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Clinical Trials | Journal Club

The Mycotic Ulcer Treatment Trial A Randomized Trial Comparing Natamycin vs Voriconazole

N. Venkatesh Prajna, MD; Tiruvengada Krishnan, MD; Jeena Mascarenhas, MD; Revathi Rajaraman, MD; Lalitha Prajna, MD; Muthiah Srinivasan, MD; Anita Raghavan, MD; Catherine E. Oldenburg, MPH; Kathryn J. Ray, MA; Michael E. Zegans, MD; Stephen D. McLeod, MD; Travis C. Porco, PhD, MPH; Nisha R. Acharya, MD, MS; Thomas M. Lietman, MD ; for the Mycotic Ulcer Treatment Trial Group
JAMA Ophthalmol. 2013;131(4):422-429. doi:10.1001/jamaophthalmol.2013.1497.
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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%]). Natamycin-treated 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

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Figure 1. The CONSORT flow diagram for the Mycotic Ulcer Topical Treatment Trial I. LOCF indicates last observation carried forward as described in “Methods.”

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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.




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