Overview of novel cefepime-based β-lactam/β-lactamase inhibitor combinations

Introduction: The global rise of multidrug-resistant (MDR) Gram-negative pathogens challenges therapy, driving development of novel β-lactam/β-lactamase inhibitor (BL/BLI) combinations. Cefepime-based combinations offer mechanistically diverse options against a broad range of resistance phenotypes. Areas covered: This review summarizes approved and investigational cefepime-based BL/BLI combinations, including cefepime/enmetazobactam (FEP/EMT), cefepime/taniborbactam (FTB), cefepime/zidebactam (FPZ), and cefepime/nacubactam (FEP/NAC). We discuss microbiological activity, resistance mechanisms, pharmacokinetics/pharmacodynamics, and available clinical evidence. In vitro data show differential activity against ESBL-, AmpC-, and carbapenemase-producing Enterobacterales, as well as difficult-to-treat Pseudomonas aeruginosa, with emerging but limited clinical outcomes. Challenges include incomplete resistance coverage, geographic variability, and limited clinical trials. Expert opinion: Cefepime-based BL/BLI therapy should be pathogen- and mechanism-driven. FEP/EMT is suited for ESBL- and AmpC-producing Enterobacterales, potentially sparing carbapenems and covering OXA producers if susceptible. FTB may target severe carbapenem-resistant Enterobacterales infections resistant to existing BL/BLI agents, considering coverage for metallo-β-lactamases (MBL). FPZ combines β-lactamase inhibition and β-lactam-enhancer activity, retaining activity against XDR Enterobacterales and P. aeruginosa, including cefiderocol- or aztreonam/avibactam (ATM/AVI)-resistant strains. FEP/NAC shows promise against carbapenem- and MBL-producing strains, though clinical data remain limited. Optimal use relies on rapid molecular diagnostics, susceptibility testing, and antimicrobial stewardship to maximize efficacy and limit the emergence of resistance.