Cefepime/Enmetazobactam: A Novel β-Lactam/β-Lactamase Inhibitor Combination for Multidrug-Resistant Gram-Negative Infections

Antimicrobial Resistance (AMR) among gram-negative pathogens poses a major global threat, with limited new antibacterials approved. Cefepime/ enmetazobactam, a novel β-lactam/β-lactamase inhibitor, restores cefepime activity against extendedspectrum β-lactamase (ESBL)-producing Enterobacterales and other multidrug-resistant gramnegatives, offering an option for complicated Urinary Tract Infections (cUTIs). This narrative review synthesises phase 1–3 trials, in vitro surveillance, pharmacokinetic data, and network meta-analyses on cefepime/enmetazobactam versus comparators in cUTIs and related infections. Enmetazobactam inactivates class A β-lactamases (KPC-2, CTX-M-15, SHV-1), boosting cefepime susceptibility from 2% to 98% against ESBL-Enterobacterales; activity is robust against AmpC-producers but limited against metallo-β-lactamases, OXA-types, Acinetobacter baumannii, and Stenotrophomonas maltophilia. In the phase 3 ALLIUM trial (n=1034), cefepime/enmetazobactam achieved superior composite cure rates versus piperacillin/ tazobactam (79.1% vs 58.9%; difference 21.2%) in cUTIs/pyelonephritis, including ESBLsubgroups. Network meta-analyses confirm outcomes comparable to carbapenems, with similar safety (mainly hepatic/infusion events). Cefepime/enmetazobactam shows favourable outcomes as a newer agent for ESBLcUTIs compared to piperacillin/tazobactam, although evidence remains cUTI-focused with modest ESBL representation and spectrum gaps against key resistant pathogens. Pathogendirected use within stewardship is essential. Cefepime/enmetazobactam may contribute to AMR management for susceptible cUTIs/pyelonephritis and HAP/VAP, but its role beyond these indications will depend on further trials in high-risk ESBL/carbapenemase infections.