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
PURPOSE: To perform a Bayesian analysis of the Mycotic Ulcer Treatment Trial I (MUTT I) using expert opinion as a prior belief.
METHODS: MUTT I was a randomized clinical trial comparing topical natamycin or voriconazole for treating filamentous fungal keratitis. A questionnaire elicited expert opinion on the best treatment of fungal keratitis before MUTT I results were available. A Bayesian analysis was performed using the questionnaire data as a prior belief and the MUTT I primary outcome (3-month visual acuity) by frequentist analysis as a likelihood.
RESULTS: Corneal experts had a 41.1% prior belief that natamycin improved 3-month visual acuity compared with voriconazole. The Bayesian analysis found a 98.4% belief for natamycin treatment compared with voriconazole treatment for filamentous cases as a group (mean improvement 1.1 Snellen lines, 95% credible interval 0.1-2.1). The Bayesian analysis estimated a smaller treatment effect than the MUTT I frequentist analysis result of 1.8-line improvement with natamycin versus voriconazole (95% confidence interval 0.5-3.0, P = 0.006). For Fusarium cases, the posterior demonstrated a 99.7% belief for natamycin treatment, whereas non-Fusarium cases had a 57.3% belief.
CONCLUSIONS: The Bayesian analysis suggests that natamycin is superior to voriconazole when filamentous cases are analyzed as a group. Subgroup analysis of Fusarium cases found improvement with natamycin compared with voriconazole, whereas there was almost no difference between treatments for non-Fusarium cases. These results were consistent with, though smaller in effect size than, the MUTT I primary outcome by frequentist analysis. The accordance between analyses further validates the trial results. (ClinicalTrials.gov number, NCT00996736.).
<b>PURPOSE: </b>To describe the minimum inhibitory concentration (MIC) of fungal isolates to natamycin and voriconazole, and to compare these MICs to previous ocular susceptibility studies.<b>DESIGN: </b>Experimental laboratory study using isolates from a randomized clinical trial.<b>METHODS: </b>The Mycotic Ulcer Treatment Trial I was a randomized, double-masked, multicenter trial comparing topical natamycin and voriconazole for fungal keratitis treatment. Susceptibility testing to natamycin and voriconazole were performed according to Clinical and Laboratory Standards Institute methods. The relationship between organism and MIC was assessed. A literature review was performed to compare results to previous ocular susceptibility studies.<b>RESULTS: </b>Of the 323 patients enrolled in the trial, MICs were available for 221 (68%). Fusarium (n = 126) and Aspergillus species (n = 52) were the most commonly isolated organisms. MICs to natamycin and voriconazole were significantly different across all genera (P < .001). The MIC median (MIC50) and 90th percentile (MIC90) for natamycin were equal to or higher than voriconazole for all organisms except Curvularia species. Compared to other organisms, Fusarium species isolates had the highest MICs to voriconazole and Aspergillus flavus isolates had the highest MICs to natamycin. Our results were similar to previous reports except that the voriconazole MIC90 against Aspergillus species was 2-fold higher and the natamycin MIC90 against Aspergillus fumigatus was 4-fold higher in our study.<b>CONCLUSION: </b>In this large susceptibility study, Fusarium isolates were least susceptible to voriconazole and A flavus isolates were least susceptible to natamycin when compared to other filamentous fungi. In the future, susceptibility testing may help guide therapy if performed in a timely manner.
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.
