Cefiderocol Is an Effective Topical Monotherapy for Experimental Extensively Drug-Resistant Pseudomonas aeruginosa Keratitis

Abstract

To test cefiderocol, a siderophore-cephalosporin antibiotic for topical monotherapy treatment of experimental extensively drug-resistant (XDR) Pseudomonas aeruginosa keratitis. Preclinical study. Deidentified P.aeruginosa keratitis isolates, XDR P.aeruginosa from eye drop outbreak, rabbits, saline, cefiderocol 50 mg/ml, ciprofloxacin 0.3%, and tobramycin 14 mg/ml. Cefiderocol antibacterial activity against P.aeruginosa keratitis isolates (n= 135) was evaluated by minimum inhibitory concentration (MIC) testing. Ocular toxicity/tolerability and antibacterial efficacy were tested invivo with experimental rabbit models. Corneal concentrations and stability were assessed using a bioassay. Minimum inhibitory concentration analysis for susceptibility, graded tests for ocular toxicity/tolerability, colony-forming unit (CFU) analysis for bacterial burden, corneal cefiderocol concentrations. One hundred percent of P.aeruginosa keratitis isolates were susceptible to cefiderocol (n= 135), the MIC90 was 0.125 μg/ml including the XDR isolate (MIC= 0.125 μg/ml). Topical cefiderocol 50 mg/ml was minimally toxic to the ocular surface and was well tolerated. For the XDR P.aeruginosa isolate, topical cefiderocol 50 mg/ml, significantly decreased corneal CFU compared with ciprofloxacin 0.3%, tobramycin 14 mg/ml, and saline. In addition, tobramycin 14 mg/ml was more effective than the saline control. Mean cefiderocol corneal concentrations were 191× greater than the MIC90 of the P.aeruginosa keratitis isolates. Refrigerated cefiderocol maintained antimicrobial activity over a 1-month period. These results demonstrate that cefiderocol is well tolerated on rabbit corneas and is effective against P.aeruginosa keratitis isolates invitro and was effective invivo against an XDR isolate in a rabbit keratitis model. Given the recent outbreak of keratitis caused by this XDR P.aeruginosa, cefiderocol is a promising additional antibiotic that should be further evaluated for topical treatment of keratitis caused by antibiotic resistant P.aeruginosa. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.