We propose to evaluate which topical agent, voriconazole or natamycin, is the superior treatment for fungal keratitis in a randomized, masked, controlled trial. Historically, fungal keratitis has been endemic in warm climates such as India and has been relatively uncommon in temperate regions of the United States. For example, in settings such as South India as many as 50% of infectious ulcers are fungal, while they made up about 8% of infectious ulcers seen at the Proctor Foundation at UCSF prior to 2005. However, in 2006, there was an epidemic of keratitis due to Fusarium spp in the U.S. and Asia, and there was heightened concern about how to best care for these patients. Although the peak of the epidemic has subsided, the concern over the best way to care for fungal keratitis patients remains. Fungal ulcers tend to have very poor outcomes with the commonly used treatments, natamycin and amphotericin B. There has been only a single randomized trial of anti-fungal therapy for mycotic keratitis, and no new ocular anti-fungal medications have been approved by the FDA since the 1960s. Our preliminary studies indicate that the newer triazoles are more effective than natamycin in vitro against filamentous fungi such as Fusarium and Aspergillus spp, the most common causes of fungal keratitis worldwide. We also found that although most cornea specialists indicate that voriconazole would be their preferred treatment, their actual practice often differs because of the lack of evidence supporting the newer anti-fungals. In this study, we will enroll patients with fungal ulcers at the Aravind Eye Hospital in South India and at the Proctor Foundation, UCSF. Research Question: Which topical agent, voriconazole or natamycin, is more effective in the treatment of filamentous fungal corneal ulcers? Specific Aims: 1) To determine which topical anti-fungal treatment, voriconazole or natamycin, results in better visual acuity. 2) To determine which agent, voriconazole or natamycin, results in better clinical outcomes for subgroups of organisms. 3) To determine whether there is a correlation between antifungal susceptibility and clinical outcomes in fungal keratitis. Fungal corneal ulcers are an important cause of blindness worldwide, especially in warmer climates such as in India. Currently, we do not have an evidence basis for their treatment and outcomes are poor. From in vitro studies and case reports, voriconazole may be a promising new treatment option, but there is not sufficient evidence to advocate its use over natamycin. This trial will aim to generate information to help physicians tailor their treatment of fungal ulcers in an evidence-based manner.

National Institute of Health (NIH)
National Eye Institute (NEI)
Cooperative Clinical Research--Cooperative Agreements (U10)
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Special Emphasis Panel (ZEY1-VSN (09))
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Everett, Donald F
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Oldenburg, Catherine E; Venkatesh Prajna, N; Krishnan, Tiruvengada et al. (2018) Regression Discontinuity and Randomized Controlled Trial Estimates: An Application to The Mycotic Ulcer Treatment Trials. Ophthalmic Epidemiol 25:315-322
Prajna, N Venkatesh; Krishnan, Tiruvengada; Rajaraman, Revathi et al. (2017) Predictors of Corneal Perforation or Need for Therapeutic Keratoplasty in Severe Fungal Keratitis: A Secondary Analysis of the Mycotic Ulcer Treatment Trial II. JAMA Ophthalmol 135:987-991
Ray, Kathryn J; Lalitha, Prajna; Prajna, N Venkatesh et al. (2017) The Utility of Repeat Culture in Fungal Corneal Ulcer Management: A Secondary Analysis of the MUTT-I Randomized Clinical Trial. Am J Ophthalmol 178:157-162
Oldenburg, Catherine E; Prajna, N Venkatesh; Amza, Abdou et al. (2017) Evolution of Practice Patterns for the Treatment of Fungal Keratitis. JAMA Ophthalmol 135:1448-1449
Rose-Nussbaumer, Jennifer; Prajna, N Venkatesh; Krishnan, Tiruvengada et al. (2016) Risk factors for low vision related functioning in the Mycotic Ulcer Treatment Trial: a randomised trial comparing natamycin with voriconazole. Br J Ophthalmol 100:929-932
Prajna, N Venkatesh; Lalitha, Prajna; Rajaraman, Revathi et al. (2016) Changing Azole Resistance: A Secondary Analysis of the MUTT I Randomized Clinical Trial. JAMA Ophthalmol 134:693-6
Sun, Catherine Q; Prajna, N Venkatesh; Krishnan, Tiruvengada et al. (2016) Effect of pretreatment with antifungal agents on clinical outcomes in fungal keratitis. Clin Exp Ophthalmol 44:763-767
Prajna, N Venkatesh; Krishnan, Tiruvengada; Rajaraman, Revathi et al. (2016) Effect of Oral Voriconazole on Fungal Keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II): A Randomized Clinical Trial. JAMA Ophthalmol 134:1365-1372
Prajna, N Venkatesh; Prajna, Lalitha; O'Brien, Kieran S et al. (2015) Association of pretreatment with antifungal medication and fungal resistance in the mycotic ulcer treatment trial I. JAMA Ophthalmol 133:1210-1
Lalitha, Prajna; Prajna, Namperumalsamy V; Manoharan, Geetha et al. (2015) Trends in bacterial and fungal keratitis in South India, 2002-2012. Br J Ophthalmol 99:192-4

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