Investigation of cefiderocol resistance prevalence and resistance mechanisms in carbapenem-resistant , Germany 2019-21.

BACKGROUND

Cefiderocol, a novel siderophore cephalosporin, is a promising therapeutic option for infections caused by multidrug-resistant . We evaluated the activity of cefiderocol against carbapenem-resistant (Cr-Pa) isolates and investigated the potential mechanisms involved in resistance.

METHODS

108 CR-Pa isolates collected from patients without prior exposure to the substance were studied. MICs of cefiderocol were determined by broth microdilution using iron-depleted cation-adjusted Mueller-Hinton broth. Whole genome sequencing was performed to investigate the potential resistance mechanisms by comparing resistant and susceptible isolates and identifying unique mutations in the resistant group.

RESULTS

Of the 108 isolates, nine were resistant to cefiderocol with MIC values ranging from 4 to 32 mg/L. The genetic analysis revealed a broad spectrum of mutations in the resistant isolates associated with iron uptake systems, efflux pumps, AmpC β-lactamase and penicillin-binding proteins. The most frequently observed mutations among the resistant isolates were located in , and . Notably, the presence of carbapenemases did not correlate with cefiderocol resistance.

CONCLUSIONS

Our findings show the low prevalence of cefiderocol resistance among CR-Pa isolates, showing its potential as an effective treatment option. However, the complex genetic landscape of resistance mechanisms, particularly mutations affecting iron transport and other TonB-dependent receptors, requires continuous monitoring and functional analyses to identify and manage potential resistance mechanisms. This study provides a foundation for future research to improve antimicrobial resistance prediction and develop targeted therapies against CR-Pa.