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

Cefepime-enmetazobactam is a new β-lactam-β-lactamase inhibitor (BL/BLI) combination with broad-spectrum activity against multidrug-resistant Enterobacterales including ESBL 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 BL/BLI combinations. MIC of cefepime, cefepime-enmetazobactam, ceftazidime, ceftazidime-avibactam, meropenem, meropenem-vaborbactam, imipenem, imipenem-relebactam and ertapenem were determined by broth microdilution on 2,212 CRE including 2,089 carbapenemase producers (1000 OXA-48-like, 49 KPC, 697 NDM, 180 VIM, 1 IMP, 9 IMI, 158 multiple carbapenemases) and 123 non-carbapenemase producers (CRE non-CPE) received at the French National Reference Center (1 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 while those rates rose to 96.7%/95.9%, 93.4%/95.9%, 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 compared to cefepime alone on P. aeruginosa and A. baumannii. OXA-48 producers displayed high susceptibility to cefepime-enmetazobactam which is similar to ceftazidime-avibactam, including for OXA-48 producers that co-produce a ceftazidime hydrolyzing enzyme (ESBL or AmpC). In vivo experiments have to be implemented to confim if cefepime-enmetazobactam might be a relevant alternative to ceftazidime-avibactam for the treatment of infections caused by OXA-48 producers.

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