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Published on: July 2, 2013
Cefiderocol Is an Effective Topical Monotherapy for Experimental Extensively Drug-Resistant Pseudomonas aeruginosa
Eric G Romanowski1, Sonya M Mumper1, Hazel Q Shanks1
1Charles T. Campbell Laboratory of Ophthalmic Microbiology, Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Purpose:
To test cefiderocol, a siderophore-cephalosporin antibiotic for topical monotherapy treatment of experimental extensively drug-resistant (XDR) Pseudomonas aeruginosa keratitis.
Design:
Preclinical study.
Subjects And Controls:
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.
Methods Intervention Or Testing:
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 in vivo with experimental rabbit models. Corneal concentrations and stability were assessed using a bioassay.
Main Outcome Measures:
Minimum inhibitory concentration analysis for susceptibility, graded tests for ocular toxicity/tolerability, colony-forming unit (CFU) analysis for bacterial burden, corneal cefiderocol concentrations.
Results:
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.
Conclusions:
These results demonstrate that cefiderocol is well tolerated on rabbit corneas and is effective against P. aeruginosa keratitis isolates in vitro and was effective in vivo 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.
Financial Disclosures:
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Insights
Cefiderocol, an antibiotic, effectively treated drug-resistant Pseudomonas aeruginosa keratitis in rabbit models with minimal ocular toxicity. This promising topical treatment warrants further investigation for bacterial keratitis.
Area of Science:
- Ophthalmology
- Infectious Diseases
- Pharmacology
Background:
- Antibiotic resistance in Pseudomonas aeruginosa poses a significant threat to ocular health.
- Extensively drug-resistant (XDR) P. aeruginosa strains are increasingly implicated in severe keratitis cases.
- Novel therapeutic strategies are crucial for managing resistant bacterial keratitis.
Purpose of the Study:
- To evaluate the efficacy and safety of topical cefiderocol monotherapy for experimental Pseudomonas aeruginosa keratitis.
- To assess cefiderocol's activity against clinical isolates of P. aeruginosa, including XDR strains.
- To determine cefiderocol's ocular tolerability and corneal penetration in a rabbit model.
Main Methods:
- In vitro susceptibility testing (MIC) of P. aeruginosa isolates against cefiderocol.
- In vivo efficacy studies using experimental rabbit keratitis models infected with XDR P. aeruginosa.
- Assessment of ocular toxicity, corneal bacterial burden (CFU), and cefiderocol concentrations in corneal tissue.
Main Results:
- All P. aeruginosa isolates (n=135) were susceptible to cefiderocol, with MIC90 of 0.125 μg/ml.
- Topical cefiderocol (50 mg/ml) demonstrated significant reduction in corneal CFU compared to controls and other antibiotics.
- Cefiderocol exhibited minimal ocular toxicity and good tolerability in rabbit corneas.
- Achieved mean corneal cefiderocol concentrations were substantially higher than the MIC90.
Conclusions:
- Topical cefiderocol is well-tolerated and effective against P. aeruginosa keratitis in preclinical models.
- Cefiderocol shows significant potential as a therapeutic option for antibiotic-resistant P. aeruginosa keratitis.
- Further clinical evaluation is warranted for cefiderocol in treating resistant bacterial keratitis.
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