Defining Baseline Mechanisms of Cefiderocol Resistance in the Enterobacterales

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>i.e.,</i> 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 (<i>e.g.,</i> carbapenemases in <i>Klebsiella pneumoniae</i> and AmpC β-lactamases in <i>Enterobacter cloacae</i> 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 <i>baeS</i> 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.