Development of a Novel Antimicrobial Drug Combination for the Treatment of Bacterial Keratitis - ABSTRACT Bacterial keratitis (BK) (corneal infection) is an aggressive disease, responsible for over 2 million cases of blindness annually. Healthcare concern is further exacerbated due to rising antibiotic resistance. Indeed, the 2023 US outbreak of extensively drug-resistant Pseudomonas aeruginosa from contaminated artificial tears was a stark reminder of the devastating consequences of drug-resistant corneal infections; out of 81 reported keratitis cases, 14 patients suffered permanent vision loss, 4 resulted in loss of the eye, and 4 patients died. Unfortunately, most large pharmaceutical companies have abandoned their antimicrobial drug discovery efforts in lieu of pursuing more lucrative, long-term medications. Moreover, the few entities developing antimicrobials are focused on systemic applications as opposed to alternative, ophthalmic formulations. As such there is a void in the ophthalmic antimicrobial pipeline, with no new classes of antimicrobials to market in nearly 15 years. To answer the critical need for new BK therapeutics, the central goal of this proposal is to advance the development of a novel, topical, ophthalmic antibiotic combination, polymyxin B/trimethoprim (PT) + rifampin. Through extensive screening of thousands of FDA-approved drug combinations we have identified PT + rifampin as a powerful, synergistic, broad-spectrum drug combination superior to currently available therapeutics. PT + rifampin displays rapid bacterial killing, potent anti-biofilm activity, and the ability to completely eradicate Staphylococcus aureus and P. aeruginosa infections in a murine model of keratitis, two of the most common causes of BK. Importantly, this drug combination has also been shown to completely eradicate contemporary, multi-drug resistant ocular clinical isolates. Of note, an ophthalmic formulation of polymyxin B/trimethoprim was approved by the FDA in 1988 for the treatment of conjunctivitis and rifampin is an FDA-approved systemic antibiotic that has been used for over 40 years in the treatment of tuberculosis. As such, all three components have decades-long established safety and efficacy in humans. Importantly, we have already achieved the key milestone of a pre-IND meeting with the FDA, during which a clear road map for further studies was established. Given the promise of PT + rifampin as a novel treatment for BK, we propose to pursue advance formulations with corresponding safety and efficacy studies during the R61 phase. Next, we propose to transition to the R33 phase to conduct IND-enabling studies in toxicology, pharmacokinetics, and define appropriate chemistry, manufacturing and controls (CMC). The development of new therapies for BK is well aligned to the NEI’s goals of supporting research to reduce visual impairment and the development of sight-saving treatments. We have compiled the necessary multi-disciplinary team of experts to support formulation development, perform necessary efficacy and safety studies, and guide regulatory and intellectual property strategies. As such this proposal is well poised for success to bring this exciting new technology from bench to bedside to treat this blinding disease.
