In vitro activity of the novel β-lactamase inhibitor nacubactam against a nationwide collection of carbapenem-resistant Enterobacterales in Japan

Objectives: Nacubactam is a novel diazabicyclooctane carbapenemase inhibitor that, in combination with cefepime or aztreonam, has been submitted for regulatory approval in Japan for treating serious Gram-negative infections. This study aimed to evaluate the in vitro activity of nacubactam combined with cefepime or aztreonam against a nationwide collection of clinical carbapenem-resistant Enterobacterales (CRE) isolates in Japan. Methods: Minimum inhibitory concentration (MIC) values of 376 CRE isolates from 6 medical institutions in Japan were determined according to the Clinical and Laboratory Standards Institute (CLSI) methods. Results were interpreted using clinical breakpoints of the CLSI document M100 (2025) and the European Committee on Antimicrobial Susceptibility Testing clinical breakpoints, version 15.0 (2025). Results: The predominant CRE isolates were Klebsiella pneumoniae (n = 98), Klebsiella aerogenes (n = 62) and Escherichia coli (n = 43), with the Enterobacter cloacae complex accounting for 117 isolates. Carbapenemase-producing Enterobacterales (CPE) accounted for 48.9% (n = 184), with the predominant carbapenemases being IMP-1 (n = 70), IMP-6 (n = 43) and NDM (n = 17). Cefepime–nacubactam and aztreonam–nacubactam exhibited potent antibacterial activity against CRE isolates with MIC_50/90 of 1/4 and 0.5/2 mg/L, respectively. Cefepime–nacubactam and aztreonam–nacubactam demonstrated potent activity against CPE, with MIC_50/90 of 2/4 and 0.5/2 mg/L, respectively, which were lower than those for ceftazidime–avibactam (64/>64 mg/L) and imipenem–relebactam (2/16 mg/L). Both combinations exhibited potent antibacterial activity against non-carbapenemase-producing carbapenem-resistant Enterobacterales (non-CP-CRE), with MIC_50/90 of 0.25/4 and 0.5/4 mg/L, respectively. Conclusions: Cefepime–nacubactam and aztreonam–nacubactam have excellent antibacterial activities against CPE and non-CP-CRE, supporting their potential as therapeutic options for CRE infections.