In vitro activity of cefepime-enmetazobactam on carbapenem-resistant Gram negatives

Cefepime-enmetazobactam is a new β-lactam/βlactamase inhibitor combination with broad-spectrum activity against multidrug-resistant Enterobacterales, including extended-spectrum β-lactamase producers. This study evaluated the in vitro activity of cefepime-enmetazobactam towards a collection of carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa and Acinetobacter baumannii compared to the other β-lactam/β-lactamase inhibitor combinations.

The MIC of cefepime, cefepime-enmetazobactam, ceftazidime, ceftazidime-avibactam, meropenem, meropenem-vaborbactam, imipenem, imipenem-relebactam, and ertapenem were determined by broth microdilution on 2212 CRE, including 2089 carbapenemase producers (1000 OXA-48-like, 49 KPC, 697 NDM, 180 VIM, 1 IMP, 9 IMI, and 158 multiple carbapenemases) and 123 CRE that do not produce carbapenemase received at the French National Reference Centre (from March 1, 2023 to August 31, 2023), 50 P. aeruginosa, and 30 A. baumannii. All strains were fully sequenced.

We confirmed the absence of inhibitory activity of enmetazobactam towards metallo-β-lactamases. Cefepime-enmetazobactam and ceftazidime-avibactam exhibited a similar susceptibility (96.7% vs. 99.5%, respectively) on OXA-48-producers. Cefepime-enmetazobactam exhibited 66.9% and 63.3% susceptibility for CRE non-EPC and KPC, whereas those rates rose to 96.7%/95.9%, 93.4%/95.9%, and 95.9%/98.0% for ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam, respectively. Low MICs (≤0.25 mg/L) were obtained for ceftazidime-avibactam-resistant KPC variants. Cefepime-enmetazobactam did not display a significant added value when compared with cefepime alone on Pseudomonas aeruginosa and Acinetobacter baumannii.

OXA-48 producers displayed high susceptibility to cefepime-enmetazobactam, which is similar to ceftazidime-avibactam, including for OXA-48 producers that coproduce a ceftazidime hydrolyzing enzyme (extended-spectrum β-lactamases or AmpC). In vivo experiments have to be implemented to confirm if cefepime-enmetazobactam might be a relevant alternative to ceftazidime-avibactam for the treatment of infections caused by OXA-48 producers.