ObjectivesCefepime-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. MethodsMIC 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 (1st March to 31th August 2023), 50 P. aeruginosa and 30 A. baumannii. All strains were fully sequenced. ResultsWe 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. ConclusionOXA-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.