Cefepime-enmetazobactam: first approved cefepime-β- lactamase inhibitor combination for multi-drug resistant Enterobacterales

ABSTRACT

Cefepime-enmetazobactam is a β-lactam/β-lactamase inhibitor (BL/BLI) combination that has demonstrated potent activity against extended spectrum beta-lactamase (ESBL)-producing Enterobacterales, recently approved by the US FDA for the treatment of complicated urinary tract infections (cUTI) and by the European Medicines Agency and the UK Healthcare products Regulatory Agency for the treatment of cUTI, hospital-acquired pneumonia including ventilator-associated pneumonia and bacteremia in adults. Cefepime is a 4th generation cephalosporin with a broad spectrum bactericidal activity and enhanced stability to degradation by chromosomal and plasmid-mediated AmpC cephalosporinases as well as carbapenemase OXA-48 like enzymes. Enmetazobactam is a novel penicillanic acid sulfone β-lactamase inhibitor structurally similar to tazobactam with activity against CTX-M, TEM, and SHV ESBL, and other class A β-lactamases, that restores cefepime activity in vitro and in vivo against ESBLs-producing Enterobacterales. The targeted activity of cefepime-enmetazobactam against ESBLs infections which are resistant to common antibiotics, together with its superior results against piperacillin/tazobactam in a phase 3 trial make this new BL/BLI combination an effective carbapenem sparing option for the treatment of serious infections caused by ESBLs-producing Enterobacterales. In addition, if clinical data are supportive, cefepime-enmetazobactam has a potential role in the treatment of pathogens co-producing OXA-48 like enzymes along with ESBLs.

Plain Language Summary

Enterobacterales are a type of bacteria present in the human gut. One type of Enterobacterales, known as ESBL, can cause severe infections that are sometimes fatal. ESBL is hard to treat because most drugs are no longer able to treat it. Cefepime-enmetazobactam, or FEN, is a new drug that can kill ESBL. FEN has been approved for the treatment of urinary tract infections since February 2024. In Europe, FEN is also approved for treating lung infections, particularly pneumonia. This article explains how FEN works and discuss the use of FEN and other drugs to treat urinary tract infections.

1. Introduction

Enterobacterales, which include among others Escherichia coli, Klebsiella spp, Proteus spp. and Enterobacter spp. are a common cause of infection in both inpatient and outpatient settings. The most frequent type of infection caused by Enterobacterales are urinary tract infections. However, Enterobacterales also represent the most frequently identified pathogens in more invasive infections, including hospital-acquired and ventilator-associated pneumonia [1–5]. Given their frequency in commonly encountered infections, rising rates of antimicrobial resistance among Enterobacterales are emerging threat in both the community and hospital. Worldwide, rates of resistance to fluoroquinolones and to trimethoprim-sulfamethoxazole exceed 20% in most community settings and 30% in many hospital settings (and more than 50% to 80% in many developing countries) [6–8]. Perhaps, even more concerning is the emergence and rapid spread of extended-spectrum β-lactamase (ESBL)-producing strains of Enterobacterales. ESBLs hydrolyze most traditional β-lactams and thereby mediate resistance to 3rd/4th-generation cephalosporins, and aztreonam, and in addition the use of piperacillin-tazobactam is controversial in ESBL producers [9,10]. ESBL production has been a long-standing issue with Klebsiella pneumoniae, with rates exceeding 20–30% in many countries in Europe and the United States and exceeding 50% in several other countries around the world [9]. Rates of cephalosporin-resistant E. coli exceed 20% in US hospitals [7], 30% in several European countries [11], and have been reported to be much higher throughout other parts of the world. ESBLs are an emerging problem not only in the hospital but also in the community. Recently, the rate of global pooled prevalence of ESBL E. coli intestinal carriage in the community was estimated at 16.5% [12]. ESBL-producing Enterobacterales have been deemed a Serious Threat by the CDC [13] and a critical priority in the 2024 WHO Bacterial Priority Pathogens List [14].

Infections due to ESBL-producing Enterobacterales present a therapeutic challenge. For serious, life-threatening infections such as bloodstream infections, carbapenems are the antibiotics of choice [10,15]. Due to the increased prevalence of ESBLs, carbapenem use has significantly increased over the past decade both for definitive treatment of ESBL-producers, as well as for empiric therapy of suspected ESBL-producing pathogens [16,17]. On the other hand, the increase in carbapenem use has coincided with a predictable increase in the prevalence of carbapenem-resistant Gram-negatives, notably carbapenem-resistant Enterobacterales (CRE) [18], carbapenem-resistant Pseudomonas aeruginosa [19], and carbapenem-resistant Acinetobacter baumannii [20]. These pathogens associated with devastating clinical outcomes in patients are rated as serious and urgent threats by the CDC [13] and are ranked in the high and critical priority groups in the 2024 WHO Bacterial Priority Pathogens List [14].

Due to ongoing concerns regarding antimicrobial pressure of increased carbapenem use promoting further emergence and spread of carbapenem-resistance, alternative therapies for suspected and/or confirmed ESBL-producing Enterobacterales are needed [21,22]. While multiple novel beta-lactams, including ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol, display potent in vitro activity against ESBL-producing Enterobacterales; they also demonstrate activity against carbapenem-resistant pathogens [23,24] and are, therefore, generally reserved for infections due to these difficult to treat organisms. Therefore, a therapeutic niche exists for a non-carbapenem antibiotic alternative that targets ESBL-producing Enterobacterales and against chromosomal AmpC-overproducing Enterobacterales, producing high inoculum infections, while lacking broad activity against carbapenem-resistant isolates. Such an agent could be used empirically (when coverage for an ESBL-producing pathogen is needed) as well as definitively for proven resistant infections due to ESBL-producing Enterobacterales. While there has been hope in the infectious diseases community that piperacillin-tazobactam would fill this niche, the results of the MERINO trial [10], combined with pharmacokinetic/pharmacodynamic concerns with commonly used doses, have led guidelines to recommend against the use of piperacillin-tazobactam for treatment of invasive ESBL infections [15]. Cefepime-enmetazobactam was rationally developed to fill this gap.

1.1. Cefepime-enmetazobactam overview

Cefepime-enmetazobactam, a novel intravenous β-lactam/β-lactamase inhibitor combination, was approved by the Food and Drug Administration in February 2024 for the treatment of complicated urinary tract infections (cUTI) [25], and by the European Medicines Agency and the UK Healthcare products Regulatory Agency in April 2024 for the treatment of adults patients with cUTI, hospital-acquired pneumonia and ventilator-associated pneumonia and for the treatment of patients with bacteremia that occurs in association with, or is suspected to be associated with, any of the infections listed before [26,27].

Cefepime is a 4th-generation cephalosporin that has broad spectrum bactericidal activity against gram-negative and gram-positive pathogens and is approved for the treatment of a variety of severe infections, including uncomplicated urinary tract infection (uUTI), cUTI and pyelonephritis, intra-abdominal infections (IAI), and pneumonia since 1996 at the US FDA and since 1993 in Europe. It is an oxyimino-cephalosporin targeting penicillin binding protein (PBP)-3 in gram-negative bacteria with enhanced stability to degradation by chromosomal and plasmid-mediated extended spectrum AmpC lactamases as well as OXA-48 like enzymes [28]. Cefepime’s greater activity against gram-negative bacteria that produce ESBL versus other commercially available oxyimino-cephalosporins is attributed to more rapid penetration into bacteria, the targeting of specific PBPs, or lower affinity for several β-lactamases [28,29]. However, in vitro activity of cefepime against ESBL producers is rare, with MIC₅₀ = 64 mg/L and MIC₉₀ >64 mg/L [29].

Enmetazobactam is a novel penicillanic acid sulfone β-lactamase inhibitor (BLI) that is similar in structure to tazobactam (Figure 1) but has a strategically placed methyl group that imparts a net neutral charge (zwitterionic) and enhances bacterial cell penetration. This methyl group on the triazole ring of enmetazobactam allows for many classical and nonclassical hydrogen bonding interactions not observed for tazobactam in the active site of CTX-M-15. In cell-free assays and intact isogenic strains, it demonstrated potent inhibitor activity against CTX-M, TEM, and SHV ESBL, and other class A β-lactamases. Enmetazobactam has no activity against class B β-lactamases. For class C and D β -lactamases, enmetazobactam has less of a direct impact; however, cefepime alone is not efficiently hydrolyzed by most AmpC and OXA β -lactamases, making cefepime an excellent choice as the partner for enmetazobactam [30]. These resistance mechanisms are typically expressed by gram-negative pathogens such as the Enterobacterales, E. coli, K. pneumoniae, and Enterobacter species. As many BLIs, enmetazobactam has no relevant antimicrobial activity but the addition of enmetazobactam to cefepime restores the activity of cefepime against ESBL-producing strains with MIC₅₀ of 0.06 mg/L and MIC₉₀ of 0.5 mg/L [31–33].

Figure 1.

Chemical structures of Enmetazobactam and Tazobactam.

1.2. Pharmacology of cefepime-enmetazobactam

1.2.1. In vitro susceptibility testing

During 2024, both FDA and EUCAST have established clinical breakpoints for Enterobacterales and P. aeruginosa for cefepime-enmetazobactam combination [4,34,35]. They were defined for the approved doses of 2 g of cefepime and 0.5 g of enmetazobactam every 8 h by intravenous infusion over 2 h for the treatment of complicated urinary tract infections, and by intravenous infusion over 4 h for the treatment of hospital acquired pneumonia and ventilator-associated pneumonia (both indications approved in Europe and UK only). Table 1 includes these breakpoints. Differences might be related to different PK/PD data interpretation and clinical trials analysis. MIC determination can be performed using broth microdilution according to ISO 20,776–1 using un-supplemented cation-adjusted Mueller-Hinton broth and a fixed concentration of 8 mg/L of enmetazobactam.

Table 1.

Clinical breakpoints of cefepime-enmetazobactam.

	MIC breakpoint (mg/L)				Zone diameter breakpoint (mm) Disc content (30–20 µg)
	EUCAST		FDA		EUCAST			FDA
Organisms	S ≤ mg/L	R > mg/L	S ≤ mg/L	R ≥ mg/l	S ≥ mm	R < mm	ATU mm	S ≥ mm	R ≤ mm
Enterobacterales	4*	4*	8*	8*	22	22	21–22	21	20
P. aeruginosa	Note1	Note1	8*	8*	NoteA	NoteA	–	18	17

*For MIC determination, the concentration of enmetazobactam is fixed at 8 mg/L.

^1/AThe beta-lactamases produced by the organisms either do not modify the parent cephalosporin or are insufficiently inhibited by the inhibitor. Therefore, the addition of the beta-lactamase inhibitor does not add clinical benefit. As per the EUCAST clinical breakpoints for cefepime alone for Pseudomonas spp. : S ≤ 0,001/R >8 mg/l, the best interpretation for P. aeruginosa isolates with 0,001 > MIC ≤8 mg/l is “I.” However, since cefepime-enmetazobactam already employs cefepime in high exposure, cefepime “I” could be translated to cefepime- enmetazobactam “S.”

ATU: area of technical uncertainty.

1.2.2. In vitro activity of cefepime-enmetazobactam

To define the in vitro spectrum of activity of cefepime-enmetazobactam, susceptibility testing has been performed with clinical isolates collected in different surveillance studies, clinical trials and challenge sets of isolates enriched with defined resistance mechanisms. Overall, nearly 20,000 isolates of clinically relevant gram-negative pathogens have been tested since 2014. These isolates were obtained globally from patients with cUTI, complicated IAI, hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) from North America (USA and Canada) and Europe (Germany, France, United Kingdom, Italy, Spain, the Netherlands, Sweden, Belgium andDenmark) [31,32]. One large study determined the in vitro activity of cefepime-enmetazobactam against 3rd-generation cephalosporin (3GC)-resistant Enterobacterales clinical isolates [32]. In this study, 7168 clinical Enterobacterales recovered from North America and Europe that were resistant to either ceftazidime (MIC ≥16 μg/mL) and/or ceftriaxone (MIC ≥4 μg/mL) but susceptible to meropenem (MIC ≤1 μg/mL) were assessed. Phenotypic resistance in this collection to 3GC or ESBL genotype did not change the in vitro activity of cefepime-enmetazobactam on Enterobacterales with more than 98% isolates displaying MIC values ≤2 mg/L (Table 2). The cefepime-enmetazobactam MIC₉₀ values against the different ESBL types ranged from 0.12 μg/mL to 1 μg/mL, whereas the cefepime MIC₉₀ values ranged from 8 μg/mL to >64 μg/mL demonstrating the potent in vitro activity of the combination against the different types of ESBLs (Table 2).

Table 2.

Comparison of in vitro activity between cefepime-enmetazobactam and cefepime against antibiotic-non-susceptible Enterobacterales from [6].

	Cefepime-enmetazobactam*			Cefepime
Resistance phenotype and number of isolates tested (n)	MIC50 (mg/L)	MIC90 (mg/L)	Percentage of isolates with MIC ≤2 mg/L	MIC50 (mg/L)	MIC90 (mg/L)	Percentage of isolates with MIC ≤2 mg/L
All isolates (7168)	0.03	0.25	98.3	0.06	16	87.0
3CG resistant (1252)	0.12	0.5	98.8	8	>64	39.8
ESBL genotype (801)	0.06	0.5	98.9	64	>64	12.0
CTX-M-15 (458)	0.06	0.25	99.1	>64	>64	4.1
CTX-M-27 (61)	0.06	0.06	100	8	32	19.7
CTX-M-1 type (19)	0.12	1	94.4	64	>64	0
CTX-M-14 (38)	0.03	0.12	100	8	>64	18.4
SHV (18)	0.12	1	94.4	64	>64	0
ESBL genotype+ AmpC (45)	0.12	0.5	97.8	64	>64	22.2

*fixed concentration of 8 mg/L enmetazobactam; 3CG: third-generation cephalosporins; ESBL: extended spectrum beta-lactamasases.

With respect to activity against chromosomal AmpC producers, the activity of cefepime-enmetazobactam against Enterobacterales bacteria collected in Europe from 2019 to 2021, including third-generation cephalosporin-resistant isolates was recently published [33]. A total of 2,627 isolates were collected and antimicrobial susceptibility results interpreted according to EUCAST guidelines (breakpoint of 4 mg/l). A total 320 isolates (12.2%) were resistant to 3GC but susceptible to meropenem and all of them carried an ESBL with or without an AmpC. All these isolates were susceptible to cefepime-enmetazobactam while the susceptibility to cefepime was lower in ESBL producers (1.9%) than in AmpC producers (56.9%) [33].

Although no clinical data exist regarding the use of cefepime-enmetazobactam to treat carbapenemase-producing organisms, cefepime-enmetazobactam has shown potent in vitro activity against Enterobacterales-producing OXA-48 like enzymes due to the inherent stability of cefepime against hydrolysis by OXA-48 carbapenemases along with the inhibitory activity of enmetazobactam against ESBLs, which are frequently co-produced. In a recent large in-vitro study, 1,000 clinical isolates of OXA-48-producing Enterobacterales demonstrated a bimodal distribution of cefepime MICs, with MIC >16 mg/L reported for 24.5% of all isolates (Figure 2). Combining enmetazobactam to cefepime led to a restoration of susceptibility, lowering the MIC₉₀ from >16 mg/L to 1 mg/L [36].

Figure 2.

MICs and cumulative MIC distribution of 1000 OXA-48-like-producing Enterobacterales to cefepime/cefepime-enmetazobactam.

Bonnin et al. [36], also evaluated the in vitro activity of cefepime-enmetazobactam toward a collection of carbapenem-resistant Enterobacterales (CRE) compared to the other BL/BLI combinations, and the results confirmed that cefepime-enmetazobactam and ceftazidime-avibactam exhibited a similar rate of susceptibility (96.7% vs 99.5%, respectively, using EUCAST breakpoints) against OXA-48-producers. Cefepime-enmetazobactam showed less activity against KPC carbapenemase producers, with only 63.3% of KPC producers being susceptible although it demonstrated reliable in vitro activity against ceftazidime-avibactam-resistant KPC variants. The study also confirmed no significant activity of enmetazobactam against metallo-β-lactamases (NDM, VIM) or added value for P. aeruginosa and A. baumannii [36]. In vitro activity of cefepime-enmetazobactam against carbapenem-resistant Enterobacterales is summarized in Table 3.

Table 3.

Summary of the in vitro activity of beta-lactam/beta-lactamase inhibitor combination on carbapenem-resistant Enterobacterales.

Table adapted from Bonnin et al. 2024 [36]; * it might have in vitro activity against KPC variants with mutated omega loop.

In another in-vitro analysis, Delgado Valverde et al. [37] evaluated the activity of cefepime-enmetazobactam against a well-defined collection of clinical cephalosporin-and/or carbapenem-resistant Enterobacterales and Acinetobacter baumannii strains from Southern Spain hospitals, and cefepime/enmetazobactam demonstrated potent in vitro activity against Enterobacterales, including OXA-48-producing isolates. Moreover, enmetazobactam displayed an excellent capacity to restore cefepime activity against clinical isolates of OXA-58 and non-oxacillinase producer A.baumannii, therefore, seems that the activity against oxacillinase-producing A.baumannii depends on the type of oxacillinase produced.

1.3. Mechanisms of resistance

Mechanisms of resistance to cefepime-enmetazobactam include production of beta-lactamases that can hydrolyze cefepime and which are not inhibited by enmetazobactam, such as metallo-β-lactamases, porin mutations which affect outer membrane permeability, overexpression of efflux pumps, and mutations in the penicillin-binding protein genes [38]. The propensity of resistance selection was investigated in Enterobacterales isolates using agar plates containing cefepime alone or combined with 8 μg/mL enmetazobactam at 2X, 3X, 4X, 8X or 16X MIC. The development of spontaneous resistance, i.e., breakthrough growth, occurred at a similar rate or less frequent than cefepime alone (10⁻⁶ to < 7.4 × 10⁻¹²). Isolates tested were E. coli, K. pneumoniae, and E. cloacae (MIC range 0.015 to 4 μg/mL) with genes for CTX-M-15, SHV, OXA-48, and TEM. Of the isolates which did develop resistance, mutations were observed in the OmpK proteins and the efflux pump gene acrA [39].

1.4. Pharmacokinetics/Pharmacodynamics

Like other beta lactam/beta-lactamase inhibitor combinations (BL/BLIc), the efficacy of cefepime-enmetazobactam relies on a joint PK/PD target taking into account both the BL and the BLI. An initial hollow fiber study demonstrated that resistance development was suppressed and cefepime antibacterial activity against ESBL-producing Enterobacterales was restored with an enmetazobactam concentration C_T of 2 μg/mL [37]. Human PK parameters following treatment with 2 g cefepime-0.5 g enmetazobactam via a 2 h infusion every 8 h were applied in the hollow fiber model on 10 ESBL-producing strains with MICs between 1 μg/mL and 16 μg/mL [39]. Cefepime-enmetazobactam was able to reduce the bacterial burden within 72 h for all strains only expressing ESBLs (5 out of 10 isolates). The five other isolates did not respond to cefepime-enmetazobactam in that model, their MICs were 4 μg/mL or above and they were co-expressing a carbapenemase (NDM or KPC or OXA-48) [39]. In a neutropenic murine thigh infection model caused by ESBL-producing isolates of K. pneumoniae with an MIC to cefepime-enmetazobactam up to 2 μg/mL, it was shown that the PK-PD targets granting a bactericidal effect of 1-log kill were 40–60% fT>MIC for cefepime and 44% fTC (target concentration) > 2 mg/L for enmetazobactam, respectively [40]. In vitro data showing activity against OXA-48 producers [36] have been translated in vivo in neutropenic mice where cefepime-enmetazobactam demonstrated superior activity to meropenem against OXA-48 producing K. pneumoniae (all cefepime resistant) lung infections even when the strain had a low MIC to meropenem (0.5 µg/mL) [41]. In another experimental animal model of murine pneumonia caused by ESBL-producing K. pneumoniae, it was observed that a ≥ 2-log kill in the lung in the presence of cefepime fT>MICof ≥20% and of enmetazobactam ≥ 20% fTC >2 mg/L in both plasma and epithelial lining fluid (ELF) [42]. Interestingly, in the same murine infection model, high penetration rates into the ELF were observed for both cefepime and enmetazobactam, the AUC_ELF/AUC_plasma ratio for cefepime and enmetazobactam being 0.73 and 0.61, respectively [42]. Similar mean (±) SD ELF penetration ratios of 60.59% ± 28.62% and 53.03% ± 21.05% for cefepime and enmetazobactam were demonstrated in healthy human volunteers, respectively [43].

Based on these preliminary findings, the selected PKPD targets for defining optimal dosing regimens of cefepime-enmetazobactam were set at 60% fT > MIC for cefepime and at 45% fTC >2 mg/L for enmetazobactam. Clinical trials were conducted based on these targets, and the final-approved dosing regimens of cefepime-enmetazobactam by EMA was of 2 g/0.5 g q8h over 2 h infusion in patients with normal renal function or with mild renal dysfunction (namely, CLCr >60 mL/min) [26].

The key pharmacokinetic properties of cefepime and enmetazobactam are summarized in Table 4. The major pharmacokinetic parameters of the two compounds, namely, V_ss, t_1/2 and CL, were quite similar, and renal excretion as unchanged moiety was largely prevalent for both. Accordingly, dose reductions are recommended in patients with moderate renal dysfunction (1 g/0.25 g q8h over 2 h), with severe renal dysfunction (1 g/0.25 g q12h over 2 h), with end-stage renal disease (1 g/0.25 g q24h over 2 h) and undergoing hemodialysis (1 g/0.25 g as loading dose on day 1 then 0.5 g/0.125 g q24h over 2 h). Infusion time must be extended up to 4 h in patients with augmented renal clearance (>150 mL/min) and in those with hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), regardless of the renal impairment status [26,44].

Table 4.

Pharmacokinetics properties of cefepime and enmetazobactam in humans [USPI and EPAR].

Parameter	Cefepime	Enmetazobactam
Cmax (µg/mL)	99.8 (26.4)	19.8 (6.3)
Cmin (µg/mL)
AUClast (µg.h/mL)	379.5 (23.3)	75.3 (30.8)
CL (L/h)	5.8 (1.9)	7.6 (2.9)
Vss (L)	20.02 (6.44)	25.26 (9.97)
T1/2 (h)	2.7 (1.1)	2.6 (1.1)
% bound to human plasma protein	20%	Negligible
Intrapulmonary penetration	46.8%	46.0%
Metabolism	Minimal
Renal Excretion	85%	90%

Monte-Carlo simulations based on a population PK model derived from the pooled analysis of phase 1 to phase 3 clinical studies including 649 subjects was carried out for testing the PTA of the selected PK/PD targets (namely, 60% fT cefepime > MIC coupled with 45% fC_T >2 mg/L for enmetazobactam) with the proposed dosing adjustments in patients with cUTIs or acute pyelonephritis. Monte–Carlo simulations in 4,000 simulated patients showed that these regimens granted PTA > 95% at day 7 against a wide cefepime-enmetazobactam MIC distributions of 9,905 Enterobacterales (including 1,007 ESBL-producers) having an MIC up to 8 μg/mL [31–33,45,46].

The intrapulmonary pharmacokinetics of cefepime-enmetazobactam was assessed in 20 healthy volunteers at steady state after administering 2 g/0.5 g q8h over 2 h for eight doses. The mean (±SD) total penetration rates into the ELF for cefepime and enmetazobactam were 60.59% ± 28.62% and 53.03% ± 21.05%, respectively [43].

Interestingly, Monte–Carlo simulation showed that, by considering joint PK/PD targets at the infection site of 100% fT>MIC for cefepime and 20% fTC >2 mg/L for enmetazobactam, the currently licensed dosing regimen of 2 g/0.5 g q8h over 2 h ensured ≥ 90% PTAs against Enterobacterales with an MIC up to 8 mg/L into the ELF. By merging this atter population PK model in the ELF of healthy volunteers with that derived from the pooled analysis of phase 1 to phase 3 clinical studies, Monte-Carlo simulations were also performed for testing the PTA of cefepime-enmetazobactam in ELF to support dose selections for treating pneumonia. Monte-Carlo simulations of 4,000 subjects with normal renal function receiving 2 g/0.5 g q8h over 2 h showed that, using the joint PKPD targets associated with 2-log₁₀ microbiological burden decrease in mouse lung infection model [42], namely, 20% fT>MIC for cefepime and 20% fTC >2 mg/L for enmetazobactam, the PTA in the ELF of patients was ≥ 99.7% on day 1 and 100% on day 7 of dosing against gram-negative pathogens with an MIC up to 8 mg/L. To achieve an increased PD target in the ELF (namely, 60% fT cefepime > MIC coupled with 45% fC_T >2 mg/L for enmetazobactam), Monte–Carlo simulation demonstrated that 4-h infusion was needed in pneumonia patients as defined in the European label [26,46]. Importantly, the pharmacodynamics activity of both cefepime and enmetazobactam against clinical isolates of K. pneumoniae was shown to be unaffected by the presence of alveolar surfactant [47].

To accommodate the prolonged infusion of 4 h, extra stability study has been performed post approval to confirm the stability of the reconstituted, diluted solution for 4.5 h. The diluted solutions were stored at controlled room temperature for 4.5 h. Samples were analyzed at three timepoints (initial T0, 3.5 h and 4.5 h) for assay, drug-related impurity content, N-methylpyrrolidine, appearance, pH, osmolarity, visible particulate matter, and particulate matter sub-visible particles. All results obtained after the 4.5-h storage were within the EU registered end of shelf-life specifications and also met the criteria for assay to be within the range of 98.0–102.0% of the initial value. The study concluded that the drug product is stable in solution after 4.5 h storage at controlled room temperature.

1.5. Cefepime-enmetazobactam clinical overview

The cefepime-enmetazobactam clinical development program was comprised of six clinical studies, including four phase I studies in healthy adult participants which included a mass balance and metabolite identification study and a pharmacokinetic study evaluating the concentration of cefepime-enmetazobactam in plasma and epithelial lining fluid [43]. Because cefepime and enmetazobactam are primarily renally eliminated, a dedicated phase I study in adult participants with varying degrees of renal impairment was also performed to evaluate the PK of cefepime and enmetazobactam.

One phase II trial evaluated the optimal cefepime-enmetazobactam combination dose and the probability of target attainment (PTA) in subjects with cUTI, including AP and one phase III trial was conducted in adult patients with cUTI including AP, from which the primary safety and efficacy data are derived [48].

1.6. Complicated urinary tract infections

The ALLIUM trial was a Phase 3, randomized, double-blind, multicenter, non-inferiority study to evaluate the efficacy and safety of cefepime-enmetazobactam compared to piperacillin-tazobactam in the treatment of complicated urinary tract infections, including acute pyelonephritis, in adults [48]. Eligible adult patients were randomized in a 1:1 ratio to receive either 2 g cefepime plus 500 mg enmetazobactam (2 h infusion) every 8 h (q8h) or 4.5 g piperacillin-tazobactam (2 h infusion) q8h for 7 days (up to 14 days in patients with a positive blood culture at baseline). In patients with an estimated glomerular filtration rate [eGFR] between 30 and 60 mL/min, the dose of cefepime-enmetazobactam was reduced to 1 g cefepime plus 250 mg enmetazobactam (2 h infusion) q8h. Patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) were excluded from study participation and no switch to oral therapy was permitted.

The primary efficacy outcome was the proportion of patients in the microbiological Modified Intent-to-Treat (m-MITT) population (patients who received at least 1 dose of treatment and had a gram-negative bacterium that was not resistant to either treatment in urine at more than 10⁵ CFU/mL at baseline or the same gram-negative pathogen in both urine and blood cultures) who achieved overall treatment success at Test Of Cure (TOC). For patients receiving 7 days of treatment, the TOC visit occurred 7 ± 2 days after end of therapy (EOT) and for patients receiving more than 7 days of treatment, this visit occurred 19 ± 2 days after randomization. The late follow-up visit (LFU) 14 [±2] days after EOT. Overall treatment success was defined as the composite of clinical cure and microbiological outcome of eradication (<10³ colony-forming units [CFU]/mL in urine culture) in accordance with the FDA guidelines. 678 randomized patients were included in the m-MITT population, 345 patients in the cefepime-enmetazobactam group and 333 patients in the piperacillin-tazobactam group. 273 (79.1%) patients in the cefepime-enmetazobactam arm had an overall response of success at TOC compared to 196 (58.9%) patients receiving piperacillin-tazobactam, with a treatment difference of 21.2% (95% CI: 14.3, 27.9). Based on these findings, cefepime-enmetazobactam met criteria for both non-inferiority and superiority compared to piperacillin-tazobactam. Results were also compared at the late follow-up time frame (LFU). Overall success at LFU was demonstrated in 236 (68.4%) patients who received cefepime-enmetazobactam compared to 196 (58.9%) patients in the piperacillin-tazobactam group, with a treatment difference of 10.7% (95% CI: 3.4, 17.8) again demonstrating both non-inferiority and superiority of cefepime-enmetazobactam compared to piperacillin-tazobactam (Figure 3). Furthermore, when limiting the primary analysis set to those pathogens with both a piperacillin-tazobactam minimum inhibitory concentration ≤16 μg/mL (applying the updated 2021 European Committee on Antimicrobial Susceptibility Testing (EUCAST) piperacillin-tazobactam minimum inhibitory concentration (MIC) breakpoints (i.e., susceptible ≤8 mg/L and resistant >8 mg/L)), and lacking an extended-spectrum β-lactamase genotype, results similarly favored cefepime-enmetazobactam over piperacillin-tazobactam (overall success rates of 80.9% [212/262] vs 60.7% [156/257], respectively; difference, 20.2% [95% CI, 12.4%-27.7%]).

Figure 3.

Overall success difference in the ALLIUM phase 3 clinical study in favour of cefepime-enmetazobactam versus piperacillin-tazobactam treatment group.

Importantly, at TOC, both treatment groups had a similar clinical response of cure (92.5% vs 88.9% for the cefepime-enmetazobactam and the piperacillin-tazobactam groups, respectively), and the superiority result in favor of cefepime-enmetazobactam versus piperacillin-tazobactam for the primary endpoint was driven by the microbiological eradication outcome, which was demonstrated in 286 (82.9%) patients in the cefepime-enmetazobactam group and 216 (64.9%) patients in the piperacillin-tazobactam group (treatment difference of 19.0% (95% CI: 12.3, 25.4)).

Higher microbiological eradication was consistent against the various species of Enterobacterales assessed. At the TOC, in the cefepime-emmetazobactam group patients with infections caused by E. coli, K. pneumoniae, P. mirabilis, and E. cloacae achieved a superior microbiological eradication outcome compared to those in the piperacillin-tazobactam group. As a consequence of this superior microbiological eradication, microbiological recurrence was lower in patients receiving cefepime-enmetazobactam (11.3%;39/345) compared with piperacillin-tazobactam (29.4%; 98/333) at day 14.

Overall success rates between treatment arms were assessed in various subgroups including older age, sex, baseline renal function, infection type (i.e., pyelonephritis versus cUTI), baseline Charlson Comorbidity Index, and presence/absence of baseline bacteremia. In all of these subgroups, overall success rates were consistent with those of the entire cohort. Importantly, in the subgroup analysis of patients with ESBL-producing Enterobacterales, overall success rates with cefepime-enmetazobactam were also superior than those with piperacillin-tazobactam (56/76 (73.7%) versus 34/66 (51.5%), respectively), treatment difference 30.2% (95% CI 13.5% − 45.1%).

Few patients included in the ALLIUM study were infected with P. aeruginosa, 13 patients in the cefepime-enmetazobactam treatment group and 11 patients in the piperacillin-tazobactam treatment group in the mMITT population. For these patients, the overall success rate were similar between study arms.

In this Phase III clinical study, changes in cefepime-enmetazobactam MIC of ≥ 4-fold relative to the baseline MIC for isolates obtained at either test of cure or late follow-up in the cefepime-enmetazobactam treatment group was observed in seven isolates from the 345 patients treated. Only one out of these seven isolates with increased MIC had a categorical shift consecutive to the increase in MIC from 8 μg/mL to 32 μg/mL. No molecular characterization was performed [49].

1.7. Safety

The safety data from the ALLIUM trial demonstrate that cefepime-enmetazobactam was generally well tolerated in this patient population. The safety population, defined as all patients who received at least 1 dose of study drug during the study, included 1034 patients: 516 patients in the cefepime-enmetazobactam group and 518 patients in the piperacillin-tazobactam group.

In total, 519 (50.2%) patients experienced AEs: 277 (53.7%) patients in the cefepime-enmetazobactam group and 242 (46.7%) patients in the piperacillin-tazobactam group.

In total, 177 (17.1%) patients experienced drug-related TEAEs: 102 (19.8%) patients in the cefepime-enmetazobactam group and 75 (14.5%) patients in the piperacillin-tazobactam group. The majority of the drug-related TEAEs were mild or moderate in severity. In total, there were 41 (4.0%) patients who experienced treatment-emergent SAEs: 22 (4.3%) patients in the cefepime-enmetazobactam group and 19 (3.7%) patients in the piperacillin-tazobactam group. A total of four (0.4%) patients experienced drug-related treatment-emergent SAEs: one (0.2%) patient in the cefepime-enmetazobactam group and three (0.6%) patients in the piperacillin-tazobactam group.

The most common TEAEs experienced among all patients were increased alanine aminotransferase (ALT) in 119 (11.5%) patients: 59 (11.4%) patients in the cefepime-enmetazobactam group and 60 (11.6%) patients in the piperacillin-tazobactam group; and an aspartate aminotransferase (AST) increase in 93 (9.0%) patients: 47 (9.1%) patients in the cefepime-enmetazobactam group and 46 (8.9%) patients in the piperacillin-tazobactam group.

No patients had any clinically meaningful changes from baseline in laboratory values or had any abnormal laboratory results that were considered to be an SAE or resulted in discontinuation from the study. There was no difference between the cefepime-enmetazobactam and piperacillin-tazobactam groups in the categorical and morphological ECG analyses. These analyses did not reveal any potential safety issues regarding QTc and other ECG parameter changes from baseline.

Overall, the study drugs were well tolerated in both treatment groups, encephalopathy and seizures identified as AE of interest were reported in a similar percentage (0.4 vs 0.2%) and no new or unexpected safety concerns were identified. The safety profile of cefepime-enmetazobactam appears essentially similar to that of piperacillin-tazobactam or cefepime when used alone.

1.8. Appropriate place in therapy for Cefepime-enmetazobactam

Cefepime-enmetazobactam is approved in the US for patients 18 years and older with cUTI including pyelonephritis and in the EU for patients 18 years and older with cUTI including pyelonephritis, HAP including VAP and bacteremia associated with any of these infections. Its appropriate place should take into account the approved indications and the known clinical experience with cefepime and potential added value of enmetazobactam.

1.9. Non CPE infections

Cefepime is a widely used molecule in the treatment of serious gram-negative infections. The drug has demonstrated clinical efficacy against P. aeruginosa and Enterobacterales. Cefepime is suggested for the treatment of infections caused by organisms at moderate risk of significant AmpC production (ie, E. cloacae complex, K.aerogenes, and C. freundii) [15]. However, the use of cefepime in practice in documented Enterobacterales infections is hindered by its lack of activity against ESBL. The addition of enmetazobactam to cefepime restores the MIC₉₀ to 0.25 mg/l for ESBL-producing Enterobacterales and to 1 mg/L for AmpC genotype Enterobacterales [31]. For the treatment of pneumonia, cefepime is often a preferred option due to its good penetration into lung tissue [50]. By demonstrating similar pulmonary penetration to cefepime together with a similar t_1/2 enmetazobactam is an optimal companion β-lactamase inhibitor to cefepime throughout the entire dosing interval for patients with lung infections. Cefepime-enmetazobactam might also be a suitable alternative to broad-spectrum carbapenems in cases of polymicrobial infections when P. aeruginosa susceptible to cefepime and/or Enterobacterales resistant to cefepime are still susceptible to cefepime-enmetazobactam. However, if coinfection with gram-positive bacteria or anaerobes is suspected, additional antimicrobial agents may need to be considered.

Considering all the data available to date on the cefepime-enmetazobactam combination, it seems reasonable to consider this new BL/BLI combination as a viable alternative in the treatment of serious infections caused by ESBLs. Furthermore, cefepime-enmetazobactam may be an appropriate therapeutic option for the treatment of serious infections caused by AmpC-overproducing bacteria where there is a risk of ESBLs co-production, depending on the local epidemiology, to ensure full activity against these two mechanisms of resistance.

1.10. CPE infections

Although no clinical data exist, publications have reported similar in vitro activity against OXA-48 producing bacteria between ceftazidime-avibactam, and cefepime-enmetazobactam [36] and promising animal data have been obtained in a murine pneumonia model [41]. Therefore, if clinical data are favorable, cefepime enmetazobactam has potential to be a new therapeutic alternative for the treatment of OXA-48 infections, when there is also a high probability of co-production of ESBLs, but this must now be supported by clinical experience.

Cefepime-enmetazobactam may be a possible therapeutic option for KPC isolates that become resistant to ceftazidime-avibactam and remain susceptible to cefepime-enmetazobactam [36], but this must be supported by clinical evidence in larger datasets.

Some additional factors should be considered for the use of cefepime-enmetazobactam in practice, for example its limited activity against anaerobes, suggests a limited effect on the digestive microbiota, but this also needs to be investigated. Also, given the known neurotoxicity of cefepime, especially in ICU patients with VAP [51], the neurotoxicity of the combination of cefepime-enmetazobactam using 6 g cefepime per day should be monitored even though enmetazobactam was not associated with neurotoxicity in animal models and the pivotal studies did not show adverse neurological effects. All these potential places in therapy need to be confirmed by clinical data in documented infections.

2. Conclusion

The results from the Phase 3 trial detailed above demonstrated superiority of cefepime-enmetazobactam versus piperacillin-tazobactam in the treatment of cUTI. Cefepime-enmetazobactam was well tolerated, and no unexpected safety concerns were identified by the addition of enmetazobactam to cefepime.

Cefepime-enmetazobactam has been developed primarily for the treatment of ESBL producing Enterobacterales. Contrary to recently commercialized antibiotics, it doesn’t demonstrate a strong activity in carbapenem-resistant microorganisms except against the OXA-48 producers attributable to cefepime stability. Cefepime-enmetazobactam is a promising drug for use in patients infected or suspected to be infected with ESBL-producing pathogens.

Box 1.

Drug Summary Box.

Cefepime/enmetazobactam, is a novel intravenous β-lactam/ β-lactamase inhibitor combination with targeted Gram-negative activity. Cefepime is relatively resistant to hydrolysis by AmpC and OXA-48, and enmetazobactam inhibits all Ambler Class A extended spectrum β-lactamases (ESBLs). The Food and Drug Administration, the European Medicines Agency and the UK Healthcare products Regulatory Agency have approved cefepime/enmetazobactam for the treatment of adults patients with complicated urinary tract infections, with the EMA and MHRA further giving approval for hospital acquired pneumonia including ventilator associated pneumonia and associated bacteraemia. Clinical data demonstrate the superiority of cefepime/enmetazobactam to piperacillin/tazobactam for combined clinical and microbiological cure of complicated urinary tract infections, and human pulmonary pharmacokinetic data, along with in vivo pharmacodynamic data from animal lung infection models, have demonstrated that human cefepime/enmetazobactam drug exposure in the lungs reaches very high therapeutic doses to treat hospital-acquired pneumonia. Cefepime/enmetazobactam is well tolerated with minimal side effects and toxicities. Therefore, the main potential role for cefepime/enmetazobactam could be as a carbapenem-sparing agent for the treatment of infections caused by ESBL-producing Enterobacterales including those that may co-produce AmpC or OXA-48.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Funding Statement

This paper was not funded.

Article highlights

• Enterobacterales cause severe infections that can be difficult to treat due to the high prevalence of multidrug resistance.

• Cefepime-enmetazobactam is an intravenous β-lactam/β-lactamase inhibitor combination that was approved in February 2024 by the US FDA for the treatment of adults with complicated urinary tract infections. It was also approved in Europe for the treatment of hospital-acquired pneumonia and ventilator associated pneumonia and for bacteremia associated with these infections.

• Cefepime-enmetazobactam has in vitro activity against ESBL-producing Enterobacterales but also against OXA-48 producing clinical isolates and KPC- producing clinical isolates.

• PK/PD exposure targets for cefepime-enmetazobactam have been established from in vitro and in vivo exposure response studies to guide the clinical dose.

• In a phase III, randomized, active-controlled trial, cefepime-enmetazobactam met the primary efficacy end point of noninferiority and even superiority for the composite overall success compared with piperacillin-tazobactam in the primary analysis population which was comprised of patients with a complicated urinary tract infection.

• The safety data from the phase III trial demonstrated that cefepime-enmetazobactam was generally well tolerated.

• The most common drug-related treatment emergent adverse events were elevation of hepatic enzymes, headache and infusion site reactions.

• Cefepime-enmetazobactam should be considered a treatment alternative for serious infections, including pneumonia, due to ESBL producing Enterobacterales.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.