al. Implications of COPD in patients admitted to the intensive care unit by community-acquired pneumoniae Eur Respir J 2006 27 6 1210 1216 10.1183/09031936.06.00139305 16510452
145. Vila-Corcoles A Ochoa-Gondar O Rodriguez-Blanco T Raga-Luria X Gomez-Bertomeu F, EPIVAC Study Group Epidemiology of community-acquired pneumoniae in older adults: A population-based study Respir Med 2009 103 2 309 316 10.1016/j.rmed.2008.08.006 18804355
146. Reynolds D Kollef M The epidemiology and pathogenesis and treatment of Pseudomonas aeruginosa infections: An update Drugs 2021 81 18 2117 2131 10.1007/s40265-021-01635-6 34743315
147. Carballo N De Antonio-Cuscó M Echeverría-Esnal D Luque S Salas E Grau S Community-acquired pneumoniae caused by methicillin-resistant Staphylococcus aureus in critically-ill patients: Systematic review Farm Hosp Organo Of ExpresionCient Soc Espanola Farm Hosp 2017 41 2 187 203 10.7399/fh.2017.41.2.10591
148. Mandell LA Wunderink RG Anzueto A Bartlett JG Campbell GD Dean NC et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumoniae in adults Clin Infect Dis Off Publ Infect Dis Soc Am 2007 44 Suppl 2 S27 S72 10.1086/511159
149. Lorber B Swenson RM Bacteriology of aspiration pneumoniae. A prospective study of community- and hospital-acquired cases Ann Intern Med 1974 81 3 329 331 10.7326/0003-4819-81-3-329 4850729
150. Cesar L Gonzalez C Calia FM Bacteriologic flora of aspiration-induced pulmonary infections Arch Intern Med 1975 135 5 711 714 10.1001/archinte.135.5.711 28705
151. Brook I Frazier EH Aerobic and anaerobic microbiology of empyema A retrospective review in two military hospitals. Chest 1993 103 5 1502 1507 10.1378/chest.103.5.1502 8486033
152. Bartlett JG Anaerobic bacterial infections of the lung and pleural space Clin Infect Dis 1993 16 Supplement_4 S248 S255 10.1093/clinids/16.Supplement_4.S248 8324127
153. Tahon-Castel MM Beerens H Anaerobiosis of bucco-dental origin Rev Stomatoodontol Nord Fr 1965 20 77 13 22 5849460 5849460
154. Gudiol F Manresa F Pallares R Dorca J Rufi G Boada J et al. Clindamycin vs penicillin for anaerobic lung infections. High rate of penicillin failures associated with penicillin-resistant Bacteroides melaninogenicus Arch Intern Med 1990 150 12 2525 2529 1978771 1978771
155. Bartlett JG The role of anaerobic bacteria in lung abscess Clin infect dis 2005 40 7 923 925 10.1086/428586 15824980
156. Mori T Ebe T Takahashi M Isonuma H Ikemoto H Oguri T Lung abscess: Analysis of 66 cases from 1979 to 1991 Intern Med 1993 32 4 278 284 10.2169/internalmedicine.32.278 8358116
157. Wang JL Chen KY Fang CT Hsueh PR Yang PC Chang SC Changing bacteriology of adult community-acquired lung abscess in Taiwan: Klebsiella pneumoniaee versus anaerobes Clin Infect Dis Off Publ Infect Dis Soc Am 2005 40 7 915 922 10.1086/428574
158. Yamasaki K Kawanami T Yatera K Fukuda K Noguchi S Nagata S et al. Significance of anaerobes and oral bacteria in community-acquired pneumoniae PLoS ONE 2013 8 5 10.1371/journal.pone.0063103
159. Griffith DE Aksamit T Brown-Elliott BA Catanzaro A Daley C Gordin F et al. An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases Am J Respir Crit Care Med 2007 175 4 367 416 10.1164/rccm.200604-571ST 17277290
160. Marin-Corral J Pascual-Guardia S Amati F Aliberti S Masclans JR Soni N et al. Aspiration risk factors, microbiology, and empiric antibiotics for patients hospitalized with community-acquired pneumoniae Chest 2021 159 1 58 72 10.1016/j.chest.2020.06.079 32687909
161. Levison ME Mangura CT Lorber B Abrutyn E Pesanti EL Levy RS et al. Clindamycin compared with penicillin for the treatment of anaerobic lung abscess Ann Intern Med 1983 98 4 466 471 10.7326/0003-4819-98-4-466 6838068
162. Kadowaki M Demura Y Mizuno S Uesaka D Ameshima S Miyamori I et al. Reappraisal of clindamycin IV monotherapy for treatment of mild-to-moderate aspiration pneumoniae in elderly patients Chest 2005 127 4 1276 1282 10.1378/chest.127.4.1276 15821205
163. Allewelt M Schüler P Bölcskei PL Mauch H Lode H, Study Group on Aspiration Pneumoniae Ampicillin + sulbactam vs clindamycin +/- cephalosporin for the treatment of aspiration pneumoniae and primary lung abscess Clin Microbiol Infect Off PublEur Soc Clin Microbiol Infect Dis 2004 10 2 163 170 10.1111/j.1469-0691.2004.00774.x
164. Ott SR Allewelt M Lorenz J Reimnitz P Lode H, German Lung Abscess Study Group Moxifloxacin vs ampicillin/sulbactam in aspiration pneumoniae and primary lung abscess Infection 2008 36 1 23 30 10.1007/s15010-007-7043-6 18231720
165. Sun T Sun L Wang R Ren X Sui DJ Pu C et al. Clinical efficacy and safety of moxifloxacin versus levofloxacin plus metronidazole for community-acquired pneumoniae with aspiration factors Chin Med J (Engl) 2014 127 7 1201 1205 24709166 24709166
166. Dunbar LM Wunderink RG Habib MP Smith LG Tennenberg AM Khashab MM et al. High-dose, short-course levofloxacin for community-acquired pneumoniae: A new treatment paradigm Clin Infect Dis Off Publ Infect Dis Soc Am 2003 37 6 752 760 10.1086/377539
167. Choudhury G Mandal P Singanayagam A Akram AR Chalmers JD Hill AT Seven-day antibiotic courses have similar efficacy to prolonged courses in severe community-acquired pneumoniae – A propensity-adjusted analysis Clin Microbiol Infect Off PublEur Soc Clin Microbiol Infect Dis 2011 17 12 1852 1858 10.1111/j.1469-0691.2011.03542.x
168. Wan YD Sun TW Liu ZQ Zhang SG Wang LX Kan QC Efficacy and safety of corticosteroids for community-acquired pneumoniae: A systematic review and meta-analysis Chest 2016 149 1 209 219 10.1378/chest.15-1733 26501852
169. Meduri GU Shih MC Bridges L Martin TJ El-Solh A Seam N et al. Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumoniae Intensive Care Med 2022 48 8 1009 1023 10.1007/s00134-022-06684-3 35723686
170. Saleem N Kulkarni A Snow TAC Ambler G Singer M Arulkumaran N Effect of corticosteroids on mortality and clinical cure in community-acquired pneumoniae: A systematic review, meta-analysis, and meta-regression of randomized control trials CHEST Elsevier 2023 163 3 484 497 10.1016/j.chest.2022.08.2229
171. Dequin PF Meziani F Quenot JP Kamel T Ricard JD Badie J et al. Hydrocortisone in severe community-acquired pneumoniae N Engl J Med Massachusetts Medical Society 2023 388 21 1931 1941 10.1056/NEJMoa2215145
172. Ito A Ishida T Tokumasu H Washio Y Yamazaki A Ito Y et al. Impact of procalcitonin-guided therapy for hospitalized community-acquired pneumoniae on reducing antibiotic consumption and costs in Japan J Infect Chemother Off J Jpn Soc Chemother 2017 23 3 142 147 10.1016/j.jiac.2016.11.006
173. Montassier E Javaudin F Moustafa F Nandjou D Maignan M Hardouin JB et al. Guideline-based clinical assessment versus procalcitonin-guided antibiotic use in pneumoniae: A pragmatic randomized trial Ann Emerg Med 2019 74 4 580 591 10.1016/j.annemergmed.2019.02.025 30982631
174. Kalil AC Metersky ML Klompas M Muscedere J Sweeney DA Palmer LB et al. Management of adults with hospital-acquired and ventilator-associated pneumoniae: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society Clin Infect Dis Off Publ Infect Dis Soc Am 2016 63 5 e61 111 10.1093/cid/ciw353
175. Hayashi Y Morisawa K Klompas M Jones M Bandeshe H Boots R et al. Toward improved surveillance: The impact of ventilator-associated complications on length of stay and antibiotic use in patients in intensive care units Clin Infect Dis Off Publ Infect Dis Soc Am 2013 56 4 471 477 10.1093/cid/cis926
176. Craven DE De Rosa FG Thornton D Nosocomial pneumoniae: Emerging concepts in diagnosis, management, and prophylaxis Curr Opin Crit Care 2002 8 5 421 429 10.1097/00075198-200210000-00009 12357110
177. Torres A Serra-Batlles J Ros E Piera C Puig de la Bellacasa J Cobos A et al. Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: The effect of body position Ann Intern Med 1992 116 7 540 543 10.7326/0003-4819-116-7-540 1543307
178. Melsen WG Rovers MM Groenwold RH Bergmans DC Camus C Bauer TT et al. Attributable mortality of ventilator-associated pneumoniae: A meta-analysis of individual patient data from randomized prevention studies Lancet Infect Dis 2013 13 8 665 671 10.1016/S1473-3099(13)70081-1 23622939
179. Safdar N Dezfulian C Collard HR Saint S Clinical and economic consequences of ventilator-associated pneumoniae: A systematic review Crit Care Med 2005 33 10 2184 2193 10.1097/01.ccm.0000181731.53912.d9 16215368
180. Kollef MH Shorr A Tabak YP Gupta V Liu LZ Johannes RS Epidemiology and outcomes of health-care-associated pneumoniae: Results from a large US database of culture-positive pneumoniae Chest 2005 128 6 3854 3862 10.1378/chest.128.6.3854 16354854
181. Sievert DM Ricks P Edwards JR Schneider A Patel J Srinivasan A et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: Summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010 Infect Control Hosp Epidemiol 2013 34 1 1 14 10.1086/668770 23221186
182. Chung DR Song JH Kim SH Thamlikitkul V Huang SG Wang H et al. High prevalence of multidrug-resistant nonfermenters in hospital-acquired pneumoniae in Asia Am J Respir Crit Care Med 2011 184 12 1409 1417 10.1164/rccm.201102-0349OC 21920919
183. Inchai J Liwsrisakun C Theerakittikul T Chaiwarith R Khositsakulchai W Pothirat C Risk factors of multidrug-resistant, extensively drug-resistant and pandrug-resistant Acinetobacter baumannii ventilator-associated pneumoniae in a Medical Intensive Care Unit of University Hospital in Thailand J Infect Chemother 2015 21 8 570 574 10.1016/j.jiac.2015.04.010 26026660
184. Ranjan N Chaudhary U Chaudhry D Ranjan K Ventilator-associated pneumoniae in a tertiary care intensive care unit: Analysis of incidence, risk factors and mortality Indian J Crit Care Med 2014 18 4 200 10.4103/0972-5229.130570 24872648
185. Mathur P Tak V Gunjiyal J Nair SA Lalwani S Kumar S et al. Device-associated infections at a level-1 trauma center of a developing Nation: Impact of automated surveillance, training and feedbacks Indian J Med Microbiol 2015 33 1 51 10.4103/0255-0857.148378 25560002
186. Ahmed NH Hussain T Biswal I Antimicrobial resistance of bacterial isolates from respiratory secretions of ventilated patients in a multi-specialty hospital Avicenna J Med 2015 5 3 74 78 10.4103/2231-0770.160233 26229758
187. Joseph NM Sistla S Dutta TK Badhe AS Parija SC Ventilator-associated pneumoniae in a tertiary care hospital in India: Incidence and risk factors J Infect Dev Ctries 2009 3 10 771 777 10.3855/jidc.396 20009278
188. Goel V Hogade SA Karadesai SG Ventilator-associated pneumoniae in a medical intensive care unit: Microbial etiology, susceptibility patterns of isolated microorganisms and outcome Indian J Anaesth 2012 56 6 558 10.4103/0019-5049.104575 23325941
189. Gurjar M Saigal S Baronia AK Rao BP Azim A Poddar B et al. Carbapenem-resistant Acinetobacter ventilator-associated pneumoniae: Clinical characteristics and outcome Indian J Crit Care Med Peer-Rev Off Publ Indian Soc Crit Care Med 2013 17 3 129 34 10.4103/0972-5229.117036
190. AMR Surveillance Network Indian Council of Medical Research 2022 Available from: AMRSN_Annual_Report_2022.pdf
191. Berton DC Kalil AC Teixeira PJZ Quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumoniae Cochrane Database Syst Rev 2014 10 CD006482 10.1002/14651858.CD006482.pub4
192. Suratt PM Smiddy JF Gruber B Deaths and complications associated with fiberoptic bronchoscopy Chest 1976 69 6 747 751 10.1378/chest.69.6.747 1277893
193. Li C Zhu T Ma D Chen Y Bo L Complications and safety analysis of diagnostic bronchoscopy in COPD: A systematic review and meta-analysis Expert Rev Respir Med 2022 16 5 555 565 10.1080/17476348.2022.2056023 35313123
194. Cracco C Fartoukh M Prodanovic H Azoulay E Chenivesse C Lorut C et al. Safety of performing fiberoptic bronchoscopy in critically ill hypoxemic patients with acute respiratory failure Intensive Care Med 2013 39 1 45 52 10.1007/s00134-012-2687-9 23070123
195. Pickens CO Gao CA Cuttica MJ Smith SB Pesce LL Grant RA et al. Bacterial superinfection pneumoniae in patients mechanically ventilated for covid-19 pneumoniae Am J Respir Crit Care Med 2021 204 8 921 932 10.1164/rccm.202106-1354OC 34409924
196. Saha BK Saha S Chong WH Beegle S Indications, clinical utility, and safety of bronchoscopy in COVID-19 Respir Care Respiratory Care 2022 67 2 241 251 10.4187/respcare.09405 34848547
197. Al-Omari B McMeekin P Allen AJ Akram AR Graziadio S Suklan J et al. Systematic review of studies investigating ventilator-associated pneumoniae diagnostics in intensive care BMC Pulm Med 2021 21 1 196 10.1186/s12890-021-01560-0 34107929
198. Fernando SM Tran A Cheng W Klompas M Kyeremanteng K Mehta S et al. Diagnosis of ventilator-associated pneumoniae in critically ill adult patients – A systematic review and meta-analysis Intensive Care Med 2020 46 6 1170 1179 10.1007/s00134-020-06036-z 32306086
199. Tepper J Johnson S Parker C Collins J Menard L Hinkle L Comparing the accuracy of mini-bal to bronchoscopic bal in the diagnosis of pneumoniae among ventilated patients: A systematic literature review J Intensive Care Med. SAGE Publications Inc STM 2023 38 12 1099 1107 10.1177/08850666231193379
200. Enne VI Aydin A Baldan R Owen DR Richardson H Ricciardi F et al. Multicenter evaluation of two multiplex PCR platforms for the rapid microbiological investigation of nosocomial pneumoniae in UK ICUs: The INHALE WP1 study Thorax 2022 77 12 1220 1228 10.1136/thoraxjnl-2021-216990 35027473
201. Monard C Pehlivan J Auger G Alviset S Tran Dinh A Duquaire P et al. Multicenter evaluation of a syndromic rapid multiplex PCR test for early adaptation of antimicrobial therapy in adult patients with pneumoniae Crit Care Lond Engl 2020 24 1 434 10.1186/s13054-020-03114-y
202. Song YY Zhang B Gu JW Zhang YJ Wang Y The predictive value of procalcitonin in ventilator-associated pneumoniae after cardiac valve replacement Scand J Clin Lab Invest 2020 80 5 423 426 10.1080/00365513.2020.1762242 32425062
203. Sotillo-Díaz JC Bermejo-López E García-Olivares P Peral-Gutiérrez JA Sancho-González M Guerrero-Sanz JE Role of plasma procalcitonin in the diagnosis of ventilator-associated pneumoniae: Systematic review and meta-analysis Med Intensiva 2014 38 6 337 346 10.1016/j.medin.2013.07.001 24035696
204. Coelho L Rabello L Salluh J Martin-Loeches I Rodriguez A Nseir S et al. C-reactive protein and procalcitonin profile in ventilator-associated lower respiratory infections J Crit Care 2018 48 385 389 10.1016/j.jcrc.2018.09.036 30308469
205. Torres A Niederman MS Chastre J Ewig S Fernandez-Vandellos P Hanberger H et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumoniae and ventilator-associated pneumoniae: Guidelines for the management of hospital-acquired pneumoniae (HAP)/ventilator-associated pneumoniae (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and AsociaciónLatinoamericana del Tórax (ALAT) Eur Respir J. European Respiratory Society 2017 50 3 10.1183/13993003.00582-2017
206. Stolz D Smyrnios N Eggimann P Pargger H Thakkar N Siegemund M et al. Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumoniae: A randomized study Eur Respir J 2009 34 6 1364 1375 10.1183/09031936.00053209 19797133
207. Mazlan MZ Ismail MAH Ali S Salmuna ZN Shukeri WFWM Omar M Efficacy and safety of the point-of-care procalcitonin test for determining the antibiotic treatment duration in patients with ventilator-associated pneumoniae in the intensive care unit: A randomized controlled trial Anaesthesiol Intensive Ther Termedia 2021 53 3 207 214 10.5114/ait.2021.104300
208. Pontet J Bazzano F Miraballes R Bentancourt S Cancela M Procalcitonin (PCT) guided antibiotic treatment in ventilator-associated pneumoniae (VAP). Multi–center, clinical prospective, randomized–controlled study Index Infectológico 2008 175 63
209. Langer M Cigada M Mandelli M Mosconi P Tognoni G Early onset pneumoniae: A multicenter study in intensive care units Intensive Care Med 1987 13 5 342 346 10.1007/BF00255791 3655099
210. Giantsou E Liratzopoulos N Efraimidou E Panopoulou M Alepopoulou E Kartali-Ktenidou S et al. Both early-onset and late-onset ventilator-associated pneumoniae are caused mainly by potentially multiresistant bacteria Intensive Care Med 2005 31 11 1488 1494 10.1007/s00134-005-2697-y 16151723
211. Gastmeier P Sohr D Geffers C Rüden H Vonberg RP Welte T Early- and late-onset pneumoniae: Is this still a useful classification? Antimicrob Agents Chemother 2009 53 7 2714 2718 10.1128/AAC.01070-08 19364852
212. Trouillet JL Chastre J Vuagnat A Joly-Guillou ML Combaux D Dombret MC et al. Ventilator-associated pneumoniae caused by potentially drug-resistant bacteria Am J Respir Crit Care Med 1998 157 2 531 539 10.1164/ajrccm.157.2.9705064 9476869
213. Depuydt PO Vandijck DM Bekaert MA Decruyenaere JM Blot SI Vogelaers DP et al. Determinants and impact of multidrug antibiotic resistance in pathogens causing ventilator-associated-pneumoniae Crit Care Lond Engl 2008 12 6 R142 10.1186/cc7119
214. Bouza E Giannella M Bunsow E Torres MV Pérez Granda MJ Martín-Rabadán P et al. Ventilator-associated pneumoniae due to meticillin-resistant Staphylococcus aureus: Risk factors and outcome in a large general hospital J Hosp Infect 2012 80 2 150 155 10.1016/j.jhin.2011.11.013 22226126
215. Wooten DA Winston LG Risk factors for methicillin-resistant Staphylococcus aureus in patients with community-onset and hospital-onset pneumoniae Respir Med 2013 107 8 1266 1270 10.1016/j.rmed.2013.05.006 23756035
216. Moreira MR Filho PPG Multidrug-resistant pathogens causing ventilator-associated pneumoniae: Risk factors, empirical antimicrobial therapy and outcome of patients in an intensive care unit (ICU) of a Brazilian university hospital Int J Med Med Sci 2012 4 9 204 210 10.5897/IJMMS12.084
217. Hu JN Hu SQ Li ZL Bao C Liu Q Liu C et al. Risk factors of multidrug-resistant bacteria infection in patients with ventilator-associated pneumoniae: A systematic review and meta-analysis J Infect Chemother Off J Jpn Soc Chemother 2023 29 10 942 947 10.1016/j.jiac.2023.06.008
218. Dominedò C Ceccato A Niederman M Cillóniz C Gabarrús A Martin-Loeches I et al. Predictive performance of risk factors for multidrug-resistant pathogens in nosocomial pneumoniae Ann Am Thorac Soc 2021 18 5 807 814 10.1513/AnnalsATS.202002-181OC 33264575
219. Kuti EL Patel AA Coleman CI Impact of inappropriate antibiotic therapy on mortality in patients with ventilator-associated pneumoniae and bloodstream infection: A meta-analysis J Crit Care 2008 23 1 91 100 10.1016/j.jcrc.2007.08.007 18359426
220. Arthur LE Kizor RS Selim AG van Driel ML Seoane L Antibiotics for ventilator-associated pneumoniae Cochrane Database Syst Rev 2016 10 CD004267 10.1002/14651858.CD004267.pub4 27763732
221. Schmid A Wolfensberger A Nemeth J Schreiber PW Sax H Kuster SP Monotherapy versus combination therapy for multidrug-resistant gram-negative infections: Systematic Review and Meta-Analysis Sci Rep 2019 9 15290 10.1038/s41598-019-51711-x 31664064
222. Harris PNA Tambyah PA Lye DC Mo Y Lee TH Yilmaz M et al. Effect of Piperacillin-Tazobactam vs Meropenem on 30-day mortality for patients with e coli or Klebsiella pneumoniaee bloodstream infection and ceftriaxone resistance: A randomized clinical trial JAMA 2018 320 10 984 994 10.1001/jama.2018.12163 30208454
223. Howatt M Klompas M Kalil AC Metersky ML Muscedere J Carbapenem antibiotics for the empiric treatment of nosocomial pneumoniae: A systematic review and meta-analysis Chest 2021 159 3 1041 1054 10.1016/j.chest.2020.10.039 33393468
224. Shuto H Komiya K Tone K Matsumoto H Moro H Shime N Carbapenem vs. non-carbapenem antibiotics for ventilator-associated pneumoniae: A systematic review with meta-analysis Respir Investig 2024 62 2 200 205 10.1016/j.resinv.2023.12.006
225. Walkey AJ O'Donnell MR Wiener RS Linezolid vs glycopeptide antibiotics for the treatment of suspected methicillin-resistant Staphylococcus aureus nosocomial pneumoniae: A meta-analysis of randomized controlled trials Chest 2011 139 5 1148 1155 10.1378/chest.10-1556 20864609
226. Kalil AC Klompas M Haynatzki G Rupp ME Treatment of hospital-acquired pneumoniae with linezolid or vancomycin: A systematic review and meta-analysis BMJ Open 2013 3 10 e003912 10.1136/bmjopen-2013-003912
227. Bento Talizin T Dantas de Maio Carrilho CM Magalhães Carvalho Grion C Tibery Queiroz Cardoso L Toshiyuki Tanita M Boll KM et al. Polymyxin for treatment of ventilator-associated pneumoniae in a setting of high carbapenem resistance PLoS ONE 2020 15 8 e0237880 10.1371/journal.pone.0237880 32813749
228. Vardakas KZ Falagas ME Colistin versus polymyxin B for the treatment of patients with multidrug-resistant gram-negative infections: A systematic review and meta-analysis Int J Antimicrob Agents 2017 49 2 233 238 10.1016/j.ijantimicag.2016.07.023 27686609
229. Zha L Zhang X Cheng Y Xu Q Liu L Chen S et al. Intravenous Polymyxin B as adjunctive therapy to high-dose tigecycline for the treatment of nosocomial pneumoniae due to carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniaee: A propensity score-matched cohort study. Antibiotics Multidisciplinary Digital Publishing Institute 2023 12 2 273 10.3390/antibiotics12020273
230. Samal S Samir SB Patra SK Rath A Dash A Nayak B et al. Polymyxin monotherapy vs. combination therapy for the treatment of multidrug-resistant infections: A systematic review and meta-analysis Indian J Crit Care Med Peer-Rev Off Publ Indian Soc Crit Care Med 2021 25 2 199 206 10.5005/jp-journals-10071-23720
231. Maruyama T Fujisawa T Okuno M Toyoshima H Tsutsui K Maeda H et al. A new strategy for healthcare-associated pneumoniae: A 2-year prospective multicenter cohort study using risk factors for multidrug-resistant pathogens to select initial empiric therapy Clin Infect Dis 2013 57 10 1373 1383 10.1093/cid/cit571 23999080
232. Peiffer-Smadja N Bouadma L Mathy V Allouche K Patrier J Reboul M et al. Performance and impact of a multiplex PCR in ICU patients with ventilator-associated pneumoniae or ventilated hospital-acquired pneumoniae Crit Care 2020 24 366 10.1186/s13054-020-03067-2 32560662
233. Murphy CN Fowler R Balada-Llasat JM Carroll A Stone H Akerele O et al. Multicenter evaluation of the biofirefilmarray pneumoniae/pneumoniae plus panel for detection and quantification of agents of lower respiratory tract infection J Clin Microbiol 2020 58 7 e00128 20 10.1128/JCM.00128-20 32350043
234. Dessajan J Timsit JF Impact of multiplex PCR in the therapeutic management of severe bacterial pneumoniae. Antibiotics Multidisciplinary Digital Publishing Institute 2024 13 1 95 10.3390/antibiotics13010095
235. Yoshimura J Yamakawa K Ohta Y Nakamura K Hashimoto H Kawada M et al. Effect of gram stain-guided initial antibiotic therapy on clinical response in patients with ventilator-associated pneumoniae: The grace-vap randomized clinical trial JAMA Netw Open 2022 5 4 e226136 10.1001/jamanetworkopen.2022.6136 35394515
236. Torres A Zhong N Pachl J Timsit JF Kollef M Chen Z et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumoniae, including ventilator-associated pneumoniae (REPROVE): A randomized, double-blind, phase 3 non-inferiority trial Lancet Infect Dis 2018 18 3 285 295 10.1016/S1473-3099(17)30747-8 29254862
237. Tumbarello M Trecarichi EM Corona A De Rosa FG Bassetti M Mussini C et al. Efficacy of Ceftazidime-Avibactam salvage therapy in patients with infections caused by Klebsiella pneumoniaee carbapenemase-producing K. pneumoniaee Clin Infect Dis Off Publ Infect Dis Soc Am 2019 68 3 355 364 10.1093/cid/ciy492
238. Wilson GM Fitzpatrick M Walding K Gonzalez B Schweizer ML Suda KJ et al. Meta-analysis of clinical outcomes using ceftazidime/avibactam, ceftolozane/tazobactam, and meropenem/vaborbactam for the treatment of multidrug-resistant gram-negative infections Open Forum Infect Dis 2021 8 2 ofaa651 10.1093/ofid/ofaa651 33598503
239. Kollef MH Nováček M Kivistik Ü Réa-Neto Á Shime N Martin-Loeches I et al. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumoniae (ASPECT-NP): A randomized, controlled, double-blind, phase 3, non-inferiority trial Lancet Infect Dis 2019 19 12 1299 1311 10.1016/S1473-3099(19)30403-7 31563344
240. Mogyoródi B Csékó AB Hermann C Gál J Iványi ZD Ceftolozane/tazobactam versus colistin in the treatment of ventilator-associated pneumoniae due to extensively drug-resistant Pseudomonas aeruginosa Sci Rep. Nature Publishing Group 2022 12 1 4455 10.1038/s41598-022-08307-9
241. Pogue JM Kaye KS Veve MP Patel TS Gerlach AT Davis SL et al. Ceftolozane/Tazobactam vs Polymyxin or Aminoglycoside-based regimens for the treatment of drug-resistant Pseudomonas aeruginosa Clin Infect Dis Off Publ Infect Dis Soc Am 2020 71 2 304 310 10.1093/cid/ciz816
242. Humphries RM Hindler JA Wong-Beringer A Miller SA Activity of ceftolozane-tazobactam and ceftazidime-avibactam against beta-lactam-resistant Pseudomonas aeruginosa isolates antimicrob agents chemother 2017 61 12 e01858 17 10.1128/AAC.01858-17 28993338
243. Titov I Wunderink RG Roquilly A Rodríguez Gonzalez D David-Wang A Boucher HW et al. A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumoniae (RESTORE-IMI 2 Study) Clin Infect Dis Off Publ Infect Dis Soc Am 2021 73 11 e4539 e4548 10.1093/cid/ciaa803
244. Motsch J Murta de Oliveira C Stus V Köksal I Lyulko O Boucher HW et al. RESTORE-IMI 1: A multicenter, randomized, double-blind trial comparing efficacy and safety of imipenem/relebactam vs colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections Clin Infect Dis Off Publ Infect Dis Soc Am 2020 70 9 1799 1808 10.1093/cid/ciz530
245. Wunderink RG Giamarellos-Bourboulis EJ Rahav G Mathers AJ Bassetti M Vazquez J et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant enterobacteriaceae infections: the tango ii randomized clinical trial Infect Dis Ther 2018 7 4 439 455 10.1007/s40121-018-0214-1 30270406
246. Ackley R Roshdy D Meredith J Minor S Anderson WE Capraro GA et al. Meropenem-vaborbactam versus ceftazidime-avibactam for treatment of carbapenem-resistant enterobacteriaceae infections Antimicrob Agents Chemother 2020 64 5 e02313 19 10.1128/AAC.02313-19 32094128
247. Kwa A Kasiakou SK Tam VH Falagas ME Polymyxin B: Similarities to and differences from colistin (polymyxin E) Expert Rev Anti Infect Ther 2007 5 5 811 821 10.1586/14787210.5.5.811 17914915
248. Sandri AM Landersdorfer CB Jacob J Boniatti MM Dalarosa MG Falci DR et al. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: Implications for selection of dosage regimens Clin Infect Dis Off Publ Infect Dis Soc Am 2013 57 4 524 531 10.1093/cid/cit334
249. Cisneros JM Rosso-Fernández CM Roca-Oporto C De Pascale G Jiménez-Jorge S Fernández-Hinojosa E et al. Colistin versus meropenem in the empirical treatment of ventilator-associated pneumoniae (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial Crit Care Lond Engl 2019 23 1 383 10.1186/s13054-019-2627-y
250. Tsuji BT Pogue JM Zavascki AP Paul M Daikos GL Forrest A et al. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP) Pharmacother J Hum Pharmacol Drug Ther 2019 39 1 10 39 10.1002/phar.2209
251. Mauri C Maraolo AE Di Bella S Luzzaro F Principe L The revival of aztreonam in combination with avibactam against metallo-β-lactamase-producing gram-negatives: A systematic review of in vitro studies and clinical cases. Antibiotics Multidisciplinary Digital Publishing Institute 2021 10 8 1012 10.3390/antibiotics10081012
252. Dijkmans AC Ortiz Zacarías NV Burggraaf J Mouton JW Wilms EB van Nieuwkoop C et al. Fosfomycin: Pharmacological, clinical and future perspectives Antibiotics 2017 6 4 24 10.3390/antibiotics6040024 29088073
253. Chen TT Chang YF Wu YC Clinical use of intravenous fosfomycin in critical care patients in Taiwan Pathogens 2023 12 6 841 10.3390/pathogens12060841 37375531
254. Veeraraghavan B Pragasam AK Bakthavatchalam YD Anandan S Swaminathan S Sundaram B Colistin-sparing approaches with newer antimicrobials to treat carbapenem-resistant organisms: Current evidence and future prospects Indian J Med Microbiol 2019 37 1 72 90 10.4103/ijmm.IJMM_19_215 31424014
255. Fragkou PC Poulakou G Blizou A Blizou M Rapti V Karageorgopoulos DE et al. The role of minocycline in the treatment of nosocomial infections caused by multidrug, extensively drug and pandrug resistant Acinetobacter baumannii: a systematic review of clinical evidence Microorganisms 2019 7 6 159 10.3390/microorganisms7060159 31159398
256. Sierra-Hoffman M Redell M Benefield R Caruso P Estrada S Leuthner K et al. Minocycline intravenous for the treatment of serious infections due to gram-negative nonpseudomonal bacteria, including stenotrophomonas maltophilia, Acinetobacter baumannii, and burkholderiacepacia Infect Dis Clin Pract 2020 28 4 209 10.1097/IPC.0000000000000854
257. Yahav D Lador A Paul M Leibovici L Efficacy and safety of tigecycline: A systematic review and meta-analysis J Antimicrob Chemother 2011 66 9 1963 1971 10.1093/jac/dkr242 21685488
258. Ramirez J Dartois N Gandjini H Yan JL Korth-Bradley J McGovern PC Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumoniae Antimicrob Agents Chemother 2013 57 4 1756 1762 10.1128/AAC.01232-12 23357775
259. Zha L Pan L Guo J French N Villanueva EV Tefsen B Effectiveness and safety of high dose tigecycline for the treatment of severe infections: A systematic review and meta-analysis Adv Ther 2020 37 3 1049 1064 10.1007/s12325-020-01235-y 32006240
260. Mei H Yang T Wang J Wang R Cai Y Efficacy and safety of tigecycline in treatment of pneumoniae caused by MDR Acinetobacter baumannii: A systematic review and meta-analysis J Antimicrob Chemother 2019 74 12 3423 3431 10.1093/jac/dkz337 31377765
261. Solomkin JS Gardovskis J Lawrence K Montravers P Sway A Evans D et al. IGNITE4: Results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs meropenem in the treatment of complicated intraabdominal infections Clin Infect Dis Off Publ Infect Dis Soc Am 2019 69 6 921 929 10.1093/cid/ciy1029
262. Scott CJ Zhu E Jayakumar RA Shan G Viswesh V Efficacy of eravacycline versus best previously available therapy for adults with pneumoniae due to difficult-to-treat resistant (DTR) Acinetobacter baumannii Ann Pharmacother 2022 56 12 1299 1307 10.1177/10600280221085551 35511209
263. Pfaller MA Huband MD Shortridge D Flamm RK Surveillance of omadacycline activity tested against clinical isolates from the United States and Europe: Report from the SENTRY Antimicrobial Surveillance Program, 2016 to 2018 Antimicrob Agents Chemother 2020 64 5 e02488 19 10.1128/AAC.02488-19 32071045
264. Dong D Zheng Y Chen Q Guo Y Yang Y Wu S et al. In vitro activity of omadacycline against pathogens isolated from Mainland China during 2017–2018 Eur J Clin Microbiol Infect Dis Off PublEur Soc Clin Microbiol 2020 39 8 1559 1572 10.1007/s10096-020-03877-w
265. Niederman MS Alder J Bassetti M Boateng F Cao B Corkery K et al. Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with gram-negative pneumoniae (INHALE): A double-blind, randomized, placebo-controlled, phase 3, superiority trial Lancet Infect Dis. Elsevier 2020 20 3 330 340 10.1016/S1473-3099(19)30574-2
266. Tang R Luo R Wu B Wang F Song H Chen X Effectiveness and safety of adjunctive inhaled antibiotics for ventilator-associated pneumoniae: A systematic review and meta-analysis of randomized controlled trials J Crit Care 2021 65 133 139 10.1016/j.jcrc.2021.06.004 34144265
267. Zhang X Cui X Jiang M Huang S Yang M Nebulized colistin as the adjunctive treatment for ventilator-associated pneumoniae: A systematic review and meta-analysis J Crit Care 2023 77 154315 10.1016/j.jcrc.2023.154315 37120926
268. Liu J Shao M Xu Q Liu F Pan X Wu J et al. Low-dose intravenous plus inhaled versus intravenous polymyxin B for the treatment of extensive drug-resistant gram-negative ventilator-associated pneumoniae in the critical illnesses: A multi-center matched case–control study Ann Intensive Care 2022 12 1 72 10.1186/s13613-022-01033-5 35934730
269. Kaye KS Udeani G Cole P Friedland HD Ceftarolinefosamil for the treatment of hospital-acquired pneumoniae and ventilator-associated pneumoniae Hosp Pract 1995 2015 43 3 144 149 10.1080/21548331.2015.1037228 25956849
270. Wunderink RG Roquilly A Croce M Rodriguez Gonzalez D Fujimi S Butterton JR et al. A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumoniae Clin Infect Dis Off Publ Infect Dis Soc Am 2021 73 3 e710 e718 10.1093/cid/ciab032
271. Rubinstein E Lalani T Corey GR Kanafani ZA Nannini EC Rocha MG et al. Telavancin versus vancomycin for hospital-acquired pneumoniae due to gram-positive pathogens Clin Infect Dis Off Publ Infect Dis Soc Am 2011 52 1 31 40 10.1093/cid/ciq031
272. Corey GR Kollef MH Shorr AF Rubinstein E Stryjewski ME Hopkins A et al. Telavancin for hospital-acquired pneumoniae: Clinical response and 28-day survival Antimicrob Agents Chemother 2014 58 4 2030 2037 10.1128/AAC.02330-13 24419353
273. Awad SS Rodriguez AH Chuang YC Marjanek Z Pareigis AJ Reis G et al. A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumoniae Clin Infect Dis Off Publ Infect Dis Soc Am 2014 59 1 51 61 10.1093/cid/ciu219
274. Research C for DE and FDA Drug Safety Communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new Boxed Warning. FDA [Internet]. FDA; 2019 [cited 2024 Feb 11]; Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-increased-risk-death-iv-antibacterial-tygacil-tigecycline
275. Kollef MH Chastre J Fagon JY François B Niederman MS Rello J et al. Global prospective epidemiologic and surveillance study of ventilator-associated pneumoniae due to Pseudomonas aeruginosa Crit Care Med 2014 42 10 2178 2187 10.1097/CCM.0000000000000510 25054674
276. Parker CM Kutsogiannis J Muscedere J Cook D Dodek P Day AG et al. Ventilator-associated pneumoniae caused by multidrug-resistant organisms or Pseudomonas aeruginosa: Prevalence, incidence, risk factors, and outcomes J Crit Care 2008 23 1 18 26 10.1016/j.jcrc.2008.02.001 18359417
277. Rello J Ausina V Ricart M Puzo C Quintana E Net A et al. Risk factors for infection by Pseudomonas aeruginosa in patients with ventilator-associated pneumoniae Intensive Care Med 1994 20 3 193 198 10.1007/BF01704699 8014285
278. Montero M Sala M Riu M Belvis F Salvado M Grau S et al. Risk factors for multidrug-resistant Pseudomonas aeruginosa acquisition. Impact of antibiotic use in a double case-control study Eur J Clin Microbiol Infect Dis Off PublEur Soc Clin Microbiol 2010 29 3 335 339 10.1007/s10096-009-0850-1
279. Capellier G Mockly H Charpentier C Annane D Blasco G Desmettre T et al. Early-onset ventilator-associated pneumoniae in adults randomized clinical trial: Comparison of 8 versus 15 days of antibiotic treatment PloS One 2012 7 8 e41290 10.1371/journal.pone.0041290 22952580
280. Micek ST Ward S Fraser VJ Kollef MH A randomized controlled trial of an antibiotic discontinuation policy for clinically suspected ventilator-associated pneumoniae Chest 2004 125 5 1791 1799 10.1378/chest.125.5.1791 15136392
281. Dimopoulos G Poulakou G Pneumatikos IA Armaganidis A Kollef MH Matthaiou DK Short- vs long-duration antibiotic regimens for ventilator-associated pneumoniae: A systematic review and meta-analysis Chest 2013 144 6 1759 1767 10.1378/chest.13-0076 23788274
282. Daghmouri MA Dudoignon E Chaouch MA Baekgaard J Bougle A Leone M et al. Comparison of a short versus long-course antibiotic therapy for ventilator-associated pneumoniae: A systematic review and meta-analysis of randomized controlled trials eClinicalMedicine Elsevier 2023 58 1 11 10.1016/j.eclinm.2023.101880
283. Doré P Robert R Grollier G Rouffineau J Lanquetot H Charrière J-M et al. Incidence of anaerobes in ventilator-associated pneumoniae with use of a protected specimen brush Am J Respir Crit Care Med 1996 153 4 1292 1298 10.1164/ajrccm.153.4.8616556 8616556
284. Marik PE Careau P The role of anaerobes in patients with ventilator-associated pneumoniae and aspiration pneumoniae: A prospective study CHEST J 1999 115 1 178 183 10.1378/chest.115.1.178
285. Robertu R Grollier G Doré P Hira M Ferrand E Fauchère JL Nosocomial pneumoniae with isolation of anaerobic bacteria in ICU patients: Therapeutic considerations and outcome J Crit Care 1999 14 3 114 119 10.1016/s0883-9441(99)90023-0 10527248
286. Mokhless NA-S El-Mofty MF Hanafi NF Muhammad A Asser SL Atypical bacteria in ventilator-associated pneumoniae; An Egyptian University Hospital experience J Am Sci 2010 6 12 1074 1079 ISSN: 1545-1003
287. el-Ebiary M Torres A González J de la Bellacasa JP García C Jiménez de Anta MT et al. Quantitative cultures of endotracheal aspirates for the diagnosis of ventilator-associated pneumoniae Am Rev Respir Dis 1993 148 6 Pt 1 1552 1557 10.1164/ajrccm/148.6_Pt_1.1552 8256899
288. Apfalter P Stoiser B Barousch W Nehr M Kramer L Burgmann H Community-acquired bacteria frequently detected by means of quantitative polymerase chain reaction in nosocomial early-onset ventilator-associated pneumoniae Crit Care Med 2005 33 7 1492 1498 10.1097/01.ccm.0000169879.97129.7b 16003053
289. Carratala J Gudiol F Pallares R Dorca J Verdaguer R Ariza J et al. Risk factors for nosocomial Legionella pneumophila pneumoniae Am J Respir Crit Care Med 1994 149 3 Pt 1 625 629 10.1164/ajrccm.149.3.8118629 8118629
290. American Thoracic Society, Infectious Diseases Society of America Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumoniae Am J Respir Crit Care Med 2005 171 4 388 416 10.1164/rccm.200405-644ST 15699079
291. Schneider HG Lam QT Procalcitonin for the clinical laboratory: A review Pathology (Phila) 2007 39 4 383 390 10.1080/00313020701444564
292. Bouadma L Luyt CE Tubach F Cracco C Alvarez A Schwebel C et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): A multicenter randomized controlled trial Lancet Lond Engl 2010 375 9713 463 474 10.1016/S0140-6736(09)61879-1
293. Pugh R Grant C Cooke RPD Dempsey G Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumoniae in critically ill adults Cochrane Database Syst Rev 2015 8 CD007577 10.1002/14651858.CD007577.pub3
294. Schuetz P Briel M Christ-Crain M Stolz D Bouadma L Wolff M et al. Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: An individual patient data meta-analysis Clin Infect Dis Off Publ Infect Dis Soc Am 2012 55 5 651 662 10.1093/cid/cis464
295. A Iannella H M Luna C Treatment failure in ventilator-associated pneumoniae Curr Respir Med Rev 2012 8 3 239 244 10.1055/s-2006-933678
296. Luna CM Blanzaco D Niederman MS Matarucco W Baredes NC Desmery P et al. Resolution of ventilator-associated pneumoniae: Prospective evaluation of the clinical pulmonary infection score as an early clinical predictor of outcome Crit Care Med 2003 31 3 676 682 10.1097/01.CCM.0000055380.86458.1E 12626968
297. Dennesen PJ van der Ven AJ Kessels AG Ramsay G Bonten MJ Resolution of infectious parameters after antimicrobial therapy in patients with ventilator-associated pneumoniae Am J Respir Crit Care Med 2001 163 6 1371 1375 10.1164/ajrccm.163.6.2007020 11371403
298. Montravers P Fagon JY Chastre J Lecso M Dombret MC Trouillet JL et al. Follow-up protected specimen brushes to assess treatment in nosocomial pneumoniae Am Rev Respir Dis 1993 147 1 38 44 10.1164/ajrccm/147.1.38 8420428
299. Ioanas M Ferrer M Cavalcanti M Ferrer R Ewig S Filella X et al. Causes and predictors of nonresponse to treatment of intensive care unit-acquired pneumoniae Crit Care Med 2004 32 4 938 945 10.1097/01.ccm.0000114580.98396.91 15071382
300. Luna CM Aruj P Niederman MS Garzón J Violi D Prignoni A et al. Appropriateness and delay to initiate therapy in ventilator-associated pneumoniae Eur Respir J 2006 27 1 158 164 10.1183/09031936.06.00049105 16387949
301. Deb M Mittal G Gaind R Verma PK Central venous Catheter-related bloodstream infections in an intensive care unit from a tertiary care teaching hospital International Journal of Infection Control 2016 12 1 1 6 10.3396/ijic.v12i1.15542
302. Gahlot R Nigam C Kumar V Yadav G Anupurba S Catheter-related bloodstream infections Int J Crit IllnInj Sci 2014 4 2 161 10.4103/2229-5151.134184
303. Mermel LA Allon M Bouza E Craven DE Flynn P O'Grady NP et al. Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter‐Related Infection: 2009 Update by the Infectious Diseases Society of America Clin Infect Dis 2009 49 1 1 45 10.1086/599376 19489710
304. National Nosocomial Infections Surveillance (NNIS) System Report, Data Summary from January 1990–May 1999, Issued June 1999 Am J Infect Control 1999 27 6 520 532 10.1016/S0196-6553(99)70031-3 10586157
305. National Nosocomial Infections Surveillance System National Nosocomial Infections Surveillance (NNIS) system report, data summary from January 1992 through June 2004, issued October 2004 Am J Infect Control 2004 32 8 470 485 10.1016/S0196655304005425 15573054
306. Chitnis AS Edwards JR Ricks PM Sievert DM Fridkin SK Gould CV Device-associated infection rates, device utilization, and antimicrobial resistance in long-term acute care hospitals reporting to the national healthcare safely network, 2010 Infect Control Hosp Epidemiol 2012 33 10 993 1000 10.1086/667745 22961018
307. Vincent J-L International study of the prevalence and outcomes of infection in intensive care units JAMA 2009 302 21 2323 10.1001/jama.2009.1754 19952319
308. Vincent J-L Sakr Y Singer M Martin-Loeches I Machado FR Marshall JC et al. Prevalence and outcomes of infection among patients in intensive care units in 2017 JAMA 2020 323 15 1478 1487 10.1001/jama.2020.2717 32207816
309. Lorente L Henry C Martín MM Jiménez A Mora ML Central venous catheter-related infection in a prospective and observational study of 2, 595 catheters Crit Care 2005 9 6 R631 35 10.1186/cc3824 16280064
310. Hajjej Z Nasri M Sellami W Gharsallah H Labben I Ferjani M Incidence, risk factors and microbiology of central vascular catheter-related bloodstream infection in an intensive care unit J Infect Chemother 2014 20 3 163 168 10.1016/j.jiac.2013.08.001 24508422
311. Rosenthal VD Device-associated nosocomial infections in 55 intensive care units of 8 developing countries Ann Intern Med 2006 145 8 582 10.7326/0003-4819-145-8-200610170-00007 17043340
312. Tarpatzi A Avlamis A Papaparaskevas J Daikos GL Stefanou I Katsandri A et al. Incidence and risk factors for central vascular catheter-related bloodstream infections in a tertiary care hospital New Microbiol 2012 35 4 429 437 23109010 23109010
313. Chen HS Wang FD Lin M Lin YC Huang LJ Liu CY Risk factors for central venous catheter-related infections in general surgery J Microbiol Immunol Infect Wei Mian Yu Gan Ran Za Zhi 2006 39 3 231 236 10.1017/9781107153165.016 16783454
314. Agarwal R Gupta D Ray P Aggarwal A Jindal S Epidemiology, Risk factors and outcome of nosocomial infections in a respiratory intensive care unit in North India J Infect 2006 53 2 98 105 10.1016/j.jinf.2005.10.021 16343637
315. Haq J Fatema K Faruq M Mansur F Barai L Karim M Intravascular Catheter-related infections and antimicrobial susceptibility pattern of isolated bacteria in a tertiary care hospital of Bangladesh Indian J Med Microbiol 2014 32 1 68 10.4103/0255-0857.124321 24399393
316. Chin BS Han SH Lee HS Jeong SJ Choi H Kim CO et al. Risk factors for recurrent catheter-related infections after catheter-related bloodstream infections Int J Infect Dis 2010 14 1 e16 21 10.1016/j.ijid.2009.01.016 19375968
317. Peng S Lu Y Clinical epidemiology of central venous catheter–related bloodstream infections in an intensive care unit in China J Crit Care 2013 28 3 277 283 10.1016/j.jcrc.2012.09.007 23265289
318. Bicudo D Batista R Furtado GH Sola A Medeiros EAS de Risk factors for catheter-related bloodstream infection: A prospective multicenter study in Brazilian intensive care units Braz J Infect Dis 2011 15 4 328 331 10.1016/S1413-8670(11)70200-8 21861002
319. Oncü S Ozsüt H Yildirim A Ay P Cakar N Eraksoy H et al. Central venous Catheter-related infections: Risk factors and the effect of glycopeptide antibiotics Ann Clin Microbiol Antimicrob 2003 2 3 1 6 10.1186/1476-0711-2-3 12556245
320. Parameswaran R Sherchan JB Varma D M Mukhopadhyay C Vidyasagar S Intravascular catheter-related infections in an Indian tertiary care hospital J Infect Dev Ctries 2011 5 6 452 458 10.3855/jidc.1261 21727644
321. Çaylan HR Yilmaz G Sözen EE Aydin K Köksal İ Incidence and risk factors for bloodstream infections stemming from temporary hemodialysis catheters Turk J Med Sci 2010 40 6 835 841 10.3906/sag-0908-236
322. A report from the NNIS System National Nosocomial Infections Surveillance (NNIS) system report, data summary from January 1992 through June 2004, issued October 2004 Am J Infect Control 2004 32 8 470 485 10.1016/j.ajic.2004.10.001 15573054
323. Kaur M Gupta V Gombar S Chander J Sahoo T Incidence, risk factors, microbiology of venous catheter associated bloodstream infections - A prospective study from a tertiary care hospital Indian J Med Microbiol 2015 33 2 248 10.4103/0255-0857.153572 25865976
324. Datta P Rani H Chauhan R Gombar S Chander J Health-care-associated infections: Risk factors and epidemiology from an intensive care unit in Northern India Indian J Anaesth 2014 58 1 30 10.4103/0019-5049.126785 24700896
325. Chen Y Huang H-B Peng J-M Weng L Du B Efficacy and safety of ceftazidime-avibactam for the treatment of carbapenem-resistant enterobacterales bloodstream infection: A systematic review and meta-analysis Microbiol Spectr. American Society for Microbiology; 2022 10 2 e02603 21 10.1128/spectrum.02603-21
326. Khanna V Mukhopadhayay C, K E V Verma M Dabke P Evaluation of central venous catheter associated bloodstream infections: A microbiological observational study J Pathog 2013 2013 936864 10.1155/2013/936864 23936657
327. S DSR Joseph MP Lavi R Macaden R Infections related to vascular catheters in a pediatric intensive care unit INDIAN Pediatr 2005 42 6 16085967
328. Chakrabarti A Sood P Rudramurthy SM Chen S Kaur H Capoor M et al. Incidence, characteristics and outcome of ICU-acquired candidemia in India Intensive Care Med 2015 41 2 285 295 10.1007/s00134-014-3603-2 28975963 25510301
329. Li J Zhao Q-H Huang K-C Li Z-Q Zhang L-Y Qin D-Y et al. Linezolid vs. vancomycin in treatment of methicillin-resistant staphylococcus aureus infections: A meta-analysis Eur Rev Med Pharmacol Sci 2017 21 17 3974 3979 28975963 28975963
330. Wilcox MH Tack KJ Bouza E Herr DL Ruf BR Ijzerman MM et al. Complicated skin and skin‐structure infections and catheter‐related bloodstream infections: Noninferiority of linezolid in a phase 3 study Clin Infect Dis 2009 48 2 203 212 10.1086/595686 19072714
331. Yoon YK Park DW Sohn JW Kim HY Kim Y-S Lee C-S et al. Multicenter prospective observational study of the comparative efficacy and safety of vancomycin versus teicoplanin in patients with health care-associated methicillin-resistant staphylococcus aureus bacteremia Antimicrob Agents Chemother 2014 58 1 317 324 10.1128/AAC.00520-13 24165181
332. Raad I Bompart F Hachem R Prospective, randomized dose-ranging open phase II pilot study of quinupristin/dalfopristin versus vancomycin in the treatment of catheter-related staphylococcal bacteremia Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol 1999 18 3 199 202 10.1007/s100960050258
333. Fowler VG Boucher HW Corey GR Abrutyn E Karchmer AW Rupp ME et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus N Engl J Med 2006 355 7 653 665 10.1056/NEJMoa053783 16914701
334. Raad I Darouiche R Vazquez J Lentnek A Hachem R Hanna H et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens Clin Infect Dis 2005 40 3 374 480 10.1086/427283 15668859
335. Chong YP Lee S-O Song EH Lee EJ Jang E-Y Kim S-H et al. Quinupristin-dalfopristin versus linezolid for the treatment of vancomycin-resistant enterococcus faecium bacteremia: efficacy and development of resistance Scand J Infect Dis 2010 42 6–7 491 499 10.3109/00365541003699623 20524781
336. Mora-Duarte J Betts R Rotstein C Colombo AL Thompson-Moya L Smietana J et al. Comparison of caspofungin and amphotericin B for invasive candidiasis N Engl J Med 2002 347 25 2020 2029 10.1056/NEJMoa021585 12490683
337. Rex JH Bennett JE Sugar AM Pappas PG van der Horst CM Edwards JE et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute N Engl J Med 1994 331 20 1325 1330 10.1056/NEJM199411173312001 7935701
338. Kotey FC Dayie NT Tetteh-Uarcoo PB Donkor ES Candida bloodstream infections: Changes in epidemiology and increase in drug resistance. infect dis res treat SAGE Publications Ltd STM; 2021 14 11786337211026927 10.1177/11786337211026927
339. Lee I Zaoutis TE Fishman NO Morales KH Nachamkin I Lautenbach E Risk factors for fluconazole resistance in patients with Candida glabrata bloodstream infection: Potential impact of control group selection on characterizing the association between previous fluconazole use and fluconazole resistance Am J Infect Control. Elsevier; 2010 38 6 456 460 10.1016/j.ajic.2009.12.011
340. Pappas PG Kauffman CA Andes DR Clancy CJ Marr KA Ostrosky-Zeichner L et al. Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of america Clin Infect Dis Off Publ Infect Dis Soc Am 2016 62 4 e1 50 10.1093/cid/civ933
341. Peri AM Bauer MJ Bergh H Butkiewicz D Paterson DL Harris PN Performance of the BioFire Blood Culture Identification 2 panel for the diagnosis of bloodstream infections Heliyon 2022 8 7 e09983 10.1016/j.heliyon.2022.e09983 35874050
342. Caméléna F Péan de Ponfilly G Pailhoriès H Bonzon L Alanio A Poncin T et al. Multicenter evaluation of the filmarray blood culture identification 2 panel for pathogen detection in bloodstream infections Microbiol Spectr 2023 11 1 e0254722 10.1128/spectrum.02547-22 36519852
343. Havey TC Fowler RA Daneman N Duration of antibiotic therapy for bacteremia: A systematic review and meta-analysis Crit Care 2011 15 6 R267 10.1186/cc10545 22085732
344. Muff S Tabah A Que Y-A Timsit J-F Mermel L Harbarth S et al. Short-course versus long-course systemic antibiotic treatment for uncomplicated intravascular catheter-related bloodstream infections due to gram-negative bacteria, enterococci or coagulase-negative staphylococci: A systematic review Infect Dis Ther 2021 10 3 1591 1605 10.1007/s40121-021-00464-0 34169480
345. Hooton TM Bradley SF Cardenas DD Colgan R Geerlings SE Rice JC et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the infectious diseases society of America Clin Infect Dis Off Publ Infect Dis Soc Am 2010 50 5 625 663 10.1086/650482
346. Dudeck MA Horan TC Peterson KD Allen-Bridson K Morrell G Pollock DA et al. National healthcare safety network (nhsn) report, data summary for 2010, device-associated module Am J Infect Control 2011 39 10 798 816 10.1016/j.ajic.2011.10.001 22133532
347. Centers for disease control urinary tract infection (Catheter-associated urinary tract infection [CAUTI] and non-catheter-associated Urinary tract infection [UTI]) and other urinary system infection [USI]) events Device-Assoc Module UTI 2018 17
348. Laupland KB Bagshaw SM Gregson DB Kirkpatrick AW Ross T Church DL Intensive care unit-acquired urinary tract infections in a regional critical care system Crit Care Lond Engl 2005 9 2 R60 65 10.1186/cc3023
349. Rosser CJ Bare RL Meredith JW Urinary tract infections in the critically ill patient with a urinary catheter Am J Surg 1999 177 4 287 290 10.1016/s0002-9610(99)00048-3 10326844
350. van der Kooi TII de Boer AS Manniën J Wille JC Beaumont MT Mooi BW et al. Incidence and risk factors of device-associated infections and associated mortality at the intensive care in the Dutch surveillance system Intensive Care Med 2007 33 2 271 278 10.1007/s00134-006-0464-3 17146632
351. Alvarez-Lerma F Palomar M Olaechea P Otal JJ Insausti J Cerdá E [National Study of Control of Nosocomial Infection in Intensive Care Units. Evolutive report of the years 2003-2005] Med Intensiva 2007 31 1 6 17 10.1016/S0210-5691(07)74764-2 17306135
352. Chant C Smith OM Marshall JC Friedrich JO Relationship of catheter-associated urinary tract infection to mortality and length of stay in critically ill patients: A systematic review and meta-analysis of observational studies Crit Care Med 2011 39 5 1167 1173 10.1097/CCM.0b013e31820a8581 21242789
353. Laupland KB Zygun DA Davies HD Church DL Louie TJ Doig CJ Incidence and risk factors for acquiring nosocomial urinary tract infection in the critically ill J Crit Care 2002 17 1 50 57 10.1053/jcrc.2002.33029 12040549
354. Tay MKX Lee JYC Wee IYJ, Oh HML Evaluation of intensive care unit-acquired urinary tract infections in Singapore Ann Acad Med Singapore 2010 39 6 460 465 20625622 20625622
355. Xie D Fu X Wang H Wang L Li R Luo Q et al. Annual point-prevalence of healthcare-associated infection surveys in a university hospital in China, 2007–2011 J Infect Public Health 2013 6 6 416 422 10.1016/j.jiph.2013.04.009 23999334
356. Leone M Albanèse J Garnier F Sapin C Barrau K Bimar M-C et al. Risk factors of nosocomial catheter-associated urinary tract infection in a polyvalent intensive care unit Intensive Care Med 2003 29 6 929 932 10.1007/s00134-003-1741-z 12684747
357. Parlak E Erol S Kizilkaya M Altoparlak U Parlak M [Nosocomial urinary tract infections in the intensive care unit patients] Mikrobiyol Bul 2007 41 1 39 49 17427551 17427551
358. Karlowsky JA Lagacé-Wiens PRS Simner PJ DeCorby MR Adam HJ Walkty A et al. Antimicrobial resistance in urinary tract pathogens in Canada from 2007 to 2009: CANWARD surveillance study Antimicrob Agents Chemother 2011 55 7 3169 3175 10.1128/AAC.00066-11 21537027
359. Temiz E Piskin N Aydemir H Oztoprak N Akduman D Celebi G et al. Factors associated with catheter-associated urinary tract infections and the effects of other concomitant nosocomial infections in intensive care units Scand J Infect Dis 2012 44 5 344 349 10.3109/00365548.2011.639031 22200187
360. Lewis SS Knelson LP Moehring RW Chen LF Sexton DJ Anderson DJ Comparison of non-intensive care unit (ICU) versus ICU rates of catheter-associated urinary tract infection in community hospitals Infect Control Hosp Epidemiol 2013 34 7 744 747 10.1086/671000 23739080
361. Alvarez-Lerma F Gracia-Arnillas MP Palomar M Olaechea P Insausti J López-Pueyo MJ et al. Urethral catheter-related urinary infection in critical patients admitted to the ICU. Descriptive data of the ENVIN-UCI study Med Intensiva 2013 37 2 75 82 10.1016/j.medin.2012.02.013 22579562
362. Habibi S Wig N Agarwal S Sharma SK Lodha R Pandey RM et al. Epidemiology of nosocomial infections in medicine intensive care unit at a tertiary care hospital in northern India Trop Doct 2008 38 4 233 235 10.1258/td.2008.070395 18820195
363. Dasgupta S Das S Chawan NS Hazra A Nosocomial infections in the intensive care unit: Incidence, risk factors, outcome and associated pathogens in a public tertiary teaching hospital of Eastern India Indian J Crit Care Med Peer-Rev Off Publ Indian Soc Crit Care Med 2015 19 1 14 20 10.4103/0972-5229.148633
364. Sahu MK Siddharth B Choudhury A Vishnubhatla S Singh SP Menon R et al. Incidence, microbiological profile of nosocomial infections, and their antibiotic resistance patterns in a high volume Cardiac Surgical Intensive Care Unit Ann Card Anaesth 2016 19 2 281 287 10.4103/0971-9784.179625 27052070
365. Vardakas KZ Tansarli GS Rafailidis PI Falagas ME Carbapenems versus alternative antibiotics for the treatment of bacteremia due to Enterobacteriaceae producing extended-spectrum β-lactamases: A systematic review and meta-analysis J Antimicrob Chemother 2012 67 12 2793 2803 10.1093/jac/dks301 22915465
366. Savas L Guvel S Onlen Y Savas N Duran N Nosocomial urinary tract infections: Micro-organisms, antibiotic sensitivities and risk factors West Indian Med J 2006 55 3 188 193 10.1590/s0043-31442006000300011 17087104
367. Yoon BI Kim HS Kim SD Cho KJ Kim SW Ha U-S et al. Changes in bacterial species and antibiotic sensitivity in intensive care unit: Acquired urinary tract infection during 10 years interval (2001-2011) Urol J 2014 11 2 1478 1484 24807764 24807764
368. Karlowsky JA Hoban DJ Hackel MA Lob SH Sahm DF Resistance among gram-negative ESKAPE pathogens isolated from hospitalized patients with intra-abdominal and urinary tract infections in Latin American countries: SMART 2013-2015 Braz J Infect Dis Off Publ Braz Soc Infect Dis 2017 21 3 343 348 10.1016/j.bjid.2017.03.006
369. Seo YB Lee J Kim YK Lee SS Lee J-A Kim HY et al. Randomized controlled trial of piperacillin-tazobactam, cefepime and ertapenem for the treatment of urinary tract infection caused by extended-spectrum beta-lactamase-producing Escherichia coli BMC Infect Dis 2017 17 1 404 10.1186/s12879-017-2502-x 28592240
370. Maraki S Samonis G Rafailidis PI Vouloumanou EK Mavromanolakis E Falagas ME Susceptibility of urinary tract bacteria to fosfomycin antimicrob agents chemother 2009 53 10 4508 4510 10.1128/AAC.00721-09 19687248
371. Patel B Patel K Shetty A Soman R Rodrigues C Fosfomycin susceptibility in urinary tract enterobacteriaceae J Assoc Physicians India 2017 65 9 14 16 29313570
372. Mir MA Chaudhary S Payasi A Sood R Mavuduru RS Shameem M Ceftriaxone+sulbactam+disodium EDTA versus meropenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: Plea, a double-blind, randomized noninferiority trial Open Forum Infect Dis 2019 6 10 ofz373 10.1093/ofid/ofz373 31433059
373. Samantaray S Kumar D Bohra GK Meena DS Agarwal A Chaudhary GR et al. 381. Effect of Ceftriaxone+sulbactam+disodium EDTA combination in treatment of complicated urinary tract infections caused by metallo beta-lactamase producing enterobacterales: An open label randomized controlled trial Open Forum Infect Dis 2023 10 Supplement_2 ofad500.451 10.1093/ofid/ofad500.451
374. Popejoy MW Paterson DL Cloutier D Huntington JA Miller B Bliss CA et al. Efficacy of ceftolozane/tazobactam against urinary tract and intra-abdominal infections caused by ESBL-producing Escherichia coli and Klebsiella pneumoniaee: A pooled analysis of Phase 3 clinical trials J Antimicrob Chemother 2017 72 1 268 272 10.1093/jac/dkw374 27707990
375. Carmeli Y Armstrong J Laud PJ Newell P Stone G Wardman A et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): A randomized, pathogen-directed, phase 3 study Lancet Infect Dis 2016 16 6 661 673 10.1016/S1473-3099(16)30004-4 27107460
376. Kaye KS Bhowmick T Metallidis S Bleasdale SC Sagan OS Stus V et al. Effect of meropenem-vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: The tango i randomized clinical trial JAMA 2018 319 8 788 799 10.1001/jama.2018.0438 29486041
377. Wagenlehner FME Cloutier DJ Komirenko AS Cebrik DS Krause KM Keepers TR et al. Once-daily plazomicin for complicated urinary tract infections N Engl J Med 2019 380 8 729 740 10.1056/NEJMoa1801467 30786187
378. Sojo-Dorado J López-Hernández I Rosso-Fernandez C Morales IM Palacios-Baena ZR Hernández-Torres A et al. Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections: A Randomized Clinical Trial JAMA Netw Open 2022 5 1 e2137277 10.1001/jamanetworkopen.2021.37277 35024838
379. Johnson JR Russo TA Acute pyelonephritis in adults N Engl J Med 2018 378 1 48 59 29298155 29298155
380. Dinh A Toumi A Blanc C Descatha A Bouchand F Salomon J et al. Management of febrile urinary tract infection among spinal cord injured patients BMC Infect Dis 2016 16 156 10.1186/s12879-016-1484-4 27084753
381. Osawa K Shigemura K Yoshida H Fujisawa M Arakawa S Candida urinary tract infection and Candida species susceptibilities to antifungal agents J Antibiot (Tokyo) 2013 66 11 651 654 10.1038/ja.2013.68 23801184
382. World Health Organization The treatment of diarrhea. a manual of physicians and other senior health workers. geneva World health organization 1990 Available from: https://www.who.int/publications/i/item/9241593180
383. McFarland LV Epidemiology of infectious and iatrogenic nosocomial diarrhea in a cohort of general medicine patients Am J Infect Control 1995 23 5 295 305 10.1016/0196-6553(95)90060-8 8585641
384. Polage CR Solnick JV Cohen SH Nosocomial diarrhea: Evaluation and treatment of causes other than clostridium difficile Clin Infect Dis Off Publ Infect Dis Soc Am 2012 55 7 982 989 10.1093/cid/cis551
385. Thibault R Graf S Clerc A Delieuvin N Heidegger CP Pichard C Diarrhea in the ICU: Respective contribution of feeding and antibiotics Crit Care 2013 17 4 R153 10.1186/cc12832 23883438
386. Elpern EH Stutz L Peterson S Gurka DP Skipper A Outcomes associated with enteral tube feedings in a medical intensive care unit Am J Crit Care Off Publ Am Assoc Crit-Care Nurses 2004 13 3 221 227 15149056
387. Wiesen P Van Gossum A Preiser J-C Diarrhea in the critically ill Curr Opin Crit Care 2006 12 2 149 154 10.1097/01.ccx.0000216583.64804.46 16543792
388. Bouza E Muñoz P Alonso R Clinical manifestations, treatment and control of infections caused by Clostridium difficile Clin Microbiol Infect 2005 11 57 64 10.1111/j.1469-0691.2005.01165.x
389. Bobo LD Dubberke ER Recognition and prevention of hospital-associated enteric infections in the intensive care unit Crit Care Med 2010 38 8 0 S324 334 10.1097/CCM.0b013e3181e69f05 20647790
390. Surawicz CM Brandt LJ Binion DG Ananthakrishnan AN Curry SR Gilligan PH et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections Am J Gastroenterol 2013 108 4 478 498; quiz 499 10.1038/ajg.2013.4 23439232
391. Planche T Wilcox M Reference assays for Clostridium difficile infection: One or two gold standards? J Clin Pathol 2011 64 1 1 5 10.1136/jcp.2010.080135 21118850
392. Tirlapur N Puthucheary ZA Cooper JA Sanders J Coen PG Moonesinghe SR et al. Diarrhea in the critically ill is common, associated with poor outcome, and rarely due to Clostridium difficile Sci Rep 2016 6 24691 10.1038/srep24691 27094447
393. Ingle M Deshmukh A Desai D Abraham P Joshi A Rodrigues C et al. Prevalence and clinical course of Clostridium difficile infection in a tertiary-care hospital: A retrospective analysis Indian J Gastroenterol Off J Indian Soc Gastroenterol 2011 30 2 89 93 10.1007/s12664-011-0097-5
394. Vishwanath S Singhal A D'Souza A Mukhopadhyay C Varma M Bairy I Clostridium difficile infection at a tertiary care hospital in south India J Assoc Physicians India 2013 61 11 804 806 24974492 24974492
395. Marcon AP Gamba MA Vianna LAC Nosocomial diarrhea in the intensive care unit Braz J Infect Dis Off Publ Braz Soc Infect Dis 2006 10 6 384 389 10.1590/s1413-86702006000600005
396. Guallar C Ariza J Dominguez MA Peña C Grau I Verdaguer R et al. An insidious nosocomial outbreak due to Salmonella enteritidis Infect Control Hosp Epidemiol 2004 25 1 10 15 10.1086/502284 14763444
397. Johnston CP Qiu H Ticehurst JR Dickson C Rosenbaum P Lawson P et al. Outbreak management and implications of a nosocomial norovirus outbreak Clin Infect Dis Off Publ Infect Dis Soc Am 2007 45 5 534 540 10.1086/520666
398. Vasa CV Glatt AE Effectiveness and appropriateness of empiric metronidazole for Clostridium difficile-associated diarrhea Am J Gastroenterol 2003 98 2 354 358 10.1111/j.1572-0241.2003.07227.x 12591054
399. Minson Q Mok S Relationship between antibiotic exposure and subsequent clostridium difficile-associated diarrhea Hosp Pharm 2007 42 5 430 434 10.1310/hpj4205-430
400. Muto CA Pokrywka M Shutt K Mendelsohn AB Nouri K Posey K et al. A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use Infect Control Hosp Epidemiol 2005 26 3 273 280 10.1086/502539 15796280
401. Polgreen PM Chen YY Cavanaugh JE Ward M Coffman S Hornick DB et al. An outbreak of severe Clostridium difficile-associated disease possibly related to inappropriate antimicrobial therapy for community-acquired pneumoniae Infect Control Hosp Epidemiol 2007 28 2 212 214 10.1086/512174 17265406
402. Sundram F Guyot A Carboo I Green S Lilaonitkul M Scourfield A Clostridium difficile ribotypes 027 and 106: clinical outcomes and risk factors J Hosp Infect 2009 72 2 111 118 10.1016/j.jhin.2009.02.020 19386381
403. Baxter R Ray GT Fireman BH Case-control study of antibiotic use and subsequent Clostridium difficile-associated diarrhea in hospitalized patients Infect Control Hosp Epidemiol 2008 29 1 44 50 10.1086/524320 18171186
404. Hensgens MPM Goorhuis A Dekkers OM Kuijper EJ Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics J Antimicrob Chemother 2012 67 3 742 748 10.1093/jac/dkr508 22146873
405. Kallen AJ Thompson A Ristaino P Chapman L Nicholson A Sim B-T et al. Complete restriction of fluoroquinolone use to control an outbreak of Clostridium difficile infection at a community hospital Infect Control Hosp Epidemiol 2009 30 3 264 272 10.1086/595694 19215193
406. Loo VG Poirier L Miller MA Oughton M Libman MD Michaud S et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality N Engl J Med 2005 353 23 2442 2449 10.1056/NEJMoa051639 16322602
407. McCusker ME Harris AD Perencevich E Roghmann M-C Fluoroquinolone use and clostridium difficile–associated diarrhea Emerg Infect Dis 2003 9 6 730 733 10.3201/eid0906.020385 12781017
408. Slimings C Riley TV Antibiotics and hospital-acquired Clostridium difficile infection: Update of systematic review and meta-analysis J Antimicrob Chemother 2014 69 4 881 891 10.1093/jac/dkt477 24324224
409. Thomas C Stevenson M Williamson DJ Riley TV Clostridium difficile-associated diarrhea: Epidemiological data from western australia associated with a modified antibiotic policy Clin Infect Dis 2002 35 12 1457 1462 10.1086/342691 12471563
410. Musa SA Robertshaw H Thomson SJ Cowan ML Rahman TM Clostridium difficile-associated disease acquired in the neurocritical care unit Neurocrit Care 2010 13 1 87 92 10.1007/s12028-010-9374-x 20443154
411. Tripathy S Nair P Rothburn M Clostridium difficile-associated disease in a neurointensive Care Unit Front Neurol 2013 4 10.3389/fneur.2013.00082 23408773
412. Alvarez-Lerma F Palomar M Villasboa A Amador J Almirall J Posada MP et al. Epidemiological study of Clostridium difficile infection in critical patients admitted to the Intensive Care Unit Med Intensiva 2014 38 9 558 566 10.1016/j.medin.2013.11.007 24503331
413. Ingle M Deshmukh A Desai D Abraham P Joshi A Gupta T et al. Clostridium difficile as a cause of acute diarrhea: A prospective study in a tertiary care center Indian J Gastroenterol Off J Indian Soc Gastroenterol 2013 32 3 179 183 10.1007/s12664-013-0303-8
414. Ibrahim EH Mehringer L Prentice D Sherman G Schaiff R Fraser V et al. Early versus late enteral feeding of mechanically ventilated patients: Results of a clinical trial JPEN J Parenter Enteral Nutr 2002 26 3 174 181 10.1177/0148607102026003174 12005458
415. Lawrence SJ Puzniak LA Shadel BN Gillespie KN Kollef MH Mundy LM Clostridium difficile in the Intensive Care Unit: Epidemiology, Costs, and Colonization Pressure Infect Control Hosp Epidemiol 2007 28 02 123 130 10.1086/511793 17265392
416. Lübbert C Johann C Kekulé AS Worlitzsch D Weis S Mössner J et al. [Immunosuppressive treatment as a risk factor for the occurrence of clostridium difficile infection (CDI)] Z Gastroenterol 2013 51 11 1251 1258 10.1055/s-0033-1335505 23696115
417. Wang X Cai L Yu R Huang W Zong Z McDowell A, editor. Icu-onset Clostridium difficile infection in a university hospital in china: A prospective cohort study PLoS ONE 2014 9 11 e111735 10.1371/journal.pone.0111735 25372033
418. Kaneria MV Paul S Incidence of Clostridium difficile-associated diarrhea in a tertiary care hospital J Assoc Physicians India 2012 60 26 28 23767199
419. Buendgens L Bruensing J Matthes M Dückers H Luedde T Trautwein C et al. Administration of proton pump inhibitors in critically ill medical patients is associated with increased risk of developing Clostridium difficile-associated diarrhea J Crit Care 2014 29 4 696.e11 15 10.1016/j.jcrc.2014.03.002
420. Barletta JF Sclar DA Proton pump inhibitors increase the risk for hospital-acquired Clostridium difficile infection in critically ill patients Crit Care Lond Engl 2014 18 6 714 10.1186/s13054-014-0714-7
421. Nelson RL Suda KJ Evans CT Antibiotic treatment for Clostridium difficile-associated diarrhea in adults Cochrane Database Syst Rev 2017 3 CD004610 10.1002/14651858.CD004610.pub5 28257555
422. Johnson S Louie TJ Gerding DN Cornely OA Chasan-Taber S Fitts D et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: Results from two multinational, randomized, controlled trials Clin Infect Dis Off Publ Infect Dis Soc Am 2014 59 3 345 354 10.1093/cid/ciu313
423. Zar FA Bakkanagari SR Moorthi KMLST Davis MB A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity Clin Infect Dis Off Publ Infect Dis Soc Am 2007 45 3 302 307 10.1086/519265
424. Teasley DG Gerding DN Olson MM Peterson LR Gebhard RL Schwartz MJ et al. Prospective randomized trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhea and colitis Lancet Lond Engl 1983 2 8358 1043 1046 10.1016/s0140-6736(83)91036-x
425. Wenisch C Parschalk B Hasenhündl M Hirschl AM Graninger W Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea Clin Infect Dis Off Publ Infect Dis Soc Am 1996 22 5 813 818 10.1093/clinids/22.5.813
426. Louie TJ Miller MA Mullane KM Weiss K Lentnek A Golan Y et al. Fidaxomicin versus vancomycin for Clostridium difficile infection N Engl J Med 2011 364 5 422 431 10.1056/NEJMoa0910812 21288078
427. Mullane KM Miller MA Weiss K Lentnek A Golan Y Sears PS et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections Clin Infect Dis Off Publ Infect Dis Soc Am 2011 53 5 440 447 10.1093/cid/cir404
428. Cornely OA Nathwani D Ivanescu C Odufowora-Sita O Retsa P Odeyemi IAO Clinical efficacy of fidaxomicin compared with vancomycin and metronidazole in Clostridium difficile infections: A meta-analysis and indirect treatment comparison J Antimicrob Chemother 2014 69 11 2892 2900 10.1093/jac/dku261 25074856
429. de Lalla F Nicolin R Rinaldi E Scarpellini P Rigoli R Manfrin V et al. Prospective study of oral teicoplanin versus oral vancomycin for therapy of pseudomembranous colitis and Clostridium difficile-associated diarrhea Antimicrob Agents Chemother 1992 36 10 2192 2196 10.1128/AAC.36.10.2192 1444298
430. Drekonja DM Amundson WH Decarolis DD Kuskowski MA Lederle FA Johnson JR Antimicrobial use and risk for recurrent Clostridium difficile infection Am J Med 2011 124 11 1081.e1 7 10.1016/j.amjmed.2011.05.032
431. McFarland LV Surawicz CM Greenberg RN Fekety R Elmer GW Moyer KA et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease JAMA 1994 271 24 1913 1918 8201735 8201735
432. Pillai A Nelson R Probiotics for treatment of Clostridium difficile-associated colitis in adults Cochrane Database Syst Rev 2008 1 CD004611 10.1002/14651858.CD004611.pub2
433. Lau CS Chamberlain RS Probiotics are effective at preventing Clostridium difficile-associated diarrhea: A systematic review and meta-analysis Int J Gen Med 2016 9 27 37 10.2147/IJGM.S98280 26955289
434. O'Horo JC Jindai K Kunzer B Safdar N Treatment of recurrent Clostridium difficile infection: a systematic review Infection 2014 42 1 43 59 10.1007/s15010-013-0496-x 23839210
435. McFarland LV Elmer GW Surawicz CM Breaking the cycle: Treatment strategies for 163 cases of recurrent Clostridium difficile disease Am J Gastroenterol 2002 97 7 1769 1775 10.1111/j.1572-0241.2002.05839.x 12135033
436. Pépin J Routhier S Gagnon S Brazeau I Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada Clin Infect Dis Off Publ Infect Dis Soc Am 2006 42 6 758 764 10.1086/501126
437. Surawicz CM McFarland LV Greenberg RN Rubin M Fekety R Mulligan ME et al. The search for a better treatment for recurrent Clostridium difficile disease: Use of high-dose vancomycin combined with Saccharomyces boulardii Clin Infect Dis Off Publ Infect Dis Soc Am 2000 31 4 1012 1017 10.1086/318130
438. Cornely OA Miller MA Louie TJ Crook DW Gorbach SL Treatment of first recurrence of Clostridium difficile infection: Fidaxomicin versus vancomycin Clin Infect Dis Off Publ Infect Dis Soc Am 2012 55 Suppl 2 S154 161 10.1093/cid/cis462
439. Friedman-Korn T Livovsky DM Maharshak N Aviv Cohen N Paz K Bar-Gil Shitrit A et al. Fecal transplantation for treatment of Clostridium difficile infection in elderly and debilitated patients Dig Dis Sci 2018 63 1 198 203 10.1007/s10620-017-4833-2 29134299
440. Banks PA Bollen TL Dervenis C Gooszen HG Johnson CD Sarr MG et al. Classification of acute pancreatitis--2012: Revision of the Atlanta classification and definitions by international consensus Gut 2013 62 1 102 111 10.1136/gutjnl-2012-302779 23100216
441. Yadav D Lowenfels AB Trends in the epidemiology of the first attack of acute pancreatitis: A systematic review Pancreas 2006 33 4 323 330 10.1097/01.mpa.0000236733.31617.52 17079934
442. Coté GA Yadav D Slivka A Hawes RH Anderson MA Burton FR et al. Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 2011 9 3 266 273; quiz e27 10.1016/j.cgh.2010.10.015
443. Marshall JC Cook DJ Christou NV Bernard GR Sprung CL Sibbald WJ Multiple organ dysfunction score: A reliable descriptor of a complex clinical outcome Crit Care Med 1995 23 10 1638 1652 10.1097/00003246-199510000-00007 7587228
444. de-Madaria E Pamies-Guilabert J García G Benito JL de Hinojosa-Guadix J Álamo FFG del et al. Su1890 local and systemic complications of acute pancreatitis according to the revised atlanta classification: A nation-wide multicenter prospective study Gastroenterology 2015 148 4 S 545 10.1016/S0016-5085(15)31826-6
445. Baron TH Morgan DE Acute necrotizing pancreatitis N Engl J Med 1999 340 18 1412 1417 10.1056/NEJM199905063401807 10228193
446. Beger HG Rau B Mayer J Pralle U Natural course of acute pancreatitis World J Surg 1997 21 2 130 135 10.1007/s002689900204 8995067
447. Balthazar EJ Robinson DL Megibow AJ Ranson JH Acute pancreatitis: Value of CT in establishing prognosis Radiology 1990 174 2 331 336 10.1148/radiology.174.2.2296641 2296641
448. Werge M Novovic S Schmidt PN Gluud LL Infection increases mortality in necrotizing pancreatitis: A systematic review and meta-analysis Pancreatol Off J Int Assoc Pancreatol IAP Al 2016 16 5 698 707 10.1016/j.pan.2016.07.004
449. Beger HG Rau B Isenmann R Natural history of necrotizing pancreatitis Pancreatol Off J Int Assoc Pancreatol IAP Al 2003 3 2 93 101 10.1159/000070076
450. Tenner S Baillie J DeWitt J Vege SS American college of gastroenterology guideline: management of acute pancreatitis Am J Gastroenterol 2013 108 9 1400 1415 10.1038/ajg.2013.218 23896955
451. Yokoe M Takada T Mayumi T Yoshida M Isaji S Wada K et al. Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015 J Hepato-Biliary-Pancreat Sci 2015 22 6 405 432 10.1002/jhbp.259
452. Garg PK Khanna S Bohidar NP Kapil A Tandon RK Incidence, spectrum and antibiotic sensitivity pattern of bacterial infections among patients with acute pancreatitis J Gastroenterol Hepatol 2001 16 9 1055 1059 10.1046/j.1440-1746.2001.02589.x 11595073
453. Dellinger EP Tellado JM Soto NE Ashley SW Barie PS Dugernier T et al. Early antibiotic treatment for severe acute necrotizing pancreatitis: A randomized, double-blind, placebo-controlled study Ann Surg 2007 245 5 674 10.1097/01.sla.0000250414.09255.84 17457158
454. Isenmann R Rau B Beger HG Bacterial infection and extent of necrosis are determinants of organ failure in patients with acute necrotizing pancreatitis BJS 1999 86 8 1020 1024 10.1046/j.1365-2168.1999.01176.x
455. Büchler MW Gloor B Müller CA Friess H Seiler CA Uhl W Acute necrotizing pancreatitis: Treatment strategy according to the status of infection Ann Surg 2000 232 5 619 626 10.1097/00000658-200011000-00001 11066131
456. Mutinga M Rosenbluth A Tenner SM Odze RR Sica GT Banks PA Does mortality occur early or late in acute pancreatitis? Int J Pancreatol 2000 28 2 91 95 10.1385/IJGC:28:2:091 11128978
457. Mann DV Hershman MJ Hittinger R Glazer G Multicenter audit of death from acute pancreatitis BJS 1994 81 6 890 893 10.1002/bjs.1800810632
458. Padhan RK Jain S Agarwal S Harikrishnan S Vadiraja P Behera S et al. Primary and secondary organ failures cause mortality differentially in acute pancreatitis and should be distinguished Pancreas 2018 47 3 302 307 10.1097/MPA.0000000000000998 29401171
459. Gerzof SG Banks PA Robbins AH Johnson WC Spechler SJ Wetzner SM et al. Early diagnosis of pancreatic infection by computed tomography-guided aspiration Gastroenterology 1987 93 6 1315 1320 10.1016/0016-5085(87)90261-7 3678750
460. Noor MT Radhakrishna Y Kochhar R Ray P Wig JD Sinha SK et al. Bacteriology of infection in severe acute pancreatitis JOP J Pancreas 2011 12 1 19 25 21206096
461. Runkel N Bacterial translocation in acute pancreatitis Dig Surg 1996 13 4–5 269 272 10.1159/000172445
462. Moody FG Haley-Russell D Muncy DM Intestinal transit and bacterial translocation in obstructive pancreatitis Dig Dis Sci 1995 40 8 1798 1804 10.1007/BF02212705 7648983
463. Jain S Mahapatra SJ Gupta S Shalimar Garg PK Infected pancreatic necrosis due to multidrug-resistant organisms and persistent organ failure predict mortality in acute pancreatitis Clin Transl Gastroenterol 2018 9 10 190 10.1038/s41424-018-0056-x 30287818
464. Bassi C Falconi M Girelli R Nifosi F Elio A Martini N et al. Microbiological findings in severe pancreatitis Surg Res Commun 1989 5 1 1 4 10.1159/000070076
465. Widdison AL Karanjia ND Pancreatic infection complicating acute pancreatitis Br J Surg 1993 80 2 148 154 10.1002/bjs.1800800208 8443638
466. Talukdar R Nechutova H Clemens M Vege SS Could rising BUN predict the future development of infected pancreatic necrosis? Pancreatol Off J Int Assoc Pancreatol IAP Al 2013 13 4 355 359 10.1016/j.pan.2013.05.003
467. Howard TJ Temple MB Prophylactic antibiotics alter the bacteriology of infected necrosis in severe acute pancreatitis J Am Coll Surg 2002 195 6 759 767 10.1016/s1072-7515(02)01494-1 12495307
468. Ji L Lv J-C Song Z-F Jiang M-T Li L Sun B Risk factors of infected pancreatic necrosis secondary to severe acute pancreatitis Hepatobiliary Pancreat Dis Int 2016 15 4 428 433 10.1016/S1499-3872(15)60043-1 27498584
469. Ding N Sun Y-H Wen L-M Wang J-H Yang J-H Cheng K et al. Assessment of prophylactic antibiotics administration for acute pancreatitis: A meta-analysis of randomized controlled trials Chin Med J (Engl) 2020 133 2 212 10.1097/CM9.0000000000000603 31929369
470. Poropat G Goričanec K Lacković A Kresović A Lončarić A Marušić M Systematic review with trial sequential analysis of prophylactic antibiotics for acute pancreatitis Antibiot Basel Switz 2022 11 9 1191 10.3390/antibiotics11091191
471. Guo D Dai W Shen J Zhang M Shi Y Jiang K et al. Assessment of prophylactic carbapenem antibiotics administration for severe acute pancreatitis: An updated systematic review and meta-analysis Digestion 2022 103 3 183 191 10.1159/000520892 35026770
472. Li F Zhang F Wan X Wu K Liu Q Qiu C et al. Infections in acute pancreatitis: Organisms, resistance-patterns and effect on mortality Dig Dis Sci 2023 68 2 630 643 10.1007/s10620-022-07793-1 36562889
473. Bassi C Pederzoli P Vesentini S Falconi M Bonora A Abbas H et al. Behavior of antibiotics during human necrotizing pancreatitis Antimicrob Agents Chemother 1994 38 4 830 836 10.1128/AAC.38.4.830 8031054
474. Büchler M Malfertheiner P Frieβ H Isenmann R Vanek E Grimm H et al. Human pancreatic tissue concentration of bactericidal antibiotics Gastroenterology 1992 103 6 1902 1908 10.1016/0016-5085(92)91450-i 1451983
475. Ibrahim Noor Chan Louisa Ling Tai Mat Nor Mohd Basri 2017 Guide to Antimicrobial Therapy 2017
476. Runzi M Niebel W Goebell H Gerken G Layer P Severe acute pancreatitis: Nonsurgical treatment of infected necroses Pancreas 2005 30 3 195 199 10.1097/01.mpa.0000153613.17643.b3 15782093
477. Hartwig W Maksan S-M Foitzik T Schmidt J Herfarth C Klar E Reduction in mortality with delayed surgical therapy of severe pancreatitis J Gastrointest Surg 2002 6 3 481 487 10.1016/s1091-255x(02)00008-2 12023003
478. Garg PK Sharma M Madan K Sahni P Banerjee D Goyal R Primary conservative treatment results in mortality comparable to surgery in patients with infected pancreatic necrosis Clin Gastroenterol Hepatol 2010 8 12 1089 1094 10.1016/j.cgh.2010.04.011 20417724
479. Mouli VP Sreenivas V Garg PK Efficacy of conservative treatment, without necrosectomy, for infected pancreatic necrosis: A systematic review and meta-analysis Gastroenterology 2013 144 2 333 340 10.1053/j.gastro.2012.10.004 23063972
480. Adler DG Chari ST Dahl TJ Farnell MB Pearson RK Conservative management of infected necrosis complicating severe acute pancreatitis Am J Gastroenterol 2003 98 1 98 10.1111/j.1572-0241.2003.07162.x 12526943
481. Leung JW Ling TK Chan RC Cheung SW Lai CW Sung JJ et al. Antibiotics, biliary sepsis, and bile duct stones Gastrointest Endosc 1994 40 6 716 721 7859970 7859970
482. Kiriyama S Takada T Strasberg SM Solomkin JS Mayumi T Pitt HA et al. New diagnostic criteria and severity assessment of acute cholangitis in revised Tokyo Guidelines J Hepato-Biliary-Pancreat Sci 2012 19 5 548 556 10.1007/s00534-012-0537-3
483. Williams EJ Green J Beckingham I Parks R Martin D Lombard M Guidelines on the management of common bile duct stones (CBDS) Gut 2008 57 7 1004 1021 10.1136/gut.2007.121657 18321943
484. Friedman GD Natural history of asymptomatic and symptomatic gallstones Am J Surg 1993 165 4 399 404 10.1016/s0002-9610(05)80930-4 8480871
485. McSherry CK Ferstenberg H Calhoun WF Lahman E Virshup M The natural history of diagnosed gallstone disease in symptomatic and asymptomatic patients Ann Surg 1985 202 1 59 10.1097/00000658-198507000-00009 4015212
486. Andriulli A Loperfido S Napolitano G Niro G Valvano MR Spirito F et al. Incidence rates of post-ERCP complications: A systematic survey of prospective studies Am J Gastroenterol 2007 102 8 1781 10.1111/j.1572-0241.2007.01279.x 17509029
487. Anderson DJ Shimpi RA McDonald JR Branch MS Kanafani ZA Harger J et al. Infectious complications following endoscopic retrograde cholangiopancreatography: An automated surveillance system for detecting postprocedure bacteremia Am J Infect Control 2008 36 8 592 594 10.1016/j.ajic.2007.10.023 18926314
488. Lipsett PA Pitt HA Acute cholangitis Surg Clin North Am 1990 70 6 1297 1312 10.1016/s0039-6109(16)45285-0 2247816
489. Gigot JF Leese T Dereme T Coutinho J Castaing D Bismuth H Acute cholangitis. Multivariate analysis of risk factors Ann Surg 1989 209 4 435 10.1097/00000658-198904000-00008 2930289
490. Melzer M Toner R Lacey S Bettany E Rait G Biliary tract infection and bacteremia: Presentation, structural abnormalities, causative organisms and clinical outcomes Postgrad Med J 2007 83 986 773 776 10.1136/pgmj.2007.064683 18057178
491. Saharia PC Zuidema GD Cameron JL Primary common duct stones Ann Surg 1977 185 5 598 10.1097/00000658-197705000-00013 857748
492. Sung YK Lee JK Lee KH Lee KT Kang C-I The clinical epidemiology and outcomes of bacteremic biliary tract infections caused by antimicrobial-resistant pathogens Am J Gastroenterol 2012 107 3 473 10.1038/ajg.2011.387 22334249
493. Bapat RD Supe AN Patwardhan A Kocher HM Parab S Sathe MJ Biliary sepsis: An ascending infection Indian J Gastroenterol Off J Indian Soc Gastroenterol 1996 15 4 126 128 8916575
494. Shenoy SM Shenoy S Gopal S Tantry BV Baliga S Jain A Clinicomicrobiological analysis of patients with cholangitis Indian J Med Microbiol 2014 32 2 157 10.4103/0255-0857.129802 24713902
495. Ortega M Marco F Soriano A Almela M Martinez JA Lopez J et al. Epidemiology and prognostic determinants of bacteraemic biliary tract infection J Antimicrob Chemother 2012 67 6 1508 1513 10.1093/jac/dks062 22408140
496. Sahu MK Chacko A Dutta AK Prakash JAJ Microbial profile and antibiotic sensitivity pattern in acute bacterial cholangitis Indian J Gastroenterol 2011 30 5 204 10.1007/s12664-011-0135-3 22006165
497. Englesbe MJ Dawes LG Resistant pathogens in biliary obstruction: Importance of cultures to guide antibiotic therapy Hpb 2005 7 2 144 148 10.1080/13651820510028792 18333179
498. Lavillegrand J-R Mercier-Des-Rochettes E Baron E Pène F Contou D Favory R et al. Acute cholangitis in intensive care units: Clinical, biological, microbiological spectrum and risk factors for mortality: A multicenter study Crit Care 2021 25 1 49 10.1186/s13054-021-03480-1 33549136
499. Kruis T Güse-Jaschuck S Siegmund B Adam T Epple H-J Use of microbiological and patient data for choice of empirical antibiotic therapy in acute cholangitis BMC Gastroenterol 2020 20 65 10.1186/s12876-020-01201-6 32164573
500. Miura F Okamoto K Takada T Strasberg SM Asbun HJ Pitt HA et al. Tokyo Guidelines 2018: Initial management of acute biliary infection and flowchart for acute cholangitis J Hepato-Biliary-Pancreat Sci 2018 25 1 31 40 10.1002/jhbp.509
501. Tanaka A Takada T Kawarada Y Nimura Y Yoshida M Miura F et al. Antimicrobial therapy for acute cholangitis: Tokyo guidelines J Hepatobiliary Pancreat Surg 2007 14 1 59 67 10.1007/s00534-006-1157-6 17252298
502. Solomkin JS Mazuski JE Bradley JS Rodvold KA Goldstein EJ Baron EJ et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America Clin Infect Dis 2010 50 2 133 164 10.1089/sur.2009.9930 20034345
503. Kaplan G Gregson D Laupland K Population-based study of the epidemiology of and the risk factors for pyogenic liver abscess Clin Gastroenterol Hepatol 2004 2 11 1032 1038 10.1016/S1542-3565(04)00459-8 15551257
504. Chan K-S Chen C-M Cheng K-C Hou C-C Lin H-J Yu W-L Pyogenic liver abscess: A retrospective analysis of 107 patients during a 3-year period Jpn J Infect Dis 2005 58 6 366 368 16377869 16377869
505. Tsai F-C Huang Y-T Chang L-Y Wang J-T Pyogenic liver abscess as endemic disease, taiwan Emerg Infect Dis 2008 14 10 1592 1600 10.3201/eid1410.071254 18826824
506. Abbas MT Khan FY Muhsin SA Al-Dehwe B Abukamar M Elzouki A-N Epidemiology, clinical features and outcome of liver abscess: A single reference center experience in Qatar Oman Med J 2014 29 4 260 263 10.5001/omj.2014.69 25170406
507. Jain V Manjavkar S Kapur P Durfishan Rajput D Mir T Clinical and biochemical profile of liver abscess patients Int J Res Med Sci 2017 5 6 2596 10.18203/2320-6012.ijrms20172454
508. Lok K-H Li K-F Li K-K Szeto M-L Pyogenic liver abscess: Clinical profile, microbiological characteristics, and management in a Hong Kong hospital J Microbiol Immunol Infect Wei Mian Yu Gan Ran Za Zhi 2008 41 6 483 490 19255692 19255692
509. Huang C-J Pitt HA Lipsett PA Osterman FA Lillemoe KD Cameron JL et al. Pyogenic hepatic abscess: Changing trends over 42 years Ann Surg 1996 223 5 600 9 10.1097/00000658-199605000-00016 8651751
510. Mohsen AH Liver abscess in adults: Ten years experience in a UK center QJM 2002 95 12 797 802 10.1093/qjmed/95.12.797 12454322
511. Ng FH Wong WM Wong BCY Kng C Wong SY Lai KC et al. Sequential intravenous/oral antibiotic vs. continuous intravenous antibiotic in the treatment of pyogenic liver abscess Aliment Pharmacol Ther 2002 16 6 1083 90 10.1046/j.1365-2036.2002.01266.x 12030949
512. Rahimian J Wilson T Oram V Holzman RS Pyogenic liver abscess: Recent trends in etiology and mortality Clin Infect Dis 2004 39 11 1654 9 10.1086/425616 15578367
513. Luo M Yang X-X Tan B Zhou X-P Xia H-M Xue J et al. Distribution of common pathogens in patients with pyogenic liver abscess in China: A meta-analysis Eur J Clin Microbiol Infect Dis 2016 35 10 1557 1565 10.1007/s10096-016-2712-y 27401906
514. Ghosh S Sharma S Gadpayle AK Gupta HK Mahajan RK Sahoo R et al. Clinical, laboratory, and management profile in patients of liver abscess from Northern India J Trop Med 2014 2014 1 8 10.1155/2014/142382
515. Poovorawan K Pan-ngum W Soonthornworasiri N Kulrat C Kittitrakul C Wilairatana P et al. Burden of liver abscess and survival risk score in thailand: A population-based study Am J Trop Med Hyg 2016 95 3 683 688 10.4269/ajtmh.16-0228 27325801
516. Peris J Bellot P Roig P Reus S Carrascosa S González-Alcaide G et al. Clinical and epidemiological characteristics of pyogenic liver abscess in people 65 years or older versus people under 65: A retrospective study BMC Geriatr 2017 17 1 161 10.1186/s12877-017-0545-x 28732474
517. Sharma MP Rai RR Acharya SK Ray JC Tandon BN Needle aspiration of amoebic liver abscess BMJ 1989 299 6711 1308 1309 10.1136/bmj.299.6711.1308 2513931
518. Lasserre R Jaroonvesama N Kurathong S Soh C-T Single-day drug treatment of amebic liver abscess Am J Trop Med Hyg 1983 32 4 723 726 10.4269/ajtmh.1983.32.723 6881419
519. Bhatia S Karnad DR Oak JL Randomized double-blind trial of metronidazole versus secnidazole in amebic liver abscess Indian J Gastroenterol Off J Indian Soc Gastroenterol 1998 17 2 53 54 9563220
520. McGarr PL Madiba TE Thomson SR Corr P Amoebic liver abscess — results of a conservative management policy 2003 93 2 5 12640885
521. Cheng H-P Siu LK Chang F-Y Extended-spectrum cephalosporin compared to cefazolin for treatment of klebsiella pneumoniaee-caused liver abscess Antimicrob Agents Chemother 2003 47 7 2088 2092 10.1128/AAC.47.7.2088-2092.2003 12821451
522. Liu Y Wang J Jiang W An increasing prominent disease of klebsiella pneumoniaee liver abscess: Etiology, diagnosis, and treatment Gastroenterol Res Pract 2013 2013 1 12 10.1155/2013/258514
523. Lübbert C Wiegand J Karlas T Therapy of liver abscesses Viszeralmedizin 2014 30 5 3 3 10.1159/000366579
524. Pal P Ray S Moulick A Dey S Jana A Banerjee K Liver abscess caused by Burkholderia pseudomallei in a young man: A case report and review of literature World J Clin Cases WJCC 2014 2 10 604 10.12998/wjcc.v2.i10.604 25325075
525. Sentochnik DE Eliopoulos GM Ferraro MJ Moellering RC Jr. Comparative in vitro activity of SM7338, a new carbapenem antimicrobial agent Antimicrob Agents Chemother 1989 33 8 1232 10.1128/AAC.33.8.1232 2508543
526. Pastagia M Arumugam V Klebsiella pneumoniaee liver abscesses in a public hospital in Queens, New York Travel Med Infect Dis 2008 6 4 228 233 10.1016/j.tmaid.2008.02.005 18571114
527. Yu SCH Ho SSM Lau WY Yeung DTK Yuen EHY Lee PSF et al. Treatment of pyogenic liver abscess: Prospective randomized comparison of catheter drainage and needle aspiration Hepatol Baltim Md 2004 39 4 932 938 10.1002/hep.20133
528. Zerem E Hadzic A Sonographically guided percutaneous catheter drainage versus needle aspiration in the management of pyogenic liver abscess AJR Am J Roentgenol 2007 189 3 W138 142 10.2214/AJR.07.2173 17715080
529. Cai Y-L Xiong X-Z Lu J Cheng Y Yang C Lin Y-X et al. Percutaneous needle aspiration versus catheter drainage in the management of liver abscess: A systematic review and meta-analysis HPB 2015 17 3 195 201 10.1111/hpb.12332 25209740
530. Heneghan HM Healy NA Martin ST Ryan RS Nolan N Traynor O et al. Modern management of pyogenic hepatic abscess: A case series and review of the literature BMC Res Notes 2011 4 80 10.1186/1756-0500-4-80 21435221
531. Andreu M Sola R Sitges-Serra A Alia C Gallen M Vila MC et al. Risk factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites Gastroenterology 1993 104 4 1133 1138 10.1016/0016-5085(93)90284-j 8462803
532. Uncu N Bülbül M Yildiz N Noyan A Koşan C Kavukçu S et al. Primary peritonitis in children with nephrotic syndrome: Results of a 5-year multicenter study Eur J Pediatr 2010 169 1 73 76 10.1007/s00431-009-0989-x 19430812
533. Mishra SP Tiwary SK Mishra M Gupta SK An introduction of tertiary peritonitis J Emerg Trauma Shock 2014 7 2 121 10.4103/0974-2700.130883 24812458
534. Weiss G Steffanie W Lippert H [Peritonitis: main reason of severe sepsis in surgical intensive care] Zentralbl Chir 2007 132 2 130 137 10.1055/s-2006-960478 17516319
535. Calandra T Cohen J International sepsis forum definition of infection in the ICU consensus conference The international sepsis forum consensus conference on definitions of infection in the intensive care unit Crit Care Med 2005 33 7 1538 1548 10.1097/01.ccm.0000168253.91200.83 16003060
536. Reemst PH van Goor H Goris RJ SIRS, MODS and tertiary peritonitis Eur J Surg Suppl 1996 576 47 49 8908471
537. Buijk SE Bruining HA Future directions in the management of tertiary peritonitis Intensive Care Med 2002 28 8 1024 1029 10.1007/s00134-002-1383-6 12185420
538. Evans HL Raymond DP Pelletier SJ Crabtree TD Pruett TL Sawyer RG Diagnosis of intra-abdominal infection in the critically ill patient Curr Opin Crit Care 2001 7 2 117 121 10.1097/00075198-200104000-00010 11373520
539. Ballus J Lopez-Delgado JC Sabater-Riera J Perez-Fernandez XL Betbese AJ Roncal JA Factors associated with the development of tertiary peritonitis in critically ill patients Surg Infect 2017 18 5 588 595 10.1089/sur.2016.018
540. França A Giordano HM Sevá-Pereira T Soares EC Five days of ceftriaxone to treat spontaneous bacterial peritonitis in cirrhotic patients J Gastroenterol 2002 37 2 119 122 10.1007/s005350200006 11871762
541. Marshall JC Innes M Intensive care unit management of intra-abdominal infection Crit Care Med 2003 31 8 2228 2237 10.1097/01.CCM.0000087326.59341.51 12973184
542. Nathens AB Rotstein OD Marshall JC Tertiary peritonitis: Clinical features of a complex nosocomial infection World J Surg 1998 22 2 158 163 10.1007/s002689900364 9451931
543. Rimola A Salmerón JM Clemente G Rodrigo L Obrador A Miranda ML et al. Two different dosages of cefotaxime in the treatment of spontaneous bacterial peritonitis in cirrhosis: Results of a prospective, randomized, multicenter study Hepatol Baltim Md 1995 21 3 674 679 7875666
544. European Association for the Study of the Liver EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis J Hepatol 2010 53 3 397 417 10.1016/j.jhep.2010.05.004 20633946
545. Navasa M Follo A Llovet JM Clemente G Vargas V Rimola A et al. Randomized, comparative study of oral ofloxacin versus intravenous cefotaxime in spontaneous bacterial peritonitis Gastroenterology 1996 111 4 1011 1017 10.1016/s0016-5085(96)70069-0 8831596
546. Terg R Cobas S Fassio E Landeira G Ríos B Vasen W et al. Oral ciprofloxacin after a short course of intravenous ciprofloxacin in the treatment of spontaneous bacterial peritonitis: Results of a multicenter, randomized study J Hepatol 2000 33 4 564 569 10.1034/j.1600-0641.2000.033004564.x 11059861
547. Biggins SW Angeli P Garcia-Tsao G Ginès P Ling SC Nadim MK et al. Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 practice guidance by the American Association for the study of liver diseases Hepatol Baltim Md 2021 74 2 1014 1048 10.1002/hep.31884
548. Fernández J Bert F Nicolas-Chanoine M-H The challenges of multidrug-resistance in hepatology J Hepatol 2016 65 5 1043 1054 10.1016/j.jhep.2016.08.006 27544545
549. Jindal A Kumar M Bhadoria AS Maiwall R Sarin SK A randomized open label study of “imipenem vs. cefepime” in spontaneous bacterial peritonitis Liver Int Off J Int Assoc Study Liver 2016 36 5 677 687 10.1111/liv.12985
550. Brismar B Malmborg AS Tunevall G Wretlind B Bergman L Mentzing LO et al. Piperacillin-tazobactam versus imipenem-cilastatin for treatment of intra-abdominal infections Antimicrob Agents Chemother 1992 36 12 2766 2773 10.1128/AAC.36.12.2766 1336347
551. Montravers P Lepape A Dubreuil L Gauzit R Pean Y Benchimol D et al. Clinical and microbiological profiles of community-acquired and nosocomial intra-abdominal infections: Results of the French prospective, observational EBIIA study J Antimicrob Chemother 2009 63 4 785 794 10.1093/jac/dkp005 19196742
552. Steinbach CL Töpper C Adam T Kees MG Spectrum adequacy of antibiotic regimens for secondary peritonitis: A retrospective analysis in intermediate and intensive care unit patients Ann Clin Microbiol Antimicrob 2015 14 48 10.1186/s12941-015-0110-4 26541549
553. Montravers P Blot S Dimopoulos G Eckmann C Eggimann P Guirao X et al. Therapeutic management of peritonitis: A comprehensive guide for intensivists Intensive Care Med 2016 42 8 1234 1247 10.1007/s00134-016-4307-6 26984317
554. Sawyer RG Claridge JA Nathens AB Rotstein OD Duane TM Evans HL et al. Trial of short-course antimicrobial therapy for intraabdominal infection N Engl J Med 2015 372 21 1996 2005 10.1056/NEJMoa1411162 25992746
555. Thigpen MC Whitney CG Messonnier NE Zell ER Lynfield R Hadler JL et al. Bacterial meningitis in the United States, 1998-2007 N Engl J Med 2011 364 21 2016 2025 10.1056/NEJMoa1005384 21612470
556. Ghia CJ Rambhad GS Meningococcal disease burden in india: A systematic review and meta-analysis Microbiol Insights 2021 14 11786361211053344 10.1177/11786361211053344 34866912
557. Moon S-Y Chung DR Kim S-W Chang HH Lee H Jung DS et al. Changing etiology of community-acquired bacterial meningitis in adults: A nationwide multicenter study in Korea Eur J Clin Microbiol Infect Dis 2010 29 7 793 800 10.1007/s10096-010-0929-8 20432052
558. Durand ML Calderwood SB Weber DJ Miller SI Southwick FS Caviness VS et al. Acute bacterial meningitis in adults – a review of 493 episodes N Engl J Med 1993 328 1 21 28 10.1056/NEJM199301073280104 8416268
559. Faustini A Arca’ M Fusco D Perucci CA Prognostic factors and determinants of fatal outcome due to bacterial meningitis in the Lazio region of Italy, 1996–2000 Int J Infect Dis 2007 11 2 137 144 10.1016/j.ijid.2005.12.004 16762581
560. Dzupova O Rozsypal H Prochazka B Benes J Acute bacterial meningitis in adults: Predictors of outcome Scand J Infect Dis 2009 41 5 348 354 10.1080/00365540902849391 19306157
561. Glimaker M Johansson B Grindborg O Bottai M Lindquist L Sjolin J Adult bacterial meningitis: Earlier treatment and improved outcome following guideline revision promoting prompt lumbar puncture Clin Infect Dis 2015 60 8 1162 1169 10.1093/cid/civ011 25663160
562. Grindborg ö Naucler P Sjölin J Glimåker M Adult bacterial meningitis—a quality registry study: Earlier treatment and favorable outcome if initial management by infectious diseases physicians Clin Microbiol Infect 2015 21 6 560 566 10.1016/j.cmi.2015.02.023 25752223
563. Armstrong D Ashworth M Dregan A White P The relationship between prior antimicrobial prescription and meningitis: A case-control study Br J Gen Pract 2016 66 645 e228 233 10.3399/bjgp16X684313 26965030
564. Domingo P Pomar V de Benito N Coll P The spectrum of acute bacterial meningitis in elderly patients BMC Infect Dis 2013 13 108 10.1186/1471-2334-13-108 23446215
565. Tankhiwale S S Jagtap P M Khadse R K Jalgaonkar S V Bacteriological study of pyogenic meningitis with special reference to C-reactive protein Indian J Med Microbiol 2001 19 3 159 17664824 17664824
566. Chandramuki A Mani R Pradhan S Nagarathna S Wasiulla R Bacteriological profile of community-acquired acute bacterial meningitis: A ten-year retrospective study in a tertiary neurocare center in South India Indian J Med Microbiol 2007 25 2 108 10.4103/0255-0857.32715 17582179
567. Madhumita P Gupta N Clinical and bacteriological spectrum of community-acquired acute bacterial meningitis in adults at a tertiary care hospital in northern India Int J Nutr Pharmacol Neurol Dis 2011 1 2 194 10.4103/2231-0738.84214
568. Vibha D Bhatia R Prasad K Srivastava MVP Tripathi M Singh MB Clinical features and independent prognostic factors for acute bacterial meningitis in adults Neurocrit Care 2010 13 2 199 204 10.1007/s12028-010-9396-4 20577910
569. Ghia CJ Rambhad GS A systematic literature review on the prevalence and etiology of meningitis among critically ill and hospitalized patients in India Ther Adv Infect Dis 2021 8 20499361211046453 10.1177/20499361211046453 34589213
570. Jayaraman Y Veeraraghavan B Chethrapilly Purushothaman GK Sukumar B Kangusamy B Nair Kapoor A et al. Burden of bacterial meningitis in India: Preliminary data from a hospital based sentinel surveillance network PloS One 2018 13 5 e0197198 10.1371/journal.pone.0197198 29768458
571. Williamson RA Phillips-Bute BG McDonagh DL Gray MC Zomorodi AR Olson DM et al. Predictors of extraventricular drain–associated bacterial ventriculitis J Crit Care 2014 29 1 77 82 10.1016/j.jcrc.2013.08.012 24125770
572. Chi H Chang K-Y Chang H-C Chiu N-C Huang F-Y Infections associated with indwelling ventriculostomy catheters in a teaching hospital Int J Infect Dis 2010 14 3 e216 219 10.1016/j.ijid.2009.04.006 19647466
573. Chen C-H Chang C-Y Lin L-J Chen WL Chang Y-J Wang S-H et al. Risk factors associated with postcraniotomy meningitis: A retrospective study Medicine (Baltimore) 2016 95 31 e4329 10.1097/MD.0000000000004329 27495035
574. Murthy SB Moradiya Y Shah J Hanley DF Ziai WC Incidence, predictors, and outcomes of ventriculostomy-associated infections in spontaneous intracerebral hemorrhage Neurocrit Care 2016 24 3 389 396 10.1007/s12028-015-0199-5 26337068
575. Citerio G Signorini L Bronco A Vargiolu A Rota M Latronico N External ventricular and lumbar drain device infections in icu patients: A prospective multicenter italian study Crit Care Med 2015 43 8 1630 1637 10.1097/CCM.0000000000001019 25867904
576. Arabi Y Memish ZA Balkhy HH Francis C Ferayan A Al Shimemeri A et al. Ventriculostomy-associated infections: Incidence and risk factors Am J Infect Control 2005 33 3 137 143 10.1016/j.ajic.2004.11.008 15798667
577. Beer R Lackner P Pfausler B Schmutzhard E Nosocomial ventriculitis and meningitis in neurocritical care patients J Neurol 2008 255 11 1617 1624 10.1007/s00415-008-0059-8 19156484
578. Korinek A-M Korinek A-M Laisne M-J Achou C Bromberg N Dagreou F et al. Risk factors for neurosurgical site infections after craniotomy: A prospective multicenter study of 2944 patients Neurosurgery 1997 41 5 1073 1081 10.1097/00006123-199711000-00010 9361061
579. Kourbeti IS Vakis AF Ziakas P Karabetsos D Potolidis E Christou S et al. Infections in patients undergoing craniotomy: Risk factors associated with post-craniotomy meningitis J Neurosurg 2014 122 5 1113 1119 10.3171/2014.8.JNS132557 25343179
580. Inoue T Shimizu H Fujimura M Sato K Endo H Niizuma K et al. Risk factors for meningitis after craniotomy in patients with subarachnoid hemorrhage due to anterior circulation aneurysms rupture Clin Neurol Neurosurg 2015 139 302 306 10.1016/j.clineuro.2015.10.029 26562195
581. Chen C Zhang B Yu S Sun F Ruan Q Zhang W et al. The incidence and risk factors of meningitis after major craniotomy in china: A retrospective cohort study PLOS ONE 2014 9 7 e101961 10.1371/journal.pone.0101961 25003204
582. Patir R Mahapatra AK Banerji AK Risk factors in postoperative neurosurgical infection: A prospective study Acta Neurochir (Wien) 1992 119 1–4 80 84 10.1007/BF01541786 1481758
583. Lietard C Thébaud V Besson G Lejeune B Risk factors for neurosurgical site infections: An 18-month prospective survey: Clinical article J Neurosurg 2008 109 4 729 734 10.3171/JNS/2008/109/10/0729 18826362
584. De Bels D Korinek A-M Bismuth R Trystram D Coriat P Puybasset L Empirical treatment of adult postsurgical nosocomial meningitis Acta Neurochir (Wien) 2002 144 10 989 995 10.1007/s00701-002-1001-y 12382127
585. Chidambaram S Nair MN Krishnan SS Cai L Gu W Vasudevan MC Postoperative central nervous system infection after neurosurgery in a modernized, resource-limited tertiary neurosurgical center in South Asia World Neurosurg 2015 84 6 1668 1673 10.1016/j.wneu.2015.07.006 26171888
586. Alotaibi AF Hulou MM Vestal M Alkholifi F Asgarzadeh M Cote DJ et al. The efficacy of antibacterial prophylaxis against the development of meningitis after craniotomy: A meta-analysis World Neurosurg 2016 90 597 603.e1 10.1016/j.wneu.2016.02.048 26921699
587. Moen V Dahlgren N Irestedt L Severe neurological complications after central neuraxial blockades in Sweden 1990–1999 Anesthesiol J Am Soc Anesthesiol 2004 101 4 950 959 10.1097/00000542-200410000-00021
588. Baer ET Post-dural puncture bacterial meningitis Anesthesiology 2006 105 2 381 393 10.1097/00000542-200608000-00022 16871073
589. Baltas I Tsoulfa S Sakellariou P Vogas V Fylaktakis M Kondodimou A Posttraumatic meningitis: Bacteriology, hydrocephalus, and outcome Neurosurgery 1994 35 3 422 427 10.1227/00006123-199409000-00009 7800133
590. Kourbeti IS Vakis AF Papadakis JA Karabetsos DA Bertsias G Filippou M et al. Infections in traumatic brain injury patients Clin Microbiol Infect 2012 18 4 359 364 10.1111/j.1469-0691.2011.03625.x 21851488
591. Ratilal BO Costa J Pappamikail L Sampaio C Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures Cochrane Database Syst Rev 2015 4 CD004884 10.1002/14651858.CD004884.pub4
592. Vinchon M Dhellemmes P Cerebrospinal fluid shunt infection: Risk factors and long-term follow-up Childs Nerv Syst 2006 22 7 692 697 10.1007/s00381-005-0037-8 16534646
593. Kulkarni AV Drake JM Lamberti-Pasculli M Cerebrospinal fluid shunt infection: A prospective study of risk factors J Neurosurg 2001 94 2 195 201 10.3171/jns.2001.94.2.0195 11213954
594. Tulipan N Cleves MA Effect of an intraoperative double-gloving strategy on the incidence of cerebrospinal fluid shunt infection J Neurosurg 2006 104 1 Suppl 5 8 10.3171/ped.2006.104.1.5 16509473
595. Kar M Jamwal A Dubey A Sahu C Patel SS Bacterial meningitis among intracranial surgery patients at a university hospital in Northern India Indian J Crit Care Med Peer-Rev Off Publ Indian Soc Crit Care Med 2022 26 12 1244 1252 10.5005/jp-journals-10071-24363
596. Srinivas D Veena Kumari HB Somanna S Bhagavatula I Anandappa CB The incidence of postoperative meningitis in neurosurgery: An institutional experience Neurol India 2011 59 2 195 198 10.4103/0028-3886.79136 21483116
597. Valiente De Santis LB Márquez Gómez I Sobrino Díaz B Pérez Camacho I Mediavilla Gradolph C Caballero Martínez LF et al. Nosocomial meningitis caused by ESBL- and OXA-48-producing Klebsiella pneumoniaee and treated with ceftazidime-avibactam. Report of one case and review of the literature Rev Espanola Quimioter Publicacion Of Soc Espanola Quimioter 2022 35 6 572 576 10.37201/req/043.2022
598. Sapra H Singhal V Managing meningoencephalitis in Indian ICU Indian J Crit Care Med Peer-Rev Off Publ Indian Soc Crit Care Med 2019 23 Suppl 2 S124 128 10.5005/jp-journals-10071-23189
599. Meyer CN Samuelsson IS Galle M Bangsborg JM Adult bacterial meningitis: Etiology, penicillin susceptibility, risk factors, prognostic factors and guidelines for empirical antibiotic treatment Clin Microbiol Infect 2004 10 8 709 717 10.1111/j.1469-0961.2004.00925.x 15301673
600. Erdem H Elaldi N Öztoprak N Sengoz G Ak O Kaya S et al. Mortality indicators in pneumococcal meningitis: Therapeutic implications Int J Infect Dis 2014 19 13 19 10.1016/j.ijid.2013.09.012 24211227
601. Prasad K Kumar A Singhal T Gupta PK Third generation cephalosporins versus conventional antibiotics for treating acute bacterial meningitis Cochrane Database Syst Rev 2007 4 CD001832 10.1002/14651858.CD001832.pub3 17943757
602. Sarvepalli AK Dharana PK Clinical profile, bacterial profile and outcomes of acute bacterial meningitis in a tertiary care hospital– one year study Int J Adv Med 2017 4 2 502 10.18203/2349-3933.ijam20171050
603. Tunkel AR Hartman BJ Kaplan SL Kaufman BA Roos KL Scheld WM et al. Practice guidelines for the management of bacterial meningitis Clin Infect Dis 2004 39 9 1267 1284 10.1086/425368 15494903
604. Zheng G Cao Y Liu C Qian L Cai Y Cui M et al. Phenotype, molecular characterisation and risk factors for postoperative meningitis caused by ESBL-producing-Enterobacteriaceae: A six years multi-Center comparative cohort study BMC Infect Dis 2021 21 1 85 10.1186/s12879-021-05784-7 33468073
605. Falagas ME Bliziotis IA Tam VH Intraventricular or intrathecal use of polymyxins in patients with gram-negative meningitis: A systematic review of the available evidence Int J Antimicrob Agents 2007 29 1 9 25 10.1016/j.ijantimicag.2006.08.024 17126534
606. Ng K Mabasa VH Chow I Ensom MHH Systematic review of efficacy, pharmacokinetics, and administration of intraventricular vancomycin in adults Neurocrit Care 2014 20 1 158 171 10.1007/s12028-012-9784-z 23090839
607. Tunkel AR Hasbun R Bhimraj A Byers K Kaplan SL Scheld WM et al. 2017 infectious diseases society of America's clinical practice guidelines for healthcare-associated ventriculitis and meningitis* Clin Infect Dis 2017 64 6 e34 65 10.1093/cid/ciw861 28203777
608. Karvouniaris M Brotis A Tsiakos K Palli E Koulenti D Current perspectives on the diagnosis and management of healthcare-associated ventriculitis and meningitis Infect Drug Resist 2022 15 697 721 10.2147/IDR.S326456 35250284
609. Fried HI Nathan BR Rowe AS Zabramski JM Andaluz N Bhimraj A et al. The insertion and management of external ventricular drains: An evidence-based consensus statement: A statement for healthcare professionals from the neurocritical care society Neurocrit Care 2016 24 1 61 81 10.1007/s12028-015-0224-8 26738503
610. Zhang Z Cai X Li J Kang X Wang H Zhang L et al. Retrospective analysis of 620 cases of brain abscess in Chinese patients in a single center over a 62-year period Acta Neurochir (Wien) 2016 158 4 733 739 10.1007/s00701-016-2741-4 26883550
611. Yang SY Brain abscess: A review of 400 cases J Neurosurg 1981 55 5 794 799 10.3171/jns.1981.55.5.0794 7310502
612. Brouwer MC Coutinho JM van de Beek D Clinical characteristics and outcome of brain abscess: Systematic review and meta-analysis Neurology 2014 82 9 806 813 10.1212/WNL.0000000000000172 24477107
613. Lakshmi V Rao RR Dinakar I Bacteriology of brain abscess - observations on 50 cases J Med Microbiol 1993 38 3 187 190 10.1099/00222615-38-3-187 7681113
614. Lakshmi V Umabala P Anuradha K Padmaja K Padmasree C Rajesh A et al. Microbiological spectrum of brain abscess at a tertiary care hospital in south india: 24-Year Data and Review Pathol Res Int 2011 2011 1 12 10.4061/2011/583139
615. Prasad KN Mishra AM Gupta D Husain N Husain M Gupta RK Analysis of microbial etiology and mortality in patients with brain abscess J Infect 2006 53 4 221 227 10.1016/j.jinf.2005.12.002 16436297
616. Menon S Bharadwaj R Chowdhary A Kaundinya DV Palande DA Current epidemiology of intracranial abscesses: A prospective 5 year study J Med Microbiol 2008 57 10 1259 1268 10.1099/jmm.0.47814-0 18809555
617. Chetty M Rakhi B Rachana K Sujatha S Srinivasan GM An eight year clinico-microbiological retrospective study on brain abscesses in India Microbiol Insights 2022 15 11786361221106111 10.1177/11786361221106111 35784588
618. Bodilsen J D'Alessandris QG Humphreys H Iro MA Klein M Last K et al. “European society of clinical microbiology and infectious diseases guidelines on diagnosis and treatment of brain abscess in children and adults” Author's reply Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 2024 30 1 149 150 10.1016/j.cmi.2023.10.012
619. Arlotti M Grossi P Pea F Tomei G Vullo V De Rosa FG et al. Consensus document on controversial issues for the treatment of infections of the central nervous system: bacterial brain abscesses Int J Infect Dis 2010 14 S79 S92 10.1016/j.ijid.2010.05.010 20846891
620. Angus DC Linde-Zwirble WT Lidicker J Clermont G Carcillo J Pinsky MR Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care Crit Care Med 2001 29 7 1303 1310 10.1097/00003246-200107000-00002 11445675
621. Mayr FB Yende S Angus DC Epidemiology of severe sepsis Virulence 2014 5 1 4 11 10.4161/viru.27372 24335434
622. Eron LJ Managing skin and soft tissue infections: Expert panel recommendations on key decision points J Antimicrob Chemother 2003 52 90001 3i 17 10.1093/jac/dkg466
623. Stevens DL Bisno AL Chambers HF Dellinger EP Goldstein EJC Gorbach SL et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 Update by the Infectious Diseases Society of America Clin Infect Dis 2014 59 2 e10 e52 10.1093/cid/ciu296 24973422
624. Mohanty A Mohapatra K Pal B Isolation and identification of Staphylococcus aureus from skin and soft tissue infection in sepsis cases, Odisha J Pure Appl Microbiol 2018 12 1 419 424 10.22207/JPAM.12.1.49
625. Afroz Z Metri BC Jyothi P Bacteriological profile and antimicrobial susceptibility pattern of skin and soft tissue infections among gram-negative bacilli in a tertiary care hospital of South India Journal of Pharmaceutical Sciences and Research 2015 7 7 397 Available from: https://www.jpsr.pharmainfo.in/Documents/Volumes/vol7Issue07/jpsr07071502.pdf
626. Mohanty S Kapil A Dhawan B Das BK Bacteriological and antimicrobial susceptibility profile of soft tissue infections from Northern India Indian J Med Sci 2004 58 1 10 15 14960796 14960796
627. Joshi S Ray P Manchanda V Bajaj J Chitnis DS Gautam V et al. Methicillin resistant Staphylococcus aureus (MRSA) in India: Prevalence & susceptibility pattern Indian J Med Res 2013 137 2 363 369 23563381 23563381
628. Giuliano A Lewis F Hadley K Blaisdell FW Bacteriology of necrotizing fasciitis Am J Surg 1977 134 1 52 57 10.1016/0002-9610(77)90283-5 327844
629. Wang J-M Lim H-K Necrotizing fasciitis: eight-year experience and literature review Braz J Infect Dis Off Publ Braz Soc Infect Dis 2014 18 2 137 143 10.1016/j.bjid.2013.08.003
630. Singh G Ray P Sinha SK Adhikary S Khanna SK Bacteriology of necrotizing infections of soft tissues Aust N Z J Surg 1996 66 11 747 750 10.1111/j.1445-2197.1996.tb00735.x 8918382
631. Arabi YM Dara SI Tamim HM Rishu AH Bouchama A Khedr MK et al. Clinical characteristics, sepsis interventions and outcomes in the obese patients with septic shock: An international multicenter cohort study Crit Care Lond Engl 2013 17 2 R72 10.1186/cc12680
632. Shen H-N Lu C-L Skin and soft tissue infections in hospitalized and critically ill patients: A nationwide population-based study BMC Infect Dis 2010 10 151 10.1186/1471-2334-10-151 20525332
633. McClaine RJ Husted TL Hebbeler‐Clark RS Solomkin JS Meta‐analysis of trials evaluating parenteral antimicrobial therapy for skin and soft tissue infections Clin Infect Dis 2010 50 8 1120 1126 10.1086/651264 20210644
634. Neville LO Brumfitt W Hamilton-Miller JMT Harding I Teicoplanin vs vancomycin for the treatment of serious infections: A randomized trial Int J Antimicrob Agents 1995 5 3 187 193 10.1016/0924-8579(95)00002-P 18611667
635. Liu C-Y Lee W-S Fung C-P Cheng N-C Liu C-L Yang S-P et al. comparative study of teicoplanin vs vancomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia Clin Drug Investig 1996 12 2 80 87 10.2165/00044011-199612020-00003
636. Peng Y Ye X Li Y Bu T Chen X Bi J et al. Teicoplanin as an effective alternative to vancomycin for treatment of mrsa infection in chinese population: A meta-analysis of randomized controlled trials PLoS ONE 2013 8 11 e79782 10.1371/journal.pone.0079782 24260299
637. Davis SL McKinnon PS Hall LM Delgado G Rose W Wilson RF et al. Daptomycin versus vancomycin for complicated skin and skin structure infections: clinical and economic outcomes Pharmacotherapy 2007 27 12 1611 1618 10.1592/phco.27.12.1611 18041881
638. White B Seaton RA Complicated skin and soft tissue infections: literature review of evidence for and experience with daptomycin Infect Drug Resist 2011 4 115 127 10.2147/IDR.S13808 21753891
639. Hepburn MJ Dooley DP Skidmore PJ Ellis MW Starnes WF Hasewinkle WC Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis Arch Intern Med 2004 164 15 1669 1674 10.1001/archinte.164.15.1669 15302637
640. Shankar-Hari M Phillips GS Levy ML Seymour CW Liu VX Deutschman CS et al. Developing a new definition and assessing new clinical criteria for septic shock: For the third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA 2016 315 8 775 787 10.1001/jama.2016.0289 26903336
641. Hatfield KM Dantes RB Baggs J Sapiano MRP Fiore AE Jernigan JA et al. assessing variability in hospital-level mortality among U.S. Medicare Beneficiaries with hospitalizations for severe sepsis and septic shock* Crit Care Med 2018 46 11 1753 10.1097/CCM.0000000000003324 30024430
642. Kaukonen K-M Bailey M Suzuki S Pilcher D Bellomo R Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012 JAMA 2014 311 13 1308 10.1001/jama.2014.2637 24638143
643. Ferrer R Martin-Loeches I Phillips G Osborn TM Townsend S Dellinger RP et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program* Crit Care Med 2014 42 8 1749 1755 10.1097/CCM.0000000000000330 24717459
644. Dellinger RP Schorr CA Levy MM A users’ guide to the 2016 surviving sepsis guidelines: Crit Care Med 2017 45 3 381 385 10.1097/CCM.0000000000002257 28099222
645. Kumar A Zarychanski R Light B Parrillo J Maki D Simon D et al. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: A propensity-matched analysis*: Crit Care Med 2010 38 9 1773 1785 10.1097/CCM.0b013e3181eb3ccd 20639750
646. Kumar A Safdar N Kethireddy S Chateau D A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: A meta-analytic/meta-regression study: Crit Care Med 2010 38 8 1651 1664 10.1097/CCM.0b013e3181e96b91 20562695
647. Kullberg BJ Arendrup MC Campion EW et al. Invasive candidiasis N Engl J Med 2015 373 15 1445 1456 10.1056/NEJMra1315399 26444731
648. Horn DL Neofytos D Anaissie EJ Fishman JA Steinbach WJ Olyaei AJ et al. Epidemiology and Outcomes of Candidemia in 2019 Patients: Data from the Prospective Antifungal Therapy Alliance Registry Clin Infect Dis 2009 48 12 1695 1703 10.1086/599039 19441981
649. McKinnon PS Temporal assessment of Candida risk factors in the surgical intensive care unit Arch Surg 2001 136 12 1401 10.1001/archsurg.136.12.1401 11735868
650. Michalopoulos AS Geroulanos S Mentzelopoulos SD Determinants of candidemia and candidemia-related death in cardiothoracic ICU patients Chest 2003 124 6 2244 2255 10.1378/chest.124.6.2244 14665507
651. Muskett H Shahin J Eyres G Harvey S Rowan K Harrison D Risk factors for invasive fungal disease in critically ill adult patients: A systematic review Crit Care 2011 15 6 R287 10.1186/cc10574 22126425
652. Gøtzsche PC Johansen HK Routine versus selective antifungal administration for control of fungal infections in patients with cancer Cochrane Database Syst Rev 2014 9 CD000026 10.1002/14651858.CD000026.pub2
653. Cruciani M de Lalla F Mengoli C Prophylaxis of Candida infections in adult trauma and surgical intensive care patients: A systematic review and meta-analysis Intensive Care Med 2005 31 11 1479 1487 10.1007/s00134-005-2794-y 16172847
654. Patel TS Eschenauer GA Stuckey LJ Carver PL Antifungal prophylaxis in lung transplant recipients: Transplantation 2016 100 9 1815 1826 10.1097/TP.0000000000001050
655. Fekkar A Dannaoui E Meyer I Imbert S Brossas JY Uzunov M et al. Emergence of echinocandin-resistant Candida spp. in a hospital setting: A consequence of 10 years of increasing use of antifungal therapy? Eur J Clin Microbiol Infect Dis 2014 33 9 1489 1496 10.1007/s10096-014-2096-9 24715154
656. Lortholary O Desnos-Ollivier M Sitbon K Fontanet A Bretagne S Dromer F Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: A prospective multicenter study involving 2,441 patients Antimicrob Agents Chemother 2011 55 2 532 538 10.1128/AAC.01128-10 21078946
657. Pfaller MA Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment Am J Med 2012 125 1 S3 S13 10.1016/j.amjmed.2011.11.001 22196207
658. Garbino J Lew D Jacques AR Hugonnet S Auckenthaler R Pittet D Prevention of severe Candida infections in nonneutropenic, high-risk, critically ill patients: A randomized, double-blind, placebo-controlled trial in patients treated by selective digestive decontamination Intensive Care Med 2002 28 12 1708 1717 10.1007/s00134-002-1540-y 12447512
659. Rex JH Pappas PG Karchmer AW Sobel J Edwards JE Hadley S et al. A randomized and blinded multicenter trial of high‐dose fluconazole plus placebo versus fluconazole plus Amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects Clin Infect Dis 2003 36 10 1221 1228 10.1086/374850 12746765
660. Ostrosky-Zeichner L Al-Obaidi M Invasive fungal infections in the intensive care unit Infect Dis Clin North Am 2017 31 3 475 487 10.1016/j.idc.2017.05.005 28687215
661. Namikawa T Kitagawa H Yamatsuji T Naomoto Y Kobayashi M Hanazaki K Pre-emptive treatment of fungal infection based on plasma β-D-glucan levels after gastric surgery for gastric cancer in elderly patients: Pre-emptive therapy for fungal infection J Gastroenterol Hepatol 2013 28 9 1457 1461 10.1111/jgh.12219 23574148
662. Timsit J-F Azoulay E Schwebel C Charles PE Cornet M Souweine B et al. Empirical micafungin treatment and survival without invasive fungal infection in adults with ICU-acquired sepsis, Candida colonization, and multiple organ failure: The EMPIRICUS randomized clinical trial JAMA 2016 316 15 1555 10.1001/jama.2016.14655 27706483
663. Cortegiani A Russotto V Maggiore A Attanasio M Naro AR Raineri SM et al. Antifungal agents for preventing fungal infections in non‐neutropenic critically ill patients Cochrane Database Syst Rev 2016 1 CD004920 10.1002/14651858.CD004920.pub3
664. Mathur P Gunjiyal J Tak V Varghese P Xess I Misra M The epidemiological profile of candidemia at an Indian trauma care center J Lab Physicians 2014 6 2 96 10.4103/0974-2727.141506 25328334
665. Society for Healthcare Epidemiology of America, Infectious Diseases Society of America, Pediatric Infectious Diseases Society Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS) Infect Control Hosp Epidemiol 2012 33 4 322 327 10.1086/665010 22418625
666. Tamma PD Avdic E Li DX Dzintars K Cosgrove SE Association of adverse events with antibiotic use in hospitalized patients JAMA Intern Med 2017 177 9 1308 1315 10.1001/jamainternmed.2017.1938 28604925
667. Centers for Disease Control Core Elements of Hospital Antibiotic Stewardship Programs Antibiotic Use 2017
668. Schuts EC Hulscher MEJL Mouton JW Verduin CM Stuart JWTC Overdiek HWPM et al. Current evidence on hospital antimicrobial stewardship objectives: A systematic review and meta-analysis Lancet Infect Dis 2016 16 7 847 856 10.1016/S1473-3099(16)00065-7 26947617
669. Tabah A Cotta MO Garnacho-Montero J Schouten J Roberts JA Lipman J et al. A systematic review of the definitions, determinants, and clinical outcomes of antimicrobial de-escalation in the intensive care unit Clin Infect Dis Off Publ Infect Dis Soc Am 2016 62 8 1009 1017 10.1093/cid/civ1199
670. Leone M Bechis C Baumstarck K Lefrant J-Y Albanèse J Jaber S et al. De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: A multicenter non-blinded randomized noninferiority trial Intensive Care Med 2014 40 10 1399 1408 10.1007/s00134-014-3411-8 25091790
671. Davey P Marwick CA Scott CL Charani E McNeil K Brown E et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. In: Cochrane database of systematic reviews John Wiley & Sons, Ltd; 2017 10.1002/14651858.CD003543.pub4
672. Barlam TF Cosgrove SE Abbo LM MacDougall C Schuetz AN Septimus EJ et al. Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Clin Infect Dis 2016 62 10 e51 e77 10.1093/cid/ciw118 27080992
673. Dellit TH Owens RC McGowan JE Gerding DN Weinstein RA Burke JP et al. Infectious diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an Institutional Program to Enhance Antimicrobial Stewardship Clin Infect Dis 2007 44 2 159 177 10.1086/510393 17173212
674. Cosgrove SE Seo SK Bolon MK Sepkowitz KA Climo MW Diekema DJ et al. Evaluation of postprescription review and feedback as a method of promoting rational antimicrobial use: A multicenter intervention Infect Control Hosp Epidemiol 2012 33 4 374 380 10.1086/664771 22418633
675. Vettese N Hendershot J Irvine M Wimer S Chamberlain D Massoud N Outcomes associated with a thrice-weekly antimicrobial stewardship programme in a 253-bed community hospital J Clin Pharm Ther 2013 38 5 401 404 10.1111/jcpt.12079 23845154
676. Tamma PD Avdic E Keenan JF Zhao Y Anand G Cooper J et al. what is the more effective antibiotic stewardship intervention: preprescription authorization or postprescription review with feedback? Clin Infect Dis Off Publ Infect Dis Soc Am 2017 64 5 537 543 10.1093/cid/ciw780
677. Mehta JM Haynes K Wileyto EP Gerber JS Timko DR Morgan SC et al. Comparison of prior authorization and prospective audit with feedback for antimicrobial stewardship Infect Control Hosp Epidemiol 2014 35 9 1092 1099 10.1086/677624 25111916
678. Kollef MH Vlasnik J Sharpless L Pasque C Murphy D Fraser V Scheduled change of antibiotic classes: A strategy to decrease the incidence of ventilator-associated pneumoniae Am J Respir Crit Care Med 1997 156 4 Pt 1 1040 1048 10.1164/ajrccm.156.4.9701046 9351601
679. Gruson D Hilbert G Vargas F Valentino R Bebear C Allery A et al. Rotation and restricted use of antibiotics in a medical intensive care unit. Impact on the incidence of ventilator-associated pneumoniae caused by antibiotic-resistant gram-negative bacteria Am J Respir Crit Care Med 2000 162 3 Pt 1 837 843 10.1164/ajrccm.162.3.9905050 10988092
680. Raymond DP Pelletier SJ Crabtree TD Gleason TG Hamm LL Pruett TL et al. Impact of a rotating empiric antibiotic schedule on infectious mortality in an intensive care unit Crit Care Med 2001 29 6 1101 1108 10.1097/00003246-200106000-00001 11395583
681. Cobos-Trigueros N Solé M Castro P Torres JL Rinaudo M De Lazzari E et al. Evaluation of a mixing versus a cycling strategy of antibiotic use in critically-ill medical patients: Impact on acquisition of resistant microorganisms and clinical outcomes PloS One 2016 11 3 e0150274 10.1371/journal.pone.0150274 26982807
682. Jones M Huttner B Madaras-Kelly K Nechodom K Nielson C Goetz MB et al. Parenteral to oral conversion of fluoroquinolones: low-hanging fruit for antimicrobial stewardship programs? Infect Control Hosp Epidemiol 2012 33 04 362 367 10.1086/664767 22418631
683. Sevinç F Prins JM Koopmans RP Langendijk PN Bossuyt PM Dankert J et al. Early switch from intravenous to oral antibiotics: guidelines and implementation in a large teaching hospital J Antimicrob Chemother 1999 43 4 601 606 10.1093/jac/43.4.601 10350396
684. Mertz D Koller M Haller P Lampert ML Plagge H Hug B et al. Outcomes of early switching from intravenous to oral antibiotics on medical wards J Antimicrob Chemother 2009 64 1 188 199 10.1093/jac/dkp131 19401304
685. Oosterheert JJ Bonten MJM Schneider MME Buskens E Lammers J-WJ Hustinx WMN et al. Effectiveness of early switch from intravenous to oral antibiotics in severe community-acquired pneumoniae: Multicenter randomized trial BMJ 2006 333 7580 1193 10.1136/bmj.38993.560984.BE 17090560
686. Omidvari K de Boisblanc BP Karam G Nelson S Haponik E Summer W Early transition to oral antibiotic therapy for community-acquired pneumoniae: Duration of therapy, clinical outcomes, and cost analysis Respir Med 1998 92 8 1032 1039 10.1016/s0954-6111(98)90351-1 9893772
687. van Niekerk AC Venter DJL Boschmans S-A Implementation of intravenous to oral antibiotic switch therapy guidelines in the general medical wards of a tertiary-level hospital in South Africa J Antimicrob Chemother 2012 67 3 756 762 10.1093/jac/dkr526 22167244
688. Guo Y Gao W Yang H Ma C'en Sui S De-escalation of empiric antibiotics in patients with severe sepsis or septic shock: A meta-analysis Heart Lung J Crit Care 2016 45 5 454 459 10.1016/j.hrtlng.2016.06.001
689. Westwood M Ramaekers B Whiting P Tomini F Joore M Armstrong N et al. Procalcitonin testing to guide antibiotic therapy for the treatment of sepsis in intensive care settings and for suspected bacterial infection in emergency department settings: A systematic review and cost-effectiveness analysis Health Technol Assess Winch Engl 2015 19 96 5 25, 1–236 10.3310/hta19960
690. Darmon M Azoulay E Critical care management of cancer patients: cause for optimism and need for objectivity Curr Opin Oncol 2009 21 4 318 326 10.1097/CCO.0b013e32832b68b6 19436200
691. Ñamendys-Silva SA Plata-Menchaca EP Rivero-Sigarroa E Herrera-Gómez A Opening the doors of the intensive care unit to cancer patients: A current perspective World J Crit Care Med 2015 4 3 159 162 10.5492/wjccm.v4.i3.159 26261768
692. Jindal AK Pilania RK Rawat A Singh S Primary immunodeficiency disorders in India—A situational review Front Immunol 2017 8 714 10.3389/fimmu.2017.00714 28674536
693. Klastersky J de Naurois J Rolston K Rapoport B Maschmeyer G Aapro M et al. Management of febrile neutropaenia: ESMO clinical practice guidelines Ann Oncol Off J Eur Soc Med Oncol 2016 27 suppl 5 v111 v118 10.1093/annonc/mdw325
694. Wisplinghoff H Seifert H Wenzel RP Edmond MB Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States Clin Infect Dis Off Publ Infect Dis Soc Am 2003 36 9 1103 1110 10.1086/374339
695. Freifeld AG Bow EJ Sepkowitz KA Boeckh MJ Ito JI Mullen CA et al. clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America Clin Infect Dis 2011 52 4 e56 e93 10.1093/cid/cir073 21258094
696. Prabhash K Medhekar A Ghadyalpatil N Noronha V Biswas S Kurkure P et al. Bloodstream infections in cancer patients: A single center experience of isolates and sensitivity pattern Indian J Cancer 2010 47 2 184 188 10.4103/0019-509X.63019 20448384
697. Karanwal AB Parikh BJ Goswami P Panchal HP Parekh BB Patel KB Review of clinical profile and bacterial spectrum and sensitivity patterns of pathogens in febrile neutropenic patients in hematological malignancies: A retrospective analysis from a single center Indian J Med Paediatr Oncol Off J Indian Soc Med Paediatr Oncol 2013 34 2 85 88 10.4103/0971-5851.116184
698. Singh R Jain S Chabbra R Naithani R Upadhyay A Walia M Characterization and antimicrobial susceptibility of bacterial isolates: Experience from a tertiary care cancer center in Delhi Indian J Cancer 2014 51 4 477 480 10.4103/0019-509X.175305 26842169
699. Rajendranath R Balasubramaniyum VKK Vijayakumar V Ganesan P Tenali GS Factors predicting outcome in high risk febrile neutropenia in patients receiving intensive chemotherapy for acute sleukemia: A prospective, observational study from South India Indian J Cancer 2014 51 4 481 486 10.4103/0019-509X.175303 26842171
700. Sengar M Kelkar R Jain H Biswas S Pawaskar P Karpe A Frequency of bacterial isolates and pattern of antimicrobial resistance in patients with hematological malignancies: A snapshot from tertiary cancer center Indian J Cancer 2014 51 4 456 458 10.4103/0019-509X.175387 26842160
701. Lakshmaiah KC Abhayakumar SM Shetty R Loknath D Jayashree RS Govindbabu K Management of febrile neutropenia in solid organ malignancies following chemotherapy J Cancer Res Ther 2014 10 3 540 543 10.4103/0973-1482.137908 25313735
702. Bhat V Gupta S Kelkar R Biswas S Khattry N Moiyadi A et al. Bacteriological profile and antibiotic susceptibility patterns of clinical isolates in a tertiary care cancer center Indian J Med Paediatr Oncol Off J Indian Soc Med Paediatr Oncol 2016 37 1 20 24 10.4103/0971-5851.177010
703. Bhat S Muthunatarajan S Mulki SS Archana Bhat K Kotian KH Bacterial infection among cancer patients: Analysis of isolates and antibiotic sensitivity pattern Int J Microbiol. Hindawi; 2021 2021 e8883700 10.1155/2021/8883700
704. Laxminarayan R Chaudhury RR Antibiotic resistance in India: Drivers and opportunities for action PLoS Med 2016 13 3 e1001974 10.1371/journal.pmed.1001974 26934098
705. Sood S Gupta R Antibiotic resistance pattern of community-acquired uropathogens at a tertiary care hospital in Jaipur, Rajasthan Indian J Community Med Off Publ Indian Assoc Prev Soc Med. Wolters Kluwer -- Medknow Publications; 2012 37 1 39 10.4103/0970-0218.94023
706. Kakkar M Walia K Vong S Chatterjee P Sharma A Antibiotic resistance and its containment in India BMJ 2017 358 j2687 10.1136/bmj.j2687 28874365
707. Aggarwal S Walia K, J M Gopalkrishnan R Ohri V Gangakhedkar R Treatment guidelines for antimicrobial use in common syndromes 2019 New Delhi, India i ICMR, New Delhi treatment guidelines for antimicrobial use in common syndromes. 2nd edition. 2019 Available from: https://main.icmr.nic.in/sites/default/files/guidelines/Treatment_Guidelines_2019_Final.pdf
708. Averbuch D Orasch C Cordonnier C Livermore DM Mikulska M Viscoli C et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia Hematologica. Hematologica 2013 98 12 1826 1835 10.3324/haematol.2013.091025
709. Beyar-Katz O Dickstein Y Borok S Vidal L Leibovici L Paul M Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer Cochrane Database Syst Rev 2017 6 6 CD003914 10.1002/14651858.CD003914.pub4 28577308
710. L E A R W A M A Cm C C F et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med Intensive Care Med 2021 47 11 10.1007/s00134-021-06506-y
711. Cheng MP Stenstrom R Paquette K Stabler SN Akhter M Davidson AC et al. Blood culture results before and after antimicrobial administration in patients with severe manifestations of sepsis: A diagnostic study Ann Intern Med 2019 171 8 547 554 10.7326/M19-1696 31525774
712. Bodey G Bueltmann B Duguid W Gibbs D Hanak H Hotchi M et al. Fungal infections in cancer patients: An international autopsy survey Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol 1992 11 2 99 109 10.1007/BF01967060
713. Kibbler CC Empirical antifungal therapy in febrile neutropenic patients: current status Curr Top Med Mycol 1997 8 1–2 5 14 9504062 9504062
714. Wingard JR Leather HL Empiric antifungal therapy for the neutropenic patient Oncol Williston Park N 2001 15 3 351 363; discussion 363-364, 367–9 11301832
715. Cho SY Choi HY Opportunistic fungal infection among cancer patients. A ten-year autopsy study Am J Clin Pathol 1979 72 4 617 621 10.1093/ajcp/72.4.617 495566
716. Pagano L Caira M Candoni A Offidani M Fianchi L Martino B et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study Hematologica 2006 91 8 1068 1075 16885047
717. Goodman JL Winston DJ Greenfield RA Chandrasekar PH Fox B Kaizer H et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation N Engl J Med 1992 326 13 845 851 10.1056/NEJM199203263261301 1542320
718. Gerson SL Talbot GH Hurwitz S Strom BL Lusk EJ Cassileth PA Prolonged granulocytopenia: The major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia Ann Intern Med 1984 100 3 345 531 10.7326/0003-4819-100-3-345 6696356
719. Goldberg E Gafter-Gvili A Robenshtok E Leibovici L Paul M Empirical antifungal therapy for patients with neutropenia and persistent fever: Systematic review and meta-analysis Eur J Cancer Oxf Engl 1990 2008 44 15 2192 2203 10.1016/j.ejca.2008.06.040
720. Leeflang MM Debets‐Ossenkopp YJ Wang J Visser CE Scholten RJ Hooft L et al. Galactomannan detection for invasive aspergillosis in immunocompromised patients Cochrane Database Syst Rev 2015 2015 12 CD007394 10.1002/14651858.CD007394.pub2 26716951
721. Maertens J Theunissen K Verhoef G Verschakelen J Lagrou K Verbeken E et al. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: A prospective feasibility study Clin Infect Dis Off Publ Infect Dis Soc Am 2005 41 9 1242 1250 10.1086/496927
722. de Heer K Gerritsen MG Visser CE Leeflang MM Galactomannan detection in broncho-alveolar lavage fluid for invasive aspergillosis in immunocompromised patients Cochrane Database Syst Rev 2019 5 5 CD012399 10.1002/14651858.CD012399.pub2 31107543
723. Senn L Robinson JO Schmidt S Knaup M Asahi N Satomura S et al. 1,3-Beta-D-glucan antigenemia for early diagnosis of invasive fungal infections in neutropenic patients with acute leukemia Clin Infect Dis Off Publ Infect Dis Soc Am 2008 46 6 878 885 10.1086/527382
724. Karageorgopoulos DE Vouloumanou EK Ntziora F Michalopoulos A Rafailidis PI Falagas ME β-D-glucan assay for the diagnosis of invasive fungal infections: A meta-analysis Clin Infect Dis Off Publ Infect Dis Soc Am 2011 52 6 750 770 10.1093/cid/ciq206
725. Patterson TF Thompson GR Denning DW Fishman JA Hadley S Herbrecht R et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America Clin Infect Dis Off Publ Infect Dis Soc Am 2016 63 4 e1 e60 10.1093/cid/ciw326
726. Uneno Y Imura H Makuuchi Y Tochitani K Watanabe N Pre-emptive antifungal therapy versus empirical antifungal therapy for febrile neutropenia in people with cancer Cochrane Database Syst Rev 2022 11 11 CD013604 10.1002/14651858.CD013604.pub2 36440894
727. Maertens J Lodewyck T Donnelly JP Chantepie S Robin C Blijlevens N et al. Empiric vs Preemptive Antifungal Strategy in High-Risk Neutropenic Patients on Fluconazole Prophylaxis: A Randomized Trial of the European Organization for Research and Treatment of Cancer Clin Infect Dis Off Publ Infect Dis Soc Am 2023 76 4 674 682 10.1093/cid/ciac623
728. Walsh TJ Finberg RW Arndt C Hiemenz J Schwartz C Bodensteiner D et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med 1999 340 10 764 771 10.1056/NEJM199903113401004
729. Walsh TJ Teppler H Donowitz GR Maertens JA Baden LR Dmoszynska A et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia N Engl J Med 2004 351 14 1391 1402 10.1056/NEJMoa040446 15459300
730. Lee D-G Kim S-H Kim SY Kim C-J Park WB Song YG et al. Evidence-based guidelines for empirical therapy of neutropenic fever in Korea Korean J Intern Med 2011 26 2 220 252 10.3904/kjim.2011.26.2.220 21716917
731. Eschenauer G Depestel DD Carver PL Comparison of echinocandin antifungals Ther Clin Risk Manag 2007 3 1 71 97 10.2147/tcrm.2007.3.1.71 18360617
732. Walsh TJ Pappas P Winston DJ Lazarus HM Petersen F Raffalli J et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever N Engl J Med 2002 346 4 225 234 10.1056/NEJM200201243460403 11807146
733. Maertens JA Rahav G Lee D-G Ponce-de-León A Ramírez Sánchez IC Klimko N et al. Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: A phase 3, randomized, controlled, non-inferiority trial Lancet Lond Engl 2021 397 10273 499 509 10.1016/S0140-6736(21)00219-1
734. Maertens JA Raad II Marr KA Patterson TF Kontoyiannis DP Cornely OA et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by aspergillus and other filamentous fungi (SECURE): A phase 3, randomized-controlled, non-inferiority trial Lancet Lond Engl 2016 387 10020 760 769 10.1016/S0140-6736(15)01159-9
735. Kullberg BJ Viscoli C Pappas PG Vazquez J Ostrosky-Zeichner L Rotstein C et al. Isavuconazole versus caspofungin in the treatment of candidemia and other invasive Candida infections: The ACTIVE trial Clin Infect Dis Off Publ Infect Dis Soc Am 2019 68 12 1981 1989 10.1093/cid/ciy827
736. Boogaerts M Winston DJ Bow EJ Garber G Reboli AC Schwarer AP et al. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial Ann Intern Med 2001 135 6 412 422 10.7326/0003-4819-135-6-200109180-00010 11560454
737. Marr KA Schlamm HT Herbrecht R Rottinghaus ST Bow EJ Cornely OA et al. Combination antifungal therapy for invasive aspergillosis: A randomized trial Ann Intern Med 2015 162 2 81 89 10.7326/M13-2508 25599346
738. Martin-Garrido I Carmona EM Specks U Limper AH Pneumocystis pneumoniae in patients treated with rituximab Chest 2013 144 1 258 265 10.1378/chest.12-0477 23258406
739. Byrd JC Hargis JB Kester KE Hospenthal DR Knutson SW Diehl LF Opportunistic pulmonary infections with fludarabine in previously treated patients with low-grade lymphoid malignancies: A role for pneumocystis carinii pneumoniae prophylaxis Am J Hematol 1995 49 2 135 142 10.1002/ajh.2830490207 7771465
740. Roblot F Imbert S Godet C Kauffmann C Ragot S Le Moal G et al. Risk factors analysis for Pneumocystis jiroveci pneumoniae (PCP) in patients with hematological malignancies and pneumoniae Scand J Infect Dis 2004 36 11–12 848 854 10.1080/00365540410021180 15764172
741. Classen AY Henze L von Lilienfeld-Toal M Maschmeyer G Sandherr M Graeff LD et al. Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumoniae in patients with hematologic malignancies and solid tumors: 2020 updated guidelines of the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO/DGHO) Ann Hematol 2021 100 6 1603 1620 10.1007/s00277-021-04452-9 33846857
742. Anderson NW Buchan BW Ledeboer NA Light microscopy, culture, molecular, and serologic methods for detection of herpes simplex virus J Clin Microbiol 2014 52 1 2 8 10.1128/JCM.01966-13 24131689
743. Leland DS Ginocchio CC Role of cell culture for virus detection in the age of technology Clin Microbiol Rev 2007 20 1 49 78 10.1128/CMR.00002-06 17223623
744. Nichols WG Corey L Gooley T Davis C Boeckh M Parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome Blood 2001 98 3 573 578 10.1182/blood.v98.3.573 11468152
745. Small TN Casson A Malak SF Boulad F Kiehn TE Stiles J et al. Respiratory syncytial virus infection following hematopoietic stem cell transplantation Bone Marrow Transplant 2002 29 4 321 327 10.1038/sj.bmt.1703365 11896429
746. Noronha V Goyal G Joshi A Gupta S Ghosh J Bajpai J et al. Presentation, complications, and impact of concurrent malaria infection on anticancer therapy Indian J Cancer 2013 50 3 254 260 10.4103/0019-509X.118734 24061468
747. Advani SH Banavali SD Pattern of infection in hematologic malignancies: An Indian experience Rev Infect Dis 1989 11 Suppl 7 S1621 1628 10.1093/clinids/11.supplement_7.s1621 2602780
748. Wells CL Ferrieri P Weisdorf DJ Rhame FS The importance of surveillance stool cultures during periods of severe neutropenia Infect Control IC 1987 8 8 317 319 10.1017/s0195941700066406 3308740
749. Cohen ML Murphy MT Counts GW Buckner CD Clift RA Meyers JD Prediction by surveillance cultures of bacteremia among neutropenic patients treated in a protective environment J Infect Dis 1983 147 5 789 793 10.1093/infdis/147.5.789 6341483
750. Simojoki S-T Kirjavainen V Rahiala J Kanerva J Surveillance cultures in pediatric allogeneic hematopoietic stem cell transplantation Pediatr Transplant 2014 18 1 87 93 10.1111/petr.12177 24152015
751. Ghazal SS Stevens MP Bearman GM Edmond MB Utility of surveillance blood cultures in patients undergoing hematopoietic stem cell transplantation Antimicrob Resist Infect Control 2014 3 1 20 10.1186/2047-2994-3-20 24999384
752. de Jonge NA Sikkens JJ Zweegman S Beeker A Ypma P Herbers AH et al. Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: A non-inferiority, open-label, multicenter, randomized trial Lancet Haematol 2022 9 8 e563 e72 10.1016/S2352-3026(22)00145-4 35691326
753. Bucaneve G Micozzi A Picardi M Ballanti S Cascavilla N Salutari P et al. Results of a multicenter, controlled, randomized clinical trial evaluating the combination of piperacillin/tazobactam and tigecycline in high-risk hematologic patients with cancer with febrile neutropenia J Clin Oncol Off J Am Soc Clin Oncol 2014 32 14 1463 1471 10.1200/JCO.2013.51.6963
754. Putensen C Ellger B Sakka SG Weyland A Schmidt K Zoller M et al. Current clinical use of intravenous fosfomycin in ICU patients in two European countries Infection 2019 47 5 827 836 10.1007/s15010-019-01323-4 31190298
755. Fishman JA Infection in solid-organ transplant recipients N Engl J Med 2007 357 25 2601 2614 10.1056/NEJMra064928 18094380
756. Fishman JA Infection in organ transplantation Am J Transplant 2017 17 4 856 879 10.1111/ajt.14208 28117944
757. Timsit J-F Sonneville R Kalil AC Bassetti M Ferrer R Jaber S et al. Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients Intensive Care Med 2019 45 5 573 591 10.1007/s00134-019-05597-y 30911807
758. Florescu DF Sandkovsky U Kalil AC Sepsis and challenging infections in the immunosuppressed patient in the intensive care unit Infect Dis Clin North Am 2017 31 3 415 434 10.1016/j.idc.2017.05.009 28687212
759. Ram R Dakshina Murty KV Prasad N Time table of infections after renal transplantation–South Indian experience Indian J Nephrol 2005 15 Suppl 2 S14 S21
760. Kumar A Agarwal C Hooda AK Ojha A Dhillon M Hari Kumar KVS Profile of infections in renal transplant recipients from India J Fam Med Prim Care 2016 5 3 611 614 10.4103/2249-4863.197320
761. Sriperumbuduri S Kalidindi K Guditi S Taduri G Declining trend of infections in renal transplant recipients in a tertiary care hospital from India Indian J Transplant 2017 11 3 143 10.4103/ijot.ijot_21_17
762. Neelima A Umabala P Patil MA Padmaja K Sukanya S Teja DV Microbiological profile of transplant recipients in a tertiary care hospital in South India Trop J Pathol Microbiol 2019 5 2 107 111 10.17511/jopm.2019.i02.10
763. Al-Hasan MN Razonable RR Eckel-Passow JE Baddour LM Incidence rate and outcome of gram-negative bloodstream infection in solid organ transplant recipients Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2009 9 4 835 843 10.1111/j.1600-6143.2009.02559.x
764. van Delden C Stampf S Hirsch HH Manuel O Meylan P Cusini A et al. Burden and timeline of infectious diseases in the first year after solid organ transplantation in the swiss transplant cohort study Clin Infect Dis Off Publ Infect Dis Soc Am 2020 71 7 e159 e169 10.1093/cid/ciz1113
765. Green H Rahamimov R Gafter U Leibovitci L Paul M Antibiotic prophylaxis for urinary tract infections in renal transplant recipients: A systematic review and meta-analysis Transpl Infect Dis Off J Transplant Soc 2011 13 5 441 447 10.1111/j.1399-3062.2011.00644.x
766. van Duin D van Delden C AST Infectious Diseases Community of Practice. Multidrug-resistant gram-negative bacteria infections in solid organ transplantation Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2013 13 Suppl 4 31 S41 10.1111/ajt.12096
767. Goldman JD Julian K Urinary tract infections in solid organ transplant recipients: Guidelines from the American Society of transplantation infectious diseases community of practice Clin Transplant 2019 33 9 e13507 10.1111/ctr.13507 30793386
768. Fluoroquinolone and quinolone antibiotics: PRAC recommends new restrictions on use following review of disabling and potentially long-lasting side effects | European Medicines Agency [cited 2024 Feb 13]. Available from: https://www.ema.europa.eu/en/news/fluoroquinolone-and-quinolone-antibiotics-prac-recommends-new-restrictions-use-following-review-disabling-and-potentially-long-lasting-side-effects
769. Dulek DE Mueller NJ AST infectious diseases community of practice. Pneumoniae in solid organ transplantation: Guidelines from the American Society of transplantation infectious diseases community of practice Clin Transplant 2019 33 9 e13545 10.1111/ctr.13545 30900275
770. Danés C González-Martín J Pumarola T Rañó A Benito N Torres A et al. Pulmonary infiltrates in immunosuppressed patients: Analysis of a diagnostic protocol J Clin Microbiol 2002 40 6 2134 2140 10.1128/JCM.40.6.2134-2140.2002 12037077
771. Knollmann FD Mäurer J Bechstein WO Vogl TJ Neuhaus P Felix R Pulmonary disease in liver transplant recipients. Spectrum of CT features Acta Radiol Stockh Swed 1987 2000 41 3 230 236 10.1080/028418500127345406
772. Rhodes A Evans LE Alhazzani W Levy MM Antonelli M Ferrer R et al. Surviving sepsis campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 Intensive Care Med 2017 43 3 304 377 10.1007/s00134-017-4683-6 28101605
773. Evans L Rhodes A Alhazzani W Antonelli M Coopersmith CM French C et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 Intensive Care Med 2021 47 11 1181 1247 10.1007/s00134-021-06506-y 34599691
774. Giannella M Muñoz P Alarcón JM Mularoni A Grossi P Bouza E et al. Pneumoniae in solid organ transplant recipients: A prospective multicenter study Transpl Infect Dis Off J Transplant Soc 2014 16 2 232 241 10.1111/tid.12193
775. Hoyo I Linares L Cervera C Almela M Marcos MA Sanclemente G et al. Epidemiology of pneumoniae in kidney transplantation Transplant Proc 2010 42 8 2938 2940 10.1016/j.transproceed.2010.07.082 20970576
776. Tomotani DYV Bafi AT Pacheco ES de Sandes-Freitas TV Viana LA de Oliveira Pontes EP et al. The diagnostic yield and complications of open lung biopsies in kidney transplant patients with pulmonary disease J Thorac Dis 2017 9 1 166 175 10.21037/jtd.2017.01.09 28203420
777. Hsu JL Kuschner WG Paik J Bower N Vazquez Guillamet MC Kothary N The diagnostic yield of CT-guided percutaneous lung biopsy in solid organ transplant recipients Clin Transplant 2012 26 4 615 621 10.1111/j.1399-0012.2011.01582.x 23050274
778. Razonable RR Humar A Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice Clin Transplant 2019 33 9 e13512 10.1111/ctr.13512 30817026
779. Humar A Michaels M AST ID working group on infectious disease monitoring. American Society of transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2006 6 2 262 274 10.1111/j.1600-6143.2005.01207.x
780. Ljungman P Boeckh M Hirsch HH Josephson F Lundgren J Nichols G et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials Clin Infect Dis Off Publ Infect Dis Soc Am 2017 64 1 87 91 10.1093/cid/ciw668
781. Chemaly RF Chou S Einsele H Griffiths P Avery R Razonable RR et al. Definitions of resistant and refractory cytomegalovirus infection and disease in transplant recipients for use in clinical trials Clin Infect Dis Off Publ Infect Dis Soc Am 2019 68 8 1420 1426 10.1093/cid/ciy696
782. Manuel O Husain S Kumar D Zayas C Mawhorter S Levi ME et al. Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant recipients: A multicenter cohort study Clin Infect Dis Off Publ Infect Dis Soc Am 2013 56 6 817 824 10.1093/cid/cis993
783. Manuel O Pang XL Humar A Kumar D Doucette K Preiksaitis JK An assessment of donor-to-recipient transmission patterns of human cytomegalovirus by analysis of viral genomic variants J Infect Dis 2009 199 11 1621 1628 10.1086/598952 19385736
784. Gardiner BJ Nierenberg NE Chow JK Ruthazer R Kent DM Snydman DR absolute lymphocyte count: a predictor of recurrent cytomegalovirus disease in solid organ transplant recipients Clin Infect Dis Off Publ Infect Dis Soc Am 2018 67 9 1395 1402 10.1093/cid/ciy295
785. Meesing A Abraham RS Razonable RR Clinical correlation of cytomegalovirus infection with cmv-specific cd8+ t-cell immune competence score and lymphocyte subsets in solid organ transplant recipients Transplantation 2019 103 4 832 838 10.1097/TP.0000000000002396 30086091
786. Humar A Gregson D Caliendo AM McGeer A Malkan G Krajden M et al. Clinical utility of quantitative cytomegalovirus viral load determination for predicting cytomegalovirus disease in liver transplant recipients Transplantation 1999 68 9 1305 1311 10.1097/00007890-199911150-00015 10573068
787. Dioverti MV Lahr BD Germer JJ Yao JD Gartner ML Razonable RR Comparison of standardized cytomegalovirus (CMV) viral load thresholds in whole blood and plasma of solid organ and hematopoietic stem cell transplant recipients with cmv infection and disease Open Forum Infect Dis 2017 4 3 ofx143 10.1093/ofid/ofx143 28852681
788. Beam E Germer JJ Lahr B Yao JDC Limper AH Binnicker MJ et al. Cytomegalovirus (CMV) DNA quantification in bronchoalveolar lavage fluid of immunocompromised patients with CMV pneumoniae Clin Transplant 2018 32 1 10.1111/ctr.13149
789. Marchetti S Santangelo R Manzara S D'onghia S Fadda G Cattani P Comparison of real-time PCR and pp65 antigen assays for monitoring the development of Cytomegalovirus disease in recipients of solid organ and bone marrow transplants New Microbiol 2011 34 2 157 164 21617827 21617827
790. Paya C Humar A Dominguez E Washburn K Blumberg E Alexander B et al. Efficacy and safety of valganciclovir vs oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2004 4 4 611 620 10.1111/j.1600-6143.2004.00382.x
791. Limaye AP Budde K Humar A Vincenti F Kuypers DRJ Carroll RP et al. Letermovir vs valganciclovir for prophylaxis of cytomegalovirus in high-risk kidney transplant recipients: A Randomized Clinical Trial JAMA 2023 330 1 33 42 10.1001/jama.2023.9106 37279999
792. Asberg A Humar A Rollag H Jardine AG Mouas H Pescovitz MD et al. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2007 7 9 2106 2113 10.1111/j.1600-6143.2007.01910.x
793. Lowance D Neumayer HH Legendre CM Squifflet JP Kovarik J Brennan PJ et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir cytomegalovirus prophylaxis transplantation study group N Engl J Med 1999 340 19 1462 1470 10.1056/NEJM199905133401903 10320384
794. Atabani SF Smith C Atkinson C Aldridge RW Rodriguez-Perálvarez M Rolando N et al. Cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2012 12 9 2457 2464 10.1111/j.1600-6143.2012.04087.x
795. Razonable RR Hayden RT Clinical utility of viral load in management of cytomegalovirus infection after solid organ transplantation Clin Microbiol Rev 2013 26 4 703 727 10.1128/CMR.00015-13 24092851
796. Sia IG Wilson JA Groettum CM Espy MJ Smith TF Paya CV Cytomegalovirus (CMV) DNA load predicts relapsing CMV infection after solid organ transplantation J Infect Dis 2000 181 2 717 720 10.1086/315242 10669361
797. Humar A Kumar D Boivin G Caliendo AM Cytomegalovirus (CMV) virus load kinetics to predict recurrent disease in solid-organ transplant patients with CMV disease J Infect Dis 2002 186 6 829 833 10.1086/342601 12198618
798. Razonable RR Åsberg A Rollag H Duncan J Boisvert D Yao JD et al. Virologic suppression measured by a cytomegalovirus (CMV) DNA test calibrated to the World Health Organization international standard is predictive of CMV disease resolution in transplant recipients Clin Infect Dis Off Publ Infect Dis Soc Am 2013 56 11 1546 1553 10.1093/cid/cit096
799. Subramanian AK Theodoropoulos NM Infectious diseases community of practice of the american society of transplantation. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation Clin Transplant 2019 33 9 e13513 10.1111/ctr.13513 30817030
800. Nambiar P Silibovsky R Belden KA Infection in kidney transplantation Contemp Kidney Transplant 2018 307 327 10.1007/978-3-319-19617-6_22
801. Torre-Cisneros J Doblas A Aguado JM San Juan R Blanes M Montejo M et al. Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort Clin Infect Dis Off Publ Infect Dis Soc Am 2009 48 12 1657 1665 10.1086/599035
802. Muñoz P Rodríguez C Bouza E Mycobacterium tuberculosis infection in recipients of solid organ transplants Clin Infect Dis Off Publ Infect Dis Soc Am 2005 40 4 581 587 10.1086/427692
803. Subramanian AK Tuberculosis in solid organ transplant Candidates and recipients: Current and future challenges Curr Opin Infect Dis 2014 27 4 316 321 10.1097/QCO.0000000000000082 24977684
804. Horne DJ Narita M Spitters CL Parimi S Dodson S Limaye AP Challenging issues in tuberculosis in solid organ transplantation Clin Infect Dis Off Publ Infect Dis Soc Am 2013 57 10 1473 1482 10.1093/cid/cit488
805. Bansal SB Ramasubramanian V Prasad N Saraf N Soman R Makharia G et al. South Asian transplant infectious disease guidelines for solid organ transplant Candidates, recipients, and donors Transplantation 2023 107 9 1910 1934 10.1097/TP.0000000000004521 36749281
806. Angarone M Snydman DR AST ID Community of Practice. Diagnosis and management of diarrhea in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice Clin Transplant 2019 33 9 e13550 10.1111/ctr.13550 30913334
807. Maes B Hadaya K de Moor B Cambier P Peeters P de Meester J et al. Severe diarrhea in renal transplant patients: results of the DIDACT study Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2006 6 6 1466 1472 10.1111/j.1600-6143.2006.01320.x
808. Vyas VD Parameswaran SA Paramasivan P Sankaranarayanan K Palaniswamy KR Mohan AT et al. Etiological profile of diarrhea in solid organ transplant recipients at a tertiary care center in Southern India Transpl Infect Dis Off J Transplant Soc 2021 23 4 e13584 10.1111/tid.13584
809. Tiwari V Anand Y Gupta A Divyaveer S Bhargava V Malik M et al. Etiological spectrum of infective diarrhea in renal transplant patient by stool PCR: An Indian perspective Indian J Nephrol 2021 31 3 245 253 10.4103/ijn.IJN_169_20 34376938
810. Mullane KM Dubberke ER AST ID Community of Practice. Management of Clostridioides (formerly Clostridium) difficile infection (CDI) in solid organ transplant recipients: Guidelines from the American Society of Transplantation Community of Practice Clin Transplant 2019 33 9 e13564 10.1111/ctr.13564 31002420
811. Wong D Nanda N Clostridium difficile disease in solid organ transplant recipients: A recommended treatment paradigm Curr Opin Organ Transplant 2020 25 4 357 363 10.1097/MOT.0000000000000778 32618715
812. Kelly CR Ihunnah C Fischer M Khoruts A Surawicz C Afzali A et al. Fecal microbiota transplant for treatment of clostridium difficile infection in immunocompromised patients Am J Gastroenterol 2014 109 7 1065 1071 10.1038/ajg.2014.133 24890442
813. Senoner T Breitkopf R Treml B Rajsic S Invasive fungal infections after liver transplantation J Clin Med Multidisciplinary Digital Publishing Institute; 2023 12 9 3238 10.3390/jcm12093238
814. Pappas PG Alexander BD Andes DR Hadley S Kauffman CA Freifeld A et al. Invasive fungal infections among organ transplant recipients: results of the transplant-associated infection surveillance network (TRANSNET) Clin Infect Dis Off Publ Infect Dis Soc Am 2010 50 8 1101 1111 10.1086/651262
815. Scolarici M Jorgenson M Saddler C Smith J Fungal Infections in liver transplant recipients J Fungi 2021 7 7 524 10.3390/jof7070524
816. Sharma M Rudramurthy SM Chakrabarti A Epidemiology of invasive fungal infections in solid organ transplant recipients: An Indian Perspective Curr Fungal Infect Rep 2022 16 4 179 187 10.1007/s12281-022-00446-w 36281339
817. Soman R Rege S Jeloka T Jhaveri T Bansal S expert group opinion for diagnosis and management of fungal infections in solid organ transplant recipients in South Asia Indian J Transplant 2022 16 41 10.4103/ijot.ijot_78_21
818. Shekar M Elumalai R Elayaperumal I Yelahanka RP Anandkumar DG Bandi VK et al. Prevalence and outcome of systemic fungal infections in renal transplant recipients - A tertiary care experience Saudi J Kidney Dis Transplant Off Publ Saudi Cent Organ Transplant Saudi Arab 2019 30 5 1137 1143 10.4103/1319-2442.270270
819. Andes DR Safdar N Baddley JW Alexander B Brumble L Freifeld A et al. The epidemiology and outcomes of invasive Candida infections among organ transplant recipients in the United States: results of the transplant-associated Infection surveillance network (TRANSNET) Transpl Infect Dis Off J Transplant Soc 2016 18 6 921 931 10.1111/tid.12613
820. Aslam S Rotstein C AST infectious disease community of practice. Candida infections in solid organ transplantation: Guidelines from the American Society of transplantation infectious diseases community of practice Clin Transplant 2019 33 9 e13623 10.1111/ctr.13623 31155770
821. Husain S Camargo JF Invasive aspergillosis in solid-organ transplant recipients: Guidelines from the American Society of transplantation infectious diseases community of practice Clin Transplant 2019 33 9 e13544 10.1111/ctr.13544 30900296
822. Iversen M Burton CM Vand S Skovfoged L Carlsen J Milman N et al. Aspergillus infection in lung transplant patients: incidence and prognosis Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol 2007 26 12 879 886 10.1007/s10096-007-0376-3
823. Ullmann AJ Aguado JM Arikan-Akdagli S Denning DW Groll AH Lagrou K et al. Diagnosis and management of aspergillus diseases: Executive summary of the 2017 ESCMID-ECMM-ERS guideline Clin Microbiol Infect. Elsevier; 2018 24 e1 e38 10.1016/j.cmi.2018.01.002
824. Herbrecht R Denning DW Patterson TF Bennett JE Greene RE Oestmann J-W et al. Voriconazole versus Aamphotericin B for primary therapy of invasive aspergillosis N Engl J Med 2002 347 6 408 415 10.1056/NEJMoa020191 12167683
825. Denning DW Ribaud P Milpied N Caillot D Herbrecht R Thiel E et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis Clin Infect Dis Off Publ Infect Dis Soc Am 2002 34 5 563 571 10.1086/324620
826. Wieland T Liebold A Jagiello M Retzl G Birnbaum DE Superiority of voriconazole over amphotericin B in the treatment of invasive aspergillosis after heart transplantation J Heart Lung Transplant Off Publ Int Soc Heart Transplant 2005 24 1 102 104 10.1016/j.healun.2003.10.014
827. Wéclawiak H Garrouste C Kamar N Linas M-D Tall P Dambrin C et al. Aspergillus fumigatus-related spondylodiscitis in a heart transplant patient successfully treated with voriconazole Transplant Proc 2007 39 8 2627 2628 10.1016/j.transproceed.2007.08.014 17954195
828. Yi WM Schoeppler KE Jaeger J Mueller SW MacLaren R Fish DN et al. Voriconazole and posaconazole therapeutic drug monitoring: A retrospective study Ann Clin Microbiol Antimicrob 2017 16 1 60 10.1186/s12941-017-0235-8 28893246
829. Troke PF Hockey HP Hope WW Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients Antimicrob Agents Chemother 2011 55 10 4782 4788 10.1128/AAC.01083-10 21768513
830. Lufft V Kliem V Behrend M Pichlmayr R Koch KM Brunkhorst R Incidence of pneumocystis carinii pneumoniae after renal transplantation Impact of immunosuppression. Transplantation 1996 62 3 421 423 10.1097/00007890-199608150-00022 8779695
831. Varnas D Jankauskienė A Pneumocystis Jirovecii pneumoniae in a kidney transplant recipient 13 months after transplantation: A Case report and literature review Acta Medica Litu 2021 28 1 136 144 10.15388/Amed.2020.28.1.5
832. Hayes MJ Torzillo PJ Sheil AG McCaughan GW Pneumocystis carinii pneumoniae after liver transplantation in adults Clin Transplant 1994 8 6 499 503 7865910 7865910
833. Choi Y-I Hwang S Park G-C Namgoong J-M Jung D-H Song G-W et al. Clinical outcomes of Pneumocystis carinii pneumoniae in adult liver transplant recipients Transplant Proc 2013 45 8 3057 3060 10.1016/j.transproceed.2013.08.074 24157035
834. Martin SI Fishman JA AST infectious diseases community of practice. Pneumocystis pneumoniae in solid organ transplantation Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2013 13 Suppl 4 272 279 10.1111/ajt.12119
835. Klein NC Duncanson FP Lenox TH Forszpaniak C Sherer CB Quentzel H et al. Trimethoprim-sulfamethoxazole versus pentamidine for pneumocystis carinii pneumoniae in AIDS patients: results of a large prospective randomized treatment trial AIDS Lond Engl 1992 6 3 301 305 10.1097/00002030-199203000-00007
836. O'Brien JG Dong BJ Coleman RL Gee L Balano KB A 5-year retrospective review of adverse drug reactions and their risk factors in human immunodeficiency virus-infected patients who were receiving intravenous pentamidine therapy for Pneumocystis carinii pneumoniae Clin Infect Dis Off Publ Infect Dis Soc Am 1997 24 5 854 859 10.1093/clinids/24.5.854
837. Benfield T Atzori C Miller RF Helweg-Larsen J Second-line salvage treatment of AIDS-associated Pneumocystis jirovecii pneumoniae: A case series and systematic review J Acquir Immune Defic Syndr 1999 2008 48 1 63 67 10.1097/QAI.0b013e31816de84d
838. Kim T Hong H-L Lee Y-M Sung H Kim S-H Choi S-H et al. Is caspofungin really an effective treatment for Pneumocystis jirovecii pneumoniae in immunocompromised patients without human immunodeficiency virus infection? Experiences at a single center and a literature review Scand J Infect Dis 2013 45 6 484 488 10.3109/00365548.2012.760842 23317167
839. Fishman JA Treatment of infection due to pneumocystis carinii Antimicrob agents Chemother 1998 42 6 1309 1314 10.1128/AAC.42.6.1309 9624465
840. Roux A Gonzalez F Roux M Mehrad M Menotti J Zahar J-R et al. Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients Med Mal Infect 2014 44 5 185 198 10.1016/j.medmal.2014.01.007 24630595
841. Ewald H Raatz H Boscacci R Furrer H Bucher HC Briel M Adjunctive corticosteroids for Pneumocystis jiroveci pneumoniae in patients with HIV infection Cochrane Database Syst Rev 2015 2015 4 CD006150 10.1002/14651858.CD006150.pub2 25835432
842. Catherinot E Lanternier F Bougnoux M-E Lecuit M Couderc L-J Lortholary O Pneumocystis jirovecii pneumoniae Infect Dis Clin North Am 2010 24 1 107 138 10.1016/j.idc.2009.10.010 20171548
843. Fishman JA Gans H AST infectious diseases community of practice. Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of transplantation infectious diseases community of practice Clin Transplant 2019 33 9 e13587 10.1111/ctr.13587 31077616
844. Wright AJ Fishman JA Central nervous system syndromes in solid organ transplant recipients Clin Infect Dis Off Publ Infect Dis Soc Am 2014 59 7 1001 1011 10.1093/cid/ciu428
845. Fishman JA Infection in renal transplant recipients Semin Nephrol 2007 27 4 445 461 10.1016/j.semnephrol.2007.03.006 17616276
846. Zivković S Neuroimaging and neurologic complications after organ transplantation J Neuroimaging Off J Am Soc Neuroimaging 2007 17 2 110 123 10.1111/j.1552-6569.2007.00097.x
847. Ison MG Nalesnik MA An update on donor-derived disease transmission in organ transplantation Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2011 11 6 1123 1130 10.1111/j.1600-6143.2011.03493.x
848. Grossi PA Fishman JA AST infectious disease community of practice. Donor-derived infections in solid organ transplant recipients Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2009 9 Suppl 4 S19 S26 10.1111/j.1600-6143.2009.02889.x
849. Pedroso JL Dutra LA Braga-Neto P Abrahao A Andrade JBC de Silva GL da et al. Neurological complications of solid organ transplantation Arq Neuropsiquiatr. Academia Brasileira de Neurologia – ABNEURO 2017 75 736 747 10.1590/0004-282X20170132
850. van den Bogaart L Lang BM Rossi S Neofytos D Walti LN Khanna N et al. Central nervous system infections in solid organ transplant recipients: Results from the Swiss Transplant Cohort Study J Infect 2022 85 1 1 7 10.1016/j.jinf.2022.05.019 35605804
851. Baddley JW Forrest GN AST infectious diseases community of practice. Cryptococcosis in solid organ transplantation-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice Clin Transplant 2019 33 9 e13543 10.1111/ctr.13543 30900315
852. Henao-Martínez AF Beckham JD Cryptococcosis in solid organ transplant recipients Curr Opin Infect Dis 2015 28 4 300 307 10.1097/QCO.0000000000000171 26098495
853. Singh N Lortholary O Alexander BD Gupta KL John GT Pursell K et al. An immune reconstitution syndrome-like illness associated with cryptococcus neoformans infection in organ transplant recipients Clin Infect Dis Off Publ Infect Dis Soc Am 2005 40 12 1756 1761 10.1086/430606
854. Rakvit A Meyerrose G Vidal AM Kimbrough RC Sarria JC Cellulitis caused by cryptococcus neoformans in a lung transplant recipient J Heart Lung Transplant Off Publ Int Soc Heart Transplant 2005 24 5 642 10.1016/j.healun.2003.12.007
855. Lebeaux D Freund R van Delden C Guillot H Marbus SD Matignon M et al. Outcome and treatment of nocardiosis after solid organ transplantation: New insights from a European study Clin Infect Dis Off Publ Infect Dis Soc Am 2017 64 10 1396 1405 10.1093/cid/cix124
856. Restrepo A Clark NM Infectious diseases community of practice of the American Society of Transplantation. Nocardia infections in solid organ transplantation: Guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation Clin Transplant 2019 33 9 e13509 10.1111/ctr.13509 30817024
857. Peleg AY Husain S Qureshi ZA Silveira FP Sarumi M Shutt KA et al. Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: A matched case-control study Clin Infect Dis Off Publ Infect Dis Soc Am 2007 44 10 1307 1314 10.1086/514340
858. Clark NM Reid GE AST infectious diseases community of practice. Nocardia infections in solid organ transplantation Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2013 13 Suppl 4 83 92 10.1111/ajt.12102
859. Moylett EH Pacheco SE Brown-Elliott BA Perry TR Buescher ES Birmingham MC et al. Clinical experience with linezolid for the treatment of nocardia infection Clin Infect Dis Off Publ Infect Dis Soc Am 2003 36 3 313 318 10.1086/345907
860. Pouch SM Patel G AST infectious diseases community of practice. Multidrug-resistant gram-negative bacterial infections in solid organ transplant recipients-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice Clin Transplant 2019 33 9 e13594 10.1111/ctr.13594 31102483
861. Tamma PD Aitken SL Bonomo RA Mathers AJ van Duin D Clancy CJ infectious diseases society of America 2023 guidance on the treatment of antimicrobial resistant gram-negative infections Clin Infect Dis 2023 ciad428 10.1093/cid/ciad428 37463564
862. Pérez-Nadales E Fernández-Ruiz M Gutiérrez-Gutiérrez B Pascual Á Rodríguez-Baño J Martínez-Martínez L et al. Extended-spectrum β-lactamase-producing and carbapenem-resistant Enterobacterales bloodstream infection after solid organ transplantation: Recent trends in epidemiology and therapeutic approaches Transpl Infect Dis Off J Transplant Soc 2022 24 4 e13881 10.1111/tid.13881
863. Pereira MR Rana MM AST ID Community of Practice. Methicillin-resistant Staphylococcus aureus in solid organ transplantation-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice Clin Transplant 2019 33 9 e13611 10.1111/ctr.13611 31120612
864. WHO clinical staging of HIV disease in adults, adolescents and children In: Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection: recommendations for a public health approach. 2nd edition. [Internet] World Health Organization 2016 [cited 2024 Feb 12]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK374293/
865. Fauci AS Lane HC Four decades of HIV/AIDS - Much accomplished, Much to do N Engl J Med 2020 383 1 1 4 10.1056/NEJMp1916753 32609976
866. May MT Gompels M Delpech V Porter K Orkin C Kegg S et al. Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy AIDS Lond Engl 2014 28 8 1193 1202 10.1097/QAD.0000000000000243
867. BHIVA guidelines on antiretroviral treatment for adults living with HIV-1 2022 (2023 interim update) [Internet] [cited 2024 Feb 12]. Available from: https://www.bhiva.org/hiv-1-treatment-guidelines
868. Garland JM Levinson A Wing E Care of critically ill patients with human immunodeficiency virus Ann Am Thorac Soc 2020 17 6 659 669 10.1513/AnnalsATS.201909-694CME 32216642
869. O'Halloran C Sun S Nash S Brown A Croxford S Connor N et al. HIV in the United Kingdom: Towards Zero 2030. 2019 report. December 2019. Public Health Engl Lond Available from: https://assets.publishing.service.gov.uk/media/603d1dcae90e07055c1404c8/HIV_in_the_UK_2019_towards_zero_HIV_transmissions_by_2030.pdf
870. Akgün KM Gordon K Pisani M Fried T McGinnis KA Tate JP et al. Risk factors for hospitalization and medical intensive care unit (MICU) admission among HIV infected veterans J Acquir Immune Defic Syndr 1999 2013 62 1 52 59 10.1097/QAI.0b013e318278f3fa
871. Barbier F Mer M Szychowiak P Miller RF Mariotte É Galicier L et al. Management of HIV-infected patients in the intensive care unit Intensive Care Med 2020 46 2 329 342 10.1007/s00134-020-05945-3 32016535
872. Gutierrez J Albuquerque ALA Falzon L HIV infection as vascular risk: A systematic review of the literature and meta-analysis PloS One 2017 12 5 e0176686 10.1371/journal.pone.0176686 28493892
873. Ruiz GO Herrera CFL Bohórquez JAM Betancur JE Mortality in patients with acquired human immunodeficiency virus infection hospitalized in an intensive care unit during the period 2017–2019 Sci Rep 2022 12 1 15644 10.1038/s41598-022-19904-z 36123430
874. Turvey SL Bagshaw SM Eurich DT Sligl WI Epidemiology and outcomes in critically ill patients with human immunodeficiency virus infection in the era of combination antiretroviral therapy Can J Infect Dis Med Microbiol J Can Mal Infect Microbiol Médicale 2017 2017 7868954 10.1155/2017/7868954
875. Schulze AB Mohr M Sackarnd J Schmidt LH Tepasse P-R Rosenow F et al. Risk factors in HIV-1 positive patients on the intensive care unit: A single center experience from a tertiary care hospital. viruses Multidisciplinary Digital Publishing Institute 2023 15 5 1164 10.3390/v15051164
876. Azoulay É de Castro N Barbier F critically ill patients with hiv: 40 years later Chest 2020 157 2 293 309 10.1016/j.chest.2019.08.002 31421114
877. O'Connor J Vjecha MJ Phillips AN Angus B Cooper D Grinsztejn B et al. Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomized controlled trial Lancet HIV. Elsevier; 2017 4 3 e105 e12 10.1016/S2352-3018(16)30216-8
878. Pecego A Amâncio R Costa D Bozza F Siqueira M Oliveira M et al. Etiology, clinical, and epidemiological characteristics of severe respiratory infection in people living with HIV Int J STD AIDS 2020 31 2 100 108 10.1177/0956462419882587 31969059
879. Maartens G Griesel R Dube F Nicol M Mendelson M Etiology of pulmonary infections in human immunodeficiency virus-infected inpatients using sputum multiplex real-time polymerase chain reaction Clin Infect Dis Off Publ Infect Dis Soc Am 2020 70 6 1147 1152 10.1093/cid/ciz332
880. Elabbadi A Pichon J Visseaux B Schnuriger A Bouadma L Philippot Q et al. Respiratory virus-associated infections in HIV-infected adults admitted to the intensive care unit for acute respiratory failure: A 6-year bicenter retrospective study (HIV-VIR study) Ann Intensive Care 2020 10 123 10.1186/s13613-020-00738-9 32953200
881. Hao J Liu J Pu L Li C Yin N Li A Pulmonary infections and outcomes in AIDS patients with respiratory failure: A 10-year retrospective review Infect Drug Resist Dove Press; 2023 16 1049 10.2147/IDR.S395658
882. Kenmoe S Bigna JJ Fatawou Modiyingi A Ndangang MS Ngoupo PA Simo FBN et al. Case fatality rate and viral etiologies of acute respiratory tract infections in HIV-positive and negative people in Africa: The VARIAFRICA-HIV systematic review and meta-analysis J Clin Virol Off Publ Pan Am Soc Clin Virol 2019 117 96 102 10.1016/j.jcv.2019.06.006
883. Burtle D Marsh S Matin N Update on the management of patients with HIV infection in anaesthesia and critical care BJA Educ 2023 23 7 264 272 10.1016/j.bjae.2023.03.004 37389279
884. Gheuens S Cheeseman SH Koralnik IJ Hidden in plain view: Emergence of progressive multifocal leukoencephalopathy after treatment of CNS toxoplasmosis Acta Neurol Belg 2011 111 3 217 219 22141286 22141286
885. Gildenberg PL Gathe JC Kim JH Stereotactic biopsy of cerebral lesions in AIDS Clin Infect Dis Off Publ Infect Dis Soc Am 2000 30 3 491 499 10.1086/313685
886. Stenzel W Pels H Staib P Impekoven P Bektas N Deckert M Concomitant manifestation of primary CNS lymphoma and toxoplasma encephalitis in a patient with AIDS J Neurol 2004 251 6 764 766 10.1007/s00415-004-0440-1 15311360
887. Müller M Wandel S Colebunders R Attia S Furrer H Egger M et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: A systematic review and meta-analysis Lancet Infect Dis 2010 10 4 251 261 10.1016/S1473-3099(10)70026-8 20334848
888. Havlir DV Kendall MA Ive P Kumwenda J Swindells S Qasba SS et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis N Engl J Med 2011 365 16 1482 1491 10.1056/NEJMoa1013607 22010914
889. Huang L Quartin A Jones D Havlir DV Intensive care of patients with HIV infection N Engl J Med 2006 355 2 173 181 10.1056/NEJMra050836 16837681
890. Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services [Internet]. [cited 2024 Dec 2]. Available from: https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult-adolescent-arv/guidelines-adult-adolescent-arv.pdf
891. Grau I Pallares R Tubau F Schulze MH Llopis F Podzamczer D et al. Epidemiologic changes in bacteremic pneumococcal disease in patients with human immunodeficiency virus in the era of highly active antiretroviral therapy Arch Intern Med 2005 165 13 1533 1540 10.1001/archinte.165.13.1533 16009870
892. Huson MAM Stolp SM van der Poll T Grobusch MP Community-acquired bacterial bloodstream infections in HIV-infected patients: A systematic review Clin Infect Dis Off Publ Infect Dis Soc Am 2014 58 1 79 92 10.1093/cid/cit596
893. Nadjm B Mtove G Amos B Walker NF Diefendal H Reyburn H et al. Severe febrile illness in adult hospital admissions in Tanzania: A prospective study in an area of high malaria transmission Trans R Soc Trop Med Hyg 2012 106 11 688 695 10.1016/j.trstmh.2012.08.006 23022040
894. Kiertiburanakul S Watcharatipagorn S Chongtrakool P Santanirand P Epidemiology of bloodstream infections and predictive factors of mortality among HIV-infected adult patients in Thailand in the era of highly active antiretroviral therapy Jpn J Infect Dis 2012 65 1 28 32 22274154 22274154
895. Phe T Vlieghe E Reid T Harries AD Lim K Thai S et al. Does HIV status affect the etiology, bacterial resistance patterns and recommended empiric antibiotic treatment in adult patients with bloodstream infection in Cambodia? Trop Med Int Health TM IH 2013 18 4 485 494 10.1111/tmi.12060 23294446
896. Barr DA Lewis JM Feasey N Schutz C Kerkhoff AD Jacob ST et al. Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: A systematic review and meta-analysis of individual patient data Lancet Infect Dis Elsevier; 2020 20 6 742 752 10.1016/S1473-3099(19)30695-4
897. Qi T Zhang R Shen Y Liu L Lowrie D Song W et al. Etiology and clinical features of 229 cases of bloodstream infection among chinese HIV/AIDS patients: A retrospective cross-sectional study Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol 2016 35 11 1767 1770 10.1007/s10096-016-2724-7
898. Castagnola E FF Prevention of life-threatening infections due to encapsulated bacteria in children with hyposplenia or asplenia: A brief review of current recommendations for practical purposes Eur J Haematol 2003 71 319 326 10.1034/j.1600-0609.2003.00158.x 14667194
899. Sumaraju V Smith GL SS INFECTIOUS COMPLICATIONS IN ASPLENIC HOSTS Infect Dis Clin North Am 2001 15 551 65 10.1016/s0891-5520(05)70159-8 11447709
900. RN Davidson RAW Prevention and management of infections in patients without a Spleen Clin Microbiol Infect 2001 7 657 660 10.1046/j.1198-743x.2001.00355.x 11843905
901. DI E Postsplenectomy sepsis 10 years or more after operation J Clin Pathol 1985 38 309 311 10.1136/jcp.38.3.309 3973056
902. Pizzigallo GL E. Bacterial infections following splenectomy for malignant and nonmalignant hematologic diseases Mediterr J Hematol Infect Dis 2015 7 e2015057 10.4084/MJHID.2015.057 26543526
903. Morgan TL TEB Overwhelming post-splenectomy infection (OPSI): A case report and review of the literature J Emerg Med 2012 43 758 763 10.1016/j.jemermed.2011.10.029 22726665
904. Waghorn DJ Overwhelming infection in asplenic patients: Current best practice preventive measures are not being followed J Clin Pathol 2001 54 214 218 10.1136/jcp.54.3.214 11253134
905. ML B Overwhelming postsplenectomy infection still a problem West J Med 1992 157 440 443 1306065 1306065
906. Thomsen RW Schoonen WM Farkas DK Riis A Jacobsen J Fryzek JP et al. Risk for hospital contact with infection in patients with splenectomy: A populationbased cohort study Ann Intern Med 2009 151 546 555 10.7326/0003-4819-151-8-200910200-00008 19841456
907. Sawmiller CJ Dudrick SJ HM Postsplenectomy capnocytophaga canimorsus sepsis presenting as an acute abdomen Arch Surg 1998 133 1362 1365 10.1001/archsurg.133.12.1362 9865657
908. Gupta S Madkaikar M Singh S Sehgal S Primary immunodeficiencies in India: A perspective Ann N Y Acad Sci 2012 1250 73 79 10.1111/j.1749-6632.2011.06353.x 22224794
909. Madkaikar M Mishra A Desai M Gupta M Mhatre S Ghosh K Comprehensive report of primary immunodeficiency disorders from a tertiary care center in India J Clin Immunol 2013 33 3 507 512 10.1007/s10875-012-9829-2 23108471
910. Madkaikar M Mishra A Ghosh K Diagnostic approach to primary immunodeficiency disorders Indian Pediatr 2013 50 6 579 586 10.1007/s13312-013-0171-4 23942400
911. Halliday E Winkelstein J Webster ADB Enteroviral infections in primary immunodeficiency (PID): A survey of morbidity and mortality J Infect 2003 46 1 1 8 10.1053/jinf.2002.1066 12504601
912. ESID - European Society for Immunodeficiencies [Internet]. [cited 2024 Feb 12]. Available from: https://esid.org/Working-Parties/Registry-Working-Party/Diagnosis-criteria
913. Antachopoulos C Walsh TJ Roilides E Fungal infections in primary immunodeficiencies Eur J Pediatr 2007 166 11 1099 1117 10.1007/s00431-007-0527-7 17551753
914. Ram S Lewis LA Rice PA Infections of people with complement deficiencies and patients who have undergone splenectomy Clin Microbiol Rev 2010 23 4 740 780 10.1128/CMR.00048-09 20930072
915. Odek C Kendirli T Doğu F Yaman A Vatansever G Cipe F et al. Patients with primary immunodeficiencies in pediatric intensive care unit: Outcomes and mortality-related risk factors J Clin Immunol 2014 34 3 309 315 10.1007/s10875-014-9994-6 24510376
916. elHabbal MH Strobel S Leucocyte adhesion deficiency Arch Dis Child 1993 69 4 463 466 10.1136/adc.69.4.463 7903143
917. Bousfiha A Jeddane L Picard C Ailal F Bobby Gaspar H Al-Herz W et al. The 2017 IUIS phenotypic classification for primary immunodeficiencies J Clin Immunol 2018 38 1 129 143 10.1007/s10875-017-0465-8 29226301
918. Abolhassani H Sagvand BT Shokuhfar T Mirminachi B Rezaei N Aghamohammadi A A review on guidelines for management and treatment of common variable immunodeficiency Expert Rev Clin Immunol 2013 9 6 561 574; quiz 575 10.1586/eci.13.30 23730886
919. Boyle ML Scalchunes C Impact of intervenous immunoglobulin (IVIG) treatment among patients with Primary Immunodeficiency diseases Pharm Policy Law. IOS Press; 2008 10 1–4 133 146
920. Shabani M Nichols KE Rezaei N Primary immunodeficiencies associated with EBV-induced lymphoproliferative disorders Crit Rev Oncol Hematol 2016 108 109 127 10.1016/j.critrevonc.2016.10.014 27931829
921. Bonagura VR Using intravenous immunoglobulin (IVIG) to treat patients with primary immune deficiency disease J Clin Immunol 2013 33 Suppl 2 S90 S94 10.1007/s10875-012-9838-1 23271459
922. Freeman AF Holland SM Antimicrobial prophylaxis for primary immunodeficiencies Curr Opin Allergy Clin Immunol 2009 9 6 525 530 10.1097/ACI.0b013e328332be33 19812481
923. Rubin LG Levin MJ Ljungman P Davies EG Avery R Tomblyn M et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host Clin Infect Dis Off Publ Infect Dis Soc Am 2014 58 3 309 318 10.1093/cid/cit816
924. Committee on Infectious Diseases Meningococcal conjugate vaccines policy update: booster dose recommendations Pediatrics 2011 128 6 1213 1218 10.1542/peds.2011-2380 22123893
