In vitro activity of cefiderocol against carbapenemase-producing and meropenem-nonsusceptible gram-negative bacteria collected in the Japan Antimicrobial Resistant Bacterial Surveillance (JARBS-GNR)

The treatment options available for infections caused by multidrug-resistant gram-negative pathogens are often limited. Cefiderocol (CFDC) is a novel siderophore cephalosporin that exhibits activity against multidrug-resistant gram-negative pathogens. Several studies have reported the in vitro activity of CFDC using clinical isolates from Europe, the United States, and China. However, no large-scale studies on the in vitro activities of CFDC have been conducted using all isolates with available genomic backgrounds based on whole-genome sequencing (WGS). We evaluated the antimicrobial activities of CFDC, ceftolozane/tazobactam (CTLZ/TAZ), imipenem-relebactam (IPM/REL), and ceftazidime/avibactam (CAZ/AVI) against carbapenemase-producing Enterobacterales, carbapenemase-non-producing meropenem-nonsusceptible Enterobacterales, and carbapenemase-producing non-fermentative bacteria. We selected 603 isolates (528 Enterobacterales, 18 Pseudomonas aeruginosa , and 57 Acinetobacter spp.) from the recent surveillance of clinical isolates in Japan using WGS data. Among these, 97.7% (300/307 strains) of carbapenemase-producing Enterobacterales, 100% (18/18 strains) of carbapenemase-producing P. aeruginosa , and 91.2% (52/57 strains) of carbapenemase-producing Acinetobacter spp. were susceptible to CFDC, showing better antimicrobial activity than the other antimicrobial agents evaluated in this study. In addition, CFDC was highly effective against class A, B, and D β-lactamase harboring isolates when compared to the other antimicrobial agents in this study. While β-lactam antibiotics were essentially ineffective against CFDC-resistant Enterobacterales, minocycline was the most effective, and gentamicin and amikacin were also effective. This is the first large-scale study to systematically demonstrate the efficacy of CFDC using carbapenemase-producing strains with transparent genomic backgrounds.