In vivo efficacy of enmetazobactam combined with cefepime in a murine pneumonia model induced by OXA-48-producing Klebsiella pneumoniae.

Abstract

Third-generation cephalosporin-resistant Klebsiella pneumoniae with extended-spectrum β-lactamases as principal resistance determinants are classified as critical priority pathogens. Their increasing occurrence has led clinicians to widely use carbapenems. Accordingly, carbapenem resistance in Klebsiella pneumoniae has spread in recent decades across several countries, and OXA-48-like carbapenemases are one of the main determinants of carbapenem resistance in Enterobacterales. Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination that demonstrated excellent intrapulmonary penetration, supporting its use in the treatment of pneumonia. This study examined the efficacy of enmetazobactam, in combination with cefepime, compared to carbapenems for OXA-48-producing Klebsiella pneumoniae in a 24-h murine neutropenic pneumonia model. The combination showed a bacteriostatic effect using the 2-h controls as reference. Compared to 24-h controls, and to cefepime or meropenem monotherapies, the co-administration of enmetazobactam with cefepime demonstrated a pronounced in vivo bactericidal activity against cefepime-non-susceptible K. pneumoniae isolates with cefepime/enmetazobactam MICs up to 8 µg/mL in this model.