Antifungal activity of Propranolol against Fusarium keratitis isolates from the Mycotic Ulcer Treatment Trial (MUTT) and the United States.

Abstract

SYNOPSISO_ST_ABSBackgroundC_ST_ABSFusarium keratitis is an infection of the cornea that often results in corneal perforation requiring corneal transplantation even with topical ocular antifungal therapy. The polyene natamycin remains the current antifungal of choice for Fusarium keratitis, but prompt sterilization of the cornea is often not achieved with contemporary therapy. Recently, natamycin synergy with the beta-adrenergic antagonist timolol against Fusarium species was reported. ObjectiveOur objective in this study was to characterize the in vitro antifungal effects of additional beta-adrenergic antagonists alone or in combination with natamycin on Fusarium keratitis isolates from the Mycotic Ulcer Treatment Trial (MUTT) and USA. MethodsMicrobroth dilution assays were used to determine the minimal inhibitory concentration (MIC) of beta-adrenergic antagonists against 18 Fusarium spp. keratitis (10 from MUTT, 8 from USA) and 3 Aspergillus fumigatus isolates. The fractional inhibitory concentration index (FICI) was calculated to assess interactions with natamycin. ResultsMost beta-blockers did not show antifungal activity or synergy with natamycin with the exception of propranolol. A racemic mix of propranolol had fungicidal activity with MIC between 31 and 83 g/mL for the Fusarium isolates. The MIC of the less cardioactive R enantiomer was lower (27-83 g/mL) than the MIC of the S enantiomer (42-104 g/mL). The MICs of both propranolol and natamycin were lower in combination but were not synergistic. The MIC of propranolol was 156 g/mL for the A. fumigatus isolates. ConclusionsPropranolol has intrinsic in vitro fungicidal activity and lowers the MIC of natamycin. Both the R and S enantiomers of propranolol had antifungal activity with the MIC modestly but significantly lower for R-propranolol. These findings have relevance both for the treatment of fungal keratitis and of glaucoma in the setting of fungal keratitis. Further study of propranolols antifungal activity may lead to a novel treatment for fungal keratitis and possibly other fungal infections. Trial RegistrationClinicalTrials.gov Identifier: NCT00997035 (MUTT Trial)