2025/11/20 by Marion Dutkiewicz, Agnès B. Jousset, Agnès B Jousset +7
Biochemistry, Genetics and Molecular Biology · Medicine · #Antibiotic Resistance in Bacteria #Antibiotics Pharmacokinetics and Efficacy #Infections and bacterial resistance
paper · doi:10.1093/jac/dkaf440
BACKGROUND AND OBJECTIVES: Carbapenemase-producing Enterobacterales (CPE) are a public health concern. Developing novel antibiotics, particularly combinations of β-lactam/β-lactamase inhibitors active against carbapenemases, is critical. Three recent combinations, cefepime-enmetazobactam, cefepime-taniborbactam and cefepime-zidebactam, are among the most promising. To assess the in vitro activity of these three combinations against a collection of recent CPE clinical isolates and to analyse resistance patterns. METHODS: MICs were determined for 1600 CPE isolates collected over 6-month period in 2024 at the French National Reference Centre for Antimicrobial Resistance. All isolates were fully characterized by whole-genome sequencing. RESULTS: Among KPC producers, cefepime-enmetazobactam susceptibility was 54%, with higher MICs in Klebsiella pneumoniae ST-307, ST-101 and ST-258. It was active against 90% of OXA-48-like producers and resistance was primarily observed in Citrobacter freundii ST-22 and K. pneumoniae ST-2096.Cefepime-taniborbactam showed excellent activity against KPC- (100%), OXA-48-like (95%), and VIM producers (98%), but lower efficacy (76%) against NDM producers. Resistance was mainly found in NDM-5 producers, especially E. coli ST-140, ST-167, and K. pneumoniae ST-147. All resistant E. coli displayed a 4-amino-acid insertion in PBP3.Cefepime-zidebactam exhibited strong activity towards all CPE types; regarding MBLs, its low MIC values were comparable to aztreonam-avibactam and lower than cefiderocol. Resistant isolates were mostly clonal NDM-14-producing K. pneumoniae ST-147. No cross-resistance, including with aztreonam-avibactam, was observed. CONCLUSIONS: This study support the use of cefepime-enmetazobactam against ESBL/OXA-48-like co-producers. Cefepime-taniborbactam may be use against KPC and VIM producers and could represent a second-line option for NDM. Cefepime-zidebactam shows the most promising activity against MBLs, although already emerging resistance calls for caution.