Spanish nationwide survey of Pseudomonas aeruginosa cefiderocol antimicrobial susceptibility and resistance genomics

Abstract

Objective: Cefiderocol is a new siderophore-cephalosporin showing potent activity against Pseudomonas aeruginosa, including isolates showing extensively drug-resistant (XDR) or difficult-to-treat resistant (DTR) phenotypes. However, there is still a limited understanding of the potential resistance mechanisms. The objective of this study was to analyse the activity of cefiderocol in a nationwide Spanish survey, determine its stability against most relevant resistance mechanisms, and analyse potential drivers of resistance through whole-genome sequencing. Methods: Cefiderocol MICs were determined by broth microdilution in cation-adjusted iron-depleted Müller-Hinton broth for 1735 isolates from 66 Spanish hospitals and compared with those of a panel of 13 antipseudomonal agents. All XDR/DTR strains and those resistant to ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam or cefiderocol were subjected to whole-genome sequencing (NovaSeq, Illumina, San Diego, California, US) and bioinformatic analysis, including specific pipelines developed for the assessment of acquired resistance determinants, the mutational resistome and iron-uptake genes. Results: Cefiderocol showed the highest percentage of susceptibility (99.7%) and conserved activity (<5–10% resistance) against XDR/DTR strains and those producing carbapenemases. Only five resistant isolates were detected and the complex resistome included acquired β-lactamases or AmpC mutations along with mutations in iron-uptake systems and AmpC and/or efflux pump regulators. Novel drivers of resistance such as piuE were identified. Moreover, the production of acquired oxacillinases and mutations in ampC, mexR or piuA were statistically associated with increased MICs, whereas mutations in gyrA, parC or pvdS were associated with increased susceptibility. Conclusion: While cefiderocol shows potent activity against P. aeruginosa, active surveillance at the phenotypic and genomic level for the emergence of resistant strains should be implemented.