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

Background: Cefiderocol, a novel siderophore cephalosporin, is a promising therapeutic option for infections caused by multidrug-resistant Pseudomonas aeruginosa. We evaluated the activity of cefiderocol against carbapenem-resistant P. aeruginosa (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 P. aeruginosa 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 beta-lactamase and penicillin-binding proteins. The most frequently observed mutations among the resistant isolates were located in fptA, fpvB and chtA. 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.