Combination Therapy of Cefiderocol and Polymyxin B Against Pseudomonas aeruginosa Keratitis Isolates In Vitro.

Purpose: Antibiotic combination therapy is commonly used for empiric treatment of microbial keratitis, a potentially blinding infection of the cornea. Pseudomonas aeruginosa (P. aeruginosa) is a major cause of severe keratitis, and the 2023 outbreak linked to artificial tears involved a strain resistant to aminoglycosides and fluoroquinolones, resulting in widespread vision loss. Despite various proposed treatments, no consensus exists for management of keratitis caused by the outbreak strain. The purpose of this study was to evaluate the efficacy of cefiderocol (FDC) combined with polymyxin B (PB) against ocular P. aeruginosa keratitis isolates, including extensively drug-resistant (XDR) strains from the 2023 artificial tear-associated outbreak. Methods: Time-kill assays and epsilometer (E-test) synergy testing were performed on a panel of keratitis isolates. Genetic analysis was conducted on mutants with reduced FDC susceptibility. Results: Time-kill assays demonstrated synergy for two XDR outbreak isolates (P < 0.05), whereas the E-test used across diverse keratitis isolates showed additive to indifferent interactions. Quorum-sensing-deficient, sheen-positive strains showed reduced responsiveness (P < 0.01). Non-antagonistic interactions were observed for Serratia marcescens (S. marcescens) and Staphylococcus aureus (S. aureus) keratitis isolates, with synergy for some S. marcescens strains. Mutants with reduced FDC susceptibility harbored mutations in baeS and fepA, yet remained responsive to the antibiotic combination. Conclusions: FDC combined with PB demonstrates promising activity against drug-resistant Gram-negative keratitis pathogens, including XDR P. aeruginosa. Translational Relevance: These findings support the further development of FDC with PB as a candidate therapy for drug-resistant ocular infections.