Cefepime‐Zidebactam: Leveraging β‐Lactam Enhancement Against Difficult‐to‐Treat and Metallo‐β‐Lactamase‐Producing Gram‐Negative Pathogens

Carbapenem resistance among Gram‐negative bacteria remains a serious public health threat, with metallo‐β‐lactamase (MBL)‐producing organisms increasing substantially in prevalence and few therapeutic options available to adequately address these difficult‐to‐treat pathogens. Cefepime‐zidebactam (FEP‐ZID) is a novel β‐lactam/β‐lactam enhancer combination that offers a mechanistically distinct approach to overcoming resistance in Gram‐negative organisms. Zidebactam contributes three complementary mechanisms: inhibition of Class A and C β‐lactamases, direct antibacterial activity via PBP2 inhibition, and enhancement of cefepime activity through a reduction in the pharmacodynamic exposure required for bactericidal effect, allowing FEP‐ZID to achieve substantial reductions in bacterial burden even in isolates with elevated minimum inhibitory concentrations (MICs). FEP‐ZID was recently approved in the United States for the treatment of complicated urinary tract infection (cUTI), including acute pyelonephritis, caused by Enterobacterales and/or Pseudomonas aeruginosa . FEP‐ZID demonstrates broad in vitro and in vivo activity against isolates producing Class A, B, C, and D β‐lactamases, as well as organisms harboring PBP3 alterations that are otherwise associated with reduced susceptibility to currently available MBL‐active therapies. This spectrum extends across carbapenem‐resistant Enterobacterales, P. aeruginosa , and Acinetobacter baumannii , and includes activity against isolates with porin loss and efflux upregulation, resistance mechanisms that commonly limit the utility of other β‐lactam‐based agents. In vivo infection models utilizing humanized regimens have demonstrated bactericidal activity against isolates with FEP‐ZID MICs up to 64 μg/mL. The Phase 3 ENHANCE I trial demonstrated noninferiority and subsequent superiority over meropenem in cUTI (including acute pyelonephritis), driven primarily by microbiological response, with favorable outcomes observed across many baseline pathogens, including extended‐spectrum β‐lactamase‐producing isolates and patients with concomitant bacteremia. Compassionate use experience further suggests possible utility in severe multidrug‐resistant infections across multiple infection types, including bloodstream, osteoarticular, and intra‐abdominal infections caused by MBL‐producing organisms. Collectively, available preclinical and clinical evidence positions FEP‐ZID as a mechanistically distinct option for difficult‐to‐treat Gram‐negative infections, with additional clinical study needed to define its role beyond the currently approved indication.