Effect of Oral Voriconazole on Fungal Keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II)

The Mycotic Ulcer Treatment Trial (MUTT) was a randomized, active comparator–controlled, double-masked, clinical trial carried out in South India to determine whether topical treatment with natamycin gave better clinical and microbiological outcomes than voriconazole in patients with smear-positive filamentous fungal keratitis and visual acuity of 20/40 to 20/400. Treatments were applied topically every hour while awake until reepithelialization, then 4 times daily for at least 3 weeks. The study showed that natamycin treatment was associated with significantly better clinical and microbiological outcomes than voriconazole treatment for smear-positive filamentous fungal keratitis, with much of the difference attributed to improved results in Fusarium cases.

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

10.1101/2021.01.19.427292 ◽

2021 ◽

Author(s):

Ruina Bao ◽

Brandon S. Ross ◽

Cecilia G. Perez ◽

Galini Poimenidou ◽

N. Venkatesh Prajna ◽

...

Keyword(s):

Antifungal Activity ◽

Fungicidal Activity ◽

Inhibitory Concentration ◽

The United States ◽

Fungal Keratitis ◽

Treatment Trial ◽

Beta Adrenergic ◽

Adrenergic Antagonists ◽

Ulcer Treatment

SYNOPSISBackgroundFusarium 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 μg/mL for the Fusarium isolates. The MIC of the less cardioactive R enantiomer was lower (27-83 μg/mL) than the MIC of the S enantiomer (42-104 μg/mL). The MICs of both propranolol and natamycin were lower in combination but were not synergistic. The MIC of propranolol was 156 μg/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 propranolol’s antifungal activity may lead to a novel treatment for fungal keratitis and possibly other fungal infections.Trial RegistrationClinicalTrials.gov Identifier: NCT00997035 (MUTT Trial)

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