Deciphering new treatment options for debilitating Fusarium keratitis

Abstract

Purpose : Fusarium keratitis is a major sight-threatening infectious disease that largely affects millions of people worldwide. Natamycin is the only US Food and Drug Association (FDA) approved antifungal and was recently listed in WHO essential medicine for fungal keratitis. However, the poor penetration issue of Natamycin to the corneal stroma, which is the usual site for fungal organisms to inhabit, and low bioavailability prompt us to investigate novel antifungal discovery.

Methods : Antifungal and cytotoxicity activities of different molecular weights of C1, a cationic polymer, were investigated in in vitro and in vivo rabbit corneal wound healing model and rabbit fungal keratitis study. A new therapeutic route of antifungal application (P1 coated contact lens) was evaluated. A novel penetration enhancer, P1 was investigated to aid antifungal infiltration into the corneal stroma by in vitro Ussing chamber system and to enhance C1 antifungal activities in an in vivo rabbit fungal keratitis study.

Results : We investigated the antifungal activity of different molecular weights of C1 and it demonstrated better antifungal activity with increasing chain length. C1 at its molecular weight of 2100 dalton showed outstanding cytotoxicity in in vitro testing on human corneal fibroblast cells and human corneal epithelial cells. It does not cause a delay in rabbit corneal wound healing model comparable with Natamycin at 0.3%. Most importantly, C1 (MW-2100) displayed similar or better antifungal properties than Natamycin in in vitro and in vivo rabbit model at 0.3%. C1 showed that they are autoclaved stable and retain antifungal activities after autoclaving. A novel therapeutic route, which is a C1 eluting contact lens was investigated for the low bioavailability of fungal drug. A therapeutic amount of drug was released within 30 minutes from a C1-coated contact lens and they were visually clear, with more than 95% light transmittance recorded at 600 nm. P1 significantly increased corneal availability of Natamycin in the porcine cornea by using Ussing chamber system and addition of P1 significantly increased the efficacy of polymer C1 in in vivo rabbit Fusarium keratitis model.

Conclusions : These results highlight that C1 (MW-2100) can be further developed for treating Fusarium keratitis. C1-coated contact lens and a permeabilizer, P1 are future hopes for solving the low bioavailability issue of the antifungal drug in the eye.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.