
==== Front
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

39234228
10.5005/jp-journals-10071-24747
Guidelines
ISCCM Position Statement on the Management of Invasive Fungal Infections in the Intensive Care Unit
Bhattacharya Pradip Kumar 1https://orcid.org/0000-0002-0219-385X

Chakrabarti Arunaloke 2https://orcid.org/0000-0003-1555-3807

Sinha Saswati 3https://orcid.org/0009-0008-9954-8514

Pande Rajesh 4https://orcid.org/0000-0002-0149-727X

Gupta Sachin 5https://orcid.org/0000-0001-8663-9507

Kumar AK Ajith 6https://orcid.org/0000-0001-5134-1698

Mishra Vijay Kumar 7https://orcid.org/0000-0002-4872-6244

Kumar Sanjeev 8https://orcid.org/0000-0001-5055-9126

Bhosale Shilpushp 9https://orcid.org/0000-0002-0290-0526

Reddy Pavan Kumar 10https://orcid.org/0000-0002-2896-1810

1 Department of Critical Care Medicine, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
2 Department of Medical Microbiology, Doodhadhari Burfani Hospital, Haridwar, Uttarakhand, India
3 Department of Critical Care, Manipal Hospitals, Kolkata, West Bengal, India
4 Department of Critical Care, BLK MAX Superspeciality Hospital, Delhi, India
5 Department of Critical Care, Narayana Superspeciality Hospital, Gurugram, Haryana, India
6 Department of Critical Care Medicine, Aster Whitefield Hospital, Bengaluru, Karnataka, India
7 Department of Critical Care, Bhagwan Mahavir Medica Superspecialty Hospital, Ranchi, Jharkhand, India
8 Department of Anaesthesiology and Critical Care Medicine, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
9 Department of Critical Care Medicine, ACTREC, Tata Memorial Centre, HBNI, Mumbai, Maharashtra, India
10 Department of Critical Care Medicine, ARETE Hospitals, Hyderabad, Telangana, India
Saswati Sinha, Department of Critical Care, Manipal Hospitals, Kolkata, West Bengal, India, Phone: +91 9831632329, e-mail: sashsinha@gmail.com
8 2024
10 8 2024
28 Suppl 2 S20S41
06 5 2024
26 5 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.
Abstract

Rationale

Invasive fungal infections (IFI) in the intensive care unit (ICU) are an emerging problem owing to the use of broad-spectrum antibiotics, immunosuppressive agents, and frequency of indwelling catheters. Timely diagnosis which is imperative to improve outcomes can be challenging. This position statement is aimed at understanding risk factors, providing a rational diagnostic approach, and guiding clinicians to optimize antifungal therapy.

Objectives

To update evidence on epidemiology, risk factors, diagnostic approach, antifungal initiation strategy, therapeutic interventions including site-specific infections and role of therapeutic drug monitoring in IFI in ICU and focus on some practice points relevant to these domains.

Methodology

A committee comprising critical care specialists across the country was formed and specific aspects of fungal infections and antifungal treatment were assigned to each member. They extensively reviewed the literature including the electronic databases and the international guidelines and cross-references. The information was shared and discussed over several meetings and position statements were framed to ensure their reliability and relevance in critical practice. The draft document was prepared after obtaining inputs and consensus from all the members and was reviewed by an expert in this field.

Results

The existing evidence on the management of IFI was updated and practice points were prepared under each subheading to enable critical care practitioners to streamline diagnosis and treatment strategies for patients in the ICU with additional detail on site-specific infections therapeutic drug monitoring.

Conclusion

This position statement attempts to address the management of IFI in immunocompetent and non-neutropenic ICU patients. The practice points should guide in optimization of the management of critically ill patients with suspected or proven fungal infections.

How to cite this article

Bhattacharya PK, Chakrabarti A, Sinha S, Pande R, Gupta S, Kumar AAK, et al. ISCCM Position Statement on the Management of Invasive Fungal Infections in the Intensive Care Unit. Indian J Crit Care Med 2024;28(S2):S20–S41.

Keywords

Antifungal susceptibility
Antifungal therapy
Cryptococcus
Histoplasmosis
Intensive care unit
Invasive aspergillosis
Invasive candidiasis
Invasive fungal infections
Mucormycosis
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pmcHighlights

Invasive fungal infection is an important contributor to mortality and morbidity in the intensive care unit (ICU). Reports suggest that invasive fungal infections (IFIs) have been found to result in high mortality rates among ICU patients, ranging from 40 to 90%. The high prevalence rate in the ICU is attributed to the increased risk factors and morbidity. Successful management of these patients relies on early recognition, diagnosis, and treatment.

This comprehensive document is a valuable resource for critical care practitioners. It is based on available evidence and provides valuable information on epidemiology, risk factors, diagnostic approaches, and therapeutic interventions for IFIs in critically ill non-neutropenic patients. It also discusses site-specific infections and the importance of therapeutic drug monitoring for IFIs.

Introduction

Globally 300 million people suffer from serious fungal infections and about 2.5 million die every year. Invasive candidiasis (IC) accounts for 70% of these infections followed by aspergillosis and mucormycosis.1–3 Centers for Disease Control and Prevention (CDC) has reported crude mortality of more than 25% in patients with candidemia and 40–90% in patients with invasive aspergillosis (IA) especially in immunocompromised patients.4–6 Note that 4.1% of the Indian population has been estimated to suffer from a serious fungal disease. The reported annual incidence rates range from 188,000 for candidemia, 250,900 IA, and 195,000 for mucormycosis.7 The 30-day all-cause mortality with fungal infections was reported at 43.4%, whereas the attributable mortality in invasive candidiasis from India has been reported to be 19.6, 58.8% for IA, and 28–52% for mucormycosis.8

Methodology

This document is an effort to understand the risk factors for invasive fungal infections in critically ill patients, guide diagnostic approach, and guide the clinician to improve the existing antifungal treatment strategies in the ICU under the aegis of the Indian Society of Critical Care Medicine (ISCCM). The committee was composed of critical care specialists from across the country and the different aspects of fungal infections and antifungal treatment were assigned to the members. The team updated the evidence by extensively reviewing the literature through various electronic databases including PubMed and Embase. They also reviewed all major international guidelines on the subject and cross-references from these articles. The group further exchanged the relevant literature and follow-up meetings with thorough discussions and review, the position statements were framed to ensure their reliability and relevance in clinical practice. The draft document was reviewed by all the committee members and after incorporating comments and suggestions, the final document was prepared, and consensus was achieved from all the members.

Epidemiology and Risk Factors

Invasive Candidiasis

Most Indian studies have identified candidemia as the most common fungal infection in ICU, with non-albicans Candida (NAC) species being the predominant pathogen.9–11 An Indian multicenter epidemiological study on ICU-acquired candidemia has reported an incidence of 6.51 cases/1000 ICU admissions, with candidemia occurring after a median 8-days stay in ICU. Candida auris was identified as an emerging multidrug resistant fungus and is now the first rank order of isolates in multiple Indian ICUs. During the COVID-19 pandemic, the rates of candidemia doubled with C. auris being the dominant species (42%) followed by C. tropicalis.10,11 Observational studies have reported C. auris as being the most common isolate from Indian ICUs, followed by C. tropicalis and C. parapsilosis. C. auris was associated with a high resistance to azoles and polyenes as well as a higher crude mortality as compared to other Candida species. The evolving epidemiology emphasizes the need to utilize this data to formulate and execute region and cohort-specific guidelines to optimize therapy.12–14

Risk factors: Urinary catheterization, central venous catheter (CVC) insertion, mechanical ventilation, total parenteral nutrition (TPN), peritoneal dialysis, admission to public sector hospitals, length of ICU stay, renal failure, and steroid therapy are common risk factors.11,12

Invasive Aspergillosis (IA)

Recent global estimate data shows that IA is more frequent in critically ill and chronic obstructive pulmonary disease (COPD) patients than in the immunosuppressed group.14 It is being increasingly reported from India in patients with COPD, liver failure, and cirrhosis.1,5 The 30-day all-cause mortality in IA has been reported to be 39.8%.7 In the Indian multicenter ICU study, invasive mold infection was reported at 10.1 cases per 1,000 ICU admissions and aspergillosis was detected in 74.8% of these cases. Aspergillus flavus was isolated at an equal frequency to A. fumigatus.15 Since the early phase of the SARS-CoV-2 pandemic, cases of COVID-19-associated pulmonary aspergillosis (CAPA) in critically ill patients have been described, with a reported incidence ranging from 0 to 34.3% in the critically ill.16 The wide variation of prevalence of CAPA cases is due to difficulty and lack of consensus on diagnosis. Bronchoalveolar lavage (BAL) galactomannan index value above 1 helps in the diagnosis of CAPA.16

Risk factors: Lack of high particulate efficiency air (HEPA) facility in ICU, prolonged ICU stay and exposure to corticosteroids, diabetes mellitus, chronic liver disease (CLD), coronary artery disease (CAD), trauma, multiorgan failure.

Invasive Mucormycosis

Mucormycosis is considered a rare disease. However, in India, the disease is not so uncommon, with an estimated prevalence of 14 cases per 100,000 individuals, which is nearly 70 times higher than the global data.17,18 A single-center Indian study has shown nearly a 6-fold rise in mucormycosis cases over a period of 25 years.19 Further, a multi-center ICU study reported mucormycosis in nearly 24% of patients.17 The attributable mortality has been reported at 38.2%.17,18

Risk Factors: Reported from Indian ICUs include high APACHE II Score, mechanical ventilation, dialysis, steroid use, uncontrolled diabetes, hematological malignancy and solid organ transplant.20–23 Uncontrolled diabetes overshadows all other risk factors in India.

Although NAC species remains the commonest invasive fungal infection in Indian ICUs, mold infections are increasingly being reported from ICUs. The epidemiology of fungal infections has been changing recently with opportunistic infections like Mucorales, Fusarium, Scedosporium, and Trichosporon species being reported more frequently in immunocompromised patients. The increasing emergence of less susceptible non-Aspergillus mold infections, multidrug-resistant mold, and azole-resistant NAC species is alarming.8

Practice Points

In non-neutropenic ICU patients, NAC species is the major fungal pathogen. The risk factors include abdominal surgery, urinary catheterization, CVC insertion, mechanical ventilation, TPN, peritoneal dialysis, admission to a public hospital, renal failure, and steroid therapy.

In neutropenic patients, those with acute myeloid or acute lymphocytic leukemia or hematopoietic stem cell transplant patients, IA is common and has a high mortality. In India, it is being reported more in patients with COPD, liver failure, cirrhosis, and long-term low-dose steroid therapy.

The burden of mucormycosis in India is significantly higher than rest of the world. The likelihood of mucormycosis infection is higher in patients who are immunocompromised, have a high APACHE score, have uncontrolled diabetes, and have chronic kidney or liver disease.

Antifungal Initiation Strategies

Invasive fungal infections, with their varying clinical presentations and risk factors, demand a multifaceted approach to antifungal therapy initiation, in the form of prophylactic, preemptive, empirical, and targeted (definitive) strategies.

Prophylactic Approach

Prophylactic antifungal therapy involves administering antifungal agents in high-risk patient populations to prevent fungal infections.24,25 Prophylaxis aims to create a protective barrier during this vulnerable period, minimizing the emergence of IFIs. A patient undergoing liver transplant or allogeneic stem cell transplantation is considered at high risk for IFIs, and prophylaxis with azoles such as fluconazole, voriconazole, or posaconazole are administered as prophylactic therapy to prevent potential fungal infections in these high-risk patients.25,26

In critically ill non-neutropenic patients, anti – Candida prophylaxis is recommended only in secondary or tertiary peritonitis, repeated gut perforation, and anastomotic leakage. Its role in necrotizing pancreatitis is debatable and depends on local epidemiology. If the incidence of Candida infection in necrotizing pancreatitis is more than 10%, it qualifies for prophylaxis.

Preemptive Approach

As delay in initiation of antifungal therapy is associated with high mortality, early initiation of treatment in high-risk patients with suspicion of IFIs due to positive biomarkers is called preemptive antifungal therapy. The decision to initiate antifungal therapy is based on positive diagnostic biomarkers like β-D-glucan (pan fungal except Cryptococcus and Mucorales), galactomannan, and radiological signs in CT scans of the chest in high-risk patients.24,25 Regular monitoring of these markers two or three times per week, the appearance of radiological signs like small inflammatory clusters or masses or fluffy nodules or halo sign (ground glass opacity surrounding a pulmonary nodule or mass), or air crescent sign (crescent-shaped air space separates mass from the wall of the cavity) guides the decision to initiate antifungal therapy in high-risk populations early. While preemptive therapy minimizes unnecessary exposure to antifungal drugs, careful patient selection and ongoing monitoring are crucial to strike a balance between early intervention and avoiding overuse.26,27

The pre-emptive approach guides the decision to initiate antifungal therapy in high-risk populations early before clinical symptoms manifest.26,27 In patients undergoing hematopoietic stem cell transplant, preemptive antifungal therapy is initiated for persistent neutropenia exceeding 10 days, with positive fungal markers or radiological signs.

Empiric Approach

Empirical antifungal therapy is initiated based on clinical suspicion without confirmed microbiological evidence.26,27 This approach is commonly employed in critically ill patients with worsening clinical status like refractory fever despite appropriate antibiotic therapy, increasing respiratory insufficiency, or need for ventilatory support, where prompt intervention is crucial. In patients with septic shock, in addition to empiric broad-spectrum antibiotic therapy, empiric antifungal therapy may be added if the patient has risk factors for IFIs. The knowledge of local epidemiology and risk factors aids in selecting appropriate antifungal agents until definitive diagnostic results are available.

In the absence of specific diagnostic evidence, in initiating empirical antifungal therapy, the choice of antifungal agent is based on clinical signs, patient's risk factors, and use of various scoring systems like Candida score, Ostrosky-Zeichner rule and in situations like refractory fever, sepsis unresponsive to appropriate antibacterial therapy.26–29 Antifungal therapy in critically ill patients for putative invasive pulmonary aspergillosis may be initiated based on Blot (AspICU) or Modified Blot (MAspICU) criteria.30,31 Similarly, Bulpa and modified Bulpa criteria have been suggested for initiating antifungal therapy for putative aspergillosis in COPD patients admitted to the respiratory ward, or ICU.32,33

Targeted Approach

Targeted antifungal initiation is the therapy in patients with confirmed fungal infections based on microbiological evidence.27–29 Targeted antifungal initiation involves the presence of a positive blood or tissue culture, using antifungal drugs based on susceptibility testing.28,29 Targeted strategies encompass the use of various antifungal classes, with adjustments based on patient response and adverse effects. The duration and intensity of therapy are tailored to the severity and site of infection, ensuring targeted and effective treatment.

Practice Points

Delay in diagnosis and initiation of antifungal therapy is associated with a high mortality.

Use prophylactic antifungal therapy in high-risk populations with prevalence of fungal infections more than 10%.

Biomarkers and radiological signs in high-risk patients help in early initiation of antifungal therapy.

Clinical signs, risk factors for invasive fungal infections, and use of various scoring systems like Candida score, and Ostrosky-Zeichner rule help in identifying patients for empirical therapy.

Diagnostic Methods

As mortality associated with delayed diagnosis of IFI is very high, the most challenging issue is establishing a confirmatory diagnosis. Clinical findings, radiological findings, and biomarkers help in establishing a provisional diagnosis and help in initiating empiric or preemptive antifungal therapy. However, a definitive diagnosis generally requires a positive tissue (histopathology) or body fluid (blood, cerebrospinal fluid [CSF], etc.) report. There are specific tests available for the diagnosis of different fungal infections (Table 1).

Table 1 Diagnostic methods

Test	Description	Advantages	Limitations	Practice points	
Conventional direct microscopy, culture, and histopathology of samples like blood, respiratory specimens, and biopsy28	• Blood culture and culture of sample from apparent sterile site is the gold standard diagnostic test.
• Around 8–10 mL of blood per bottle, two bottles per set should be taken.
• For diagnosis of intra-abdominal candidiasis, per-operative sample is desirable, peritoneal fluid aspirated in spontaneous peritonitis should be tested for both bacteria and fungi isolation; Drain fluid for drain installed > 24 hours should be discarded.
• Sputum and bronchoalveolar are better samples than tracheal aspirate.
• Though collection of biopsy sample is difficult in critically ill patient, bronchoscopy, endobronchial ultrasound (EBUS), imaging guided biopsy/aspiration improve diagnosis especially mold infection	It identifies the specific causative organism and can provide antifungal susceptibility testing results	• Turnaround time is long.
• Conventional species identification method requires further 1–2 days.
• For 50% time, culture may miss the causative fungus.
• Blood culture is rarely positive in aspergillosis.
• Presence of mold in respiratory specimen (sputum and BAL) may represent colonization	• Blood culture should be obtained for all patients with suspicion of IFI.
• Aspirated samples from sterile sites help in the diagnosis.
• For suspected respiratory fungal infections, sputum, BAL samples should be processed.
• Bronchoscopy and EBUS technique improve diagnosis.
• Image-guided biopsy/aspiration should be attempted if infection site can be localized.
• Biopsies should be sent for culture and histopathology to confirm fungal infection	
T2 Candida34,35	The assay breaks yeast cells apart, releasing deoxyribonucleic acid (DNA), copies the target DNA, and detects the amplified DNA using magnetic resonance technology. This technology enhances the early detection of Candidemia	• Detects as low as 1 colony-forming unit (CFU)/mL
• Turnaround time <5 hours
• Detects C. albicans, C. tropicalis, C. parapsilosis, C. krusei, C. glabrata	• Can detect only the mentioned five Candida species.
• Expensive and not yet available in Indian market	• T2 Candida may be used when available in India along with blood culture in patients with high clinical probability of invasive candidiasis	
MALDI-TOF-MS36,37	Species identification is done from culture. Identification of fungi is also possible from broth of blood culture when there is positive signal.	• Can detect most of the yeast and mycelial fungi.
• Faster turnaround time	Expensive equipment, though consumable cost is minimal	MALDI-TOF-MS should be used for early identification of Candida species	
Serological tests— They can diagnose IFI before the symptoms develop. The sensitivity and specificity of these tests are better than the conventional tests .	
B-d-glucan (BDG)38,39	• It detects 1,3-β-d-glucan which is a component of fungal cell wall.
• It is used as a screening test for presuming the diagnosis of invasive fungal infections.
• A cut-off value of 80 Pg/mL and greater in a single test and 60 Pg/mL in two consecutive tests are considered positive (Fungitell).
• Cut-off values depend on the platform used for testing	• Non-specific pan-fungal biomarker
• Detects all species of fungal infections including Candida, Aspergillus except Cryptococcus and Mucorales40
Negative predictive value is around 80%
• Also useful in diagnosis of intra-abdominal candidiasis41
Rapid turnaround time of 2–4 hours. May vary according to the frequency at which the test is performed.	• False-positive result due to:
• Recent administration of β-lactam antibiotics
• Infusion of immunoglobulin, albumin
• Contamination with cellulose filter, gauze
• Patients on hemodialysis or after abdominal surgery
• Gram-positive bacteria septicemia, Alcaligenes faecalis	• 1,3-β-d-glucan may be used as a guide to stop empirical antifungal therapy due to its high negative predictive value	
Mannan antigen and anti-Mannan antibodies42	• Mannan is component of fungal cell wall and is specific to Candida spp.
• Tested by latex agglutination or enzyme immunoassay	• More specific and less sensitive than BDG
• Turnaround time same as BDG	• Only detects presence of Candida species.
• Most sensitive to Candida albicans and least to Candida parapsilosis.
• Sensitivity 54–65%, Specificity 79–97%	It can be used along with BDG to detect candidemia	
Candida albicans germ tube antibody (CAGTA)	Detects response against a hyphal protein (hwp1) expressed during tissue invasion and biofilm	Sensitivity—42–96%
Specificity—54–100%43
Good test when local epidemiology shows higher percentage of C. albicans infection	In India, the test may not be suitable where NAC species are prevalent	• Can combine with other biomarker tests for diagnosis of invasive candidiasis	
Galactomannan (GM)44–46	• A specific test for Aspergillus spp. The principle is testing of heteropolysaccharide which is present in Aspergillus cell wall.
• The cut-off value above 0.5 is considered positive for serum and 1.0 for bronchoalveolar lavage (BAL).
• GM can be found in serum, urine, cerebrospinal fluid, and BAL (urine and CSF are not yet FDA approved)	Combined testing of serum and BAL GM increases the sensitivity	• False negative may be found in non-neutropenic patients due to slow progression.
• Or in patients on antifungal prophylaxis.
• False positive in patients receiving piperacillin-tazobactam, plasmalyte fluid, and sodium gluconate; bacterial infection by bifidobacterium, presence of non-Aspergillus fungi including Penicilium, Alternaria, Paecilomyces, Histoplasma, Geotrichum; food intake like pasta, yoghurt.44	• GM should be performed in neutropenic patients who have lung infiltrates.
• GM testing in non-neutropenic patients should be combined with BAL GM.
• Serum GM has better sensitivity (65%) in influenza-associated aspergillosis (IPA) as compared to COVID-19-associated aspergillosis (CAPA) (20%).47	
Lateral flow device assay (LFA)	• This is a point-of-care (POC) testing
• Separate LFA tests have been developed for cryptococcosis, aspergillosis, and histoplasmosis diagnosis
• LFA Cryptococcus can be found in blood and body fluids including cerebrospinal fluid.48,49	• The sensitivity is 99%.
• It can be used in resource-limited settings.	• The test is well standardized in cryptococcosis, need further standardization in Indian context for routine use in aspergillosis and histoplasmosis	• LFA Cryptococcus may be used when suspecting cryptococcosis.
• Other two LFA tests will be utilized in routine practice after standardization.	
Molecular methods—Though these methods provide rapid results, require standardization in ICU patients	
Polymerase chain reaction (PCR) test50–52	• Detects fungal nucleic acid.
• Standardized for Aspergillus	• Highly sensitive (96.3%) compared with culture-based techniques.
• Faster turnaround time.
• Various body fluids can be tested.
• Can be used when culture fails to isolate the fungus. At least two positive tests are needed for diagnosis.
• PCR for Aspergillus species has shown good sensitivity and specificity.53,54
• BAL Aspergillus PCR has high diagnostic performance and only single BAL PCR can be recommended.55	• Not validated in large randomized controlled trials.	• PCR test can be used for diagnosis of aspergillosis. PCR for candidiasis requires more standardization.
• Commercial tests are preferred rather than in-house test, as standardization is difficult for in-house test.	
Radiology—They are non-diagnostic and require correlation with clinical history	
Chest X-ray	Non-diagnostic	No major advantage	Very low sensitivity and plain chest radiograph should not be used to diagnose invasive fungal infections	• It may be helpful in chronic pulmonary aspergillosis	
Computed tomography (CT)	• Chest CT may reveal nodules, areas of consolidation, cavitatory lesion, localized bronchiectasis, tree-in-bud lesions, or nodules in immunocompetent host
• Immunocompromised (neutropenic) patients may have halo sign (nodule surrounded by ground glass shadows) or air crescent sign56,57
• In invasive mold infection, sinus and brain CT may be used to screen mucormycosis or invasive aspergillosis	• Helps to identify the site and extent of infection
• Helps to plan further investigations like bronchoscopy or biopsy	Radiation hazard	Chest CT should be done for all patients with suspicion of invasive aspergillosis or mucormycosis	

Practice Points

Culture of blood, and fluid from sterile sites or tissue are the gold standard for fungal infections.

All biopsy specimens should be tested for both histopathology and microbiological culture.

The MALDI-TOF technique should be performed for species identification.

β-d glucan should be used to stop empiric antifungal therapy.

BAL GM is more sensitive than serum GM in diagnosing Aspergillus infections.

In most settings, positive predictive values (PPVs) of biomarker tests are low and negative predictive values (NPVs) are high.

The threshold PPVs and NPVs that justify antifungal treatment in critically ill patients is not well established.

In many instances, test performance has not been validated for different types of Candida sepsis or in different patient populations.

Clinicians must understand the pretest likelihood of invasive candidiasis or aspergillosis and test performance for the most common disease manifestation in a given patient.

NPV of ≥–85% may justify withholding treatment.

In patients suspected to have invasive mold infection, if biomarker tests are negative, suspect mucormycosis.

None of the tests is likely to have value if ordered indiscriminately each time a blood culture is collected, especially in the group of patients where the baseline rate of invasive candidiasis is low.

Caution should be maintained for false positivity and negativity of biomarker tests.

Antifungal Agents for Specific Fungal Infections

The principal classes of antifungal agents based on their inhibition targets are:58–60

Leakage in the cell wall by the development of cell membrane pores after adherence to ergosterol—Polyenes.

Ergosterol inhibitors: Azoles

1,3 β-d-glucan synthase component (GS) FKS1 inhibitors: Echinocandins including Rezafungin and Ibrexafungerp which have recently been approved. Ibrexafungerp overlaps at the site and limits cross resistance.

Flucytosine: Interferes with DNA and RNA metabolism [commonly used in combination with polyenes (Fig. 1)].

Fig. 1 Mechanism of action of antifungal drugs

Candidemia/Invasive Candidiasis

Management includes prompt initiation of appropriate antifungal, source control, and invasive device removal which needs to be individualized.

Initial Therapy (Tables 2A and B)

Table 2A Echinocandins61–67

Drug	Dose	Duration	Comments	
Caspofungin	70 mg loading dose followed by 50 mg once daily IV	14 days from last negative blood culture. However, shorter course (9 days) vs longer course (14 days) did not affect mortality or BSI recurrence in uncomplicated candidemia. More studies are required. Till then continue until 14 days from last negative blood culture	In moderate to severe hepatic impairment (Child-Pugh B and C) —70 mg on day 1 followed by 35 mg once daily
Echinocandins should be avoided when central nervous system is involved, fungal endophthalmitis, intra-abdominal candidiasis, non-Candida fungemia	
Micafungin	100 mg once daily IV	Same as above	No loading dose is required	
Anidulafungin	200 mg loading dose followed by 100 mg once daily IV	Same as above	Can be administered without dose adjustments to patients with any degree of renal/hepatic insufficiency, and also does not require dose adjustments with any concomitant drug	
Rezafungin	400 mg on day 1 followed by 200 mg once a week from day 8	Up to 4 doses	To be used when other options are limited or unavailable	

Table 2B Other drugs for invasive candidiasis

Drug	Dose	Duration	Comments	
Fluconazole	800 mg (12 mg/kg) IV on day 1 followed by 400 mg (6 mg/kg)	14 days from last negative blood culture	In patients who are not critically ill, not infected with an azole resistant Candida (glabrata, krusei) or where the prevalence of azole resistance is low. It can be used as a step-down therapy once the patient is stable and the organism is susceptible.	
Liposomal Amphotericin B	3–5 mg/kg IV	14 days from last negative blood culture	Intolerance, limited availability, CNS involvement or in case of Candida parapsilosis.
In case of renal infections, Amphotericin B deoxycholate may be used.	
Non, neutropenic

Candida auris: It is desirable to perform antifungal susceptibility testing when C. auris is isolated, as Indian isolates are under clade I, which is fluconazole resistant, 50% voriconazole resistant, and 35% polyene resistant. The initial treatment for C. auris should be with an Echinocandin. Because C. auris can develop resistance quickly, patients receiving antifungal therapy should be monitored carefully with follow-up surveillance blood cultures. If the clinical response to treatment with an Echinocandin is inadequate or candidemia persists for several days, treatment can be switched to a lipid formulation of Amphotericin B-5 mg/kg IV daily. Azoles are usually not effective for the treatment of C. auris clade I isolated in India.62,63

The following table may serve as a guide till susceptibility results are available. Echinocandin monotherapy is as effective as other antifungals and hence there is no indication of routine combination therapy in most cases (Table 3).64–66

Table 3 Susceptibility of Candida species

Organism	Azoles	Echinocandins	Polyenes	Others	
Fluconazole	Itraconazole	Voriconazole	Anidulafungin	Liposomal amphotericin B	Flucytosine	
Yeast							
Candida albicans	S	S	S	S	S	S	
Candida glabrata	SDD, high dose required	R	S	S	S	S	
Candida krusei	R	R	S	S	Check susceptibility data	Check susceptibility data	
Candida lusitaniae	S	S	S	S	R	S	
Candida parapsilosis	S	S	S	I, high dose required	S	S	
Candida tropicalis	S	S	S	S	S	S	
Candida neoformans	S	Variable	S	R	S	S	
Candida auris	R	R	Variable	S	S	S	
I, intermediate; R, resistant; S, susceptible; SDD, susceptible dose dependent. In view of emerging fluconazole resistance in Candida tropicalis and Candida parapsilosis in India—perform susceptibility testing

Invasive Aspergillosis

Treatment includes early definitive diagnosis and appropriate therapy combined with a reduction in immune suppression and surgery where feasible. The choice of agent depends upon immune status, organ function (liver, kidney), prior azole exposure, and the likelihood of resistance.

Initial Therapy

Voriconazole and isavuconazole are the primary drugs of choice unless resistance is suspected. In case of intolerance or side effects, posaconazole or liposomal amphotericin B can be used as alternatives. Posaconazole has also been found to be non- inferior to Voriconzole as primary therapy. For liposomal amphotericin B or amphotericin B lipid complex nephrotoxicity and IV administration are the limitations (Table 4).68–71 Amphotericin B deoxycholate may be used in resource-limited situation although toxicity is high.

Table 4 Treatment for invasive aspergillosis

Drug	Dose	Comments	
Voriconazole	6 mg/kg twice daily IV on day 1 followed by 4 mg/kg twice daily IV for at least 7 days—may be changed to 200 mg orally twice daily	IV preparation—contains cyclodextrin which may be nephrotoxic in case of renal impairment.
Drug–drug interactions, hepatotoxicity, hallucination and dark skin, QT prolongation	
Posaconazole	IV/Delayed release tablets—300 mg twice daily for 2 doses then 300 mg once daily	Non-inferior to voriconazole with comparatively less drug interaction. If liquid preparation is used, fatty meal should be provided to improve absorption	
Isavuconazole	IV/Oral—372 mg (Isavuconazole–200 mg) every 8 hours for 6 doses then 200 mg once daily	Noninferior to voriconazole with fewer adverse effects and drug–drug interactions	
Liposomal amphotericin B (L-Amb)	3–5 mg/kg/day
10 mg/kg/day in CNS infections	May have an advantage in case of suspected mold infection without confirmation of IA.
Nephrotoxicity is a concern	
Amphotericin B lipid complex	5 mg/kg/day	Same as liposomal amphotericin B	

Combination Therapy

Voriconazole in combination with echinocandins may be considered in case of severe disease both as initial and salvage therapy with the strongest evidence in hematological malignancies and HCT.72 However, the toxicity cost of therapy and feasibility of prolonged IV administration need to be considered.

Duration of Therapy

Till resolution of all signs and symptoms which is usually for a minimum of 6–12 weeks may need to be individualized based on site of infection, response to therapy, immunosuppression, and underlying disease. Monitoring by imaging and galactomannan measurement can also help in the termination of therapy. In cases such as endocarditis or brain abscess, lifelong therapy may need to be continued in the therapeutic dosage.

Mucormycosis

Treatment of mucormycosis includes aggressive surgical debridement with early appropriate antifungal therapy, and reducing immunosuppression and blood sugar control.

Initial Therapy

Liposomal Amphotericin B73,74

Dose

5 mg/kg/day may need to be increased to 10 mg/kg/day (CNS disease—start with 10 mg/kg/day)

Duration

Till clinical improvement and radiological resolution which may take several weeks to months and sometimes patients may need lifelong treatment if immunosuppression cannot be reversed.

Step Down

Posaconazole75 (IV or delayed released tablets) or isavuconazole75,76 may be used as step-down therapy after 2–6 weeks of amphotericin B therapy. The new antifungal fosmanogepix is effective against mucorales.

Salvage Therapy

If unable to tolerate amphotericin B or no response, isavuconazole or posaconazole IV can be used as salvage therapy and switched over to oral formulations once the patient stabilizes.77,78

Cryptococcosis

Treatment should be tailored according to immune status, site of infection, and availability of drugs. Amphotericin B, flucytosine, and azoles are effective agents. Newer agents like fosmanogepix has efficacy against Cryptococcus and may provide novel options in the future.78–82 A combination of amphotericin B with flucytosine is preferred.

Duration

Induction phase (2 weeks), consolidation phase (8 weeks), and maintenance therapy to prevent recurrence in selected patients.

Histoplasmosis83–87

Treatment depends on severity of disease and presence of CNS involvement.

Lipid formulation of amphotericin B for 2 weeks (CNS involvement–6 weeks) followed by itraconazole 200 mg twice daily for at least 12 months. Alternative agents to itraconazole are fluconazole voriconazole, posaconazole and isavuconazole.

Pneumocystis jirovecii Pneumonia (PCP)

Trimethoprim-sulfamethoxazole (TMP-SMX) is the treatment of choice for PCP of any severity without HIV with adjunctive glucocorticoids for 21 days.88

Dose

5–20 mg/kg (based upon the TMP component) intravenously or orally daily in three or four divided doses. The dose should be adjusted as per creatinine clearance.

Site-specific Fungal Infections

The details of treatment according to the individual fungi and the site of infection are elaborated in the following tables (Tables 5 to 10).

Table 5 Candidiasis

Site	Treatment options (Practice points)	
Invasive candidiasis—Empiric treatment89–94	For critically ill patients who have a high risk of getting a fungal infection, have signs that suggest a fungal infection, and further not responding to antibacterial therapy, empiric antifungal therapy is advisable.
For suspected candidiasis in non-neutropenic ICU patients, Echinocandins (Caspofungin: 70 mg loading dose, then 50 mg daily; Micafungin: 100 mg daily; Anidulafungin: 200 mg loading dose, then 100 mg daily) should be used as empiric therapy.
Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily, is an acceptable alternative where Echinocandin could not be instituted for any reason.
Lipid formulation Amphotericin B, 3–5 mg/kg daily, is recommended when other antifungals are intolerable.
Duration—Empiric therapy can be given for 2 weeks. In case of no response to therapy after 1 week, no invasive candidiasis, negative non-culture-based diagnostic assay-treatment should be stopped. Negative β-d-glucan is an ideal marker to stop empiric therapy.	
Should prophylaxis be used to prevent invasive candidiasis in the ICU setting?95–99	In high-risk patients in adult ICUs with a high rate of invasive candidiasis (in cohorts where prevalence of invasive candidiasis is more than 10%), fluconazole 400 mg (6 mg/kg) daily can be used.
Alternatively Caspofungin: 70-mg loading dose, then 50 mg daily; Anidulafungin: 200-mg loading dose and then 100 mg daily; or Micafungin: 100 mg daily can be considered.
Chlorhexidine body bath can be used to decrease Candida colonization, especially required in C. auris colonization.	
Bloodstream infections100–108	• The first treatment option is Caspofungin (70 mg loading dose, followed by 50 mg daily), Micafungin (100 mg daily), or Anidulafungin (200 mg loading dose, followed by 100 mg daily).
• For non-critically ill patients and patients unlikely to have resistance against fluconazole, fluconazole IV/Oral can be used as an alternative to Echinocandins. The recommended dosage is an 800-mg loading dose (or 12 mg/kg) followed by a daily dose of 400 mg (or 6 mg/kg).
• In stable patients and isolates that are susceptible to fluconazole and those where there is negative blood culture after initiation of antifungal therapy switching from Echinocandin to fluconazole should be done typically within 5–7 days of Echinocandin therapy.
• C. glabrata, where within susceptible dose-dependent range against fluconazole, should be treated with higher doses of fluconazole (800 mg or 12 mg/kg) on a daily basis, or Voriconazole (200–300 mg or 3–4 mg/kg) twice daily.
• When other antifungal drugs are not tolerated, or resistance is found, a lipid-based formulation of amphotericin B (AmB) at a dosage of 3–5 mg/kg per day is a good option.
• Switching from AmB to fluconazole should be done after 5–7 days for patients who have isolates that are susceptible to fluconazole, where the patient is clinically stable.
• Azole and Echinocandin-resistant cases can be treated with lipid formulation AmB at a daily dosage of 3–5 mg/kg.
• Voriconazole at a dose of 400 mg (6 mg/kg) taken twice daily for 2 doses, followed by a dose of 200 mg (3 mg/kg) taken twice daily, may be used to treat candidemia.
• In C. krusei infection, fluconazole and Amphotericin B should be avoided, treated with Echinocandin
• In C. auris infection, Echinocandins should be used and antifungal susceptibility testing should be performed for the isolate.
• Better to remove CVC when possible; Otherwise, use echinocandins or polyenes.
• Inadequate antifungal exposure has been documented in these patients due to third spacing (movement of fluid from intravascular to interstitial space), hypoalbuminemia, renal failure, hepatic failure, RRT, and ECMO (Echinocandin is extracted by ECMO circuit); should adopt PK/PD-based dosing as part of routine clinical practice.
• Due to the high toxicity of azoles and the high probability of drug–drug interactions, TDM should be considered when using itraconazole, posaconazole, or voriconazole as antifungal therapy.
• Echinocandin may have suboptimal exposure in critically ill patients and also in overweight patients, reasons that favor TDM.
• PK parameters are not well elucidated for Amphotericin B so routine TDM is not desirable, except when toxicity is a major concern.
• Routine TDM for flucytosine is recommended due to the high variability in serum concentrations following administration and severe adverse effects.
• Fundoscopy examination after 1 week of diagnosis of candidemia when neutrophil counts recover.	
Urinary tract infections109–116	Asymptomatic Candiduria
• Eliminate predisposing factors like catheters.
• Treatment is only advisable for neutropenic patients, low birth weight infants or those undergoing urologic interventions.
• Neutropenic patients and very-low-birth-weight infants should be treated for candidemia with Echinocandins.
Patients undergoing urologic procedures should be treated with oral fluconazole, 400 mg (6 mg/kg) daily, OR AmB deoxycholate, 0.3–0.6 mg/kg daily, before and after the procedure.
Treatment
Candida cystitis
• Oral fluconazole, 200 mg (3 mg/kg) daily for 2 weeks should be used for fluconazole-susceptible organisms.
• Amphotericin B (Amb) deoxycholate, 0.3–0.6 mg/kg daily for 7–10 days, with or without oral Flucytosine, 25 mg/kg 4 times daily for 7–10 days should be used for fluconazole-resistant C. glabrata.
• Deoxycholate bladder irrigation, 50 mg/L in sterile water daily for 5 days, may be used to treat fluconazole-resistant cystitis in C. glabrata and C. krusei.
Ascending Candida pyelonephritis
• Oral fluconazole 200–400 mg (3–6 mg/kg) daily for 2 weeks should be used for fluconazole-susceptible organisms.
• AmB deoxycholate, 0.3–0.6 mg/kg daily with or without oral Flucytosine, 25 mg/kg 4 times daily for 1–7 days should be used for fluconazole-resistant C. glabrata.
Any obstructions in the passage should be removed immediately.
Candida urinary tract infection associated with fungal balls
• Adults should undergo surgical intervention.
• Antifungal therapy is the same as for cystitis or pyelonephritis.
• Irrigation should be done with 25–50 mg AmB deoxycholate in 200–500 mL sterile water if nephrostomy tubes are present.	
Intra-abdominal infections 117–121	Patients with recent abdominal surgery, anastomotic leaks, necrotizing pancreatitis, intra-abdominal infection, and risk factors for candidiasis should receive
• Echinocandins (Caspofungin: 70 mg loading dose, then 50 mg daily; Micafungin: 100 mg daily; Anidulafungin: 200 mg loading dose, then 100 mg daily).
• Fluconazole, 800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily, is an acceptable alternative where azoles are restricted.
• Lipid formulation AmB, 3–5 mg/kg daily, is recommended when other antifungals are intolerable.
• Therapy can be given for 2 weeks. In case of no response to therapy after 1 week, think for an alternative. If no invasive candidiasis, negative non-culture-based diagnostic assay, the treatment should be stopped. Negative β-d-glucan can also be used to stop therapy.
Source control, drainage and/or debridement, should be implemented at the earliest.
Adequacy of source control and clinical response should determine the duration of therapy.
Ibrexafungerp can be a good alternative.	
Device-associated infections	Infected central nervous system devices122–124
Infected device should be removed if at all possible.
For patients in whom device cannot be removed, AmB deoxycholate can be administered through the device into at a dosage ranging from 0.01 to 0.5 mg in 2 mL 5% dextrose in water.
After device removal, patients should be monitored for response to treatment based on clinical parameters; monitoring of CSF cultures is recommended to ensure that they become negative. CSF Candida Mannan antigen and anti-Mannan antibodies may be useful additional tests in patients with suspected Candida meningitis in whom cultures are negative.
Candida infection of implantable cardiac devices and native valve endocarditis 125–142
Infected devices should be removed if at all possible.
• Lipid formulation Amphotericin B, 3–5 mg/kg daily, with or without Flucytosine, 25 mg/kg 4 times daily, OR high-dose Echinocandin (Caspofungin 150 mg daily, Micafungin 150 mg daily, or Anidulafungin 200 mg daily) is recommended for initial therapy.
• Switch over to fluconazole, 400–800 mg (6–12 mg/kg) daily, who have susceptible Candida isolates, have cleared Candida from the bloodstream and are clinically stable.
• Oral Voriconazole, 200–300 mg (3–4 mg/kg) two times daily, or posaconazole tablets, 300 mg daily, where fluconazole resistance is there.
For infections that are only in generator pockets, 4 weeks of antifungal therapy should be given after removal of the device.
Regarding infections that affect the wires, at least 6 weeks of antifungal therapy after wire removal should be given.
Native valve endocarditis
• Lipid formulation Amphotericin B, 3–5 mg/kg daily, with or without Flucytosine, 25 mg/kg 4 times daily, OR high-dose Echinocandin (Caspofungin 150 mg daily, Micafungin 150 mg daily, or Anidulafungin 200 mg daily) should be used as initial therapy.
• In endocarditis, Azole should be avoided as primary therapy due to biofilm issues.
• Valve replacement should be done after 1–2 weeks antifungal therapy unless contraindicated.
• Drug therapy should continue for at least 6 weeks after surgery and for a longer duration in patients with perivalvular abscesses or other complications.
• For patients who cannot undergo valve replacement, long-term suppression with fluconazole, 400–800 mg (6–12 mg/kg) daily, should be used for susceptible isolates.
Prosthetic valve endocarditis
The same antifungal regimens that are suggested for native valve endocarditis should be used.
Valve should be replaced after 1–2 weeks of antifungal therapy.
Chronic suppressive antifungal therapy with fluconazole 400–800 mg (6–12 mg/kg) daily should be used to prevent recurrence.
Ventricular assist devices
If it is not possible to remove the device, the antifungal regimen is the same as that for native valve endocarditis.
For devices that cannot be removed:
Lipid formulation AmB, 3–5 mg/kg daily with or without Flucytosine 25 mg/kg 4 times daily, OR high dose Echinocandin (Caspofungin150 mg daily, Micafungin 150 mg daily or Anidulafungin 200 mg daily is recommended for initial therapy.
Switch over to fluconazole 400–800 mg (6–12 mg/kg) daily, for those who have susceptible Candida isolates, have cleared Candida from the bloodstream, and are clinically stable.
Oral Voriconazole, 200–300 mg (3–4 mg/kg) two times daily, or posaconazole tablets, 300 mg daily, if fluconazole resistance is present.	
Septic arthritis143–146	Where prosthetic device has been used, it should be removed.
If it cannot be removed, and if the isolate is susceptible, chronic suppressive therapy with fluconazole, 400 mg (6 mg/kg) daily should be used.	
Endophthalmitis147–154	Dilated retinal examination by ophthalmologist should be done to exclude endophthalmitis.
Infectious disease physician and ophthalmologist need to jointly decide regarding type and duration of antifungal therapy. Echinocandins should be avoided.	

Table 6 Aspergillosis68,69,155–166

Site	Treatment options (Practice points)	
Invasive aspergillosis/invasive pulmonary aspergillosis (IPA)	Primary treatment
Voriconazole (6 mg/kg IV every 12 hours for 1 day, followed by 4 mg/kg IV every 12 hours/oral therapy can be used at 200–300 mg every 12 hours)
OR
Isavuconazole IV/Oral—372 mg (Isavuconazole 200 mg) every 8 hours for 6 doses then 200 mg once daily
OR
Posaconazole IV/Delayed release tablets 300 mg twice daily for 2 doses then 300 mg once daily
Alternative treatment
Primary: Liposomal AmB (3–5 mg/kg/day IV)
Salvage: ABLC (5 mg/kg/day IV), Caspofungin (70 mg/day IV × 1, then 50 mg/day IV thereafter), Micafungin (100–150 mg/day IV), posaconazole (oral suspension: 200 mg TID; tablet: 300 mg BID on day 1, then 300 mg daily, IV: 300 mg BID on day 1, then 300 mg daily, itraconazole suspension (200 mg PO every 12 hours)
AmB deoxycholate and its lipid derivatives can be used when Voriconazole cannot be administered.
Lipid formulations of AmB should be considered in settings in which Azoles are contraindicated or not tolerated.
Empiric and pre-emptive therapy
Liposomal AmB (3 mg/kg/day IV), Caspofungin (70 mg day 1 IV then 50 mg/day IV thereafter), Micafungin (100 mg/day), Voriconazole (6 mg/kg IV every 12 hours for 1 day, followed by 4 mg/kg IV every 12 hours, Oral therapy can be used at 200–300 mg every 12 hours or 3–4 mg /kg every 12 hours)
Indications of empiric/pre-emptive therapy
When broad-spectrum antibiotic therapy fails to relieve persistent febrile symptoms in high-risk patients with prolonged neutropenia, empiric anti-Aspergillus therapy should be initiated.
When patients are expected to experience short-term neutropenia, (less than 10 days), empirical anti-Aspergillus therapy should not be administered unless additional findings like a new infiltrate on imaging point to a possible IFI.
Anti-Aspergillus therapy can be guided by serum or BAL biomarkers like GM or 1-3-β-d-glucan in asymptomatic or febrile high-risk patients, reducing unnecessary treatment. The pre-emptive approach can document more IPA cases without compromising survival and replace empiric antifungal therapy.
In patients having a high suspicion of IPA, antifungal therapy should be started as soon as possible while a diagnostic assessment is being completed.
Breakthrough infection—Treatment should be individualized depending on possible etiological agent, severity of infection, and local epidemiology. Aggressive attempts at establishing diagnosis and therapeutic drug monitoring should be considered. Switching therapy to alternate drug class with anti-Aspergillus activity should be done.
Prophylaxis
Posaconazole: Oral suspension: 200 mg TID; Tablet: 300 mg BID on day 1, then 300 mg daily
Intravenous therapy: 300 mg BID on day 1, then 300 mg daily.
Voriconazole: 200 mg PO BID
Itraconazole suspension: 200 mg PO every 12 hours
Micafungin: 50–100 mg/day
Caspofungin: 50 mg/day
Indications for prophylaxis against
Aspergillus
Allogeneic HSCT recipients with GVHD throughout duration of immunosuppression
Lung transplant —for 3–4 months post-transplant
Select patients post cardiac and liver transplant based on individual risk factors and institutional epidemiology of infection (duration unclear).
Invasive pulmonary aspergillosis (IPA) treatment
Early initiation of antifungals therapy in patients with strongly suspected IPA is warranted.
Voriconazole/Isavuconazole/Posaconazole should be used for primary treatment.
Liposomal Amphotericin B or echinocandins should be used as an alternative therapy when required. Other lipid formulations of Amphotericin B may also be considered.
Combination antifungals therapy with Voriconazole and an Echinocandin may be considered in select patients.
Echinocandins (Micafungin or Caspofungin) can be used where Azoles and Polyenes are contraindicated.
Treatment of IPA should be continued for a minimum of 6–12 weeks.
For localized disease that can be easily debrided, such as invasive fungal sinusitis or localized cutaneous disease, surgery is advisable. The patient's immune system, other health issues, single focus of infection and surgical risks must be considered when interpreting the unclear indications.	

Table 7 Mucormycosis167–177

Site	Treatment options (Practice points)	
Mucormycosis—any site	Amphotericin B, liposomal, 5–10 mg/kg per day for initial 4–6 weeks
Alternative—Amphotericin B, lipid complex, 5 mg/kg/day
Amphotericin B deoxycholate—in resource-limited environment
Assess response (weekly imaging)
Stable disease or partial response
Continuation of 1st line treatment or change to oral treatment
Isavuconazole PO
3 × 200 mg day 1–2
1 × 200 mg per day from day 3
or
Posaconazole DR tablets
2 × 300 mg day 1
1 × 300 mg per day from day 2
Progressive disease or toxicity
Isavuconazole IV
3 × 200 mg day 1–2
1 × 200 mg/day 2 from day 3
or
Increase the dose of Liposomal Amphotericin B
Posaconazole IV or DR tablets
2 × 300 mg day 1
1 × 300 mg per day from day 2
Posaconazole oral suspension
4 × 200 mg per day	
CNS involvement	Amphotericin B, liposomal, 10 mg/kg per day, initial 28 days (up to 6–12 weeks)	
Orbital mucormycosis	Retrobulbar injection of amphotericin B deoxycholate in addition to systemic therapy
Enucleation of eye in case of ocular invasive disease	

Table 8 Cryptococcosis78,178,179

Site	Treatment options (Practice points)	
Pulmonary	Mild to moderate disease
(no diffuse pulmonary infiltrates/disseminated disease)
Fluconazole—400 mg (6 mg/kg) per day for 6–12 months
Alternative agents
Itraconazole—200 mg three times daily x 3 days followed by 200 mg twice a day
Voriconazole—400 mg (6 mg/kg) twice a day for 1 day then 200 mg twice a day
Posaconazole (delayed-release tablets)—300 mg orally twice daily on day 1 followed by 300 mg once daily
Isavuconazole—200 mg three times daily for 2 days followed by 200 mg once daily
Severe disease (diffuse pulmonary infiltrates/disseminated disease)
Induction therapy (2–6 weeks)
Lipid formulation Amphotericin B + Flucytosine
Liposomal Amphotericin B—3–5 mg/kg/day OR
Amphotericin B lipid complex—5 mg/kg/day
Flucytosine—100 mg/kg/day (adjusted according to renal function) in 4 divided doses
Consolidation therapy (8 weeks)
Fluconazole—800 mg (12 mg/kg in children) per day—8 weeks
Maintenance therapy (1 year from diagnosis)
Fluconazole—200–400 mg/day	
Meningitis	Lipid formulation Amphotericin B + Flucytosine—for 2–4 weeks and then fluconazole for 8 weeks
Patients with neurological complications
Induction therapy—extend to at least 6 weeks (or 4 weeks after culture negative)
Alternative in resource limited
Amphotericin B deoxycholate—0.7 mg/kg/day + Flucytosine (100 mg/kg/day in 4 divided doses)	

Table 9 Histoplasmosis 82,84,85,180

Site	Treatment options (Practice points)	
Pulmonary	Moderately severe to severe disease
Amphotericin B (Liposomal Amphotericin B 3 mg/kg/day or Amphotericin B deoxycholate 0.7–1 mg/kg/day) IV for 1–2 weeks followed by itraconazole (200 mg thrice daily for 3 days followed by 200 mg twice daily) for 3–6 months
Mild to moderate disease
Less than 4 weeks—no treatment
More than 4 weeks—Itraconazole-loading + maintenance dose for 6–12 weeks
Chronic pulmonary histoplasmosis—
treatment is always indicated	
Progressive disseminated histoplasmosis	Treatment depends on severity of disease and presence of CNS involvement	
HIV (non-infected)	Moderate to severe
Liposomal Amphotericin B (3 mg/kg/day) IV followed by itraconazole (200 mg) for 6–12 months
Mild to moderate
Itraconazole 200 mg twice daily for at least 12 months
CNS involvement
Liposomal Amphotericin B (5 mg/kg/day) IV for 4–6 weeks followed by itraconazole (200 mg) 2–3 times a day for at least 12 months	
HIV (infected)	Moderate to severe (non-meningeal)
Liposomal Amphotericin B (3 mg/kg/day) IV followed by itraconazole PO (200 mg) three times a day for 3 days followed by twice a day for at least 6–12 months
Mild to moderate (non-meningeal)
Itraconazole 200 mg thrice daily for 3 days followed by twice daily for at least 12 months
Meningeal disease
Liposomal Amphotericin B (5 mg/kg/day) IV for 4–6 weeks (total 175mg/kg) followed by itraconazole 200 mg 2–3 times a day for at least 12 months	

Table 10 Pneumocystis infection181–197

Site	Treatment options (Practice points)	
Pulmonary	Prophylaxis	
HIV +VE	First line: Trimethoprim/sulfamethoxazole one single-strength (80 mg TMP/400 mg SMX) daily or one double-strength tablet (160 mg TMP/800 mg SMX)/daily
Second line: One single strength tablet daily if patient does not require prophylaxis for toxoplasmosis
One double strength tablet daily to patients who require prophylaxis against toxoplasmosis	
	Treatment	
	First line: Trimethoprim/sulfamethoxazole (15–20 mg/kg TMP; 75–100 mg/kg SMX per day) For moderate to severe disease (i.e., hypoxemia) adjunctive corticosteroids should be used
Second line for severe disease
Primaquine and clindamycin [30 mg/(600 mg × 3)] per day Pentamidine IV (4 mg/kg/day)/Second line for mild to moderate disease: Dapsone (100 mg daily) + trimethoprim (15 mg daily) Atovaquone (750 mg BID)	

Candida from respiratory isolates—Candida is often detected in respiratory specimens from humans with and without lung disease; its significance remains uncertain.

Mucormycosis

Early diagnosis and prompt therapy remain the cornerstone of mucormycosis management. Treatment of mucormycosis involves surgical debridement, antifungal therapy, and modifying underlying immunosuppression or co-morbidities. Since it is challenging to establish a definitive diagnosis, many patients need to be offered empirical treatment for pulmonary mucormycosis if they have risk factors for infection and positive cultures from respiratory tract samples and/or compatible clinical syndromes.

Histoplasmosis

Treatment is recommended for pulmonary disease or disseminated disease (the latter could be in HIV- infected or non-HIV-infected).

Pulmonary infection—Most pulmonary infections in the community are self-limited and do not require any treatment. However, Histoplasmosis can cause severe disease if the inoculum is large or in an immunocompromised subject. Treatment should be based on clinical syndromes.

Therapeutic Drug Monitoring (TDM) in Invasive Fungal Infections

Subtherapeutic serum concentration can promote resistance to antifungals. The physiological changes causing increased permeability of vascular endothelium and altered drug metabolism resulting from hepatic and/or renal dysfunction lead to PK/PD disturbances. The increased endothelial permeability in sepsis, and the low albumin in the critically ill results in an increased volume of distribution of water-soluble drugs in the former, and of protein-bound drugs (e.g., Echinocandins) in the latter.

The challenges in therapeutic drug monitoring of antifungal agents include the lack of universal availability and the variations in recommended drug levels by various societies based on varying studies (Table 11).

Table 11 Therapeutic drug monitoring (TDM)

Drug	Comment	Reference	
Voriconazole	Routine TDM—trough levels should be considered for ICU patients especially non-responders
Voriconazole level of 0.5 mg/L (recommended target concentration between 0.5 and 3 mg/L) should be considered as lower threshold for efficacy, and trough levels more than 3.0 and 4.0 mg/L are associated with increased risks of hepatotoxicity and neurotoxicity respectively	198–200	
Itraconazole	Itraconazole level should be measured between 5th and 7th day targeting a concentration of >0.5 mg/L for both prophylactic and therapeutic indications	201–203	
Posaconazole	Measure level after 7 days of starting therapy.
Target plasma concentration of >0.7 mg/L in prophylaxis and >1–1.25 mg/L of steady-state plasma level measured within 7 days of starting the therapy lead to better outcomes.
For early TDM requirement, posaconazole level may be measured after 4 days of therapy.	204–207	
Isavuconazole	TDM not routinely required
May be considered in pre-existing liver disease, hepatic injury, obesity, solid organ transplant, and patients below 18 years of age	208,209	
Fluconazole	TDM not routinely required
May be considered in pediatric patients and patients on RRT	210	
Echinocandins	Routine TDM not required.
Echinocandins—suboptimal exposure in critically ill patients and also in overweight patients, with documented high inter-individual variability.
Hypoalbuminemia patients on ECMO and body weight >75 kg may have suboptimal levels.	211–217	
Amphotericin B	Routine TDM not required
May consider in narrow therapeutic index and major concern regarding toxicity	218	
Flucytosine	TDM should be done— measure serum concentration within 72 hours and not later than 120 hours,
Target serum concentration 25–100 mg/L	78,219	

Summary

The aforementioned position statement has been drafted for the management of critically ill patients who fall into the non-neutropenic category and are not immunosuppressed due to malignancy or post-transplant condition. The text extensively addresses infections caused by various fungal species that are accountable for invasive fungal infections in ICUs. Additionally, it explores diverse methods for initiating antifungal therapy, fundamental and advanced diagnostic techniques that are valuable in diagnosing invasive fungal infections, approaches for monitoring therapeutic response, and available antifungal agents that are beneficial for site-specific management in light of distinct fungal pathogens. However, it provides only a limited overview of special populations. The entirety of this document has been compiled using currently available literature. It will undoubtedly assist readers in promptly identifying suitable recommendations when necessary.

Orcid

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

Arunaloke Chakrabarti https://orcid.org/0000-0003-1555-3807

Saswati Sinha https://orcid.org/0009-0008-9954-8514

Rajesh Pande https://orcid.org/0000-0002-0149-727X

Sachin Gupta https://orcid.org/0000-0001-8663-9507

Ajith Kumar AK https://orcid.org/0000-0001-5134-1698

Vijay Kumar Mishra https://orcid.org/0000-0002-4872-6244

Sanjeev Kumar https://orcid.org/0000-0001-5055-9126

Shilpushp Bhosale https://orcid.org/0000-0002-0290-0526

Pavan kumar Reddy https://orcid.org/0000-0002-2896-1810

Source of support: Nil

Conflict of interest: None
==== Refs
References

1. 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 42 10.1186/s12929-023-00926-2 37337179
2. Delaloye J Calandra T Invasive candidiasis as a cause of sepsis in the critically ill patient Virulence 2014 5 1 161 169 10.4161/viru.26187 24157707
3. Denning DW Global incidence and mortality of severe fungal disease Lancet Infect Dis 2024 24 7 e428 e438 10.1016/S1473-3099(23)00692-8 38224705
4. Tsay S Williams S Mu Y Epson E Johnston H Farley MM et al. National burden of candidemia, United States Open Forum Infect Dis 2018 5 Suppl-1 S142 S143 10.1093/ofid/ofy210.374
5. Panackal AA Bennett JE Williamson PR Treatment options in invasive aspergillosis Curr Treat Options Infect Dis 2014 6 3 309 325 10.1007/s40506-014-0016-2 25328449
6. Sun KS Tsai CF Chen SC Huang WC Clinical outcome and prognostic factors associated with invasive pulmonary aspergillosis: An 11-year follow-up report from Taiwan PLoS ONE 2017 12 10 e0186422 10.1371/journal.pone.0186422 29049319
7. Ray A Aayilliath AK Banerjee S Chakrabarti A Denning DW Burden of serious fungal infections in India Open Forum Infect Dis 2022 9 ofac603 10.1093/ofid/ofac603 36589484
8. Dabas Y Xess I Pandey M Ahmed J Sachdev J Eram A et al. Epidemiology and antifungal susceptibility patterns of invasive fungal infections (IFIs) in India: A prospective observational study J Fungi (Basel) 2021 8 1 33 10.3390/jof8010033 35049974
9. ICMR Annual Report 2021: Antimicrobial Resistance Research and Surveillance Network (icmr.nic.in) ICMR; New Delhi, India: 2021 Available online from: https://main.icmr.nic.in/sites/default/files/upload_documents/AMR_Annual_Report_2021.pdf [(accessed on 18 May 2024)]
10. Rajni E Singh A Tarai B Jain K Shankar R Pawar K et al. A high frequency of Candida auris blood stream infections in coronavirus disease 2019 patients admitted to intensive care units, Northwestern India: A case control study Open Forum Infect Dis 2021 8 12 ofab452 10.1093/ofid/ofab452 34904116
11. Denning DW Global incidence and mortality of severe fungal disease Lancet Infect Dis 2024 7 E428 E438 10.1016/S1473-3099(23)00692-8
12. Chakrabarti A Kaur H Savio J Rudramurthy SM Atul Patel A Shastri P et al. Epidemiology and clinical outcomes of invasive mould infections in Indian intensive care units (FISF study) J Crit Care 2019 51 64 70 10.1016/j.jcrc.2019.02.005 30769292
13. Russo A Serraino R Serrapide F Bruni A Garofalo E Longhini F et al. COVID-19-associated pulmonary aspergillosis in intensive care unit: A real-life experience Heliyon 2024 10 2 e24298 10.1016/j.heliyon.2024.e24298 38293516
14. Ahmed A Azim A Baronia AK Marak RS Gurjar M Invasive candidiasis in non neutropenic critically ill – need for region-specific management guidelines Indian J Crit Care Med 2015 19 6 333 339 10.4103/0972-5229.158273 26195859
15. Rudramurthy SM Paul RA Chakrabarti A Mouton JW Meis JF Invasive Aspergillosis by Aspergillus flavus: Epidemiology, diagnosis, antifungal resistance, and management J Fungi (Basel) 2019 5 3 55 10.3390/jof5030055 31266196
16. Lee R Cho SY Lee DG Ahn H Choi H Choi SM et al. Risk factors and clinical impact of COVID-19-associated pulmonary aspergillosis: Multicenter retrospective cohort study Korean J Intern Med 2022 37 4 851 863 10.3904/kjim.2022.069 Epub 2022 May 26 35611611
17. Prakash H Chakrabarti A Epidemiology of Mucormycosis in India Microorganisms 2021 9 523 10.3390/microorganisms9030523 33806386
18. Chakrabarti A Sood P Denning D Estimating fungal infection burden in India: Mucormycosis burden as a case study. Available from: https://www.gaffi.org/wp-conten/uploads/P1044.pdf
19. Prakash H Ghosh AK Rudramurthy SM Singh P Xess I Savio J et al. A prospective multicenter study on mucormycosis in India: Epidemiology, diagnosis, and treatment Med Mycol 2019 57 395 402 10.1093/mmy/myy060 30085158
20. Prakash H Chakrabarti A Global Epidemiology of Mucormycosis J. Fungi 2019 5 26 10.3390/jof5010026
21. Patel A Kaur H Xess I Michael JS Savio J Rudramurthy S et al. A multi-centre observational study on the epidemiology, risk factors, management and outcomes of mucormycosis in India Clin Microbiol Infect 2020 2 7 944.e9 944.e15 10.1016/j.cmi.2019.11.021
22. Patel AK Patel KK Patel K Gohel S Chakrabarti A Mucormycosis at a tertiary care centre in Gujarat, India Mycoses 2017 60 407 411 10.1111/myc.12610
23. Kontoyiannis DP Lionakis MS Lewis RE Chamilos G Healy M Perego C et al. Zygomycosis in the era of Aspergillus-active antifungal therapy in a tertiary care cancer center: A case control observational study of 27 recent cases J Infect Dis 2005 191 1350 1360 10.1086/428780 15776383
24. Mikolajewska A Schwartz S Ruhnke M Antifungal treatment strategies in patients with haematological diseases or cancer: From prophylaxis to empirical, pre‐emptive and targeted therapy Mycoses 2012 55 1 2 16 10.1111/j.1439-0507.2010.01961.x 21554421
25. Zaragoza R Pemán J Salavert M Viudes Á Viudes A Solé A et al. Multidisciplinary approach to the treatment of invasive fungal infections in adult patients. Prophylaxis, empirical, preemptive or targeted therapy, which is the best in the different hosts? Ther Clinl Risk Manag 2008 4 6 1261 1280 10.2147/tcrm.s3994
26. Playford EG Lipman J Sorrell TC Prophylaxis, empirical and preemptive treatment of invasive candidiasis Current opinion in critical care 2010 16 5 470 474 10.1097/MCC.0b013e32833e10e8 20711078
27. Rüping MJ Vehreschild JJ Cornely OA Antifungal treatment strategies in high-risk patients Mycoses 2008 51 Suppl 2 46 51 10.1111/j.1439-0507.2008.01572.x
28. Guarner J Brandt ME Histopathologic diagnosis of fungal infections in the 21st century Clin Microbiol Rev 2011 24 247 280 10.1128/CMR.00053-10 21482725
29. Ostrosky-Zeichner L Invasive mycoses: diagnostic challenges Am J Med 2012 125 S14 S24 10.1016/j.amjmed.2011.10.008
30. Blot SI Taccone FS Van den Abeele A-M Bulpa P Meerseeman W Brusselaers N et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients Am J Respir Crit Care Med 2012 186 1 56 64 10.1164/rccm.201111-1978OC 22517788
31. Schauwvlieghe AFAD Rijnders BJA Philips N Verwijs R Vanderbeke L Tienen CV et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: A retrospective cohort study Lancet Resp Med 2018 6 10 782 792 10.1016/S2213-2600(18)30274-1
32. Bulpa P Dive A Sibille Y Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease Eur Respir J 2007 30 782 800 10.1183/09031936.00062206 17906086
33. Huang L He H Jin J Zhan Q Is Bulpa criteria suitable for the diagnosis of probable invasive pulmonary aspergillosis in critically ill patients with chronic obstructive pulmonary disease? A comparative study with EORTC/MSG and ICU criteria BMC Infect Dis 2017 17 1 209 DOI.org/10.1186/s12879-017-2307-y 28292284
34. Pfaller MA Wolk DM Lowery TJ T2MR and T2Candida: Novel technology for the rapid diagnosis of candidemia and invasive candidiasis Future Microbiol 2016 11 1 103 117 10.2217/fmb.15.111 26371384
35. Cornelius J Clancy Peter G Pappas Jose Vazquez Judson MA Kontoyiannis DP Thompson GR 3rd et al. Detecting infections rapidly and easily for Candidemia trial, part 2 (DIRECT2): A prospective, multicenter study of the T2Candida panel Clin Infect Dis 2018 66 11 1678 1686 10.1093/cid/cix1095 29438475
36. Patel R A Moldy application of MALDI: MALDI-ToF mass spectrometry for fungal identification J Fungi 2019 5 4 10.3390/jof5010004
37. Robert MG Cornet M Hennebique A Rasamoelina T Caspar Y Pondérand L et al. MALDI-TOF MS in a medical mycology laboratory: On stage and backstage Microorganisms 2021 12:9 6 1283 10.3390/microorganisms9061283
38. Karageorgopoulos DE Vouloumanou EK Ntziora F Michalpoulos A Rafailidis PI Falagas ME β-d-Glucan assay for the diagnosis of invasive fungal infections: A meta-analysis Clin Infect Dis 2011 52 750 770 10.1093/cid/ciq206 21367728
39. Hanson KE Pfeiffer CD Lease ED Balch AH Zaas AK et al. β-d-glucan Surveillance with preemptive anidulafungin for invasive candidiasis in intensive care unit patients: A randomised pilot study PLoS ONE 2012 7 8 e42282 10.1371/journal.pone.0042282 22879929
40. Onishi A Sugiyama D Kogata Y Saegusa J Sugimoto T Kawano S et al. Diagnostic accuracy of serum 1,3-β-D-glucan for pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: Systematic review and meta-analysis J Clin Microbiol 2012 50 1 7 15 10.1128/JCM.05267-11 22075593
41. Pickering JW Sant HW Bowles CA Roberts WL Woods GL Evaluation of a (1–>3)-beta-D-glucan assay for diagnosis of invasive fungal infections J Clin Microbiol 2005 43 12 5957 5962 10.1128/JCM.43.12.5957-5962.2005 16333082
42. Mikulska M Calandra T Sanguinetti M Poulain D Viscoli C Third European Conference on infections in leukemia group. The use of mannan antigen and anti-mannan antibodies in the diagnosis of invasive candidiasis: recommendations from the Third European Conference on Infections in Leukemia Crit Car 2010 14 6 R222 10.1186/cc9365
43. Poissy J Sendid B Damiens S Ishibashi KI Francois N Kauv M et al. Presence of Candida cell wall derived polysaccharides in the sera of intensive care unit patients: Relation with candidaemia and Candida colonisation Crit Care 2014 18 R135 10.1186/cc13953 24975380
44. Leeflang MM Debets-Ossenkopp YJ Wang J Visser CE Scholten RJPM Hooft L et al. Galactomannan detection for invasive aspergillosis in immunocompromised patients Cochrane Database Syst Rev 2015 12 CD007394 10.1002/14651858.CD007394.pub2
45. Maertens J Verhaegen J Lagrou K Eldere JV Boogaerts M Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: A prospective validation Blood 2001 97 1604 1610 10.1182/blood.v97.6.1604 11238098
46. Zou M Tang L Zhao S Zhao Z Chen L Chen P et al. Systematic review and meta-analysis of detecting galactomannan in bronchoalveolar lavage fluid for diagnosing invasive aspergillosis PLoS One 2012 7 8 e43347 10.1371/journal.pone.0043347 22905261
47. Rutsaert L Steinfort N Van Hunsel T et al. COVID-19-associated invasive pulmonary aspergillosis Ann Intensive Care 2020 10 1 71 10.1186/s13613-020-00686-4 32488446
48. Kwizera R Omali D Tadeo K Kasibante J Rutalingirwa MK kagimu E et al. Evaluation of the dynamiker cryptococcal antigen lateral flow assay for the diagnosis of HIV-associated cryptococcosis J Clin Micro Biol 2021 59 3 e02421 e2520 10.1128/JCM.02421-20
49. Noguera MC Escandón P Rodríguez J Parody A Camargo L Comparison of two commercial tests (Immy vs. Dynamiker) for cryptococcal capsular antigen Rev Soc Bras Med Trop 2021 54 e03072021 10.1590/0037-8682-0307-2021 34495257
50. Palka-Santini M Cleven BE Eichinger L Krönke M Krut O Large scale multiplex PCR improves pathogen detection by DNA microarrays BMC Microbiol 2009 3 9 1 10.1186/1471-2180-9-1
51. Straub J Paula H Mayr M Kasper D Assadian O Berger A et al. Diagnostic accuracy of the ROCHE Septifast PCR system for the rapid detection of blood pathogens in neonatal sepsis–A prospective clinical trial PLoS ONE 2017 12 11 e0187688 10.1371/journal.pone.0187688 29117261
52. Mercier T Reynders M Beuselinck K Guldentops E Maertens J Lagrou K Serial detection of circulating Mucorales DNA in invasive mucormycosis: A retrospective multicenter evaluation J Fungi (Basel) 2019 5 4 113 10.3390/jof5040113 31816976
53. Arvanitis M Ziakas PD Zacharioudakis IM Zervou FN Calindo AM Mylonakis E PCR in diagnosis of invasive aspergillosis: A meta-analysis of diagnostic performance J Clin Microbiol 2014 52 3731 3742 10.1128/JCM.01365-14 25122854
54. Mengoli C Cruciani M Barnes RA Loeffler J Donnelly JP Use of PCR for diagnosis of invasive aspergillosis: Systematic review and meta-analysis Lancet Infect Dis 2009 9 89 96 10.1016/S1473-3099(09)70019-2 19179225
55. Avni T Levy I Sprecher H Yahav D Leibovici L Paul M Diagnostic accuracy of PCR alone compared to galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis: A systematic review J Clin Microbiol 2012 50 11 3652 3658 10.1128/JCM.00942-12 22952268
56. Greene RE Schlamm HT Oestmann JW Stark P Durand C Lortholary O et al. Imaging findings in acute invasive pulmonary aspergillosis: Clinical significance of the halo sign Clin Infect Dis 2007 44 3 373 379 10.1086/509917 17205443
57. Caillot D Casasnovas O Bernard A Couaillier JF Durand C Cuisenier B et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery J Clin Oncol 1997 15 1 139 147 10.1200/JCO.1997.15.1.139 8996135
58. de Oliveira Santos GC Vasconcelos CC Lopes AJO Cartagenes MSS Filho AKDB do Nascimento FRF et al. Candida infections and therapeutic strategies: Mechanisms of action for traditional and alternative agents Front Microbiol 2018 9 1351 10.3389/fmicb.2018.01351 30018595
59. McCarthy MW Pharmacokinetics and pharmacodynamics of Ibrexafungerp Drugs R D 2022 22 1 9 13 10.1007/s40268-021-00376-x 34961907
60. Rezafungin label Approved by United States Federal Drug Administration (FDA), 2023. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217417s000lbl.pdf
61. Centers for Disease Control and Prevention Recommendations for identification of Candida auris. Available from: https://www.cdc.gov/fungal/diseases/candidiasis/recommendations.html
62. Zhang Z Bills GF An Z Advances in the treatment of invasive fungal disease PLoS Pathog 2023 19 5 e1011322 10.1371/journal.ppat.1011322 37141208
63. Tang BHE Bay JW Yeong FM Samuel M Efficacy and safety of echinocandin monotherapy and combination therapy for immunocompromised patients with systemic candidiasis: A systematic review and meta-analysis J Mycelia Med 2023 33 2 101362 10.1016/j.mycmed.2023.101362
64. Yang Q Xie J Cai Y Wang N Wang Y Zhang L et al. Efficacy and safety of combination antifungals as empirical, preemptive, and targeted therapies for invasive fungal infections in intensive-care units Infect Drug Resist 2022 15 5331 5344 10.2147/IDR.S381851 36110125
65. Thompson GR Soriano A Skoutelis A Vazquez J Honore PM Horcajada JP et al. The STRIVE Trial Investigators, Rezafungin Versus Caspofungin in a phase 2, randomized, double-blind Study for the treatment of candidemia and invasive candidiasis: The STRIVE trial Clin Infect Dis 2021 73 e3647 e3655 10.1093/cid/ciaa1380 32955088
66. Thompson GR 3rd Soriano A Honore PM Bassetti M Cornely OA Kollef M Efficacy and safety of rezafungin and caspofungin in candidaemia and invasive candidiasis: Pooled data from two prospective randomised controlled trials Lancet Infect Dis 2024 24 3 319 328 10.1016/S1473-3099(23)00551-0 38008099
67. Vena A Bovis F Tutino S Barbone AS Mezzogori S Ponzano M et al. Short course of antifungal therapy in patients with uncomplicated Candida bloodstream infection: Another case of less is more in the clinical setting? Open Forum Infec Dis 2023 10 1 ofac656 10.1093/ofid/ofac656 36655192
68. Patterson TF Thompson GR 3rd Denning DW Fishman JA Hadley S Herbretch R et al. Practice Guidelines for the diagnosis and management of aspergillosis: 2016 Update by the Infectious Diseases Society of America Clin Infect Dis 2016 63 4 e1 e60 10.1093/cid/ciw326 27365388
69. Maertens JA Rahav G Lee DG de Leon AP Sanchez ICR Klimko M et al. Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: A phase 3, randomised, controlled, non-inferiority trial Lancet 2021 397 10273 499 509 10.1016/S0140-6736(21)00219-1 33549194
70. 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, randomised-controlled, non-inferiority trial Lancet 2016 387 10020 760 769 10.1016/S0140-6736(15)01159-9 26684607
71. 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
72. Cornell OA Alastruey-Izquierdo A Arenz D Chen SCA Dannaoui E Hochhegger B et al. Mucormycosis ECMM MSG Global Guideline Writing Group. Global guideline for the diagnosis and management of mucormycosis: An initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium Lancet Infect Dis 2019 19 12 e405 e421 10.1016/S1473-3099(19)30312-3 31699664
73. Lanternier F Poiree S Elie C Hermoso DL Bakouboula P Sitbon K et al. Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis J Antimicrob Chemother 2015 70 11 3116 3123 10.1093/jac/dkv236 26316385
74. Arendrup MC Jensen RH Meletiadis J In vitro activity of Isavuconazole and comparators against clinical isolates of the Mucorales order Antimicrob Agents Chemother 2015 59 12 7735 7742 10.1128/AAC.01919-15 26438494
75. Thompson GR 3rd Wiederhold NP Isavuconazole: A comprehensive review of spectrum of activity of a new triazole Mycopathologia 2010 170 5 291 313 10.1007/s11046-010-9324-3 20524153
76. Egger M Bellmann R Krause R Boyer J Jaksik D Hoenigl M et al. Salvage treatment for invasive aspergillosis and mucormycosis: Challenges, recommendations and future considerations Infect Drug Resist 2023 16 2167 2178 10.2147/IDR.S372546 37077251
77. Van Burik JAH Hare RS Solomon HF Corrado ML Kontoiyanis DP et al. Posaconazole is effective as salvage therapy in Zygomycosis: A retrospective summary of 91 cases Clini Infect Dis 2006 42 7 e61 e65 10.1086/500212
78. Perfect JR Dismukes WE Dromer F Goldman DL Graybill JR Hamill RJ et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America Clin Infect Dis 2010 50 3 291 322 10.1086/649858 20047480
79. Thompson GR 3rd Rendon A Ribeiro Dos Santos R Telles FQ Zeichner LO Azie N et al. Isavuconazole treatment of Cryptococcosis and dimorphic Mycoses Clin Infect Dis 2016 63 3 356 362 10.1093/cid/ciw305 27169478
80. Sun HY Alexander BD Lortholary O Dromer F Forrest GN Lyon GN et al. Lipid formulations of Amphotericin B significantly improve outcomes in solid organ transplant recipients with central nervous system cryptococcosis Clin Infect Dis 2009 49 1721 10.1086/647948 19886800
81. Bratton EW Husseini N Chastain CA Lee MS Poole C Stermer T et al. Approaches to anti-fungal therapies and their effectiveness among patients with cryptococcosis Antimicrob Agents Chemother 2013 57 2485 10.1128/AAC.01800-12 23478968
82. Spanakis EK Aperis G Mylonakis E New agents for the treatment of fungal infections: Clinical efficacy and gaps in coverage Clin Infect Dis 2006 43 8 1060 1068 10.1086/507891 16983621
83. Wheat LJ Freifeld AG Kleiman MB Baddly JW Lyod EE Kauffman et al. Infectious Diseases Society of America. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America Clin Infect Dis 2007 45 7 807 825 10.1086/521259 17806045
84. Johnson PC Wheat LJ Cloud GA Goldman M Lancaster D Bamberger DM et al. U.S. National Institute of Allergy and Infectious Diseases Mycoses Study Group-Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS Ann Intern Med 2002 137 2 105 109 10.7326/0003-4819-137-2-200207160-00008 12118965
85. Wheat LJ Connolly P Smedema M Durkin M Brizendin Mann P et al. Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed fluconazole J Antimicrob Chemother 2006 57 6 1235 1239 10.1093/jac/dkl133 16627592
86. Restrepo A Tobón A Clark B Graham DR Corcoran G Bradshir RW et al. Salvage treatment of histoplasmosis with posaconazole J Infect 2007 54 4 319 327 10.1016/j.jinf.2006.05.006 16824608
87. Schwartz S Cornely OA Hamed K Marty FM Maertens J Rahav G et al. Isavuconazole for the treatment of patients with invasive fungal diseases involving the central nervous system Med Mycol 2020 58 4 417 424 10.1093/mmy/myz103 31613363
88. Limper AH Knox KS Sarosi GA Ampel NM Bennett JE Catanzaro A et al. American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients Am J Respir Crit Care 2011 183 1 96 128 10.1164/rccm.2008-740ST
89. Kollef M Micek S Hampton N Doherty JA Kumar A Septic shock attributed to Candida infection: Importance of empiric therapy and source control Clin Infect Dis 2012 54 1739 1746 10.1093/cid/cis305 22423135
90. Zeichner OL Kullberg BJ Bow EJ Hadley S Leon C Nucci M et al. Early treatment of candidemia in adults: A review Med Mycol 2011 49 113 120 10.3109/13693786.2010.512300 20818922
91. Morrell M Fraser VJ Kollef MH Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: A potential risk factor for hospital mortality Antimicrob Agents Chemother 2005 49 3640 3645 10.1128/AAC.49.9.3640-3645.2005 16127033
92. Garey KW Rege M Pai MP Mingo DE Suda KJ Turpin RS et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: A multi-institutional study Clin Infect Dis 2006 43 25 31 10.1086/504810 16758414
93. Eggimann P Ostrosky-Zeichner L Early antifungal intervention strategies in ICU patients Curr Opin Crit Care 2010 16 465 469 10.1097/MCC.0b013e32833e0487 20827073
94. Leon C Ruiz-Santana S Saavedra P Almirante B Salas JN Alvarez-Lerma F et al. A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization Crit Care Med 2006 34 730 737 10.1097/01.CCM.0000202208.37364.7D 16505659
95. Ostrosky-Zeichner L Shoham S Vazquez J Reboli A Betts R Barron MA et al. MSG-01: A randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting Clin Infect Dis 2014 58 1219 1226 10.1093/cid/ciu074 24550378
96. Ostrosky-Zeichner L Prophylaxis or preemptive therapy of invasive candidiasis in the intensive care unit? Crit Care Med 2004 32 2552 2553 10.1097/01.ccm.0000148226.95597.7e 15599171
97. Eggimann P Francioli P Bille J Schneider R Wu MM Chapuis G et al. Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients Crit Care Med 1999 27 1066 1072 10.1097/00003246-199906000-00019 10397206
98. 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 1479 1487 10.1007/s00134-005-2794-y 16172847
99. Ostrosky-Zeichner L Pappas PG Shoham S Reboli A Barron MA Sims C et al. Improvement of a clinical prediction rule for clinical trials on prophylaxis for invasive candidiasis in the intensive care unit Mycoses 2011 54 46 51 10.1111/j.1439-0507.2009.01756.x 19627509
100. Pappas PG Rex JH Lee J Hamill RJ Larsen RA Powderly W et al. A prospective observational study of candidemia: Epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients Clin Infect Dis 2003 37 634 643 10.1086/376906 12942393
101. Garey KW Rege M Pai MP Mingo DE Suda KJ Turpin RS et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: A multi-institutional study Clin Infect Dis 2006 43 25 31 10.1086/504810 16758414
102. Kuse ER Chetchotisakd P da Cunha CA Ruhnke M Barrios C Raghunadharao D et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidasis: A phase III randomised double-blind trial Lancet 2007 369 1519 1527 10.1016/S0140-6736(07)60605-9 17482982
103. Reboli AC Shorr AF Rotstein C Pappas PG Kett DH Schlamm HT et al. Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: A multivariate analysis of factors associated with improved outcome BMC Infect Dis 2011 11 261 10.1186/1471-2334-11-261 21961941
104. Oude Lashof AM Sobel JD Ruhnke M Pappas PG Viscoli C Schlamm HT et al. Safety and tolerability of voriconazole in patients with baseline renal insufficiency and candidemia Antimicrob Agents Chemother 2012 56 3133 3137 10.1128/AAC.05841-11 22450974
105. Mootsikapun P Hsueh PR Talwar D Co VM Rajadhyaksha V Ong ML et al. Intravenous anidulafungin followed optionally by oral voriconazole for the treatment of candidemia in Asian patients: Results from an open-label phase III trial BMC Infect Dis 2013 13 219 10.1186/1471-2334-13-219 23676114
106. Bennett JE Echinocandins for candidemia in adults without neutropenia N Engl J Med 2006 355 1154 1159 10.1056/NEJMct060052 16971721
107. Kullberg BJ Sobel JD Ruhnke M Pappas PG Viscoli C Rex JH et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: A randomised non-inferiority trial Lancet 2005 366 1435 1442 10.1016/S0140-6736(05)67490-9 16243088
108. Ruhnke M Paiva JA Meersseman W Pachl J Grigoras I Sganga G et al. Anidulafungin for the treatment of candidaemia/invasive candidiasis in selected critically ill patients Clin Microbiol Infect 2012 18 680 687 10.1111/j.1469-0691.2012.03784.x 22404732
109. Malani AN Kauffman CA Candida urinary tract infections: Treatment options Expert Rev Anti Infect Ther 2007 5 277 284 10.1586/14787210.5.2.277 17402842
110. Fisher JF Sobel JD Kauffman CA Newman CA Candida urinary tract infections treatment Clin Infect Dis 2011 52 suppl 6 S457 S466 10.1093/cid/cir112 21498839
111. Alvarez-Lerma F Nolla-Salas J Leon C Palomar M Jorda R Carrasco N et al. Candiduria in critically ill patients admitted to intensive care medical units Intensive Care Med 2003 29 1069 1076 10.1007/s00134-003-1807-y 12756441
112. Viale P Candida colonization and candiduria in critically ill patients in the intensive care unit Drugs 2009 69 suppl 1 51 57 10.2165/11315640-000000000-00000
113. Sobel JD Kauffman CA McKinsey D Zervos M Vazquez JA Karchmer AW et al. Candiduria: A randomized, double- blind study of treatment with fluconazole and placebo. The National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group Clin Infect Dis 2000 30 19 24 10.1086/313580 10619727
114. Sobel JD Bradshaw SK Lipka CJ Kartsonis NA Caspofungin in the treatment of symptomatic candiduria Clin Infect Dis 2007 44 e46 e49 10.1086/510432 17278048
115. Fisher JF Woeltje K Espinel-Ingroff A Stanfield J DiPiro JT Efficacy of a single intravenous dose of amphotericin B for Candida urinary tract infections: Further favorable experience Clin Microbiol Infect 2003 9 1024 1027 10.1046/j.1469-0691.2003.00711.x 14616745
116. Tuon FF Amato VS Penteado Filho SR Bladder irrigation with amphotericin B and fungal urinary tract infection: Systematic review with meta-analysis Int J Infect Dis 2009 13 701 706 10.1016/j.ijid.2008.10.012 19155184
117. Bassetti M Marchetti M Chakrabarti A Colizza S Garnacho-Montero J Kett DH et al. A research agenda on the management of intra-abdominal candidiasis: Results from a consensus of multinational experts Intensive Care Med 2013 39 2092 2106 10.1007/s00134-013-3109-3 24105327
118. Sandven P Qvist H Skovlund E Giercksky KE NORGAS Group and the Norwegian Yeast Study Group Significance of Candida recovered from intraoperative specimens in patients with intra-abdominal perforations Crit Care Med 2002 30 541 547 10.1097/00003246-200203000-00008 11990912
119. Vege SS Gardner TB Chari ST Baron TH Clain JE Pearson RK et al. Outcomes of intra-abdominal fungal vs. bacterial infections in severe acute pancreatitis Am J Gastroenterol 2009 104 2065 2070 10.1038/ajg.2009.280 19491825
120. de Ruiter J Weel J Manusama E Kingma WP Van der Voort PHJ The epidemiology of intra-abdominal flora in critically ill patients with secondary and tertiary abdominal sepsis Infection 2009 37 522 527 10.1007/s15010-009-8249-6 19669089
121. 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 63 785 794 10.1093/jac/dkp005 19196742
122. Montero A Romero J Vargas JA Reguerio CA Sanchez-Aloz G Prados FD et al. Candida infection of cerebrospinal fluid shunt devices: Report of two cases and review of the literature Acta Neurochir (Wien) 2000 142 67 74 10.1007/s007010050009 10664378
123. O'Brien D Stevens NT Lim CH O'Brien DF Smyth E Fitzpatrick F et al. Candida infection of the central nervous system following neurosurgery: A 12-year review Acta Neurochir (Wien) 2011 153 1347 1350 10.1007/s00701-011-0990-9 21431456
124. Pepper J Zrinzo L Mirza B Foltynie T Limousin P Hariz M et al. The risk of hardware infection in deep brain stimulation surgery is greater at impulse generator replacement than at the primary procedure Stereotact Funct Neurosurg 2013 91 56 65 10.1159/000343202 23207787
125. Tacke D Koehler P Cornely OA Fungal endocarditis Curr Opin Infect Dis 2013 26 501 507 10.1097/QCO.0000000000000009 24126720
126. Card L Lofland D Candidal endocarditis presenting with bilateral lower limb ischemia Clin Lab Sci 2012 25 130 134 22953512 22953512
127. Ellis ME Al-Abdely H Sandridge A Greer W Ventura W Fungal endocarditis: Evidence in the world literature, 1965–1995 Clin Infect Dis 2001 32 50 62 10.1086/317550 11118386
128. Steinbach WJ Perfect JR Cabell CH Fowler VG Corey GR Li JS et al. A meta-analysis of medical versus surgical therapy for candida endocarditis J Infect 2005 51 230 247 10.1016/j.jinf.2004.10.016 16230221
129. Smego RA Jr, Ahmad H The role of fluconazole in the treatment of candida endocarditis: A meta-analysis Medicine (Baltimore) 2011 90 237 249 10.1097/MD.0b013e3182259d38 21694646
130. Kuhn DM George T Chandra J Mukherjee PK Ghannoum NA Antifungal susceptibility of Candida biofilms: Unique efficacy of amphotericin B lipid formulations and echinocandins Antimicrob Agents Chemother 2002 46 1773 1780 10.1128/AAC.46.6.1773-1780.2002 12019089
131. Mrowczynski W Wojtalik M Caspofungin for candida endocarditis Pediatr Infect Dis J 2004 23 376 10.1097/00006454-200404000-00029
132. De Rosa FG D'Avolio A Corcione S Baietto L Raviolo S Centofanti P et al. Anidulafungin for Candida glabrata infective endocarditis Antimicrob Agents Chemother 2012 56 4552 4553 10.1128/AAC.00515-12 22644027
133. Lopez-Ciudad V Castro-Orjales MJ Leon C Sanz-Rodriguez C de la Torre-Fernandez MJ de-Juan Romero MAP et al. Successful treatment of Candida parapsilosis mural endocarditis with combined caspofungin and voriconazole BMC Infect Dis 2006 6 73 10.1186/1471-2334-6-73 16608509
134. Cornely OA Lasso M Betts R Klimko N Vazquez J Dobb G et al. Caspofungin for the treatment of less common forms of invasive candidiasis J Antimicrob Chemother 2007 60 363 369 10.1093/jac/dkm169 17526917
135. Roger PM Boissy C Gari-Toussaint M Foucher R Mondain V Vandenbos F et al. Medical treatment of a pacemaker endocarditis due to Candida albicans and to Candida glabrata J Infect 2000 41 176 178 10.1053/jinf.2000.0640 11023765
136. Brown LA Baddley JW Sanchez JE Bachmann LH Implantable cardioverter-defibrillator endocarditis secondary to Candida albicans Am J Med Sci 2001 322 160 162 10.1097/00000441-200109000-00010 11570782
137. Halawa A Henry PD Sarubbi FA Candida endocarditis associated with cardiac rhythm management devices: Review with current treatment guidelines Mycoses 2011 54 e168 e174 10.1111/j.1439-0507.2010.01866.x 21672037
138. Boland JM Chung HH Roberts FJ Wilson WR Steckelberg JL Baddour LM et al. Fungal prosthetic valve endocarditis: Mayo Clinic experience with a clinicopathological analysis Mycoses 2011 54 354 360 10.1111/j.1439-0507.2010.01884.x 20406395
139. Lye DC Hughes A O'Brien D Athan E Candida glabrata prosthetic valve endocarditis treated successfully with fluconazole plus caspofungin without surgery: A case report and literature review Sur J Clin Microbial Infect Dis 2005 24 753 755 10.1007/s10096-005-0038-2
140. Bagdasarian NG Malani AN Pagani FD Malani PN Fungemia associated with left ventricular assist device support J Card Sur 2009 24 763 765 10.1111/j.1540-8191.2009.00919.x
141. Shoham S Shaffer R Sweet L Cooke R Donegan N Boyce S et al. Candidemia in patients with ventricular assist devices Clin Infect Dis 2007 44 e9 e12 10.1086/509640 17173211
142. Aslam S Hernandez M Thornby J Zeluff B Darouiche R Risk factors and outcomes of fungal ventricular assist device infections Clin Infect Dis 2010 50 664 671 10.1086/650454 20113174
143. Merrer J Dupont B Niezkowska A Jonghe BD Outin H Candida albicans prosthetic arthritis treated with fluconazole alone Infect 2001 42 890 895 10.1053/jinf.2001.0819
144. Dutronc H Dauchy FA Cazanave C Rougie C Lafarie-Castet S Couprie B et al. Candida prosthetic infections: Case series and literature review Stand J Infect Dis 2010 42 890 895 10.3109/00365548.2010.498023
145. Anagnostakos k Kelm J Schmitt E Jung J Fungal periprosthetic hip and knee joint infections clinical experience with a 2-stage treatment protocol J Arthroplasty 2012 27 293 298 10.1016/j.arth.2011.04.044 21752583
146. Ueng SW Lee CY Hu CC Hsieh PH Chang Y What is the success of treatment of hip and knee candidal periprosthetic joint infection? Clin Orthop Relat Res 2013 471 3002 3009 10.1007/s11999-013-3007-6 23633184
147. Khan FA Slain D Khakoo RA Candida endophthalmitis: Focus on current and future antifungal treatment options Pharmacotherapy 2007 27 1711 1721 10.1592/phco.27.12.1711 18041891
148. Riddell J Comer GM Kauffman CA Treatment of endogenous fungal endophthalmitis: Focus on new antifungal agents Clin Infect Dis 2011 52 648 653 10.1093/cid/ciq204 21239843
149. Chhablani J Fungal endophthalmitis Expert Rev Anti Infect Ther 2011 9 1191 1201 10.1586/eri.11.139 22114969
150. Essman TF Flynn HW Jr, Smiddy WE Brod RD Murray TG Davis JL et al. Treatment outcomes in a 10-year study of endogenous fungal endophthalmitis Ophthalmic Surg Lasers 1997 28 185 194 9076791
151. Akler ME Vellend H McNeely DM Walmsley SL Gold WL Use of fluconazole in the treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657 664 10.1093/clinids/20.3.657 7756492
152. Luttrull JK Wan WL Kubak BM Smith MD Oster HA Treatment of ocular fungal infections with oral fluconazole Am J Ophthalmol 1995 119 477 481 10.1016/s0002-9394(14)71234-6 7709972
153. Breit SM Hariprasad SM Mieler WF Shah GK Mills MD Grand MG Management of endogenous fungal endophthalmitis with voriconazole and caspofungin Am J Ophthalmic 2005 139 135 140 10.1016/j.ajo.2004.08.077
154. Sarria JC Bradley JC Habash R Mitchell KT Kimbrough RC Vidal AM Candida glabrata endophthalmitis treated successfully with caspofungin Clin Infect Dis 2005 40 e46 e48 10.1086/427753 15714407
155. Cornely OA Maertens J Bresnik M Ebrahimi R Ullmann AJ Bouza E et al. Liposomal amphotericin B as initial therapy for invasive mold infection: A randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial) Clin Infect Dis 2007 44 1289 1297 10.1086/514341 17443465
156. Herbrecht R Denning DW Patterson TF Bennett JE Greene RE Oestmann JW et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis N Engl J Med 2002 347 408 415 10.1056/NEJMoa020191 12167683
157. Martin-Pena A Aguilar-Guisado M Espigado I Cisneros JM Antifungal combination therapy for invasive aspergillosis Clin Infect Dis 2014 59 1437 1444 10.1093/cid/ciu581 25048847
158. Steinbach WJ Stevens DA Denning DW Combination and sequential antifungal therapy for invasive aspergillosis: Review of published in vitro and in vivo interactions and 6281 clinical cases from 1966 to 2001 Clin Infect Dis 2003 37 suppl 3 S188 S224 10.1086/376524 12975752
159. Garbati MA Alasmari FA Al-Tannir MA Tleyjeh IM The role of combination antifungal therapy in the treatment of invasive aspergillosis: A systematic review Int J Infect Dis 2012 16 e76 e81 10.1016/j.ijid.2011.10.004 22137271
160. Cornely OA Vehreschild JJ Vehreschild MJGT Wurthwein G Arenz D Schwartz S et al. Phase II dose escalation study of caspofungin for invasive aspergillosis Antimicrob Agents Chemother 2011 55 5798 5803 10.1128/AAC.05134-11 21911573
161. 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 2005 41 1242 1250 10.1086/496927 16206097
162. Herbrecht R Patterson TF Slavin MA Marchetti O Maertens J Johnson EM et al. Application of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versus amphotericin B for therapy of invasive aspergillosis: A collaborative study of the Mycoses Study Group (MSG 05) and the European Organization for Research and Treatment of Cancer Infectious Diseases Group Clin Infect Dis 2015 60 713 720 10.1093/cid/ciu911 25414266
163. Herbrecht R Kuessner D Pooley N Posthumus J Escrig C Systematic review and network meta-analysis of clinical outcomes associated with isavuconazole versus relevant comparators for patients with invasive aspergillosis Curr Med Res Opin 2018 34 2187 2195 10.1080/03007995.2018.1502659 30022696
164. Maertens JA Raad II Marr KA Patterson TF 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 2016 387 760 769 10.1016/S0140-6736(15)01159-9 26684607
165. Maertens J Rahav G Lee D-G et al. Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: A phase 3, randomised, controlled, noninferiority trial Lancet 2021 397 499 509 10.1016/S0140-6736(21)00219-1 33549194
166. Denning DW Marr KA Lau WM Facklam DP Ratanatharathorn V Becker C et al. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis J Infect 2006 53 337 349 10.1016/j.jinf.2006.03.003 16678903
167. Marty FM Ostrosky-Zeichner L Cornely OA Mullane KM Perfect JR Thompson 3rd GR et al. Isavuconazole treatment for mucormycosis: A single-arm open-label trial and case-control analysis Lancet Infect Dis 2016 16 828 837 10.1016/S1473-3099(16)00071-2 26969258
168. Vehreschild JJ Birtel A Vehreschild MJGT Liss B Farowski F Kochanek M et al. Mucormycosis treated with posaconazole: Review of 96 case reports Crit Rev Microbiol 2013 39 310 324 10.3109/1040841X.2012.711741 22917084
169. Shoham S Magill SS Merz WG Gonzalez C Seibel N Buchanan WL Knudsen TA et al. Primary treatment of zygomycosis with liposomal amphotericin B: Analysis of 28 cases Med Mycol 2010 48 511 517 10.3109/13693780903311944 19824881
170. Walsh TJ Goodman JL Pappas P Bekersky I Buell DN Roden M et al. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: Maximum tolerated dose study Antimicrob Agents Chemother 2001 45 3487 3496 10.1128/AAC.45.12.3487-3496.2001 11709329
171. Ullmann AJ Sanz MA Tramarin A Barnes RA Wu W Gerlack BA et al. Prospective study of amphotericin b formulations in immunocompromised patients in 4 European countries Clin Infect Dis 2006 43 e29 e38 10.1086/505969 16838223
172. Skiada A Pagano L Groll A Zimmerli S Dupont B Lagrou K et al. Zygomycosis in Europe: Analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) working group on zygomycosis between 2005 and 2007 Clin Microbiol Infect 2011 17 1859 1867 10.1111/j.1469-0691.2010.03456.x 21199154
173. Greenberg RN Mullane K Van Burik JAH Raad I Abzug MJ Anstead G et al. Posaconazole as salvage therapy for zygomycosis Antimicrob Agents Chemother 2006 50 126 133 10.1128/AAC.50.1.126-133.2006 16377677
174. Kyvernitakis A Torres HA Jiang Y Chamilos G Lewis RE Kontoyiannis DP Initial use of combination treatment does not impact survival of 106 patients with hematologic malignancies and mucormycosis: A propensity score analysis Clin Microbiol Infect 2016 22 811 e1 e8 10.1016/j.cmi.2016.03.029 26363405
175. Rodriguez CJ Tribble DR Malone DL Murray CK Jessie EM Khan M et al. Treatment of suspected invasive fungal infection in war wounds Mil Med 2018 183 142 146 10.1093/milmed/usy079 30189071
176. Gebremariam T Wiederhold NP Alqarihi A Uppuluri P Azie N Edwards Jr JE et al. Monotherapy or combination therapy of isavuconazole and micafungin for treating murine mucormycosis J Antimicrob Chemother 2017 72 462 466 10.1093/jac/dkw433 27798213
177. Chakrabarti A Singh S Management of Mucormycosis Curr Fungal Infect Rep 2020 14 348 360 10.1007/s12281-020-00406-2
178. Sun HY Alexander BD Lortholary O Dromer F Forrest GN Lyon GM et al. Lipid formulations of Amphotericin B significantly improve outcomes in solid organ transplant recipients with central nervous system cryptococcosis Clin Infect Dis 2009 49 1721 10.1086/647948 19886800
179. Bratton EW Husseini N Chastain CA Lee MS Poole C Sturmer T et al. Approaches to antifungal therapies and their effectiveness among patients with cryptococcosis Antimicrob Agents Chemother 2013 57 2485 10.1128/AAC.01800-12 23478968
180. Wheat J MaWhinney S Hafner R McKinsey D Chen D Korjun A et al. Treatment of histoplasmosis with fluconazole in patients with a quired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Acquired Immunodeficiency Syndrome Clinical Trials Group and Mycoses Study Group Am J Med 1997 103 3 223 232 10.1016/s0002-9343(97)00151-4 9316555
181. El-Sadr WM Luskin-Hawk R Yurik TM Walker J Abrams D John SL et al. A randomized trial of daily and thrice-weekly trimethoprim sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) Clin Infect Dis 1999 29 4 775 783 10.1086/520433 10589887
182. Girard PM Landman R Gaudebout C Olivares R Saimot AG Jelazko P et al. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. The PRIO Study Group N Engl J Med 1993 328 21 1514 1520 10.1056/NEJM199305273282102 8479488
183. Centers for Disease Control (CDC) Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus MMWR Suppl 16 38 5 1 9 2524643
184. El-Sadr WM Murphy RL Yurik TM Luskin-Hawk R Cheung TW Balfour HH et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group N Engl J Med 1998 339 26 1889 1895 10.1056/NEJM199812243392604 9862944
185. Briel M Bucher HC Boscacci R Furrer H Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV-infection Cochrane Database Syst Rev 2006 3 CD006150 10.1002/14651858.CD006150
186. Black JR Feinberg J Murphy RL Fass RJ Finkelstein D Akil B et al. Clindamycin and primaquine therapy for mild-to-moderate episodes of Pneumocystis carinii pneumonia in patients with AIDS: AIDS Clinical Trials Group 044 Clin Infect Dis 1994 18 6 905 913 10.1093/clinids/18.6.905 8086551
187. Toma E Thorne A Singer J Raboud J Lemieux C Trottier S et al. Clindamycin with primaquine vs. Trimethoprim-sulfamethoxazole therapy for mild and moderately severe Pneumocystis carinii pneumonia in patients with AIDS: A multicenter, double-blind, randomized trial (CTN 004). CTN-PCP Study Group Clin Infect Dis 1998 27 3 524 530 10.1086/514696 9770152
188. Kim T Kim SH Park KH Cho OH Sung H Kim MN et al. Clindamycin-primaquine versus pentamidine for the second-line treatment of Pneumocystis pneumonia J Infect Chemother 2009 15 5 343 346 10.1007/s10156-009-0710-z 19856077
189. Helweg-Larsen J Benfield T Atzori C Miller RF Clinical efficacy of first- and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: A tri-centre cohort study J Antimicrob Chemother 2009 64 6 1282 1290 10.1093/jac/dkp372 19858161
190. Marras TK Sanders K Lipton JH Messner HA Conly J Chan CK Aerosolized pentamidine prophylaxis for Pneumocystis carinii pneumonia after allogeneic marrow transplantation Transpl Infect Dis 2002 4 66 74 10.1034/j.1399-3062.2002.t01-1-00008.x 12220242
191. Hughes WT Use of dapsone in the prevention and treatment of Pneumocystis carinii pneumonia: A review Clin Infect Dis 1998 27 191 204 10.1086/514626 9675476
192. Chan C Montaner J Lefebvre EA Morey G Dohn M Mclvor RA et al. Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides J Infect Dis 1999 180 369 376 10.1086/314893 10395851
193. Munoz P Munoz RM Palomo J Rodriguez-Creixems M Munoz R Bouza E Efficacy of a weekend prophylaxis schedule Medicine (Baltimore) 1997 76 415 422 10.1097/00005792-199711000-00004 9413427
194. Gabardi S Millen P Hurwitz S Martin S Roberts K Chandraker A Atovaquone versus trimethoprim-sulfamethoxazole as Pneumocystis jirovecii pneumonia prophylaxis following renal transplantation Clin Transplant 2012 26 E184 E190 10.1111/j.1399-0012.2012.01624.x 22487221
195. Levine SJ Masur H Gill VJ Feuerstein I Suffredini AF Brown D et al. Effect of aerosolized pentamidine prophylaxis on the diagnosis of Pneumocystis carinii pneumonia by induced sputum examination in patients infected with the human immunodeficiency virus Am Rev Respir Dis 1991 144 760 764 10.1164/ajrccm/144.4.760 1928945
196. Kovacs JA Gill VJ Meshnick S Masur H New insights into transmission, diagnosis, and drug treatment of Pneumocystis carinii pneumonia JAMA 2001 286 2450 2460 10.1001/jama.286.19.2450 11712941
197. Fishman JA Treatment of infection due to Pneumocystis carinii Antimicrob Agents Chemother 1998 42 1309 1314 10.1128/AAC.42.6.1309 9624465
198. Elewa H El-Mekaty E El-Bardissy A Ensom MHH Wilby KJ Therapeutic Drug Monitoring of Voriconazole in the Management of invasive fungal infections: A critical review Clin Pharmacokinet 2015 54 12 1223 1235 10.1007/s40262-015-0297-8 26070947
199. Jin H Wang T Falcione BA Olsen KM Chen K Tang H et al. Trough concentration of voriconazole and its relationship with efficacy and safety: A systematic review and meta-analysis J Antimicrob Chemother 2016 71 7 1772 1785 10.1093/jac/dkw045 26968880
200. Luong ML Al-Dabbagh M Groll AH Racil Z Nannya Y Mitsani D et al. Utility of voriconazole therapeutic drug monitoring: A meta-analysis J Antimicrob Chemother 2016 71 7 1786 1799 10.1093/jac/dkw099 27165788
201. Vandewoude K Vogelaers D Decruyenaere J Jaqmin P Beule KD Peer AV et al. Concentrations in plasma and safety of 7 days of intravenous itraconazole followed by 2 weeks of oral itraconazole solution in patients in intensive care units Antimicrob Agents Chemother 1997 41 12 2714 2718 10.1128/AAC.41.12.2714 9420044
202. Ashbee HR Barnes RA Johnson EM Richardson MD Gorton R Hope WW Therapeutic drug monitoring (TDM) of antifungal agents: Guidelines from the British Society for Medical Mycology J Antimicrob Chemother 2014 69 5 1162 1176 10.1093/jac/dkt508 24379304
203. McCreary EK Bayless M Lepak AJ Weibe DA Schulz LT Andes DR Impact of Triazole therapeutic drug monitoring availability and timing Antimicrob Agents Chemother 2019 63 e01245 19 10.1128/AAC.01245-19 31332058
204. Ray J Campbell L Rudham S Nguyen Q Mariott D Posaconazole plasma concentrations in critically ill patients Ther Drug Monit 2011 33 4 387 392 10.1097/FTD.0b013e31821fb197 21654350
205. Andes D Marchillo K Conklin R Krishna G Ezzet F Cacciapuoti A Loebenberg D Pharmacodynamics of a New Triazole, Posaconazole, in a murine model of disseminated Candidiasis Antimicrob Agents Chemother 2004 48 1 137 142 10.1128/AAC.48.1.137-142.2004 14693531
206. Dekkers BGJ Bakker M van der Elst KCM Sturkenboom MGG Veringa A Span LFR et al. Therapeutic Drug Monitoring of Posaconazole: An Update Curr Fungal Infect Rep 2016 10 51 61 10.1007/s12281-016-0255-4 27358662
207. Seyedmousavi S Mouton JW Verweij PE Bruggemann JM Therapeutic drug monitoring of voriconazole and posaconazole for invasive aspergillosis Expert Rev Anti Infect Ther 2013 11 9 931 941 10.1586/14787210.2013.826989 24053274
208. Andes D Kovanda L Desai A Kitt T Zhao M Walsh TJ Isavuconazole concentration in real-world practice: Consistency with results from clinical trials Antimicrob Agents Chemother 2018 62 7 e00585 18 10.1128/AAC.00585-18 29735569
209. Prayag PS Soman RN Panchakshari SP Ajapuje PS Mahale NP Dhupad S et al. Therapeutic drug monitoring of Isavuconazole: Lessons learnt from a real-life setting in a tertiary care center in India Indian J Crit Care Med 2023 27 4 260 264 10.5005/jp-journals-10071-24443 37378040
210. Righi E Carnelutti A Baccarani U Sartor A Cojutti P Bassetti M et al. Treatment of candida infections with fluconazole in adult liver transplant recipients: Is TDM-guided dosing adaptation helpful? Transpl Infect Dis 2019 21 4 e13113 10.1111/tid.13113 31106504
211. Liu X Liu D Pan Y Yimin L Pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients: A systematic review and meta-analysis J Clin Pharm Ther 2020 45 6 1207 1217 10.1111/jcpt.13211 32672361
212. Yang YL Xiang ZJ Yang JH Wang WJ Xu ZC Xiang RL Adverse effects associated with currently commonly used antifungal agents: A network meta-analysis and systematic review Front Pharmacol 2021 12 697330 10.3389/fphar.2021.697330 34776941
213. Sinnollareddy MG Roberts JA Lipman J Akova M Bassetti M Waele JJD et al. DALI Study authors. Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: Data from multinational Defining antibiotic levels in intensive care unit (DALI) patients study Crit Care 2015 19 1 33 10.1186/s13054-015-0758-3 25888060
214. van der Elst KC Veringa A Zijlstra JG Beishuizen A Klont R Brummelhuis Visser P et al. Low Caspofungin exposure in patients in intensive care units Antimicrob Agents Chemother 2017 61 2 e01582 16 10.1128/AAC.01582-16 27855112
215. Adembri C Villa G Rosi E Tofani L Fallani S Gaudio ARD et al. Caspofungin PK in critically ill patients after the first and fourth doses: Suggestions for therapeutic drug monitoring? J Chemother 2020 32 3 124 131 10.1080/1120009X.2020.1737783 32202224
216. Jullien V Azoulay E Schwebel C Saux TL Charles PE Cornet M et al. EMPIRICUS Trial Study Group. Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation J Antimicrob Chemother 2017 72 1 181 189 10.1093/jac/dkw352 27609051
217. Maseda E Grau S Luque S Castillo-Mafla MP Suárez-de-la-Rica A Montero-Feijoo A et al. Population pharmacokinetics/pharmacodynamics of micafungin against Candida species in obese, critically ill, and morbidly obese critically ill patients Crit Care 2018 22 1 94 10.1186/s13054-018-2019-8 29655372
218. Groll AH Rijnders BJA Walsh TJ Adler-Moore J Lewis RE Brüggemann RJM et al. Clinical pharmacokinetics, pharmacodynamics, safety and efficacy of liposomal Amphotericin B Clin Infect Dis 2019 68 Suppl 4 S260 S274 10.1093/cid/ciz076 31222253
219. Andes D Pascual A Marchetti O Antifungal therapeutic drug monitoring: Established and emerging indications Antimicrob Agents Chemother 2009 53 1 24 34 10.1128/AAC.00705-08 18955533
