Cefiderocol activity against planktonic and biofilm forms of ß-lactamase-producing Pseudomonas aeruginosa from people with cystic fibrosis
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 antimicrobial resistance of clinical P. aeruginosa isolates from pwCF, focusing on cefiderocol efficacy against planktonic and biofilm-associated forms.  Whole genome sequencing (WGS) analysis was conducted on eight P. aeruginosa isolates from the sputum of pwCF, along with three laboratory strains. Biofilm was characterized by the quantitative assessment of biomass, cell count, metabolic activity, and extracellular DNA (eDNA). The reference broth microdilution method was performed to evaluate the minimum inhibitory concentration (MIC90) and the minimum biofilm eradication concentration (MBEC90) of cefiderocol.  WGS revealed significant genomic diversity among the isolates, with ten distinct sequence types (STs) identified. Antibiotic susceptibility testing (AST) demonstrated that 90.9% of the strains were susceptible to cefiderocol, though one strain (MPA9) exhibited resistance. ß-lactamase genes varied significantly among strains, with blaOXA486 identified in the cefiderocol-resistant MPA9 isolate. Adding the ß-lactamase inhibitor avibactam (AVI) restored cefiderocol susceptibility in the resistant strain. Iron metabolism genes were highly conserved across isolates, but the MPA9 isolate notably lacked the iron receptor fpvA, potentially contributing to its cefiderocol resistance profile. Biofilm phenotypic assays showed significant variability. Biofilm formation conferred increased tolerance to cefiderocol, with an 8-fold median increase in the MBEC90 compared to MIC90. This study highlights the genomic diversity and adaptive potential of P. aeruginosa in pwCF. Cefiderocol demonstrated efficacy against planktonic and biofilm-associated P. aeruginosa. Combining cefiderocol with AVI may help overcome ß-lactamase-mediated resistance, supporting its potential as a therapeutic option.