Mycotic Antimicrobial Localized Injection (MALIN): A Randomized Clinical Trial Evaluating Intrastromal Injection of Voriconazole

Abstract Objective To determine if there is a benefit to adjuvant intrastromal voriconazole injections (ISV) for primary treatment of filamentous fungal keratitis. Design Outcome-masked, randomized controlled clinical trial Study Participants Patients presenting with moderate vision loss from a smear-positive fungal ulcer. Intervention Study eyes were randomized to topical natamycin plus ISV versus topical natamycin alone. Main Outcome Measures The primary outcome of the trial was microbiological cure on 3-day repeat culture. Secondary outcomes included microbiological cure on 7-day repeat culture, 3 week and 3 month best spectacle-corrected visual acuity (BSCVA), infiltrate and/or scar size, rate of perforation, therapeutic penetrating keratoplasty (TPK) and other adverse events. Results A total of 151 patients with smear positive ulcers were screened and 70 were enrolled at Aravind Eye Hospital, Pondicherry. Baseline cultures grew Fusarium in 19(27%), Aspergillus in 17(24%), other filamentous fungi in 19 (27%) and were negative in 13(19%). Those randomized to ISV had 1.82 times the odds of 3-day culture positivity after controlling for baseline culture status (95% CI 0.65 to 5.23; P =0.26, bias-corrected logistic regression) and 1.98 times the odds of a positive 7 day culture, after controlling for baseline culture status (95% CI 0.69 to 5.91, P =0.20, bias-corrected logistic regression). Those randomized to ISV had 0.5 logMAR lines (approximately ½ Snellen lines) decreased visual acuity (95% CI -2.6 to 3.6; P =0.75) and 0.55 mm worse infiltrate and/or scar size at 3 month after controlling for baseline values (95% CI -0.13 to 1.25; P =0.11). ISV had 2.85-fold increased hazard of perforation after controlling for baseline infiltrate depth (95%CI 0.76 to 10.75; P =0.12) but no difference in rate of TPK (HR 0.95, 95% CI 0.44 to 2.04; P =0.90). Conclusions There appears to be no benefit to adding intrastromal voriconazole injections to topical natamycin in the primary treatment of moderate to severe filamentous fungal ulcers. Studies consistently suggest that voriconazole has a limited role in the treatment of filamentous fungal ulcers.