In vitro activity of cefiderocol against carbapenemase-producing and meropenem-non-susceptible Gram-negative bacteria collected in the Japan Antimicrobial Resistant Bacterial Surveillance

J Glob Antimicrob Resist. 2024 Sep:38:12-20. doi: 10.1016/j.jgar.2024.05.009. Epub 2024 May 22.

Abstract

Objectives: 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 these pathogens. Several studies have reported the in vitro activity of CFDC against isolates from Europe, the United States, and China, but the activity against carbapenem-resistant bacteria with IMP-type carbapenemase has not been extensively studied. We, therefore, studied the in vitro activities of CFDC against carbapenem-resistant bacteria with available genomic backgrounds based on whole-genome sequencing (WGS) in Japan, where the IMP-type is the predominant carbapenemase produced by Gram-negative rods.

Methods: We selected 603 isolates (528 Enterobacterales, 18 Pseudomonas aeruginosa, and 57 Acinetobacter spp.) from a collection of Gram-negative clinical isolates collected during a Japan Antimicrobial Resistance Bacterial Surveillance program and 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-non-susceptible Enterobacterales, and carbapenemase-producing nonfermentative bacteria.

Results: Among these, 97.7% of carbapenemase-producing Enterobacterales (99.2% of IMP-type carbapenemase-producing Enterobacterales), 100% of carbapenemase-producing P. aeruginosa, and 91.2% of carbapenemase-producing Acinetobacter spp. were susceptible to CFDC, showing better antimicrobial activity than the other antimicrobial agents evaluated in this study. CFDC was highly effective against class A-, B-, and D β-lactamase-harbouring isolates when compared to the other antimicrobial agents. In addition, the relationship between CFDC resistance and three genetic factors involved in resistance was discussed.

Conclusions: This is the first large-scale study to systematically demonstrate the efficacy of CFDC against IMP-type carbapenemase-producing strains with known genomic backgrounds.

Keywords: Cefiderocol; CirA; NDM; Penicillin-binding protein 3.

MeSH terms

  • Acinetobacter* / drug effects
  • Acinetobacter* / genetics
  • Acinetobacter* / isolation & purification
  • Anti-Bacterial Agents* / pharmacology
  • Azabicyclo Compounds / pharmacology
  • Bacterial Proteins* / genetics
  • Bacterial Proteins* / metabolism
  • Cefiderocol*
  • Ceftazidime / pharmacology
  • Cephalosporins* / pharmacology
  • Drug Combinations
  • Drug Resistance, Multiple, Bacterial / genetics
  • Epidemiological Monitoring
  • Gram-Negative Bacteria* / drug effects
  • Gram-Negative Bacteria* / enzymology
  • Gram-Negative Bacteria* / genetics
  • Gram-Negative Bacterial Infections / microbiology
  • Humans
  • Imipenem / pharmacology
  • Japan
  • Meropenem* / pharmacology
  • Microbial Sensitivity Tests*
  • Pseudomonas aeruginosa* / drug effects
  • Pseudomonas aeruginosa* / enzymology
  • Pseudomonas aeruginosa* / genetics
  • Tazobactam / pharmacology
  • Whole Genome Sequencing*
  • beta-Lactamases* / genetics
  • beta-Lactamases* / metabolism

Substances

  • beta-Lactamases
  • Cephalosporins
  • carbapenemase
  • Cefiderocol
  • Bacterial Proteins
  • Anti-Bacterial Agents
  • Meropenem
  • Azabicyclo Compounds
  • ceftolozane, tazobactam drug combination
  • Tazobactam
  • Drug Combinations
  • avibactam, ceftazidime drug combination
  • Imipenem
  • Ceftazidime