
==== Front
Pharmacy (Basel)
Pharmacy (Basel)
pharmacy
Pharmacy
2226-4787
MDPI

10.3390/pharmacy12050142
pharmacy-12-00142
Review
Antibiotic Treatment of Infections Caused by AmpC-Producing Enterobacterales
Tebano Gianpiero 1*†
Zaghi Irene 2†
https://orcid.org/0000-0002-2815-3119
Cricca Monica 34
https://orcid.org/0000-0001-8643-2565
Cristini Francesco 45
Modun Darko Academic Editor
1 Infectious Diseases Unit, Ravenna Hospital, AUSL Romagna, 48100 Ravenna, Italy
2 Department of Infectious Diseases, University Hospital of Galway, H91 Galway, Ireland; irene.zaghi@gmail.com
3 Unit of Microbiology, The Greater Romagna Area Hub Laboratory, 47522 Cesena, Italy; monica.cricca3@unibo.it
4 Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; francesco.cristini@ausltromagna.it
5 Infectious Diseases Unit, Forlì and Cesena Hospitals, AUSL Romagna, 47121 Forlì and Cesena, Italy
* Correspondence: gianpiero.tebano@auslromagna.it; Tel.: +390544285545; Fax: +390544285884
† These authors contributed equally to this work.

21 9 2024
10 2024
12 5 14214 7 2024
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© 2024 by the authors.
2024
https://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
AmpC enzymes are a class of beta-lactamases produced by Gram-negative bacteria, including several Enterobacterales. When produced in sufficient amounts, AmpCs can hydrolyze third-generation cephalosporins (3GCs) and piperacillin/tazobactam, causing resistance. In Enterobacterales, the AmpC gene can be chromosomal- or plasmid-encoded. Some species, particularly Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii, harbor an inducible chromosomal AmpC gene. The expression of this gene can be derepressed during treatment with a beta-lactam, leading to AmpC overproduction and the consequent emergence of resistance to 3GCs and piperacillin/tazobactam during treatment. Because of this phenomenon, the use of carbapenems or cefepime is considered a safer option when treating these pathogens. However, many areas of uncertainty persist, including the risk of derepression related to each beta-lactam; the role of piperacillin/tazobactam compared to cefepime; the best option for severe or difficult-to-treat cases, such as high-inoculum infections (e.g., ventilator-associated pneumonia and undrainable abscesses); the role of de-escalation once clinical stability is obtained; and the best treatment for species with a lower risk of derepression during treatment (e.g., Serratia marcescens and Morganella morganii). The aim of this review is to collate the most relevant information about the microbiological properties of and therapeutic approach to AmpC-producing Enterobacterales in order to inform daily clinical practice.

AmpC enzyme
ampC gene
Enterobacter cloacae complex
Klebsiella aerogenes
Citrobacter freundii
beta-lactams
beta-lactamases
antibiotic resistance
This research received no external funding.
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pmc1. Introduction

Antibiotic resistance is a widespread phenomenon and represents a global threat [1]. Antibiotic resistance in Gram-negative pathogens can be caused by a variety of mechanisms, including enzymatic inactivation of the antibiotic, porin mutations, overexpression of efflux pumps, and target modification. Enzymatic inactivation is particularly relevant to beta-lactam antibiotics, which are pivotal agents in treating severe infections [2,3,4,5,6].

Overall, beta-lactam-inactivating enzymes are identified as beta-lactamases [2,6,7,8]. All beta-lactamases can hydrolyze the beta-lactam ring, and this structural modification compromises the activity of the antibiotic. However, beta-lactamases are a vast group of enzymes and can differ significantly with regard to molecular structure, genetic features, regulation of genetic expression, potential for clonal spreading and horizontal transmission, efficacy in hydrolyzing their substrate, range of action, and resistance to different beta-lactamase inhibitors [8,9,10,11].

AmpC enzymes represent a vast and concerning family of beta-lactamases. AmpC enzymes (hereinafter defined for brevity as AmpCs) are found in many critically relevant human pathogens, including many Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii [9]. They can compromise the effectiveness of most beta-lactams, leaving few therapeutic options. The treatment of AmpC-producing pathogens can be complex, with many areas of uncertainty and possible pitfalls. Some authoritative reviews about this topic exist in the literature [3], but recent advances have occurred, justifying an updated revision of available data. The aim of this review is to provide a practical overview of the most relevant microbiological properties of AmpC-producing Enterobacterales and the antibiotic treatment of infections caused by these microorganisms, with a special focus on inducible chromosomal AmpCs.

2. Microbiological Properties

2.1. What Are AmpC Enzymes?

AmpCs are beta-lactamases produced by a wide range of Gram-negative bacteria [9,12]. Like several other beta-lactamases, they are structurally similar to the beta-lactam target, i.e., the penicillin-binding proteins (PBPs). They contain a serine in the active site and belong to class C according to the Ambler structural classification [7] and to group 1 according to the Bush functional classification [2].

The first evidence of AmpC production is dated back to 1940. It appears that the very first bacterial enzyme reported to be able to destroy penicillin was structurally an AmpC, produced by Escherichia coli, although it was so named only several years later [13]. Afterwards, several enzymes have been discovered and assigned to the AmpC class according to their molecular structure and target substrate [12].

The AmpC gene carried by Enterobacterales can be chromosomally or plasmid-encoded [3,12]. The first AmpC originally described in 1940 was chromosomally encoded [14,15]. In the late 1980s, the first plasmid-encoded AmpC gene was reported [16], and subsequently, several plasmid-mediated class C beta-lactamases have been discovered worldwide, both in clinical samples [17] and environmental settings [18].

All AmpCs produced by Enterobacterales are able to hydrolyze penicillins, monobactams, and cephalosporins, including ceftaroline and ceftobiprole. The only notable exception is cefepime. AmpC-producing strains remain susceptible to carbapenems and to most newer beta-lactam/beta-lactamase inhibitor combinations (BL-BLICs) (Table 1) [9,12,19,20].

Despite a wide overlap in the spectrum of activity, AmpCs can usually be differentiated phenotypically from extended-spectrum beta-lactamases (ESBLs). ESBLs are inhibited by older beta-lactamase inhibitors (clavulanic acid, tazobactam), do not hydrolyze cephamycins (cefoxitin), and frequently confer resistance to cefepime. AmpCs produced by Enterobacterales are not inhibited by clavulanic acid and tazobactam and confer resistance to cefoxitin; in contrast, they do not efficiently hydrolyze cefepime (Table 1) [4,9,12,21].

2.2. How Can AmpC Enzymes Be Classified?

One peculiar characteristic that differentiates AmpCs from other beta-lactamases is that their expression can be either constitutive or inducible [3,9,12]. This can have relevant implications in a clinical setting.

According to this characteristic, AmpCs can be classified into three groups (Figure 1):(1) Inducible chromosomal AmpCs.

(2) Non-inducible chromosomal AmpCs.

(3) Plasmid-encoded AmpCs.

(1) Inducible chromosomal AmpCs follow a complex mechanism. AmpC production is usually maintained at a low level by the presence of a negative regulatory element named AmpR, which down-regulates the expression of the AmpC gene. AmpR’s activity can be disabled when it is bound by some peptides, which can induce conformational changes; such peptides derive from bacterial cell wall degradation, and their production is increased by beta-lactam antibacterial action. Thus, beta-lactam exposure can determine the derepression of the AmpC gene, with consequent hyperproduction of AmpC, a phenomenon usually called AmpC derepression [22,23,24].

Other molecules are implicated in the regulation of AmpC production, such as AmpD, a cell wall enzyme that removes peptides derived from cell wall disruption, preventing AmpC derepression [25].

AmpC derepression due to beta-lactam exposure is usually a reversible phenomenon; thus, AmpC production can be down-regulated again when the exposure to beta-lactam is discontinued. However, mutations can further occur in regulatory genes, such as ampR or ampD (coding for AmpR and AmpD, respectively), determining a stable (non-reversible) derepression of AmpC production [3,26].

Inducible chromosomal resistance is mainly found in Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii, but can be present in many other Enterobacterales, as we will discuss later in more detail [17,27,28,29,30]. When inducible chromosomal AmpC is not derepressed, these bacteria appear phenotypically resistant to amoxicillin/ampicillin, amoxicillin/clavulanic acid, and first-generation cephalosporins but susceptible to ticarcillin, piperacillin, and third-generation cephalosporins. When inducible chromosomal AmpC is derepressed, the only beta-lactams preserving phenotypic (and clinical) activity are cefepime, carbapenems, and most newer BL-BLICs [3,12,31,32].

(2) Non-inducible chromosomal ampC genes are present in the genomes of some very frequently encountered Enterobacterales, particularly E. coli but also Shigella spp. They determine the production of a very small quantity of AmpC enzymes, which do not produce a phenotypical or clinically relevant effect on beta-lactam activity [3,17,33,34]. However, some mutations in the regulatory system of these genes (promotor and/or attenuator mutations) can determine their stable overexpression/derepression, resulting in AmpC non-inducible and non-reversible hyperproduction that is independent of beta-lactam exposure and confers resistance to third-generation cephalosporins. This mechanism remains rare [3,35].

(3) Plasmid-encoded ampC genes are derived from inducible chromosomal genes, which have been mobilized on plasmids, with subsequent spreading among various organisms. Plasmid-encoded AmpCs are non-inducible and non-reversible. They have been found in Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Salmonella enterica, and Shigella spp. [2,16,17,36,37].

Non-inducible but overexpressed/derepressed chromosomal AmpCs (group 2) and plasmid-encoded AmpCs (group 3) confer phenotypical resistance to third-generation cephalosporins, such as ceftriaxone, cefotaxime, and ceftazidime [3,12]. These resistance mechanisms can have a relevant impact on the appropriateness of empirical treatments from a stewardship standpoint, but they do not create special challenges in interpreting phenotypic antibiotic susceptibility testing (AST) once the isolate is available, since AST is reliable in guiding antibiotic choice.

Inducible chromosomal AmpCs (group 1) are a more relevant and challenging phenomenon. When this resistance mechanism is present, but in the absence of derepression, third-generation cephalosporins display phenotypical susceptibility. During antibiotic treatment, derepression of the ampC gene can result in an increased production of AmpCs, with the emergence of clinically relevant antibiotic resistance to third-generation cephalosporins (Table 1). As a result, AST can be misleading, as it may initially show susceptibility to ceftriaxone, cefotaxime, and ceftazidime, but resistance to these agents can emerge during antibiotic treatment, leading to clinical failure [3,22,23,24,25,26,27,28,32,38].

Because of these considerations, the next paragraphs will focus particularly on inducible chromosomal AmpC-producing Enterobacterales and their treatment.

2.3. Which Enterobacterales Produce Inducible Chromosomal AmpCs?

Inducible chromosomal AmpCs can be produced by a variety of Enterobacterales. However, the probability of derepression during antibiotic treatment and the degree of derepression (i.e., the amount of enzyme produced) can differ significantly from one species to another.

Enterobacter cloacae complex, Klebsiella aerogenes (formerly known as Enterobacter aerogenes), and Citrobacter freundii are the Enterobacterales at higher risk for derepression [3,32]. However, the exact risk of derepression during treatment with third-generation cephalosporins is unknown. In some observational studies, it has been estimated at an average of 20% (8% to 40%), but these data require further validation [27,28,29,30,39,40].

Other Enterobacterales that can harbor inducible chromosomal AmpCs are Serratia marcescens, Providencia spp., Morganella morganii, Hafnia alvei, and Yersinia enterocolitica [3,32]. The exact rate of derepression is unknown for these pathogens as well, but it is estimated to be <5% [3,27,38,39,41]. Furthermore, the derepression of the ampC gene determines a production of AmpC that is up to 10 times less abundant than for Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii [24,39,42].

2.4. Which Antibiotics Can Induce AmpC Derepression?

When an inducible chromosomal AmpC is present, some antibiotics can induce AmpC derepression more efficiently than others. On the other hand, some antibiotics are more susceptible to AmpC-mediated hydrolysis than others. According to these characteristics, beta-lactams can be classified into four groups (Table 2) [3,12,22,27,28,29,30,43,44,45,46]:Potent inducers, susceptible to hydrolysis: aminopenicillins (ampicillin, amoxicillin), amoxicillin/clavulanic acid, first-generation cephalosporins, and cephamycins (cefoxitin) are potent inducers of AmpC and are rapidly hydrolyzed by AmpC, even when inducible chromosomal AmpC is not derepressed.

Weak inducers, susceptible to hydrolysis: third-generation cephalosporins, piperacillin/tazobactam, and aztreonam are weak inducers but are substrates of AmpC. Increased minimal inhibitory concentrations (MICs) are observed in the absence of AmpC derepression, and clinically relevant resistance is present in cases of derepression.

Potent inducers, resistant to hydrolysis: carbapenems are potent inducers, but like cefepime, they remain resistant to hydrolysis through the formation of a stable acyl/enzyme complex.

Weak inducers, resistant to hydrolysis: cefepime is a weak AmpC inducer and has the advantage of withstanding AmpC hydrolysis through the formation of a stable acyl/enzyme complex that determines low enzyme affinity and low hydrolysis rate.

3. Treatment

The treatment of AmpC-producing Enterobacterales is not well established. Only one small, pilot randomized clinical trial (RCT), showing conflicting results, is available to date [47]. The remaining evidence to guide treatment comes from extrapolation from in vitro data, or observational studies, which suffer from several limitations, including small sample size (limiting the ability to show significant differences between groups), heterogeneous populations, heterogeneous treatment strategies, heterogeneous outcome measures, and high risk of bias due to the inherent impossibility to control for confounders [32,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66].

Despite these limitations, the Infectious Diseases Society of America (IDSA) released in 2023 the updated version of the Guidance on the treatment of antimicrobial-resistant Gram-negative infections, including a chapter on the treatment of AmpC-producing Enterobacterales [32]. In contrast, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) provided only some general indications about the use of cefepime and carbapenems in these conditions in the Guidelines for the treatment of infections caused by MDR Gram-negative bacilli, without issuing any specific recommendations [67].

In order to summarize the best available evidence on antibiotic treatment of AmpC-producing Enterobacterales, it is worthwhile to distinguish between species at moderate-to-high risk of derepression (Enterobacter cloacae complex, Citrobacter freundii, and Klebsiella aerogenes) and species at low risk of derepression (Serratia marcescens, Providencia spp., Morganella morganii, Hafnia alvei, and Yersinia enterocolitica).

3.1. How to Treat Species at Moderate-to-High Risk of AmpC Derepression?

Carbapenems are considered the reference treatment for Enterobacterales at moderate-to-high risk of AmpC derepression (Enterobacter cloacae complex, Citrobacter freundii, and Klebsiella aerogenes) (Table 3). They are not susceptible to AmpC-mediated hydrolysis, remaining active even in cases of AmpC derepression. Carbapenems preserve their activity in cases of high-inoculum infections or if other additional resistance mechanisms are present, such as ESBLs [68]. Meropenem and imipenem/cilastatin are the reference carbapenems [32,48,49,50,51,52,53,54,55,56,57,58,59,60,62,63,65,69,70], but ertapenem has also been investigated and may be a valid option [64,71]. However, susceptibility to ertapenem needs to be confirmed and cannot be directly inferred from that of meropenem, as ertapenem resistance due to the combination of AmpC hyperproduction and porin loss in ESBLs has been documented [72,73].

Despite the reliable antibacterial activity of carbapenems, carbapenem-sparing regimens are desirable from an antibiotic stewardship perspective. Thus, other narrower-spectrum antibiotics should be considered when AST shows phenotypical susceptibility.

3.1.1. Third-Generation Cephalosporins

The use of third-generation cephalosporins (3GCs: ceftriaxone, cefotaxime, ceftazidime) for the treatment of Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii infections is generally discouraged in the case of invasive infections since it is associated with a clinically relevant risk (5–40%) of AmpC derepression and subsequent treatment failure (Table 3) [32,65,74]. In a recent retrospective observational study using a propensity score-based analysis, Maillard et al. included 575 patients with bloodstream infection (BSI) or pneumonia due to AmpC-producing Enterobacterales. They compared patients treated with ceftriaxone or piperacillin/tazobactam (investigational groups) to patients treated with cefepime or meropenem (reference group). They found that the likelihood of clinical failure was higher in the patients treated with ceftriaxone or piperacillin/tazobactam, even if the 30-day mortality was not significantly different [65]. Clinical failure associated with ceftriaxone treatment was also found in another observational study on pulmonary infections [75]. Third-generation cephalosporins retain a role, together with non-beta-lactam options, for the treatment of non-invasive infections, such as uncomplicated urinary tract infections (UTIs) (Table 3) [32,41,76].

However, even if this paradigm is widely shared, some areas of uncertainty remain. Evidence from well-designed RCTs is lacking, and data from observational studies are not univocal in showing an increased risk of clinical failure compared with cefepime or carbapenems [77]. Moreover, several studies did not investigate on a molecular basis whether concomitant ESBL production was present when clinical failure with 3GCs was described. Finally, many studies on the use of ceftriaxone were based on the old CLSI breakpoints (pre-2010: ceftriaxone susceptibility for MICs ≤ 8 mg/L), making the translation of evidence challenging when the current EUCAST and CLSI ceftriaxone susceptibility breakpoints are considered (≤1 mg/L) [77,78,79]. Thus, from an antibiotic stewardship perspective, the role of 3GCs deserves further investigation.

3.1.2. Cefepime

Cefepime is a weak inducer of AmpC derepression, and it is stable against AmpC’s hydrolytic activity. Moreover, unlike other cephalosporins, cefepime is a zwitterion, and it can cross the bacterial outer membrane more quickly, thus being less exposed to the action of β-lactamases [12,80,81].

Because of these biochemical and pharmacological properties, and according to clinical data [32,48,49,50,52,53,54,55,56,57,64,66], cefepime is considered a reliable option for the treatment of invasive infections resulting from AmpC-producing Enterobacterales (Table 3).

However, evidence regarding the clinical use of cefepime when treating cefepime-susceptible AmpC-producing Enterobacterales relies only on observational studies. Overall, when compared to carbapenems, cefepime seems to perform well, without any clear evidence of worse outcomes, but evidence from RCTs is lacking [32,48,49,50,52,53,55,56,57,58,64,66,69,70]. Tamma et al. included patients with BSI, respiratory, and intra-abdominal infections caused by Enterobacter cloacae complex, Citrobacter freundii, and Serratia marcescens. They showed similar 30-day mortality (31% for cefepime and 34% for carbapenems) in a propensity score-matched cohort (32 patients for each group, after balancing with propensity score matching) [69]. In a well-balanced population of 144 patients, Lee et al. showed the non-inferiority of cefepime (72 patients) compared to meropenem (72 patients) when treating Enterobacter cloacae BSI. In the small subgroup of 18 patients having an MIC for cefepime >2 mg/L, there was a higher risk of death [50]. Similar findings were reported in other observational studies [32,48,49,52,53,55,56,57,58,64].

A high dose, i.e., 6 g per day (in 3 administrations or continuous infusion), should be preferred for this indication since a twice-daily dose has been associated with an increased risk of clinical failure [50,58,82].

It is worthwhile to highlight that a discrepancy exists between EUCAST and CLSI MIC breakpoints for cefepime in Enterobacterales. The MIC breakpoint for cefepime susceptibility is ≤1 mg/L for EUCAST and ≤2 mg/L for CLSI; the breakpoint for resistance is >4 mg/L for EUCAST and ≥16 mg/L for CLSI, with an MIC of 4–8 considered susceptible dose-dependent (SDD) [78,79]. The epidemiological cut-off (ECOFF) is 0.125 mg/L according to EUCAST [83]. The more conservative breakpoints proposed by EUCAST appear to be more cautious, particularly in cases of severe infection. In fact, an MIC ≤ 1 mg/L is generally considered a reliable phenotypic proxy to rule out the co-presence of other resistance mechanisms, such as ESBLs or porin mutations, which may affect cefepime efficacy [32,50,84,85,86]. When the MIC is in the range of 4 to 8 mg/l, other mechanisms of resistance cannot be ruled out; there is a higher risk of clinical failure with cefepime, and carbapems become a safer treatment option [3,32,50,53,87]. Real AmpC-mediated resistance (i.e., without the co-participation of other resistance mechanisms) has been reported because of structurally modified AmpC resulting from ampC gene mutations; however, this phenomenon has been rarely described [88,89,90].

The use of high cefepime doses has to be weighed against the risk of adverse reactions. Cefepime-related neurotoxicity is a topic of growing interest, and it is usually associated with renal dysfunction and high trough concentrations [91,92]. Cefepime therapeutic drug monitoring has been suggested to improve cefepime’s safety profile in patients at risk of toxicity [93].

3.1.3. Piperacillin/Tazobactam

Tazobactam is vulnerable to AmpC-mediated hydrolysis, but piperacillin/tazobactam is a weak inducer of AmpC derepression, making the probability of clinical failure when treating a piperacillin/tazobactam-susceptible strain theoretically low [12]. Consequently, piperacillin/tazobactam is considered a possible option for the treatment of wild-type Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii (Table 3).

A small, pilot RCT (MERINO 2) enrolling 72 patients compared piperacillin/tazobactam versus meropenem for definitive treatment of bloodstream infections caused by Enterobacter spp., Citrobacter freundii, Serratia marcescens, Morganella morganii, and Providencia spp. The study considered a composite outcome, including death, clinical failure, microbiological failure, and microbiological relapse at 30 days [47]. The study did not show a statistically significant difference in the piperacillin/tazobactam arm versus the meropenem arm, with 28% and 21% of patients meeting the composite outcome, respectively (risk difference: 8%; 95% confidence interval: −12 to 28%). However, the study included only 38 and 34 patients for each arm, and no sample size calculation was performed; thus, it was very probably underpowered to detect meaningful differences between the two groups. Moreover, when the authors considered the subcomponents of the primary outcome, microbiological failure was significantly more probable in the piperacillin/tazobactam group. In conclusion, the results of the trial have to be considered as purely exploratory, and further studies are needed to confirm their validity [47].

Data from observational studies are conflicting. Some studies showed that piperacillin/tazobactam was non-inferior to carbapenems, but several limitations apply, including small sample size and imbalanced populations [51,53,54,66,70,94]. Cheng et al. performed a propensity score-matched analysis, including 41 patients in each group (piperacillin/tazobactam versus cefepime or meropenem), showing no statistically significant differences in 30-day mortality. However, there was a trend toward increased mortality in the piperacillin/tazobactam group (15% versus 7%), and the small sample size raises concerns about a possible type II error. Chaubey et al. came to some different conclusions, showing that piperacillin/tazobactam was inferior to cefepime and to meropenem in terms of in-hospital mortality; however, the study was limited by a small sample size as well. In the aforementioned larger observational study, Maillard et al. found that ceftriaxone or piperacillin/tazobactam treatment had a higher risk of clinical failure (but similar 30-day mortality) compared to cefepime or meropenem as a control [65].

In terms of ecological impact (selective pressure) and risk for MDR selection, piperacillin/tazobactam and cefepime are probably comparable [95]. Piperacillin/tazobactam has been associated with a higher risk of nephrotoxicity, particularly when associated with other nephrotoxic drugs, such as vancomycin [96,97,98,99], but this difference was not confirmed in a recent RCT [92]. Cefepime has been associated with a higher rate of drug-induced neurotoxicity [92].

IDSA guidelines suggest a preference for cefepime or carbapenems over piperacillin/tazobactam for severe infections caused by AmpC-producing Enterobacterales. Piperacillin/tazobactam remains a viable option for non-severe infections, such as UTIs; its role in cases of severe infection deserves further investigation [32,76].

3.1.4. Ceftolozane/Tazobactam, New Beta-Lactam/Beta-Lactamase Inhibitor Combinations, and Cefiderocol

Ceftolozane/tazobactam has shown good activity against AmpC-producing Pseudomonas aeruginosa, unless an AmpC-Ω-loop mutation is present. This is due to the intrinsic resistance of ceftolozane to pseudomonal AmpC-mediated hydrolysis [5]. In contrast, data about the activity of ceftolozane/tazobactam against AmpC-producing Enterobacterales are scarce and less encouraging, making this drug a non-preferred choice for this indication (Table 3) [32,73,100].

New commercially available beta-lactam/beta-lactamase inhibitor combinations (BL-BLICs, i.e., ceftazidime/avibactam, imipenem/cilastatin/relebactam, meropenem/vaborbactam) and cefiderocol have shown good activity in vitro against AmpC-producing Enterobacterales [101,102,103]. However, the available clinical data are very limited and focused mainly on ceftazidime/avibactam [104,105]. Moreover, the emergence of resistance in AmpC-producing Enterobacterales has been described for ceftazidime/avibactam and cefiderocol, even if it probably remains very rare [89,106]. Because of these elements, and from an antibiotic stewardship perspective, it is advisable to reserve the use of new commercially available BL-BLICs and cefiderocol for the treatment of carbapenem-resistant strains (Table 3) [32,101].

3.1.5. Non-Beta-Lactam Antibiotics

Non-beta-lactam antibiotics do not induce AmpC derepression and are not susceptible to AmpC-mediated hydrolysis. They can be considered for two main indications: as first-line agents or as oral step-down therapy [32,70]. Fluoroquinolones and trimethoprim/sulfamethoxazole are the most relevant non-beta-lactam antibiotics in this context, particularly because of their clinical efficacy and high oral bioavailability [32,107].

Fluoroquinolones and trimethoprim/sulfamethoxazole can be considered for uncomplicated UTIs [3,32,107,108,109]. Moreover, due to their good intra-prostatic penetration, they are considered drugs of choice for both acute and chronic prostatitis [109,110]. Nitrofurantoin can also play a role in uncomplicated female cystitis [109,111]. In contrast, the use of fosfomycin for uncomplicated female cystitis should be mainly reserved for infections caused by Escherichia coli [112].

In recent years, there has been growing interest in early oral step-down treatment for several serious infections, such as uncomplicated BSI [113,114,115,116,117,118], infective endocarditis [119], and bone and joint infections (BJIs) [120]. Evidence showed that oral step-down can be as effective as intravenous treatment when patients are appropriately selected, with a decrease in the duration of hospital stay [113,114,115,116,117,118,119]. Fluoroquinolones and trimethoprim/sulfamethoxazole play a major role in this context because of their excellent bioavailability, particularly when treating Gram-negative uncomplicated BSI with a urinary source [113,114,118,121]. Major studies included mostly infections caused by Escherichia coli and Klebsiella pneumoniae, with relatively few AmpC-producing Enterobacterales [114,115]. A partial exception was the retrospective multicenter study by Tamma et al., which included a propensity score-matched cohort of 4967 unique patients hospitalized with monomicrobial BSI caused by Enterobacterales. In the study, Enterobacter spp. and Citrobacter spp. accounted for around 15% of included patients in total [118].

In summary, data about the efficacy and safety of partial oral treatment of Gram-negative infections, particularly uncomplicated BSI caused by Enterobacterales (including AmpC-producing strains), are solid and encouraging, supporting oral step-down as a reliable strategy [32,113]. The best evidence is available for fluoroquinolones and, to a lesser extent, for trimethoprim/sulfamethoxazole [114,115,116,117,118].

3.2. What Is the Treatment for Species at Low Risk of AmpC Derepression?

Some species considered at low risk of derepression are Serratia marcescens, Providencia spp., Morganella morganii, Hafnia alvei, and Yersinia enterocolitica.

As already underlined in Section 2.3, the real risk of derepression is unknown, but it is estimated to be <5% [3,27,38,39,41]. Furthermore, AmpC gene derepression led to a much less relevant production of AmpC enzyme (up to 10 times less) than in Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii [24,39,42].

Once confirmed that the strain does not carry any ESBL enzyme and the MIC for 3GCs falls into the wild-type range, it seems reasonable to propose ceftriaxone or cefotaxime as first-line therapy, as proposed by the IDSA guidelines [32,122]. Some concerns may arise in cases of high-inoculum infection, particularly when source control is unfeasible or in cases of very severe infections. In these carefully selected cases, some may consider cefepime or carbapenems as a more cautious choice. However, the risk/benefit ratio of such a choice is unclear, particularly for infections needing prolonged treatment (i.e., osteoarticular infections or complex, undrainable abscesses), where a prolonged exposure to antibiotics is unavoidable [41].

Concerning difficult-to-treat infections, it is worthwhile to remember that Serratia marcescens has been categorized as a typical pathogen for prosthetic valve endocarditis, according to the 2023 Duke-International Society for Cardiovascular Infectious Diseases Criteria for Infective Endocarditis [123]. The 2023 European Society of Cardiology Guidelines for the Management of Endocarditis suggested a combination treatment for endocarditis caused by non-HACEK Gram-negative pathogens, including Serratia marcescens (beta-lactam plus aminoglycosides or fluoroquinolones), but this approach is not well supported by clinical evidence [124,125,126].

4. Future Perspectives

The treatment of AmpC-producing Enterobacterales is a challenging and evolving field. Many aspects deserve further investigation, including the following:(1) The exact risk of derepression in different species and related to different antibiotics (including newer molecules, such as ceftolozane/tazobactam, new BL-BLICs, and cefiderocol);

(2) The clinical efficacy of 3GCs and piperacillin/tazobactam, depending on the clinical context and causative pathogen (low or moderate-to-high risk of derepression). This would ideally require data from well-conducted RCTs;

(3) The role of cefepime and ertapenem, compared to meropenem or imipenem/cilastatin, in difficult-to-treat infections (e.g., BJIs), high-inoculum infections (e.g., undrainable abscesses), and very severe infections (e.g., septic shock);

(4) The role of ceftolozane/tazobactam;

(5) The role of non-beta-lactam options beyond UTIs and oral step-down;

(6) The eventual need for escalation when the clinical isolate becomes available but the patient has already achieved clinical stability and has been empirically treated with second-line agents, such as 3GC;

(7) The role of de-escalation to 3GC (particularly for prolonged treatment courses) when the patient has already reached clinical stability and is not eligible for oral step-down.

Acknowledgments

English editing has been provided by Lisa Duffy, Galway University Hospital.

Author Contributions

Conceptualization: G.T., I.Z., and F.C.; methodology: G.T., I.Z., and F.C.; investigation/literature search: G.T., I.Z., M.C., and F.C.; writing—original draft preparation: G.T. and I.Z.; writing—review and editing: M.C. and F.C.; supervision: M.C. and F.C. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Figure 1 Classification of AmpC enzymes produced by Enterobacterales. * During antibiotic treatment with beta-lactams (each beta-lactam is associated with a different risk of derepression).

pharmacy-12-00142-t001_Table 1 Table 1 AmpC-producing Enterobacterales: expected phenotypes for wild-type strains and in cases of AmpC derepression and ESBL production.

Antibiotic	Wild-Type Expected Phenotype	Expected Phenotype in Cases of AmpC Derepression	Expected Phenotype in Cases of ESBLs	
aminopenicillins (ampicillin, amoxicillin)	R	R	R	
Amoxicillin/clavulanic acid	R	R	S/R 3	
ticarcillin	S	R	R	
piperacillin	S	R	R	
piperacillin/tazobactam	S	R	S/R 3	
first-generation cephalosporins	R	R	R	
cephamycins (2ndG cef)	R	R	S	
third-generation cephalosporins	S	R	R	
fourth-generation cephalosporins (cefepime)	S	S 1	S/R 3	
ceftaroline and ceftobiprole	S	R	R	
ceftolozane/tazobactam	S	S/R	S/R 4	
aztreonam	S	R	S/R 3	
carbapenems	S	S 2	S 2	
ceftazidime/avibactam, imipenem/cilastatin/relebactam, meropenem/vaborbactam, cefiderocol	S	S	S	
ESBLs: extended-spectrum beta-lactamases. 1: Expected MIC: ≤1 mg/L in absence of ESBL co-production; >2 in presence of ESBL co-production. 2: Susceptibility to ertapenem has to be tested and cannot be inferred from susceptibility to meropenem or imipenem/cilastatin. 3: In case of susceptibility, MICs will not be in wild-type range. 4: Resistance to ceftolozane/tazobactam due to ESBL production is infrequent.

pharmacy-12-00142-t002_Table 2 Table 2 Ability to induce ampC gene derepression and subsequent AmpC production and susceptibility to AmpC-mediated hydrolysis of different beta-lactams.

		Ability to Induce AmpC Gene Derepression and Subsequent AmpC Production	
Low	High	
Susceptibility to AmpC-mediated
hydrolysis	low	cefepime	carbapenems	
high	third-generation cephalosporins, piperacillin/tazobactam, aztreonam	aminopenicillins (ampicillin, amoxicillin), amoxicillin/clavulanic acid, first-generation cephalosporins,
cephamycins (cefoxitin)	

pharmacy-12-00142-t003_Table 3 Table 3 Microbiological and clinical properties of the most relevant beta-lactams used for treating infections caused by AmpC-producing Enterobacterales with moderate-to-high risk of AmpC derepression (Enterobacter cloacae, Klebsiella aerogenes, and Citrobacter freundii).

Antibiotic	Substrate for AmpC-Mediated Hydrolysis	Induction of AmpC Derepression	Clinical Data	Clinical Use	Antibiotic Stewardship Additional Considerations	
Third-generation cephalosporins	Yes	Strong inducers	Observational studies	Discouraged, except for low-risk UTIs	Good choice in cases of AmpC-producing Enterobacterales with low risk of derepression 1, except for very severe infections	
Cefepime	No 2	Weak inducer	Observational studies	Drug of choice. Non-inferiority to carbapenems has not been demonstrated in RCTs	Preferable to carbapenems from a stewardship perspective	
Piperacilin/tazobactam	Yes	Weak inducer	One pilot RCT + observational studies	More commonly considered as a second choice compared to cefepime and carbapenems. Probably avoided for more severe and high-inoculum infections	Probably comparable to cefepime in terms of selective pressure (ecological impact)	
Ceftolozane/tazobactam	Insufficient evidence	Insufficient evidence	Insufficient evidence (mainly in vitro data)	Not indicated except when treating polymicrobial infections, including P. aeruginosa	The exact extent of its ecological impact is unknown but should theoretically be less relevant than for carbapenems. Use can be limited also by high cost	
Ertapenem	No 3	Strong inducer
(? few data)	Few observational studies	Reasonable alternative to meropenem and imipenem/cilastatin	Cefepime is preferable from a stewardship perspective	
Imipenem/cilastatin and meropenem	No	Strong inducer	Observational studies, one pilot RCT. Usually used as comparators for other investigational drugs	Drug of choice	
New BL-BLICs and cefiderocol	No 4	Insufficient evidence	Few observational studies	Drugs of choice for carbapenem-resistant strains	To be reserved for carbapenem-resistant strains	
1: Serratia marcescens, Providencia spp., Morganella morganii, Hafnia alvei, Yersinia enterocolitica. 2: Stable against AmpC-mediated hydrolysis. True AmpC-mediated resistance has been described because of mutated AmpC. Otherwise (and more commonly), cefepime resistance is determined by coexistence of AmpCs and ESBLs or porinmutations. 3: Resistance has been described when AmpC derepression and porin mutations coexist. 4: Resistance to ceftazidime/avibactam and cefiderocol had been associated with mutated AmpC. BL-BLICs: beta-lactam/beta-lactamase inhibitor combinations; RCT: randomized controlled trial; UTI: urinary tract infection.

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References

1. Antimicrobial Resistance Collaborators Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis Lancet 2022 399 629 655 10.1016/S0140-6736(21)02724-0 35065702
2. Bush K. Jacoby G.A. Medeiros A.A. A Functional Classification Scheme for Beta-Lactamases and Its Correlation with Molecular Structure Antimicrob. Agents Chemother. 1995 39 1211 1233 10.1128/AAC.39.6.1211 7574506
3. Tamma P.D. Doi Y. Bonomo R.A. Johnson J.K. Simner P.J. Antibacterial Resistance Leadership Group A Primer on AmpC β-Lactamases: Necessary Knowledge for an Increasingly Multidrug-Resistant World Clin. Infect. Dis. 2019 69 1446 1455 10.1093/cid/ciz173 30838380
4. Rodríguez-Baño J. Gutiérrez-Gutiérrez B. Machuca I. Pascual A. Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae Clin. Microbiol. Rev. 2018 31 e00079-17 10.1128/CMR.00079-17 29444952
5. Oliver A. Rojo-Molinero E. Arca-Suarez J. Beşli Y. Bogaerts P. Cantón R. Cimen C. Croughs P.D. Denis O. Giske C.G. Pseudomonasaeruginosa Antimicrobial Susceptibility Profiles, Resistance Mechanisms and International Clonal Lineages: Update from ESGARS-ESCMID/ISARPAE Group Clin. Microbiol. Infect. 2024 30 469 480 10.1016/j.cmi.2023.12.026 38160753
6. Bush K. Past and Present Perspectives on β-Lactamases Antimicrob. Agents Chemother. 2018 62 e01076-18 10.1128/AAC.01076-18 30061284
7. Ambler R.P. The Structure of Beta-Lactamases Philos. Trans. R. Soc. Lond. B Biol. Sci. 1980 289 321 331 10.1098/rstb.1980.0049 6109327
8. Bush K. Jacoby G.A. Updated Functional Classification of Beta-Lactamases Antimicrob. Agents Chemother. 2010 54 969 976 10.1128/AAC.01009-09 19995920
9. Philippon A. Arlet G. Labia R. Iorga B.I. Class C β-Lactamases: Molecular Characteristics Clin. Microbiol. Rev. 2022 35 e0015021 10.1128/cmr.00150-21 35435729
10. Yoon E.-J. Jeong S.H. Class D β-Lactamases J. Antimicrob. Chemother. 2021 76 836 864 10.1093/jac/dkaa513 33382875
11. Pitout J.D.D. Laupland K.B. Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae: An Emerging Public-Health Concern Lancet Infect. Dis. 2008 8 159 166 10.1016/S1473-3099(08)70041-0 18291338
12. Jacoby G.A. AmpC β-Lactamases Clin. Microbiol. Rev. 2009 22 161 182 10.1128/CMR.00036-08 19136439
13. Abraham E.P. Chain E. An Enzyme from Bacteria Able to Destroy Penicillin. 1940 Rev. Infect. Dis. 1988 10 677 678 3055168
14. Reuland E.A. Halaby T. Hays J.P. de Jongh D.M.C. Snetselaar H.D.R. van Keulen M. Elders P.J.M. Savelkoul P.H.M. Vandenbroucke-Grauls C.M.J.E. Al Naiemi N. Plasmid-Mediated AmpC: Prevalence in Community-Acquired Isolates in Amsterdam, the Netherlands, and Risk Factors for Carriage PLoS ONE 2015 10 e0113033 10.1371/journal.pone.0113033 25587716
15. Zhou Q. Tang M. Zhang X. Lu J. Tang X. Gao Y. Detection of AmpC β-Lactamases in Gram-Negative Bacteria Heliyon 2022 8 e12245 10.1016/j.heliyon.2022.e12245 36582676
16. Papanicolaou G.A. Medeiros A.A. Jacoby G.A. Novel Plasmid-Mediated Beta-Lactamase (MIR-1) Conferring Resistance to Oxyimino- and Alpha-Methoxy Beta-Lactams in Clinical Isolates of Klebsiella Pneumoniae Antimicrob. Agents Chemother. 1990 34 2200 2209 10.1128/AAC.34.11.2200 1963529
17. Philippon A. Arlet G. Jacoby G.A. Plasmid-Determined AmpC-Type Beta-Lactamases Antimicrob. Agents Chemother. 2002 46 1 11 10.1128/AAC.46.1.1-11.2002 11751104
18. Coertze R.D. Bezuidenhout C.C. Global Distribution and Current Research of AmpC Beta-Lactamase Genes in Aquatic Environments: A Systematic Review Environ. Pollut. 2019 252 1633 1642 10.1016/j.envpol.2019.06.106 31284205
19. Duin D.v. Bonomo R.A. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-Generation β-Lactam/β-Lactamase Inhibitor Combinations Clin. Infect. Dis. 2016 63 234 241 10.1093/cid/ciw243 27098166
20. Bush K. Bradford P.A. Interplay between β-Lactamases and New β-Lactamase Inhibitors Nat. Rev. Microbiol. 2019 17 295 306 10.1038/s41579-019-0159-8 30837684
21. Paterson D.L. Bonomo L.A. Extended-spectrum beta-lactamases: A clinical update Clin. Microbiol. Rev. 2005 18 657 686 10.1128/CMR.18.4.657-686.2005 16223952
22. Weber D.A. Sanders C.C. Diverse Potential of Beta-Lactamase Inhibitors to Induce Class I Enzymes Antimicrob. Agents Chemother. 1990 34 156 158 10.1128/AAC.34.1.156 2327752
23. Guérin F. Isnard C. Cattoir V. Giard J.C. Complex Regulation Pathways of AmpC-Mediated β-Lactam Resistance in Enterobacter Cloacae Complex Antimicrob. Agents Chemother. 2015 59 7753 7761 10.1128/AAC.01729-15 26438498
24. Lindberg F. Westman L. Normark S. Regulatory Components in Citrobacter Freundii ampC Beta-Lactamase Induction Proc. Natl. Acad. Sci. USA 1985 82 4620 4624 10.1073/pnas.82.14.4620 2991883
25. Schmidtke A.J. Hanson N.D. Model System to Evaluate the Effect of ampD Mutations on AmpC-Mediated Beta-Lactam Resistance Antimicrob. Agents Chemother. 2006 50 2030 2037 10.1128/AAC.01458-05 16723562
26. Kaneko K. Okamoto R. Nakano R. Kawakami S. Inoue M. Gene Mutations Responsible for Overexpression of AmpC Beta-Lactamase in Some Clinical Isolates of Enterobacter Cloacae J. Clin. Microbiol. 2005 43 2955 2958 10.1128/JCM.43.6.2955-2958.2005 15956430
27. Choi S.-H. Lee J.E. Park S.J. Choi S.-H. Lee S.-O. Jeong J.-Y. Kim M.-N. Woo J.H. Kim Y.S. Emergence of Antibiotic Resistance during Therapy for Infections Caused by Enterobacteriaceae Producing AmpC Beta-Lactamase: Implications for Antibiotic Use Antimicrob. Agents Chemother. 2008 52 995 1000 10.1128/AAC.01083-07 18086837
28. Chow J.W. Fine M.J. Shlaes D.M. Quinn J.P. Hooper D.C. Johnson M.P. Ramphal R. Wagener M.M. Miyashiro D.K. Yu V.L. Enterobacter Bacteremia: Clinical Features and Emergence of Antibiotic Resistance during Therapy Ann. Intern. Med. 1991 115 585 590 10.7326/0003-4819-115-8-585 1892329
29. Kaye K.S. Cosgrove S. Harris A. Eliopoulos G.M. Carmeli Y. Risk Factors for Emergence of Resistance to Broad-Spectrum Cephalosporins among Enterobacter Spp. Antimicrob. Agents Chemother. 2001 45 2628 2630 10.1128/AAC.45.9.2628-2630.2001 11502540
30. Jacobson K.L. Cohen S.H. Inciardi J.F. King J.H. Lippert W.E. Iglesias T. VanCouwenberghe C.J. The Relationship between Antecedent Antibiotic Use and Resistance to Extended-Spectrum Cephalosporins in Group I Beta-Lactamase-Producing Organisms Clin. Infect. Dis. 1995 21 1107 1113 10.1093/clinids/21.5.1107 8589129
31. Johnson C.C. Livornese L. Gold M.J. Pitsakis P.G. Taylor S. Levison M.E. Activity of Cefepime against Ceftazidime-Resistant Gram-Negative Bacilli Using Low and High Inocula J. Antimicrob. Chemother. 1995 35 765 773 10.1093/jac/35.6.765 7559188
32. Tamma P.D. Aitken S.L. Bonomo R.A. Mathers A.J. van Duin D. Clancy C.J. Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections Clin. Infect. Dis. 2023 ciad428 10.1093/cid/ciad428 37463564
33. Forward K.R. Willey B.M. Low D.E. McGeer A. Kapala M.A. Kapala M.M. Burrows L.L. Molecular Mechanisms of Cefoxitin Resistance in Escherichia Coli from the Toronto Area Hospitals Diagn. Microbiol. Infect. Dis. 2001 41 57 63 10.1016/S0732-8893(01)00278-4 11687315
34. Honoré N. Nicolas M.H. Cole S.T. Inducible Cephalosporinase Production in Clinical Isolates of Enterobacter Cloacae Is Controlled by a Regulatory Gene That Has Been Deleted from Escherichia Coli EMBO J. 1986 5 3709 3714 10.1002/j.1460-2075.1986.tb04704.x 3030737
35. Peter-Getzlaff S. Polsfuss S. Poledica M. Hombach M. Giger J. Böttger E.C. Zbinden R. Bloemberg G.V. Detection of AmpC Beta-Lactamase in Escherichia Coli: Comparison of Three Phenotypic Confirmation Assays and Genetic Analysis J. Clin. Microbiol. 2011 49 2924 2932 10.1128/JCM.00091-11 21653764
36. Hall B.G. Barlow M. Evolution of the Serine Beta-Lactamases: Past, Present and Future Drug Resist. Updat. 2004 7 111 123 10.1016/j.drup.2004.02.003 15158767
37. Black J.A. Thomson K.S. Buynak J.D. Pitout J.D.D. Evaluation of Beta-Lactamase Inhibitors in Disk Tests for Detection of Plasmid-Mediated AmpC Beta-Lactamases in Well-Characterized Clinical Strains of Klebsiella Spp. J. Clin. Microbiol. 2005 43 4168 4171 10.1128/JCM.43.8.4168-4171.2005 16081967
38. Harris P.N.A. Alder L. Paterson D.L. Antimicrobial Susceptibility Reporting and Treatment Selection for AmpC-Producing Enterobacteriaceae: What Do Microbiologists and Infectious Disease Practitioners Actually Practice? Pathology 2015 47 386 388 10.1097/PAT.0000000000000255 25938360
39. Kohlmann R. Bähr T. Gatermann S.G. Species-Specific Mutation Rates for ampC Derepression in Enterobacterales with Chromosomally Encoded Inducible AmpC β-Lactamase J. Antimicrob. Chemother. 2018 73 1530 1536 10.1093/jac/dky084 29566147
40. Hilty M. Sendi P. Seiffert S.N. Droz S. Perreten V. Hujer A.M. Bonomo R.A. Mühlemann K. Endimiani A. Characterisation and Clinical Features of Enterobacter Cloacae Bloodstream Infections Occurring at a Tertiary Care University Hospital in Switzerland: Is Cefepime Adequate Therapy? Int. J. Antimicrob. Agents 2013 41 236 249 10.1016/j.ijantimicag.2012.10.022 23313399
41. Mizrahi A. Delerue T. Morel H. Le Monnier A. Carbonnelle E. Pilmis B. Zahar J.R. on behalf the Saint-Joseph/Avicenna Study Group Infections Caused by Naturally AmpC-Producing Enterobacteriaceae: Can We Use Third-Generation Cephalosporins? A Narrative Review Int. J. Antimicrob. Agents 2020 55 105834 10.1016/j.ijantimicag.2019.10.015 31682902
42. Power P. Galleni M. Ayala J.A. Gutkind G. Biochemical and Molecular Characterization of Three New Variants of AmpC Beta-Lactamases from Morganella Morganii Antimicrob. Agents Chemother. 2006 50 962 967 10.1128/AAC.50.3.962-967.2006 16495258
43. Meini S. Tascini C. Cei M. Sozio E. Rossolini G.M. AmpC β-Lactamase-Producing Enterobacterales: What a Clinician Should Know Infection 2019 47 363 375 10.1007/s15010-019-01291-9 30840201
44. Sanders C.C. Bradford P.A. Ehrhardt A.F. Bush K. Young K.D. Henderson T.A. Sanders W.E. Penicillin-Binding Proteins and Induction of AmpC Beta-Lactamase Antimicrob. Agents Chemother. 1997 41 2013 2015 10.1128/AAC.41.9.2013 9303404
45. Fung-Tomc J.C. Gradelski E. Huczko E. Dougherty T.J. Kessler R.E. Bonner D.P. Differences in the Resistant Variants of Enterobacter Cloacae Selected by Extended-Spectrum Cephalosporins Antimicrob. Agents Chemother. 1996 40 1289 1293 10.1128/AAC.40.5.1289 8723487
46. Hancock R.E. Bellido F. Antibacterial in Vitro Activity of Fourth Generation Cephalosporins J. Chemother. 1996 8 (Suppl. S2) 31 36 8738844
47. Stewart A.G. Paterson D.L. Young B. Lye D.C. Davis J.S. Schneider K. Yilmaz M. Dinleyici R. Runnegar N. Henderson A. Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Caused by AmpC β-Lactamase-Producing Enterobacter Spp, Citrobacter Freundii, Morganella Morganii, Providencia Spp, or Serratia Marcescens: A Pilot Multicenter Randomized Controlled Trial (MERINO-2) Open Forum Infect. Dis. 2021 8 ofab387 10.1093/ofid/ofab387 34395716
48. Harris P.N.A. Tambyah P.A. Paterson D.L. β-Lactam and β-Lactamase Inhibitor Combinations in the Treatment of Extended-Spectrum β-Lactamase Producing Enterobacteriaceae: Time for a Reappraisal in the Era of Few Antibiotic Options? Lancet Infect. Dis. 2015 15 475 485 10.1016/S1473-3099(14)70950-8 25716293
49. Tan S.H. Ng T.M. Chew K.L. Yong J. Wu J.E. Yap M.Y. Heng S.T. Ng W.H.W. Wan S. Cheok S.J.H. Outcomes of Treating AmpC-Producing Enterobacterales Bacteraemia with Carbapenems vs. Non-Carbapenems Int. J. Antimicrob. Agents 2020 55 105860 10.1016/j.ijantimicag.2019.105860 31841674
50. Lee N.-Y. Lee C.-C. Li C.-W. Li M.-C. Chen P.-L. Chang C.-M. Ko W.-C. Cefepime Therapy for Monomicrobial Enterobacter Cloacae Bacteremia: Unfavorable Outcomes in Patients Infected by Cefepime-Susceptible Dose-Dependent Isolates Antimicrob. Agents Chemother. 2015 59 7558 7563 10.1128/AAC.01477-15 26416853
51. Marcos M. Iñurrieta A. Soriano A. Martínez J.A. Almela M. Marco F. Mensa J. Effect of Antimicrobial Therapy on Mortality in 377 Episodes of Enterobacter Spp. Bacteraemia J. Antimicrob. Chemother. 2008 62 397 403 10.1093/jac/dkn155 18420813
52. Chaubey V.P. Pitout J.D.D. Dalton B. Gregson D.B. Ross T. Laupland K.B. Clinical and Microbiological Characteristics of Bloodstream Infections Due to AmpC β-Lactamase Producing Enterobacteriaceae: An Active Surveillance Cohort in a Large Centralized Canadian Region BMC Infect. Dis. 2014 14 647 10.1186/s12879-014-0647-4 25494640
53. Huh K. Kang C.-I. Kim J. Cho S.Y. Ha Y.E. Joo E.-J. Chung D.R. Lee N.Y. Peck K.R. Song J.-H. Risk Factors and Treatment Outcomes of Bloodstream Infection Caused by Extended-Spectrum Cephalosporin-Resistant Enterobacter Species in Adults with Cancer Diagn. Microbiol. Infect. Dis. 2014 78 172 177 10.1016/j.diagmicrobio.2013.11.002 24321352
54. Lin T.-Y. Chan M.-C. Yang Y.-S. Lee Y. Yeh K.-M. Lin J.-C. Chang F.-Y. Clinical Manifestations and Prognostic Factors of Morganella Morganii Bacteremia Eur. J. Clin. Microbiol. Infect. Dis. 2015 34 231 236 10.1007/s10096-014-2222-8 25107625
55. Davin-Regli A. Lavigne J.-P. Pagès J.-M. Enterobacter spp.: Update on Taxonomy, Clinical Aspects, and Emerging Antimicrobial Resistance Clin. Microbiol. Rev. 2019 32 e00002-19 10.1128/CMR.00002-19 31315895
56. Siedner M.J. Galar A. Guzmán-Suarez B.B. Kubiak D.W. Baghdady N. Ferraro M.J. Hooper D.C. O’Brien T.F. Marty F.M. Cefepime vs Other Antibacterial Agents for the Treatment of Enterobacter Species Bacteremia Clin. Infect. Dis. 2014 58 1554 1563 10.1093/cid/ciu182 24647022
57. O’Neal C.S. O’Neal H.R. Daniels T.L. Talbot T.R. Treatment Outcomes in Patients with Third-Generation Cephalosporin-Resistant Enterobacter Bacteremia Scand. J. Infect. Dis. 2012 44 726 732 10.3109/00365548.2012.681694 22681412
58. Kunz Coyne A.J. El Ghali A. Lucas K. Witucki P. Rebold N. Holger D.J. Veve M.P. Rybak M.J. High-Dose Cefepime vs Carbapenems for Bacteremia Caused by Enterobacterales with Moderate to High Risk of Clinically Significant AmpC β-Lactamase Production Open Forum Infect. Dis. 2023 10 ofad034 10.1093/ofid/ofad034 36968970
59. Qureshi Z.A. Paterson D.L. Pakstis D.L. Adams-Haduch J.M. Sandkovsky G. Sordillo E. Polsky B. Peleg A.Y. Bhussar M.K. Doi Y. Risk Factors and Outcome of Extended-Spectrum β-Lactamase-Producing Enterobacter Cloacae Bloodstream Infections Int. J. Antimicrob. Agents 2011 37 26 32 10.1016/j.ijantimicag.2010.09.009 21075605
60. Moy S. Sharma R. Treatment Outcomes in Infections Caused by “SPICE” (Serratia, Pseudomonas, Indole-Positive Proteus, Citrobacter, and Enterobacter) Organisms: Carbapenem versus Noncarbapenem Regimens Clin. Ther. 2017 39 170 176 10.1016/j.clinthera.2016.11.025 28034519
61. Erlanger D. Assous M.V. Wiener-Well Y. Yinnon A.M. Ben-Chetrit E. Clinical Manifestations, Risk Factors and Prognosis of Patients with Morganella Morganii Sepsis J. Microbiol. Immunol. Infect. 2019 52 443 448 10.1016/j.jmii.2017.08.010 28919283
62. Noguchi T. Matsumura Y. Yamamoto M. Nagao M. Takakura S. Ichiyama S. Clinical and Microbiologic Characteristics of Cefotaxime-Non-Susceptible Enterobacteriaceae Bacteremia: A Case Control Study BMC Infect. Dis. 2017 17 44 10.1186/s12879-016-2150-6 28061869
63. Cheng M.P. Lee R.S. Cheng A.P. De L’étoile-Morel S. Demir K. Yansouni C.P. Harris P. Mcdonald E.G. Lee T.C. Beta-Lactam/Beta-Lactamase Inhibitor Therapy for Potential AmpC-Producing Organisms: A Systematic Review and Meta-Analysis Open Forum Infect. Dis. 2019 6 ofz248 10.1093/ofid/ofz248 31363762
64. Blanchette L.M. Kuti J.L. Nicolau D.P. Nailor M.D. Clinical Comparison of Ertapenem and Cefepime for Treatment of Infections Caused by AmpC Beta-Lactamase-Producing Enterobacteriaceae Scand. J. Infect. Dis. 2014 46 803 808 10.3109/00365548.2014.954262 25262922
65. Maillard A. Delory T. Bernier J. Villa A. Chaibi K. Escaut L. Contejean A. Bercot B. Robert J. El Alaoui F. Effectiveness of Third-Generation Cephalosporins or Piperacillin Compared with Cefepime or Carbapenems for Severe Infections Caused by Wild-Type AmpC β-Lactamase-Producing Enterobacterales: A Multi-Centre Retrospective Propensity-Weighted Study Int. J. Antimicrob. Agents 2023 62 106809 10.1016/j.ijantimicag.2023.106809 37028731
66. Harris P.N.A. Wei J.Y. Shen A.W. Abdile A.A. Paynter S. Huxley R.R. Pandeya N. Doi Y. Huh K. O’Neal C.S. Carbapenems versus Alternative Antibiotics for the Treatment of Bloodstream Infections Caused by Enterobacter, Citrobacter or Serratia Species: A Systematic Review with Meta-Analysis J. Antimicrob. Chemother. 2016 71 296 306 10.1093/jac/dkv346 26542304
67. Paul M. Carrara E. Retamar P. Tängdén T. Bitterman R. Bonomo R.A. Waele J.d. Daikos G.L. Akova M. Harbarth S. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines for the Treatment of Infections Caused by Multidrug-Resistant Gram-Negative Bacilli (Endorsed by European Society of Intensive Care Medicine) Clin. Microbiol. Infect. 2022 28 521 547 10.1016/j.cmi.2021.11.025 34923128
68. Shah P.M. Parenteral Carbapenems Clin. Microbiol. Infect. 2008 14 (Suppl. S1) 175 180 10.1111/j.1469-0691.2007.01868.x 18154543
69. Tamma P.D. Girdwood S.C.T. Gopaul R. Tekle T. Roberts A.A. Harris A.D. Cosgrove S.E. Carroll K.C. The Use of Cefepime for Treating AmpC β-Lactamase-Producing Enterobacteriaceae Clin. Infect. Dis. 2013 57 781 788 10.1093/cid/cit395 23759352
70. Ávila-Núñez M. Lima O. Sousa A. Represa M. Rubiñán P. Celestino P. Garrido-Ventín M. García-Formoso L. Vasallo-Vidal F. Martinez-Lamas L. Carbapenem Alternatives for Treatment of Bloodstream Infections Due to AmpC Producing Enterobacterales Ann. Clin. Microbiol. Antimicrob. 2023 22 75 10.1186/s12941-023-00624-9 37592268
71. Livermore D.M. Oakton K.J. Carter M.W. Warner M. Activity of Ertapenem (MK-0826) versus Enterobacteriaceae with Potent Beta-Lactamases Antimicrob. Agents Chemother. 2001 45 2831 2837 10.1128/AAC.45.10.2831-2837.2001 11557477
72. Woodford N. Dallow J.W.T. Hill R.L.R. Palepou M.-F.I. Pike R. Ward M.E. Warner M. Livermore D.M. Ertapenem Resistance among Klebsiella and Enterobacter Submitted in the UK to a Reference Laboratory Int. J. Antimicrob. Agents 2007 29 456 459 10.1016/j.ijantimicag.2006.11.020 17293088
73. Robin F. Auzou M. Bonnet R. Lebreuilly R. Isnard C. Cattoir V. Guérin F. In Vitro Activity of Ceftolozane-Tazobactam against Enterobacter Cloacae Complex Clinical Isolates with Different β-Lactam Resistance Phenotypes Antimicrob. Agents Chemother. 2018 62 e00675-18 10.1128/AAC.00675-18 29914962
74. de Lastours V. Goulenok T. Guérin F. Jacquier H. Eyma C. Chau F. Cattoir V. Fantin B. Ceftriaxone Promotes the Emergence of AmpC-Overproducing Enterobacteriaceae in Gut Microbiota from Hospitalized Patients Eur. J. Clin. Microbiol. Infect. Dis. 2018 37 417 421 10.1007/s10096-018-3186-x 29318461
75. Carrié C. Bardonneau G. Petit L. Ouattara A. Gruson D. Pereira B. Biais M. Piperacillin-Tazobactam Should Be Preferred to Third-Generation Cephalosporins to Treat Wild-Type Inducible AmpC-Producing Enterobacterales in Critically Ill Patients with Hospital or Ventilator-Acquired Pneumonia J. Crit. Care 2020 56 6 11 10.1016/j.jcrc.2019.11.005 31765910
76. Sapozhnikov J. Huang A. Zeeck K. Gibble A. Comparison of Outcomes in Urinary Tract Infections Caused by AmpC-Harboring Organisms Treated with AmpC Stable versus AmpC Susceptible Agents Diagn. Microbiol. Infect. Dis. 2021 101 115472 10.1016/j.diagmicrobio.2021.115472 34303084
77. Mounier R. Le Guen R. Woerther P.-L. Nacher M. Bonnefon C. Mongardon N. Langeron O. Levesque E. Couffin S. Houcke S. Clinical Outcome of Wild-Type AmpC-Producing Enterobacterales Infection in Critically Ill Patients Treated with β-Lactams: A Prospective Multicenter Study Ann. Intensive Care 2022 12 107 10.1186/s13613-022-01079-5 36394673
78. European Committee on Antimicrobial Susceptibility Testing: Breakpoint Tables for Interpretation of MICs and Zone Diameters. Version 14.0 Available online: https://www.eucast.org/clinical_breakpoints (accessed on 8 January 2024)
79. CLSI M100 Performance Standards for Antimicrobial Susceptibility Testing, 33rd Edition Available online: https://clsi.org/ast-2023/ (accessed on 8 January 2024)
80. Hoellinger B. Kaeuffer C. Boyer P. Lefebvre N. Hansmann Y. Robert A. Severac F. Gravet A. Danion F. Ruch Y. Cefepime vs Carbapenems for Treating Third-Generation Cephalosporin-Resistant AmpC β-Lactamase-Hyperproducing Enterobacterales Bloodstream Infections: A Multicenter Retrospective Study Int. J. Infect. Dis. 2023 134 273 279 10.1016/j.ijid.2023.07.004 37453486
81. Hancock R.E. Bellido F. Factors Involved in the Enhanced Efficacy against Gram-Negative Bacteria of Fourth Generation Cephalosporins J. Antimicrob. Chemother. 1992 29 (Suppl. A) 1 6 10.1093/jac/29.suppl_A.1
82. Limaye A.P. Gautom R.K. Black D. Fritsche T.R. Rapid Emergence of Resistance to Cefepime during Treatment Clin. Infect. Dis. 1997 25 339 340 10.1086/516917 9332545
83. European Committee on Antimicrobial Susceptibility Testing: MIC and Zone Diameter Distributions and ECOFFs Available online: https://www.eucast.org/mic_and_zone_distributions_and_ecoffs (accessed on 25 September 2023)
84. Hareza D. Simner P.J. Bergman Y. Jacobs E. Cosgrove S.E. Tamma P.D. The Frequency of Extended-Spectrum β-Lactamase Genes Harbored by Enterobacterales Isolates at High Risk for Clinically Significant Chromosomal ampC Expression Open Forum Infect. Dis. 2023 10 ofad175 10.1093/ofid/ofad175 37065982
85. Hawkey P.M. Warren R.E. Livermore D.M. McNulty C.A.M. Enoch D.A. Otter J.A. Wilson A.P.R. Treatment of Infections Caused by Multidrug-Resistant Gram-Negative Bacteria: Report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party J. Antimicrob. Chemother. 2018 73 iii2 iii78 10.1093/jac/dky027 29514274
86. Charrel R.N. Pagès J.M. De Micco P. Mallea M. Prevalence of Outer Membrane Porin Alteration in Beta-Lactam-Antibiotic-Resistant Enterobacter Aerogenes Antimicrob. Agents Chemother. 1996 40 2854 2858 10.1128/AAC.40.12.2854 9124854
87. Herrmann J. Burgener-Gasser A.-V. Goldenberger D. Roth J. Weisser M. Tamma P.D. Tschudin-Sutter S. Cefepime versus Carbapenems for Treatment of AmpC Beta-Lactamase-Producing Enterobacterales Bloodstream Infections Eur. J. Clin. Microbiol. Infect. Dis. 2024 43 213 221 10.1007/s10096-023-04715-5 37993680
88. Kawai A. McElheny C.L. Iovleva A. Kline E.G. Sluis-Cremer N. Shields R.K. Doi Y. Structural Basis of Reduced Susceptibility to Ceftazidime-Avibactam and Cefiderocol in Enterobacter Cloacae Due to AmpC R2 Loop Deletion Antimicrob. Agents Chemother. 2020 64 e00198-20 10.1128/AAC.00198-20 32284381
89. Rodríguez-Martínez J.M. Fernández-Echauri P. Fernández-Cuenca F. Diaz de Alba P. Briales A. Pascual A. Genetic Characterization of an Extended-Spectrum AmpC Cephalosporinase with Hydrolysing Activity against Fourth-Generation Cephalosporins in a Clinical Isolate of Enterobacter Aerogenes Selected in Vivo J. Antimicrob. Chemother. 2012 67 64 68 10.1093/jac/dkr423 22001269
90. Mammeri H. Poirel L. Bemer P. Drugeon H. Nordmann P. Resistance to Cefepime and Cefpirome Due to a 4-Amino-Acid Deletion in the Chromosome-Encoded AmpC Beta-Lactamase of a Serratia Marcescens Clinical Isolate Antimicrob. Agents Chemother. 2004 48 716 720 10.1128/AAC.48.3.716-720.2004 14982755
91. Maan G. Keitoku K. Kimura N. Sawada H. Pham A. Yeo J. Hagiya H. Nishimura Y. Cefepime-Induced Neurotoxicity: Systematic Review J. Antimicrob. Chemother. 2022 77 2908 2921 10.1093/jac/dkac271 35971666
92. Qian E.T. Casey J.D. Wright A. Wang L. Shotwell M.S. Siemann J.K. Dear M.L. Stollings J.L. Lloyd B.D. Marvi T.K. Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized with Acute Infection: The ACORN Randomized Clinical Trial JAMA 2023 330 1557 1567 10.1001/jama.2023.20583 37837651
93. Venugopalan V. Casaus D. Kainz L. Slaton C.N. Hurst N. Bruzzone M. Hu C. Sword G. Cherabuddi K. Iovine N. Use of Therapeutic Drug Monitoring to Characterize Cefepime-Related Neurotoxicity Pharmacotherapy 2023 43 6 14 10.1002/phar.2744 36401796
94. Cheng L. Nelson B.C. Mehta M. Seval N. Park S. Giddins M.J. Shi Q. Whittier S. Gomez-Simmonds A. Uhlemann A.-C. Piperacillin-Tazobactam versus Other Antibacterial Agents for Treatment of Bloodstream Infections Due to AmpC β-Lactamase-Producing Enterobacteriaceae Antimicrob. Agents Chemother. 2017 61 e00276-17 10.1128/AAC.00276-17 28320724
95. Weiss E. Zahar J.-R. Lesprit P. Ruppe E. Leone M. Chastre J. Lucet J.-C. Paugam-Burtz C. Brun-Buisson C. Timsit J.-F. Elaboration of a Consensual Definition of De-Escalation Allowing a Ranking of β-Lactams Clin. Microbiol. Infect. 2015 21 649.e1 649.e10 10.1016/j.cmi.2015.03.013 25882363
96. Chen A.Y. Deng C.-Y. Calvachi-Prieto P. Armengol de la Hoz M.Á. Khazi-Syed A. Chen C. Scurlock C. Becker C.D. Johnson A.E.W. Celi L.A. A Large-Scale Multicenter Retrospective Study on Nephrotoxicity Associated with Empiric Broad-Spectrum Antibiotics in Critically Ill Patients Chest 2023 164 355 368 10.1016/j.chest.2023.03.046 37040818
97. Mullins B.P. Kramer C.J. Bartel B.J. Catlin J.S. Gilder R.E. Comparison of the Nephrotoxicity of Vancomycin in Combination with Cefepime, Meropenem, or Piperacillin/Tazobactam: A Prospective, Multicenter Study Ann. Pharmacother. 2018 52 639 644 10.1177/1060028018757497 29442542
98. Buckley M.S. Komerdelj I.A. D’Alessio P.A. Rangan P. Agarwal S.K. Tinta N.C. Martinez B.K. Ziadat D.S. Yerondopoulos M.J. Kobic E. Vancomycin with Concomitant Piperacillin/Tazobactam vs. Cefepime or Meropenem Associated Acute Kidney Injury in the Critically Ill: A Multicenter Propensity Score-Matched Study J. Crit. Care 2022 67 134 140 10.1016/j.jcrc.2021.10.018 34768175
99. Rutter W.C. Cox J.N. Martin C.A. Burgess D.R. Burgess D.S. Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime Antimicrob. Agents Chemother. 2017 61 e02089-16 10.1128/AAC.02089-16 27895019
100. García-Fernández S. García-Castillo M. Melo-Cristino J. Pinto M.F. Gonçalves E. Alves V. Vieira A.R. Ramalheira E. Sancho L. Diogo J. In Vitro Activity of Ceftolozane-Tazobactam against Enterobacterales and Pseudomonas Aeruginosa Causing Urinary, Intra-Abdominal and Lower Respiratory Tract Infections in Intensive Care Units in Portugal: The STEP Multicenter Study Int. J. Antimicrob. Agents 2020 55 105887 10.1016/j.ijantimicag.2020.105887 31926283
101. Yahav D. Giske C.G. Grāmatniece A. Abodakpi H. Tam V.H. Leibovici L. New β-Lactam-β-Lactamase Inhibitor Combinations Clin. Microbiol. Rev. 2020 34 e00115-20 10.1128/CMR.00115-20
102. Golden A.R. Adam H.J. Baxter M. Walkty A. Lagacé-Wiens P. Karlowsky J.A. Zhanel G.G. In Vitro Activity of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacilli Isolated from Patients in Canadian Intensive Care Units Diagn. Microbiol. Infect. Dis. 2020 97 115012 10.1016/j.diagmicrobio.2020.115012 32081522
103. Karlowsky J.A. Biedenbach D.J. Kazmierczak K.M. Stone G.G. Sahm D.F. Activity of Ceftazidime-Avibactam against Extended-Spectrum- and AmpC β-Lactamase-Producing Enterobacteriaceae Collected in the INFORM Global Surveillance Study from 2012 to 2014 Antimicrob. Agents Chemother. 2016 60 2849 2857 10.1128/AAC.02286-15 26926635
104. Isler B. Ezure Y. Romero J.L.G.-F. Harris P. Stewart A.G. Paterson D.L. Is Ceftazidime/Avibactam an Option for Serious Infections Due to Extended-Spectrum-β-Lactamase- and AmpC-Producing Enterobacterales?: A Systematic Review and Meta-Analysis Antimicrob. Agents Chemother. 2020 65 e01052-20 10.1128/AAC.01052-20 33046493
105. Mendes R.E. Castanheira M. Gasink L. Stone G.G. Nichols W.W. Flamm R.K. Jones R.N. β-Lactamase Characterization of Gram-Negative Pathogens Recovered from Patients Enrolled in the Phase 2 Trials for Ceftazidime-Avibactam: Clinical Efficacies Analyzed against Subsets of Molecularly Characterized Isolates Antimicrob. Agents Chemother. 2015 60 1328 1335 10.1128/AAC.01173-15 26666936
106. Shields R.K. Iovleva A. Kline E.G. Kawai A. McElheny C.L. Doi Y. Clinical Evolution of AmpC-Mediated Ceftazidime-Avibactam and Cefiderocol Resistance in Enterobacter Cloacae Complex Following Exposure to Cefepime Clin. Infect. Dis. 2020 71 2713 2716 10.1093/cid/ciaa355 32236408
107. Novelli A. Rosi E. Pharmacological Properties of Oral Antibiotics for the Treatment of Uncomplicated Urinary Tract Infections J. Chemother. 2017 29 10 18 10.1080/1120009X.2017.1380357 29271734
108. Gupta K. Hooton T.M. Naber K.G. Wullt B. Colgan R. Miller L.G. Moran G.J. Nicolle L.E. Raz R. Schaeffer A.J. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases Clin. Infect. Dis. 2011 52 e103 e120 10.1093/cid/ciq257 21292654
109. Caron F. Galperine T. Flateau C. Azria R. Bonacorsi S. Bruyère F. Cariou G. Clouqueur E. Cohen R. Doco-Lecompte T. Practice Guidelines for the Management of Adult Community-Acquired Urinary Tract Infections Med. Mal. Infect. 2018 48 327 358 10.1016/j.medmal.2018.03.005 29759852
110. Rees J. Abrahams M. Doble A. Cooper A. the Prostatitis Expert Reference Group (PERG) Diagnosis and Treatment of Chronic Bacterial Prostatitis and Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Consensus Guideline BJU Int. 2015 116 509 525 10.1111/bju.13101 25711488
111. Huttner A. Kowalczyk A. Turjeman A. Babich T. Brossier C. Eliakim-Raz N. Kosiek K. Martinez de Tejada B. Roux X. Shiber S. Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial JAMA 2018 319 1781 1789 10.1001/jama.2018.3627 29710295
112. European Committee on Antimicrobial Susceptibility Testing EUCAST Guidance on Use of Fosfomycin i.v. Breakpoints Available online: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Guidance_documents/Use_of_fosfomycin_iv_breakpoints_General_advice_20240528.pdf (accessed on 12 July 2024)
113. Heil E.L. Bork J.T. Abbo L.M. Barlam T.F. Cosgrove S.E. Davis A. Ha D.R. Jenkins T.C. Kaye K.S. Lewis J.S. Optimizing the Management of Uncomplicated Gram-Negative Bloodstream Infections: Consensus Guidance Using a Modified Delphi Process Open Forum Infect. Dis. 2021 8 ofab434 10.1093/ofid/ofab434 34738022
114. Tingsgård S. Bastrup Israelsen S. Jørgensen H.L. Østergaard C. Benfield T. Early Switch From Intravenous to Oral Antibiotics for Patients with Uncomplicated Gram-Negative Bacteremia JAMA Netw. Open 2024 7 e2352314 10.1001/jamanetworkopen.2023.52314 38261322
115. Engers D.W. Tamma P.D. Fiawoo S. Fong K. Jariwala R. Jenkins T.C. Kendall R.E. Lee J.H. McCreary E.K. Patel P.K. Transition to Oral Antibiotic Therapy for Hospitalized Adults with Gram-Negative Bloodstream Infections JAMA Netw. Open 2024 7 e2349864 10.1001/jamanetworkopen.2023.49864 38165674
116. Alzaidi S. Veillette J.J. May S.S. Olson J. Jackson K. Waters C.D. Butler A.M. Hutton M.A. Buckel W.R. Webb B.J. Oral β-Lactams, Fluoroquinolones, or Trimethoprim-Sulfamethoxazole for Definitive Treatment of Uncomplicated Escherichia Coli or Klebsiella Species Bacteremia From a Urinary Tract Source Open Forum Infect. Dis. 2024 11 ofad657 10.1093/ofid/ofad657 38370295
117. Kaasch A.J. López-Cortés L.E. Rodríguez-Baño J. Cisneros J.M. Dolores Navarro M. Fätkenheuer G. Jung N. Rieg S. Lepeule R. Coutte L. Efficacy and Safety of an Early Oral Switch in Low-Risk Staphylococcus Aureus Bloodstream Infection (SABATO): An International, Open-Label, Parallel-Group, Randomised, Controlled, Non-Inferiority Trial Lancet Infect. Dis. 2024 24 523 534 10.1016/S1473-3099(23)00756-9 38244557
118. Tamma P.D. Conley A.T. Cosgrove S.E. Harris A.D. Lautenbach E. Amoah J. Avdic E. Tolomeo P. Wise J. Subudhi S. Association of 30-Day Mortality with Oral Step-Down vs Continued Intravenous Therapy in Patients Hospitalized with Enterobacteriaceae Bacteremia JAMA Intern. Med. 2019 179 316 323 10.1001/jamainternmed.2018.6226 30667477
119. Iversen K. Ihlemann N. Gill S.U. Madsen T. Elming H. Jensen K.T. Bruun N.E. Høfsten D.E. Fursted K. Christensen J.J. Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis N. Engl. J. Med. 2019 380 415 424 10.1056/NEJMoa1808312 30152252
120. Li H.-K. Rombach I. Zambellas R. Walker A.S. McNally M.A. Atkins B.L. Lipsky B.A. Hughes H.C. Bose D. Kümin M. Oral versus Intravenous Antibiotics for Bone and Joint Infection N. Engl. J. Med. 2019 380 425 436 10.1056/NEJMoa1710926 30699315
121. Punjabi C. Tien V. Meng L. Deresinski S. Holubar M. Oral Fluoroquinolone or Trimethoprim-Sulfamethoxazole vs. ß-Lactams as Step-Down Therapy for Enterobacteriaceae Bacteremia: Systematic Review and Meta-Analysis Open Forum Infect. Dis. 2019 6 ofz364 10.1093/ofid/ofz364 31412127
122. Hardy M.E. Kenney R.M. Tibbetts R.J. Shallal A.B. Veve M.P. Leveraging Stewardship to Promote Ceftriaxone Use in Severe Infections with Low- and No-Risk AmpC Enterobacterales Antimicrob. Agents Chemother. 2023 67 e0082623 10.1128/aac.00826-23 37882541
123. Fowler V.G. Durack D.T. Selton-Suty C. Athan E. Bayer A.S. Chamis A.L. Dahl A. DiBernardo L. Durante-Mangoni E. Duval X. The 2023 Duke-International Society for Cardiovascular Infectious Diseases Criteria for Infective Endocarditis: Updating the Modified Duke Criteria Clin. Infect. Dis. 2023 77 518 526 10.1093/cid/ciad271 37138445
124. Delgado V. Ajmone Marsan N. de Waha S. Bonaros N. Brida M. Burri H. Caselli S. Doenst T. Ederhy S. Erba P.A. 2023 ESC Guidelines for the Management of Endocarditis Eur. Heart J. 2023 44 3948 4042 10.1093/eurheartj/ehad193 37622656
125. Lorenz A. Sobhanie M.M.E. Orzel L. Coe K. Wardlow L. Clinical Outcomes of Combination versus Monotherapy for Gram Negative Non-HACEK Infective Endocarditis Diagn. Microbiol. Infect. Dis. 2021 101 115504 10.1016/j.diagmicrobio.2021.115504 34375862
126. Veve M.P. McCurry E.D. Cooksey G.E. Shorman M.A. Epidemiology and Outcomes of Non-HACEK Infective Endocarditis in the Southeast United States PLoS ONE 2020 15 e0230199 10.1371/journal.pone.0230199 32155223
