Defining Baseline Mechanisms of Cefiderocol Resistance in the Enterobacterales

Patricia J. Simner*, Stephan Beisken, Yehudit Bergman, Michael Ante, Andreas E. Posch, Pranita D. Tamma

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

The objective of this study was to identify putative mechanisms contributing to baseline cefiderocol resistance among carbapenem-resistant Enterobacterales (CRE). We evaluated 56 clinical CRE isolates with no previous exposure to cefiderocol. Cefiderocol and comparator agent minimum inhibitory concentrations (MICs) were determined by broth microdilution. Short-read and/or long-read whole genome sequencing was pursued. Cefiderocol nonwild type (NWT; i.e., MICs ≥4 mg/L) CRE were compared with species-specific reference genomes and with cefiderocol wild type (WT) CRE isolates to identify genes or missense mutations, potentially contributing to elevated cefiderocol MICs. A total of 14 (25%) CRE isolates met cefiderocol NWT criteria. Of the 14 NWT isolates, various β-lactamases (e.g., carbapenemases in Klebsiella pneumoniae and AmpC β-lactamases in Enterobacter cloacae complex) in combination with permeability defects were associated with a ≥ 80% positive predictive value in identifying NWT isolates. Unique mutations in the sensor kinase gene baeS were identified among NWT isolates. Cefiderocol NWT isolates were more likely to be resistant to colistin than WT isolates (29% vs. 0%). Our findings suggest that no consistent antimicrobial resistance markers contribute to baseline cefiderocol resistance in CRE isolates and, rather, cefiderocol resistance results from a combination of heterogeneous mechanisms.

Original languageAmerican English
Pages (from-to)161-170
Number of pages10
JournalMicrobial Drug Resistance
Volume28
Issue number2
DOIs
StatePublished - Feb 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© Copyright 2022, Mary Ann Liebert, Inc., publishers 2022.

Keywords

  • carbapenem-resistant Enterobacterales
  • cefiderocol
  • mechanisms of resistance

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