Enhanced Efficacy of Cefiderocol With PolyTrim Combination Therapy in a Rabbit Model of Extensively Drug-Resistant <i>Pseudomonas aeruginosa</i> Keratitis

Purpose: The 2023 Pseudomonas aeruginosa keratitis outbreak linked to contaminated artificial tears underscored the need for new therapies against extensively drug-resistant ocular pathogens. In vitro data suggested additive or synergistic activity between the siderophore-cephalosporin cefiderocol (FDC) and either moxifloxacin (MOX) or polymyxin B sulfate (PB). Here, we tested whether combining FDC with the commercial formulations of MOX (0.5%) or PolyTrim (PT; PB 10,000 U/mL + trimethoprim 0.1%) improved in vivo outcomes. Methods: New Zealand White rabbits were injected intrastromally with 5000 CFU of Pseudomonas aeruginosa strain CDC1270. After 16 hours, established infections were treated every 30 minutes for 8 hours with FDC, followed 5 minutes later by MOX or PT. Additional groups received monotherapies or saline. Bacterial burden (CFU/cornea) and anterior chamber cultures were determined, and ocular inflammation was assessed. Results: FDC + MOX reduced bacterial burden by 2.8 log10 CFU, outperforming FDC and MOX monotherapies, although no eyes were sterilized. PT monotherapy produced a significant 3.2 log10 reduction in CFU. The FDC + PT combination yielded the most potent activity, with almost 6.9 log10 reduction and sterilization of 10 of 12 corneas. Notably, anterior chamber invasion occurred in saline and MOX groups but in none of the FDC-containing groups, and perforations were absent in all FDC and PT treatments. Conclusions: FDC + PT was superior to monotherapies and to FDC + MOX, achieving frequent sterilization and preventing intraocular spread and corneal perforations. These data support PT alone or in combination with FDC as promising therapeutic candidates for the treatment of XDR P. aeruginosa keratitis.