Genomic and Clinical Features Associated With Reduced Susceptibility to Cefiderocol and Cross-Resistance to β-Lactam/β-Lactamase Inhibitors in a Global Cohort of Pseudomonas aeruginosa.

backgroundCefiderocol retains high rates of activity against carbapenem-resistant P. aeruginosa (CRPA) and is being introduced as a last resort antibiotic in developing countries. This study assessed the clinical and genotypic characteristics associated with decreased cefiderocol susceptibility among a global collection of CRPA isolates.

methodsClinical isolates (n = 186) selected from 972 patients enrolled from 10 countries as part of the Prospective Observational Pseudomonas (POP) study were characterized by whole-genome sequencing, cefiderocol broth microdilution, and population analysis profile. We compared clinical and genomic characteristics between susceptible isolates and those with reduced cefiderocol susceptibility (defined as heteroresistant by population analysis, or intermediate or resistant using current breakpoints). A hollow fiber infection model was used to evaluate the emergence of resistance under human serum simulated cefiderocol exposures.

resultsOf the 186 isolates, 11 (5.9%) were cefiderocol nonsusceptible and 28 (15.1%) were heteroresistant using CLSI breakpoints. With EUCAST breakpoints, 20 (10.8%) were cefiderocol resistant and 20 (10.8%) were heteroresistant. Reduced susceptibility isolates were present across all geographic regions and harbored changes in PirRS-regulated siderophore receptors, AmpC β-lactamase mutations associated with decreased ceftolozane/tazobactam susceptibility, cpxS mutations, and the β-lactamases blaNDM and blaVEB. Resistance to ceftolozane/tazobactam and ceftazidime/avibactam were independently associated with reduced cefiderocol susceptibility. Cefiderocol resistance emerged in a heteroresistant, but not susceptible isolate at human simulated exposures.

conclusionsDecreased cefiderocol susceptibility is present worldwide and is not restricted to a clonal high-risk lineage. This raises concerns about the use of cefiderocol as a salvage regimen in patients with multidrug-resistant P. aeruginosa infection.