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Objective-To conduct a therapeutic exploratory clinical trial comparing clinical outcomes of treatment with topical natamycin vs topical voriconazole for fungal keratitis.Methods-The multicenter, double-masked, clinical trial included 120 patients with fungal keratitis at Aravind Eye Hospital in India who were randomized to receive either topical natamycin or topical voriconazole and either had repeated scraping of the epithelium or not.Main Outcome Measures-The primary outcome was best spectacle-corrected visual acuity (BSCVA) at 3 months. Other outcomes included scar size, perforations, and a sub-analysis of BSCVA at 3 months in patients with an enrollment visual acuity of 20/40 to 20/400.Results-Compared with those who received natamycin, voriconazole-treated patients had an approximately 1-line improvement in BSCVA at 3 months after adjusting for scraping in a multivariate regression model but the difference was not statistically significant (P=.29). Scar size at 3 months was slightly greater with voriconazole after adjusting for scraping (P=.48). Corneal perforations in the voriconazole group (10 of 60 patients) were not significantly different than in the natamycin-treated group (9 of 60 patients) (P>.99). Scraping was associated with worse BSCVA at 3 months after adjusting for drug (P=.06). Patients with baseline BSCVA of 20/40 to 20/400 showed a trend toward a 2-line improvement in visual acuity with voriconazole (P=.07).Conclusions-Overall, there were no significant differences in visual acuity, scar size, and perforations between voriconazole-and natamycin-treated patients. There was a trend toward scraping being associated with worse outcomes.

for the Mycotic Ulcer Treatment Trial II Group OBJECTIVE To compare oral voriconazole with placebo in addition to topical antifungals in the treatment of filamentous fungal keratitis. DESIGN, SETTING, AND PARTICIPANTSThe Mycotic Ulcer Treatment Trial II (MUTT II), a multicenter, double-masked, placebo-controlled, randomized clinical trial, was conducted in India and Nepal, with 2133 individuals screened for inclusion. Patients with smear-positive filamentous fungal ulcers and visual acuity of 20/400 (logMAR 1.3) or worse were randomized to receive oral voriconazole vs oral placebo; all participants received topical antifungal eyedrops. The study was conducted from May 24, 2010, to November 23, 2015. All trial end points were analyzed on an intent-to-treat basis.INTERVENTIONS Study participants were randomized to receive oral voriconazole vs oral placebo; a voriconazole loading dose of 400 mg was administered twice daily for 24 hours, followed by a maintenance dose of 200 mg twice daily for 20 days, with dosing altered to weight based during the trial. All participants received topical voriconazole, 1%, and natamycin, 5%. MAIN OUTCOMES AND MEASURESThe primary outcome of the trial was rate of corneal perforation or the need for therapeutic penetrating keratoplasty (TPK) within 3 months. Secondary outcomes included microbiologic cure at 6 days, rate of re-epithelialization, best-corrected visual acuity and infiltrate and/or scar size at 3 weeks and 3 months, and complication rates associated with voriconazole use.RESULTS A total of 2133 patients in India and Nepal with smear-positive ulcers were screened; of the 787 who were eligible, 240 (30.5%) were enrolled. Of the 119 patients (49.6%) in the oral voriconazole treatment group, 65 were male (54.6%), and the median age was 54 years (interquartile range, 42-62 years). Overall, no difference in the rate of corneal perforation or the need for TPK was determined for oral voriconazole vs placebo (hazard ratio, 0.82; 95% CI, 0.57-1.18; P = .29). In prespecified subgroup analyses comparing treatment effects among organism subgroups, there was some suggestion that Fusarium species might have a decreased rate of perforation or TPK in the oral voriconazole-treated arm; however, this was not a statistically significant finding after Holms-Šidák correction for multiple comparisons (effect coefficient, 0.49; 95% CI, 0.26-0.92; P = .03). Patients receiving oral voriconazole experienced a total of 58 adverse events (48.7%) compared with 28 adverse events (23.1%) in the placebo group (P < .001 after Holms-Šidák correction for multiple comparisons). CONCLUSIONS AND RELEVANCEThere appears to be no benefit to adding oral voriconazole to topical antifungal agents in the treatment of severe filamentous fungal ulcers. All patients in this study were enrolled in India and Nepal; therefore, it is possible that organisms in this region may exhibit characteristics different from those in other regions of the world. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00996736

Targeted delivery of voriconazole by intrastromal injection (50 µg/0.1 mL) is a safe and effective way to treat deep recalcitrant fungal keratitis, though some may need repeated injections. Fusarium keratitis may show suboptimal response but this needs further study.

Purpose To analyze the minimum inhibitory concentration (MIC) of isolates from fungal keratitis to natamycin and voriconazole, and to assess the relationship between organism, MIC, and clinical outcome. Methods Data were collected as part of a randomized, controlled, double-masked clinical trial. Main outcome measures included best spectacle-corrected visual acuity (BSCVA), infiltrate/scar size, time to re-epithelialization, and perforation. Speciation and analysis of MIC to natamycin and voriconazole was done according to NCCLS standards. The relationship between MIC and organism, organism and outcome measure, and each outcome measure and MIC was assessed. Results Of 120 samples obtained in the trial, 84 isolates had an identifiable organism and were available for further analyses. Fusarium spp and Aspergillus spp were the most commonly-isolated organisms. MIC was significantly different across the groups of organisms (P=0.0001). A higher MIC was significantly associated with an increased likelihood of perforation (OR 2.03, 95%CI 1.02 to 4.04, P=0.04). There was no significant association between MIC and 3-week visual acuity (0.058, 95%CI -0.01 to 0.13, P=0.11), 3-month visual acuity (0.01, 95%CI -0.08 to 1.04, P=0.79), 3-week infiltrate/scar size (0.12, 95% CI -0.02 to 0.27, P=0.10), 3-month infiltrate/scar size (0.12, 95%CI -0.02 to 0.25, P=0.09), or time to re-epithelialization (HR 1.19, 95%CI 0.98 to 1.45, P=0.08). Conclusion A higher MIC was associated with an increased odds of perforation. The results of this study suggest that resistance to antifungal medication may be associated with worse outcomes in fungal keratitis.