Efficacy of natamycin monotherapy versus combination therapy with voriconazole for fungal keratitis: a randomised clinical trial

Background: To assess whether adjunctive topical voriconazole 1% offers additional benefit over natamycin 5% monotherapy in fungal keratitis, focusing on ulcer resolution, visual outcomes and safety. Methods: This prospective, double-masked, randomised clinical trial was conducted at L.V. Prasad Eye Institute, India. A total of 108 adults with smear- or culture-positive fungal keratitis were randomised 1:1 to receive either natamycin 5% plus voriconazole 1% (combination therapy) or natamycin 5% plus placebo (monotherapy). Drops were instilled hourly for 72 hours, then tapered over 2 weeks. All patients also received oral ketoconazole and cycloplegics. The primary outcome was complete ulcer resolution with medical therapy alone, defined as epithelial closure with scarring without therapeutic penetrating keratoplasty. Secondary outcomes included time to epithelial healing, best-corrected visual acuity (BCVA) and adverse events. Results: Of 94 eyes completing follow-up (mean (SD) age, 50.4 (12.4) years; 66 (70%) male), complete healing occurred in 38 of 48 eyes (79.2%) in the combination group and 35 of 46 eyes (76.1%) in the monotherapy group (absolute difference, 3.1%; 95% CI -13.2% to 19.4%; p=0.70). Median time to epithelial healing was 38 days (IQR, 20-60) for combination therapy and 39 days (IQR, 21-61) for monotherapy (p=0.86). Final mean BCVA was 0.43 logMAR (logarithm of the minimum angle of resolution) versus 0.58 logMAR, respectively (p=0.07). In non-Aspergillus cases, natamycin monotherapy yielded better visual outcomes (p=0.048). Conclusions: Adjunctive topical voriconazole did not significantly improve clinical outcomes compared with natamycin monotherapy. Natamycin 5% remains an effective first-line treatment, particularly in non-Aspergillus keratitis. Further studies are warranted to explore targeted roles for combination therapy. Trial registration number: NCT03230058.