Cefiderocol Susceptibility in Acinetobacter baumannii Driven by Clonal Lineage, Class D ß-Lactamases, and Biofilm Formation

Acinetobacter baumannii is a critical nosocomial pathogen, particularly in immunocompromised patients, with carbapenem-resistant A. baumannii (CRAB) representing a major therapeutic challenge. Cefiderocol, a siderophore cephalosporin, offers a promising treatment option; however, factors influencing its efficacy remain underexplored. This study utilized whole-genome sequencing to analyze 25 A. baumannii isolates, identifying ten distinct sequence types (STs), with ST2 as the predominant lineage (56%), while non-ST2 (NST) isolates accounted for 44%. Antimicrobial susceptibility testing assessed cefiderocol activity across planktonic and biofilm-embedded cells. All ST2 isolates harbored blaOXA-23 in association with blaOXA-66 or blaOXA-82 and were classified as CRAB. While cefiderocol exhibited broad-spectrum activity against all isolates, ST2 strains displayed higher minimum inhibitory concentrations (MICs) than NST isolates. Notably, ST2 isolates co-harboring blaOXA-23 and blaOXA-82 showed significantly higher MICs than those carrying blaOXA-23 and blaOXA-66 alone. The addition of avibactam markedly reduced cefiderocol MICs in blaOXA-23-positive ST2 isolates, implicating class D ß-lactamases in modulating cefiderocol susceptibility. NST strains exhibited greater biofilm-forming capacity, with higher biomass and biofilm cell counts than ST2 isolates. Biofilm-embedded cells demonstrated reduced cefiderocol susceptibility, with minimum biofilm eradication concentration (MBEC90) values significantly exceeding the MIC90 of planktonic cells. These findings reveal a complex interplay between genetic resistance determinants and biofilm formation in shaping cefiderocol susceptibility in A. baumannii. The data emphasize the need for molecular surveillance to guide antimicrobial stewardship strategies and highlight the critical role of biofilm-targeted interventions in addressing persistent A. baumannii infections.