Cefiderocol is an effective topical monotherapy for experimental extensively-drug resistantPseudomonas aeruginosakeratitis

Abstract

ABSTRACTPurposeTo test cefiderocol, a siderophore-cephalosporin antibiotic for topical monotherapy treatment of experimental extensively drug resistant (XDR)Pseudomonas aeruginosakeratitis.DesignPreclinical study.Subjects and ControlsDeidentifiedP. aeruginosakeratitis isolates, XDRP. aeruginosafrom eye drop outbreak, rabbits, saline, cefiderocol 50 mg/ml, ciprofloxacin 0.3%, and tobramycin 14 mg/ml.Methods, Intervention, or TestingCefiderocol antibacterial activity againstP. aeruginosakeratitis isolates (n=135) was evaluated by minimum inhibitory concentration (MIC) testing. Ocular toxicity/tolerability and antibacterial efficacy were testedin vivowith experimental rabbit models. Corneal concentrations and stability were assessed using a bioassay.Main Outcome MeasuresMIC analysis for susceptibility, graded tests for ocular toxicity/tolerability, CFU analysis for bacterial burden, corneal cefiderocol concentrations.Results100% ofP. aeruginosakeratitis isolates were susceptible to cefiderocol (n=135), the MIC90was 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 XDRP. aeruginosaisolate, topical cefiderocol 50 mg/ml, significantly decreased corneal CFU compared to 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 191x greater than the MIC90of theP. aeruginosakeratitis isolates. Refrigerated cefiderocol maintained antimicrobial activity over a one-month period.ConclusionsThese results demonstrate that cefiderocol is well tolerated on rabbit corneas and is effective againstP. aeruginosakeratitis isolatesin vitroand was effectivein vivoagainst an XDR isolate in a rabbit keratitis model. Given the recent outbreak of keratitis caused by this XDRP. aeruginosa, cefiderocol is a promising additional antibiotic that should be further evaluated for topical treatment of keratitis caused by antibiotic resistantP. aeruginosa.