Cefiderocol is an effective topical monotherapy for experimental extensively-drug resistant Pseudomonas aeruginosa keratitis.

Abstract

Purpose : In the spring of 2023, an outbreak of extensively drug resistant (XDR) Pseudomonas aeruginosa (PA) infections occurred in patients in the USA. Studies determined these infections originated from non-preserved, multiuse, artificial tears bought online. At least 68 patients have been infected with this XDR PA strain which has led to eight confirmed accounts of blindness, four cases of enucleation, and three deaths. The only antibiotic to which the XDR PA strain was susceptible was cefiderocol (CEF), a β-lactam which contains a novel siderophore side group. CEF mimics substrates Gram-negative bacteria require and actively absorb using iron uptake machinery. However, CEF has never been used for topical ocular therapy. The goals of this study were to evaluate CEF susceptibility of PA keratitis isolates, the ocular tolerability and toxicity of topical CEF, and the efficacy of CEF for topical monotherapy treatment of experimental XDR PA keratitis.

Methods : CEF antibacterial activity against 135 PA keratitis isolates was evaluated by minimum inhibitory concentration (MIC) testing. Ocular toxicity/tolerability of topical CEF and its antibacterial efficacy against the outbreak XDR PA strain were assessed in vivo with experimental rabbit models. Corneal concentrations and CEF stability were assessed using a bioassay.

Results : 100% of PA keratitis isolates were susceptible to CEF, the MIC₉₀ was 0.125 µg/ml including the XDR outbreak isolate (MIC = 0.125 µg/ml). Topical CEF 50 mg/ml was minimally toxic to the ocular surface and was well tolerated. For the XDR PA isolate, topical CEF 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 CEF corneal concentrations were 191x greater than the MIC₉₀ of the PA keratitis isolates. Refrigerated CEF maintained antimicrobial activity over a one-month period.

Conclusions : These results demonstrate that CEF is well tolerated on rabbit corneas and is effective against PA keratitis isolates in vitro and was effective in vivo against an XDR PA isolate in a rabbit keratitis model. Given the recent outbreak of keratitis caused by this XDR PA, CEF is a promising additional antibiotic that should be further evaluated for topical treatment of keratitis caused by antibiotic resistant PA.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.