Cefepime 2g / Enmetazobactam 500mg powder for solution for infusion vials

Cefepime-enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination showing good activity against multidrug-resistant (MDR) Gram-negative bacteria producing a variety of β-lactamases. In this systematic review, we aimed to evaluate the available data on resistance to this drug. We performed a thorough search of four databases (Embase, PubMed, Scopus, and Web of Science), as well as backward citation searching, to identify studies containing data on resistance to cefepime-enmetazobactam. The data were extracted and analyzed according to the breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Food and Drug Administration (FDA), or the specific breakpoints reported by the authors of the respective studies. Analysis based on the type of lactamases produced by the isolates was also performed. Ten studies reported in vitro susceptibility testing and mechanisms of antimicrobial resistance. The total number of isolates was 15,408. The activity of cefepime-enmetazobactam against β-lactamase-producing isolates was variable. The resistance of the studied extended-spectrum β-lactamase (ESBL)-producing and ampicillin C β-lactamase (AmpC)-producing isolates was low (0–2.8% and 0%, respectively). The resistance was higher among oxacillinase-48 β-lactamase (OXA-48)-producing and Klebsiella pneumoniae carbapenemase (KPC)-producing isolates (3.4–13.2% and 36.7–57.8%, respectively). High resistance was noted among metallo-β-lactamase (MBL)-producing isolates (reaching 87.5% in one study), especially those producing New Delhi metallo-β-lactamase (NDM) and Verona integron-encoded metallo-β-lactamase (VIM), which had the highest rates of resistance. The high activity of cefepime-enmetazobactam against Enterobacterales and selected lactose non-fermenting Gram-negative pathogens, including ESBL-producing and AmpC-producing isolates, makes it a potential carbapenem-sparing agent. The drug should be used after in vitro antimicrobial susceptibility testing in patients with infections caused by OXA-48, KPC, and MBL-producing isolates.

Abstract licence: CC BY 4.0

Aim: Compared with uncomplicated urinary tract infections (UTIs), complicated UTIs (cUTIs) including acute pyelonephritis (AP) present with significant morbidity, a higher risk of treatment failure and typically require longer courses of treatment, or alternative antibiotics. The emergence of drug-resistant organisms represents a considerable challenge in the treatment of patients with cUTIs/AP and has limited antibiotic options. Carbapenems are considered the current last line of therapy, however, carbapenem resistance represents a growing problem. Although several established and novel treatment options are available, direct comparative evidence is lacking. Methods: Randomized controlled trials (RCTs) were identified by systematic literature review of Embase®, MEDLINE® and Cochrane databases (database inception to 15th June 2022). Relevant conference proceedings (2020-2022) were also reviewed. Following feasibility assessment to verify network connectivity at an overall level, outcome specific networks were prepared. Bayesian network meta-analysis (NMA) was performed (using R version 4.2.1) to determine the relative efficacy of various treatments for cUTI/AP, including cefepime + enmetazobactam. Convergence was assessed by visual inspection of trace plots. The accuracy of the posterior estimates was assessed using the Monte Carlo error for each parameter. Published study results were included in the synthesis of the relative risk (RR) of efficacy end points, using a logit link with binomial likelihood distribution. Results: Feasibility assessment was conducted for 40 RCTs identified, to assess the viability of constructing a network of interlinked RCTs. Of those, 28 studies were included in the master NMA network. A fixed effects model (FEM) was selected due to low statistical heterogeneity, according to I2 values. For composite outcome at test of cure (TOC), ceftolozane + tazobactam, cefepime + enmetazobactam, cefiderocol, levofloxacin and plazomicin demonstrated significantly higher RRs versus carbapenems. For microbiological eradication at TOC, cefepime + enmetazobactam, plazomicin, cefiderocol, fosfomycin, meropenem + vaborbactam and ceftazidime + avibactam demonstrated significantly higher RRs versus carbapenems. RRs for cefepime + enmetazobactam were also significantly higher versus several established and novel treatment options for composite outcome, microbiological eradication and clinical cure. Conclusion: Against the backdrop of increasing bacterial resistance, these findings suggest that cefepime + enmetazobactam may represent an effective carbapenem-sparing treatment option in patients with cUTI including AP.

Abstract licence: CC BY-NC-ND

The growing problem of infections due to pathogens with antimicrobial resistance, especially Gram-negative bacteria, has led to the development of new β-lactam/β-lactamase inhibitor combination antibiotics. During the last 2 years from the writing of this article, cefepime/enmetazobactam, aztreonam/avibactam, and sulbactam/durlobactam were approved for use in clinical practice. Cefepime/enmetazobactam targets extended-spectrum β-lactamase (ESBL)-producing Pseudomonas aeruginosa and Enterobacterales. It is indicated for the treatment of patients with complicated urinary tract infections, including pyelonephritis, in Europe and the USA, and also for hospital-acquired pneumonia, ventilator-associated pneumonia, and bacteremia associated with those infections (only in Europe). The antimicrobial spectrum of aztreonam/avibactam includes carbapenem-resistant Enterobacterales. Aztreonam/avibactam is indicated for the treatment of adult patients who suffer from complicated intra-abdominal infections, complicated urinary tract infections including pyelonephritis, hospital-acquired pneumonia, and ventilator-associated pneumonia due to aerobic Gram-negative infections with limited therapeutic options. Sulbactam/durlobactam, a combination of 2 β-lactamase inhibitors, is indicated for the treatment of adult patients with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia due to the Acinetobacter baumannii–calcoaceticus complex [including carbapenem-resistant Acinetobacter baumannii (CRAB) infections].

Abstract licence: CC BY

ABSTRACT Introduction Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor (BL-BLI) combination with broad Gram-positive and -negative activity. Cefepime is relatively resistant to hydrolysis by AmpC, and enmetazobactam inhibits all Ambler Class A extended spectrum β-lactamases (ESBLs). Hence, the combination is resistant to hydrolysis by many ESBLs. Important spectrum gaps are MRSA, enterococci, Acinetobacter spp. and anaerobes. There is no completely reliable activity against carbapenem-resistant organisms. Areas covered We describe the chemistry, pharmacodynamics, pharmacokinetics, toxicities, drug–drug interactions, clinical efficacy, and current regulatory position of cefepime/enmetazobactam, following a review of available published literature relating to cefepime/enmetazobactam. Expert Opinion The main potential role for cefepime/enmetazobactam is as a carbapenem-sparing agent for the treatment of infections caused by ESBL-producing Enterobacterales to prevent the use of carbapenems and to avoid the toxicities of non-β-lactam alternatives. There may be potential uses for cefepime/enmetazobactam for the treatment of reproductive tract infections, abdominal infections and neonatal sepsis, given the spectrum of activity and pharmacokinetic properties. However, additional non-clinical and clinical studies are required before use in these settings.

Abstract licence: CC BY-NC-ND 4.0