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2018 Agenda and Abstracts | < Previous Next >

2018 OMIG Abstract

Development of a Novel Ophthalmic Antibiotic

R. A. F. Wozniak1,3, M. Chojnacki2, A. Philbrick2 and P. D. Dunman2,3
1Department of Ophthalmology, University of Rochester School of Medicine and Dentistry,
2Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry,
and 3Arcum Therapeutics, Rochester, New York


Purpose: Bacterial infectious keratitis is responsible for 2 million annual cases of blindness worldwide causing rapid, vision-threatening tissue destruction requiring immediate antibacterial treatment. While topically administered broad-spectrum fourth generation fluoroquinolones, such as moxifloxacin, have been a therapeutic mainstay, the emergence of resistant isolates has necessitated the development of new therapeutic options. Accordingly, we developed and characterized the in vitro and in vivo antimicrobial performance of a novel ophthalmic antibiotic drug combination, polymyxin B/trimethoprim (PT) + rifampicin against Staphylococcus aureus and Pseudomonas aeruginosa, two of the most common etiologies of bacterial keratitis.

Methods: The Selleck library of 853 FDA-approved drugs was screened to identify agents that potentiate the activity of PT against P. aeruginosa and S. aureus. Fractional Inhibition Concentration (FIC) testing was utilized to demonstrate synergistic activity of PT + rifampicin in combination against standard laboratory strains as well as a diverse panel of clinical isolates. Antimicrobial activity was assessed in both planktonic cultures and against biofilm-associated cells and resistance frequencies measured. PT + rifampicin was then evaluated in anin vivo murine model of bacterial keratitis.

Results: Of 16 potential compounds identified with potential additive or synergistic activity with PT, rifampicin was selected for further study. FIC studies revealed improved activity of PT + rifampicin compared to either compound in isolation, and this activity extended to a diverse panel of P. aeruginosa and S. aureus keratitis clinical isolates. PT + rifampicin demonstrated rapid bactericidal activity against both planktonic and biofilm-associated cells comparable or superior to moxifloxacin, and a reduced propensity to develop resistance. In a murine model of corneal infection PT + rifampicin demonstrated superiority in comparison to commercially available antimicrobials.

Conclusion: In an era of increasing antibiotic resistance, particularly among fluoroquinolones, this data suggests that the topical combination of rifampicin and PT may represent a much needed and promising alternative for the treatment of bacterial keratitis.

Disclosure: O, S

Support: American Society of Cataract and Refractive Surgery Foundation award, Research to Prevent Blindness unrestricted departmental grant (R.W.) and University of Rochester Technology Development Fund Award (P.D. and R.W.)


2018 Agenda and Abstracts | < Previous Next >