ABSTRACT
Bacterial keratitis causes significant blindness, yet antimicrobial resistance has rendered current treatments ineffective. Polymyxin B-trimethoprim (PT) plus rifampin has potent in vitro activity against Staphylococcus aureus and Pseudomonas aeruginosa, two important causes of keratitis. Here we further characterize this combination against P. aeruginosa in a murine keratitis model. PT plus rifampin performed comparably to or better than moxifloxacin, the gold standard, suggesting that the combination may be a promising therapy for bacterial keratitis.
Subject(s)
Anti-Bacterial Agents/pharmacology , Eye Infections, Bacterial/drug therapy , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/drug effects , Animals , Cornea/drug effects , Cornea/microbiology , Drug Resistance, Multiple, Bacterial/drug effects , Drug Therapy, Combination/methods , Eye Infections, Bacterial/microbiology , Female , Keratitis/drug therapy , Keratitis/microbiology , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests/methods , Polymyxin B/pharmacology , Rifampin/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/drug effects , Trimethoprim/pharmacologyABSTRACT
Staphylococcus aureus and Pseudomonas aeruginosa are two of the most common causes of bacterial keratitis and corresponding corneal blindness. Accordingly, such infections are predominantly treated with broad-spectrum fluoroquinolones, such as moxifloxacin. Yet, the rising fluoroquinolone resistance has necessitated the development of alternative therapeutic options. Herein, we describe the development of a polymyxin B-trimethoprim (PT) ophthalmic formulation containing the antibiotic rifampin, which exhibits synergistic antimicrobial activity toward a panel of contemporary ocular clinical S. aureus and P. aeruginosa isolates, low spontaneous resistance frequency, and in vitro bactericidal kinetics and antibiofilm activities equaling or exceeding the antimicrobial properties of moxifloxacin. The PT plus rifampin combination also demonstrated increased efficacy in comparison to those of either commercial PT or moxifloxacin in a murine keratitis model of infection, resulting in bacterial clearance of 70% in the animals treated. These results suggest that the combination of PT and rifampin may represent a novel antimicrobial agent in the treatment of bacterial keratitis.
