Efficacy of new antimicrobial agents against carbapenemase-producing and non-carbapenemase-producing carbapenem-resistant Enterobacterales in Japan: national genomic surveillance (JARBS 2.0) study.

Abstract

Background: Integrated genomic and phenotypic surveillance is essential to address the global spread of antimicrobial resistance. Conventional surveillance systems monitor resistance to established agents but often lack susceptibility data for newly developed antimicrobials, limiting evidence-based treatment selection.

Objectives: To characterize the genomic epidemiology and antimicrobial susceptibility of Enterobacterales with reduced meropenem susceptibility in Japan using the upgraded Japan Antimicrobial Resistant Bacterial Surveillance system (JARBS 2.0).

Methods: In 2023, 873 Enterobacterales isolates with reduced meropenem susceptibility were collected from 82 hospitals and subjected to whole-genome sequencing. Standardized quantitative susceptibility testing, including seven recently developed antimicrobial agents (particularly nacubactam-based combinations under regulatory review), was performed for carbapenemase-producing Enterobacterales (CPE) and non-carbapenemase-producing carbapenem-resistant Enterobacterales (non-CP CRE).

Results: Carbapenemase genes were detected in 101 isolates (11.6%), predominantly blaIMP (85%) and blaNDM (9%), demonstrating the predominance of metallo-β-lactamases (MBLs) in Japan. Among MBL producers, susceptibility rates were ≥96% for cefiderocol, cefepime/nacubactam, aztreonam/nacubactam, and aztreonam/avibactam. Among non-CP CRE isolates, only cefepime/nacubactam maintained similarly high activity. Notably, 13% of carbapenemase-producing isolates remained phenotypically susceptible to meropenem (MIC ≤1 mg/L), representing "stealth" MBL carriers.

Conclusions: Nacubactam-based combinations, cefiderocol and aztreonam/avibactam show promise against MBL-producing Enterobacterales in Japan, whereas cefepime/nacubactam demonstrated the greatest activity against non-CP CRE. The upgraded JARBS 2.0 framework enables high-resolution genomic and phenotypic surveillance, bridging the gap between molecular resistance mechanisms and the clinical efficacy of emerging antimicrobial agents. These findings highlight the value of integrating genomic surveillance into routine monitoring to guide antimicrobial therapy and inform infection prevention and control strategies.