Cefiderocol activity against planktonic and biofilm forms of β-lactamase-producing pseudomonas aeruginosa from people with cystic fibrosis

Objectives: Chronic Pseudomonas aeruginosa infections are a leading cause of acute pulmonary exacerbations in people with cystic fibrosis (pwCF). Intrinsic antibiotic resistance and biofilm formation complicate treatment. This study investigates the genomic diversity and cefiderocol efficacy against planktonic and biofilm-associated forms of P. aeruginosa isolates from pwCF. Methods: Eight P. aeruginosa clinical isolates and three laboratory strains underwent whole genome sequencing (WGS). Biofilm formation was assessed through biomass, cell count, metabolic activity, and extracellular DNA (eDNA). The minimum bactericidal concentration (MBC90) and biofilm eradication concentration (MBEC90) were also determined. Results: WGS revealed significant genomic diversity, identifying ten distinct sequence types (STs). Antibiotic susceptibility testing (AST) showed that 10/11 strains were susceptible to cefiderocol, with one isolate (MPA9) displaying resistance linked to the blaOXA486 gene. Adding the β-lactamase inhibitor avibactam (AVI) restored susceptibility in this resistant strain. Although iron metabolism genes were highly conserved across isolates, MPA9 lacked the fpvA iron receptor, potentially contributing to cefiderocol resistance. Biofilm formation significantly increased tolerance to cefiderocol, with an 8-fold rise in MBEC90 compared to MBC90. Conclusion: These findings highlight the genomic diversity and adaptive potential of P. aeruginosa in pwCF. Cefiderocol shows promise against planktonic and biofilm-associated P. aeruginosa, and combining it with AVI may counteract β-lactamase-mediated resistance.