The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole

Abstract

Objective: To compare topical natamycin vs voriconazole in the treatment of filamentous fungal keratitis.

Methods: This phase 3, double-masked, multicenter trial was designed to randomize 368 patients to voriconazole (1%) or natamycin (5%), applied topically every hour while awake until reepithelialization, then 4 times daily for at least 3 weeks. Eligibility included smear-positive filamentous fungal ulcer and visual acuity of 20/40 to 20/400.

Main outcome measures: The primary outcome was best spectacle-corrected visual acuity at 3 months; secondary outcomes included corneal perforation and/or therapeutic penetrating keratoplasty.

Results: A total of 940 patients were screened and 323 were enrolled. Causative organisms included Fusarium (128 patients [40%]), Aspergillus (54 patients [17%]), and other filamentous fungi (141 patients [43%]). Natamycintreated cases had significantly better 3-month best spectacle-corrected visual acuity than voriconazole-treated cases (regression coefficient=0.18 logMAR; 95% CI, 0.30 to 0.05; P=.006). Natamycin-treated cases were less likely to have perforation or require therapeutic penetrating keratoplasty (odds ratio=0.42; 95% CI, 0.22 to 0.80; P=.009). Fusarium cases fared better with natamycin than with voriconazole (regression coefficient=0.41 logMAR; 95% CI,0.61 to 0.20; P<.001; odds ratio for perforation=0.06; 95% CI, 0.01 to 0.28; P<.001), while non-Fusarium cases fared similarly (regression coefficient=0.02 logMAR; 95% CI, 0.17 to 0.13; P=.81; odds ratio for perforation=1.08; 95% CI, 0.48 to 2.43; P=.86).

Conclusions: Natamycin treatment was associated with significantly better clinical and microbiological outcomes than voriconazole treatment for smear-positive filamentous fungal keratitis, with much of the difference attributable to improved results in Fusarium cases.

Application to clinical practice: Voriconazole should not be used as monotherapy in filamentous keratitis.

Trial registration: clinicaltrials.gov Identifier: NCT00996736

Figure 1

The CONSORT flow diagram for the Mycotic Ulcer Topical Treatment Trial I. LOCF indicates last observation carried forward as described in “Methods.”

Figure 2

Three-month best spectacle-corrected visual acuity (BSCVA) vs baseline BSCVA for patients receiving voriconazole and natamycin, with Fusarium species (A) and non-Fusarium species (B) as the causative organism. The curve is a nonparametric locally weighted scatterplot smoothing regression fit, with the shaded bands indicating ±1 estimated SD. Patients who experienced perforation or corneal transplantation prior to the 3-month observation may have excellent visual acuity despite this adverse outcome and were assigned a low-vision score of 1.7 logMAR (or the 3-week BSCVA, whichever was worse). Observations over 1.5 logMAR were jittered for plotting.