Title: SEVERE CORNEAL INFECTIONS: PREVENTION, DIAGNOSIS AND TREATMENT
Funder: Wellcome Trust

Abstract: Context: Blinding corneal infections (Microbial keratitis, MK), caused by bacteria or fungi, are a major ophthalmic public health problem in low and middle-income countries. There are multiple critical issues: delayed presentation, traditional eye medicine use, limited health-worker training, limited availability and efficacy of anti-fungals, diagnostic uncertainty. Eyes are lost through progressive corneal ulceration and perforation, mediated by human and pathogen-derived proteases. Proposed Research: 1. Randomised controlled trial (RCT) of topical chlorhexidine 0.2% vs. topical natamycin 5% for fungal keratitis. Pilot trials of chlorhexidine, a cheap and readily available antiseptic, suggest it might be at least as effective as natamycin (current standard). 2. RCT of topical ilomastat 0.08% vs. placebo, to reduce corneal perforation from MK. Ilomastat, a potent matrix metalloproteinase inhibitor, reduced severe ulceration in animal models and earlier human clinical trials. Full-scale treatment trials are needed for translation into practice. 3. Cluster RCT of early intervention package (topical chlorhexidine, smartphone-assisted diagnosis, treatment, referral support) vs. standard practices, to reduce blindness from MK through reducing delay between infection onset and initiating intensive treatment, with an agent covering fungi and bacteria. 4. Evaluation of diagnostic approaches for identifying causative organism in MK (clinical, automated image-analysis, confocal microsopy, PCR) and testing potential isothermal point-of-care tests.

Lay abstract: Context: Infection of the cornea (clear “window” of eye), caused by bacteria or fungi, is an important, painful cause of blindness in low and middle-income countries. There are many challenges: delayed presentation, traditional eye medicine use, limited health-worker training, limited availability and efficacy of anti-fungals, diagnostic uncertainty. Eyes are lost through progressive corneal destruction, mediated by human and pathogen-derived enzymes (proteases) that destroy tissue. Proposed Research: 1. Affordable, effective and readily available anti-fungal eye drops are needed; one possibility is a simple formulation of chlorhexidine (antiseptic). We will compare this in a trial to natamycin (current standard). 2. Treatments to stop protease-mediated corneal destruction during infection are urgently needed (no treatment at present). A medicine called ilomastat has shown promise in halting it. We will compare this to placebo eye drops in a trial, to stop holes developing in eyes. 3. Reducing delay (typically ~14 days) in patients starting effective antimicrobials is critical to preventing blindness. We will test in a cluster trial whether a combination of interventions together can achieve this. The package includes giving chlorhexidine eye drops in the community and smartphone-assisted diagnosis, treatment and referral support. 4. Evaluate which diagnostic tools are most useful in determining the type of infection.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: EYE;INFECTION