CLINICAL SCIENCE Comparison of Oral Voriconazole Versus Oral Ketoconazole as an Adjunct to Topical Natamycin in Severe Fungal Keratitis: A Randomized Controlled Trial Namrata Sharma, MD,* Deepali Singhal, MD,* Prafulla K. Maharana, MD,* Rajesh Sinha, MD,* Tushar Agarwal, MD,* Ashish D. Upadhyay, PhD,† Thirumurthy Velpandian, PhD,‡ Gita Satpathy, MD,‡ and Jeewan S. Titiyal, MD* Purpose: To compare the efficacy of oral voriconazole (VCZ) with oral ketoconazole (KCZ) as an adjunct to topical natamycin in severe fungal keratitis. Methods: Fifty eyes of 50 patients with proven severe fungal keratitis, (.5 mm size, involving .4 mm central cornea and .50% stromal depth), smear, and/or culture positive were randomized to receive either oral VCZ (n = 25) or oral KCZ (n = 25) 200 mg twice a day. Both groups received topical natamycin along with oral medication. The primary outcome measure was best spectacle- corrected visual acuity (BSCVA) at 3 months of follow-up. Secondary outcomes were the percentage of healed cases and scar size. Results: The mean BSCVA after treatment was 1.3 6 0.35 logarithm of minimum angle of resolution units in the VCZ group and 1.6 6 0.39 logarithm of minimum angle of resolution units in the KCZ group [P = 0.004, 95% confidence interval (CI), 20.10 to 0.54]. The final mean scar size was smaller for oral VCZ than for oral KCZ (P = 0.04, 95% CI, 20.01 to 0.93 mm). The percentage of cases healed were 80% and 72% in VCZ and KCZ groups, respectively (P = 0.51, 95% CI, 20.15 to 0.31). The ratio of tear film to serum concentration of oral VCZ was better than oral KCZ at days 14 (P = 0.002) and 21 (P = 0.006). Conclusions: Although the duration and percentage of healing was similar in both groups, oral VCZ attained a significantly better tear film concentration with a smaller scar size and better BSCVA compared with oral KCZ. Thus, oral VCZ may be preferred over oral KCZ in severe fungal keratitis. Key Words: fungal keratitis, voriconazole, ketoconazole (Cornea 2017;0:1–7) T he standard medical therapy recommended for fungal keratitis is topical natamycin 5%. Although it has a broad spectrum of activity, it has poor penetration through the intact corneal epithelium. 1 Hence, systemic antifungals, as an adjunct to topical treatment, are indicated in ulcers .5 mm in size or involvement of .50% stromal depth. 2,3 The commonly used systemic antifungals are ketoconazole (KCZ), itraconazole, fluconazole, and voriconazole (VCZ). 2–5 Oral KCZ is rela- tively inexpensive and well absorbed with good tissue distribution after oral administration. In a recent trial, it was shown that oral KCZ did not add significant benefit to topical natamycin therapy in treating deep fungal keratitis involving .50% stromal depth with size varying from 2 to 60 mm 2 . 6 The in vitro susceptibility profile of VCZ has been shown to be superior to KCZ with MIC90 against Aspergillus species reported to be 0.5 mg/mL much less than that of KCZ (4 mg/mL). 7,8 Similarly, MIC90 for VCZ against Fusarium species was 2.0 mg/mL much less than that of KCZ (16 mg/mL). 7 In addition, oral VCZ has less systemic side effects compared with oral KCZ. 9,10 Recently, the MUTT 2 trial, which compared the effect of oral VCZ and oral placebo in severe filamentous fungal keratitis, concluded that there was no clinical benefit of adding oral VCZ to topical antifungal agents. But, in a subsequent subgroup analysis, a favorable response was noted in cases of severe Fusarium keratitis after addition of oral VCZ to topical natamycin. 11 We conducted a randomized controlled trial to compare the efficacy of oral VCZ with oral KCZ as an adjunct to topical natamycin in severe fungal keratitis with the hypoth- esis that the 2 drugs compared are not equal in terms of primary outcome, that is, final best spectacle-corrected visual acuity (BSCVA) at the end of 3 months. MATERIAL AND METHODS Patients were recruited from the Cornea Clinic of Dr. Rajendra Prasad Centre for Ophthalmic Sciences, a tertiary eye care hospital, from March 2014 to August 2015. Written informed consent was obtained from all participants. Institu- tional ethics committee approval was obtained from the Institutional Review Board/Ethics Committee, AIIMS, New Delhi. The research was conducted adhering to the tenets of the Declaration of Helsinki. The study has been registered Received for publication April 29, 2017; revision received July 15, 2017; accepted July 18, 2017. From the *Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India; †Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India; and ‡Department of Ocular Pharmacology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. The authors have no funding or conflicts of interest to disclose. Reprints: Namrata Sharma, MD, Department of Ophthalmology, Cornea, Cataract and Refractive Surgery Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi 110029, India (e-mail: namrata.sharma@gmail.com). Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. 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