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.