Synergistic cefiderocol-containing antibiotic combinations active against highly drug-resistant Acinetobacter baumannii patient isolates with diverse resistance mechanisms

Background Acinetobacter baumannii is a nosocomial pathogen known for rapidly developing resistance to nearly all antibiotics, including last-line agents. Cefiderocol, a novel siderophore cephalosporin, has shown in vitro activity against A. baumannii and is now used clinically, but resistance is emerging. Data on cefiderocol-based antibiotic combinations are limited. Objectives To evaluate the in vitro activity of cefiderocol alone and in combination with other antibiotics against XDR and PDR A. baumannii clinical isolates, and to explore resistance mechanisms underlying cefiderocol synergy. Methods We tested 21 XDR/PDR clinical isolates and one NDM-1-producing strain using broth microdilution and checkerboard assays with cefiderocol and 17 antibiotics, including ceftazidime/avibactam, sulbactam/durlobactam, and amikacin. Synergy was determined through checkerboard assays and calculating fractional inhibitory concentration indices (FICI). WGS was used to identify resistance genes in selected strains. Results Cefiderocol alone was active against 66.7% of strains and demonstrated synergy with ceftazidime/avibactam and sulbactam/durlobactam in 100% and 95.2% of strains, respectively, and with amikacin, doxycycline and sulbactam in over half of strains. Cefiderocol-based combinations also reduced cefiderocol MICs against an NDM-1-producing strain. WGS revealed β-lactamases and resistance determinants among both susceptible and resistant isolates. Conclusions Several cefiderocol-containing combinations show strong in vitro synergy against XDR and PDR A. baumannii. These combinations, especially cefiderocol-ceftazidime/avibactam and cefiderocol–sulbactam/durlobactam, may enhance treatment of highly resistant A. baumannii strains and warrant further clinical investigation.