Association of pretreatment with antifungal medication and fungal resistance in the mycotic ulcer treatment trial I.
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ABSTRACT:
SUBMITTER: Prajna NV
PROVIDER: S-EPMC4962690 | biostudies-literature | 2015 Oct
REPOSITORIES: biostudies-literature
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Association of pretreatment with antifungal medication and fungal resistance in the mycotic ulcer treatment trial I.
Prajna N Venkatesh NV Prajna Lalitha L O'Brien Kieran S KS Sun Catherine Q CQ Acharya Nisha N Lietman Thomas M TM Rose-Nussbaumer Jennifer J
JAMA ophthalmology 20151001 10
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Project description:ObjectiveTo compare oral voriconazole with placebo in addition to topical antifungals in the treatment of filamentous fungal keratitis.Design, setting, and participantsThe Mycotic Ulcer Treatment Trial II (MUTT II), a multicenter, double-masked, placebo-controlled, randomized clinical trial, was conducted in India and Nepal, with 2133 individuals screened for inclusion. Patients with smear-positive filamentous fungal ulcers and visual acuity of 20/400 (logMAR 1.3) or worse were randomized to receive oral voriconazole vs oral placebo; all participants received topical antifungal eyedrops. The study was conducted from May 24, 2010, to November 23, 2015. All trial end points were analyzed on an intent-to-treat basis.InterventionsStudy participants were randomized to receive oral voriconazole vs oral placebo; a voriconazole loading dose of 400 mg was administered twice daily for 24 hours, followed by a maintenance dose of 200 mg twice daily for 20 days, with dosing altered to weight based during the trial. All participants received topical voriconazole, 1%, and natamycin, 5%.Main outcomes and measuresThe primary outcome of the trial was rate of corneal perforation or the need for therapeutic penetrating keratoplasty (TPK) within 3 months. Secondary outcomes included microbiologic cure at 6 days, rate of re-epithelialization, best-corrected visual acuity and infiltrate and/or scar size at 3 weeks and 3 months, and complication rates associated with voriconazole use.ResultsA total of 2133 patients in India and Nepal with smear-positive ulcers were screened; of the 787 who were eligible, 240 (30.5%) were enrolled. Of the 119 patients (49.6%) in the oral voriconazole treatment group, 65 were male (54.6%), and the median age was 54 years (interquartile range, 42-62 years). Overall, no difference in the rate of corneal perforation or the need for TPK was determined for oral voriconazole vs placebo (hazard ratio, 0.82; 95% CI, 0.57-1.18; P = .29). In prespecified subgroup analyses comparing treatment effects among organism subgroups, there was some suggestion that Fusarium species might have a decreased rate of perforation or TPK in the oral voriconazole-treated arm; however, this was not a statistically significant finding after Holms-Šidák correction for multiple comparisons (effect coefficient, 0.49; 95% CI, 0.26-0.92; P = .03). Patients receiving oral voriconazole experienced a total of 58 adverse events (48.7%) compared with 28 adverse events (23.1%) in the placebo group (P < .001 after Holms-Šidák correction for multiple comparisons).Conclusions and relevanceThere appears to be no benefit to adding oral voriconazole to topical antifungal agents in the treatment of severe filamentous fungal ulcers. All patients in this study were enrolled in India and Nepal; therefore, it is possible that organisms in this region may exhibit characteristics different from those in other regions of the world.Trial registrationclinicaltrials.gov Identifier: NCT00996736.
| S-EPMC6044431 | biostudies-literature
Project description:ObjectiveTo compare topical natamycin vs voriconazole in the treatment of filamentous fungal keratitis.MethodsThis 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 measuresThe primary outcome was best spectacle-corrected visual acuity at 3 months; secondary outcomes included corneal perforation and/or therapeutic penetrating keratoplasty.ResultsA 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).ConclusionsNatamycin 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 practiceVoriconazole should not be used as monotherapy in filamentous keratitis.Trial registrationclinicaltrials.gov Identifier: NCT00996736
| S-EPMC3769211 | biostudies-literature
Project description:To perform a Bayesian analysis of the Mycotic Ulcer Treatment Trial I (MUTT I) using expert opinion as a prior belief.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.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.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.).
| S-EPMC3684218 | biostudies-literature
Project description:ImportanceIdentifying patients with infectious keratitis who are at risk of experiencing a poor outcome may be useful to allocate resources toward high-risk patients, particularly in resource-poor settings.ObjectiveTo determine baseline patient and ulcer characteristics that predict a high risk of developing corneal perforation and/or the need to undergo therapeutic penetrating keratoplasty (TPK).Design, setting, and participantsThis is a secondary analysis of Mycotic Ulcer Treatment Trial II, a multicenter, double-masked, placebo-controlled randomized clinical trial that enrolled 240 patients with smear-positive filamentous fungal corneal ulcers who enrolled between May 2010 and August 2015. Participants had a baseline visual acuity of 20/400 or worse and were randomized to receive oral voriconazole or a placebo (all participants received topical voriconazole, 1%). After 39 participants (16.3%) were enrolled, topical natamycin, 5%, was also added.Main outcomes and measuresThe primary outcome of this secondary analysis was the rate of corneal perforation or the need to undergo TPK.ResultsThe mean (SD) age at enrollment was 49 (13) years, 104 participants (43.3%) were women, and all were of Southeast Asian descent. The presence of hypopyon at baseline indicated 2.28 times the odds of the patient developing corneal perforation and/or needing TPK (95% CI, 1.18-4.40; P = .01). Study participants whose infiltrate involved the posterior one-third had a 71.4% risk of developing corneal perforation and/or needing TPK. For each 1-mm increase in the geometric mean of the infiltrate, there was 1.37 (95% CI, 1.12-1.67; P = .002) increased odds of developing perforation and/or needing TPK. Other clinical features such as visual acuity, baseline culture positivity, type of filamentous fungal organism and duration of symptoms, and demographic characteristics, such as sex and occupation, were not significant predictors in the multivariable regression analysis.Conclusions and relevanceThese results suggest that risk stratification from baseline ulcer characteristics can identify those at highest risk for developing corneal perforation and/or needing TPK.Trial registrationclinicaltrials.gov Identifier: NCT00996736.
| S-EPMC6038821 | biostudies-literature
Project description:ImportanceGiven the limitations in health care resources, quality-of-life measures for interventions have gained importance.ObjectiveTo determine whether vision-related quality-of-life outcomes were different between the natamycin and voriconazole treatment arms in the Mycotic Ulcer Treatment Trial I, as measured by an Indian Vision Function Questionnaire.Design, setting, and participantsSecondary analysis (performed October 11-25, 2014) of a double-masked, multicenter, randomized, active comparator-controlled, clinical trial at multiple locations of the Aravind Eye Care System in South India that enrolled patients with culture- or smear-positive filamentous fungal corneal ulcers who had a baseline visual acuity of 20/40 to 20/400 (logMAR of 0.3-1.3).InterventionsStudy participants were randomly assigned to topical voriconazole, 1%, or topical natamycin, 5%.Main outcomes and measuresSubscale score on the Indian Vision Function Questionnaire from each of the 4 subscales (mobility, activity limitation, psychosocial impact, and visual function) at 3 months.ResultsA total of 323 patients were enrolled in the trial, and 292 (90.4%) completed the Indian Vision Function Questionnaire at 3 months. The majority of study participants had subscale scores consistent with excellent function. After adjusting for baseline visual acuity and organism, we found that study participants in the natamycin-treated group scored, on average, 4.3 points (95% CI, 0.1-8.5) higher than study participants in the voriconazole-treated group (P = .046). In subgroup analyses looking at ulcers caused by Fusarium species and adjusting for baseline best spectacle-corrected visual acuity, the natamycin-treated group scored 8.4 points (95% CI, 1.9-14.9) higher than the voriconazole-treated group (P = .01). Differences in quality of life were not detected for patients with Aspergillus or other non-Fusarium species as the causative organism (1.5 points [95% CI, -3.9 to 6.9]; P = .52).Conclusions and relevanceWe found evidence of improvement in vision-related quality of life among patients with fungal ulcers who were randomly assigned to natamycin compared with those randomly assigned to voriconazole, and especially among patients with Fusarium species as the causative organism. Incorporation of quality-of-life measures in clinical trials is important to fully evaluate the effect of the studied interventions.Trial registrationclinicaltrials.gov Identifier:NCT00996736.
| S-EPMC4962866 | biostudies-literature
Project description:ImportanceFusarium keratitis is common and often results in poor outcomes. No new treatments since natamycin have become available.ObjectiveTo explore the role of adjuvant oral voriconazole on clinical outcomes in Fusarium keratitis.Design, setting, and participantsIn this prespecified subgroup analysis of a multicenter, double-masked, placebo-controlled randomized clinical trial, 240 patients from the Aravind Eye Care System in India, the Lumbini Eye Hospital and Bharatpur Eye Hospital in Nepal, and the University of California, San Francisco, who had culture-positive fungal ulcer and baseline visual acuity of 20/400 or worse were randomized to receive oral voriconazole vs placebo. Enrollment started May 24, 2010, and the last patient study visit was November 23, 2015. All patients received topical voriconazole, 1%, and after the results of the Mycotic Ulcer Treatment Trial (MUTT) II became available, topical natamycin, 5%, was added for all patients. Data analysis was performed from September 2 to October 28, 2016.Main outcomes and measuresThe primary outcome of the trial was the rate of corneal perforation or the need for therapeutic penetrating keratoplasty. Secondary outcomes included rate of reepithelialization, best spectacle-corrected visual acuity, and infiltrate or scar size at 3 months.ResultsOf the 240 study participants, 72 (30.4%) were culture positive for Fusarium species (41 [56.9%] male and 31 [43.1%] female; median [interquartile range] age, 50 [45-57] years). Of these, 33 (45.8%) were randomized to oral voriconazole and 39 (54.2%) to placebo. Fusarium ulcers randomized to oral voriconazole had a 0.43-fold decreased hazard of perforation or therapeutic penetrating keratoplasty compared with placebo after controlling for baseline infiltrate depth (95% CI, 0.22-fold to 0.84-fold; P = .01). Multiple linear regression revealed a 1.89-mm decreased infiltrate and/or scar size at 3 weeks (95% CI, -2.69 to -1.09 mm; P < .001) and a 0.83-mm decreased infiltrate and/or scar size at 3 months after correcting for baseline values (95% CI, -1.33 to -0.32 mm; P = .001) in eyes randomized to oral voriconazole vs placebo. Eyes treated with oral voriconazole also had a mean 0.29 decreased logMAR (improved) (Snellen equivalent 20/40) visual acuity at 3 months after controlling for baseline visual acuity, although this finding was not statistically significant (95% CI, -0.57 to 0.002; P = .052).Conclusions and relevanceAlthough MUTT II could not find a benefit for all corneal ulcers, Fusarium keratitis may benefit from the addition of oral voriconazole to topical natamycin, and physicians should consider prescribing oral voriconazole in these cases.Trial registrationclinicaltrials.gov Identifier: NCT00996736.
| S-EPMC5847083 | biostudies-literature
Project description:PURPOSE:We compare results from regression discontinuity (RD) analysis to primary results of a randomized controlled trial (RCT) utilizing data from two contemporaneous RCTs for treatment of fungal corneal ulcers. METHODS:Patients were enrolled in the Mycotic Ulcer Treatment Trials I and II (MUTT I & MUTT II) based on baseline visual acuity: patients with acuity ≤ 20/400 (logMAR 1.3) enrolled in MUTT I, and >20/400 in MUTT II. MUTT I investigated the effect of topical natamycin versus voriconazole on best spectacle-corrected visual acuity. MUTT II investigated the effect of topical voriconazole plus placebo versus topical voriconazole plus oral voriconazole. We compared the RD estimate (natamycin arm of MUTT I [N = 162] versus placebo arm of MUTT II [N = 54]) to the RCT estimate from MUTT I (topical natamycin [N = 162] versus topical voriconazole [N = 161]). RESULTS:In the RD, patients receiving natamycin had mean improvement of 4-lines of visual acuity at 3 months (logMAR -0.39, 95% CI: -0.61, -0.17) compared to topical voriconazole plus placebo, and 2-lines in the RCT (logMAR -0.18, 95% CI: -0.30, -0.05) compared to topical voriconazole. CONCLUSIONS:The RD and RCT estimates were similar, although the RD design overestimated effects compared to the RCT.
| S-EPMC5980795 | biostudies-literature
Project description:ObjectiveTo compare oral voriconazole vs placebo in addition to topical antifungals in the treatment of filamentous fungal keratitis.DesignNon-prespecified, secondary case-control analysis from a multicenter, double-masked, randomized placebo-controlled clinical trial.MethodsStudy Participants: Patients with smear-positive filamentous fungal ulcers and visual acuity of 20/400 or worse who eventuated to therapeutic penetrating keratoplasty (TPK).InterventionStudy participants were randomized to oral voriconazole vs oral placebo; all received topical antifungal drops.Main outcome measuresTPK button culture positivity.ResultsA total of 95 of 194 (49.5%) study participants enrolled at Madurai, Coimbatore, or Pondicherry, India eventuated to TPK in an average of 20.9 days (standard deviation 15.2 days, range 2-71 days). TPK button cultures were available for 67 of 95 (71%) of the TPKs performed and were positive for filamentous fungus in 45 of 67 (67%) cases. For each 1-day increase in the time to TPK there was 0.94-fold decreased odds of fungal culture positivity (95% confidence interval [CI] 0.90-0.98, P = .005). Those randomized to oral voriconazole had 1.26-fold increased odds of TPK button culture positivity after controlling for time to TPK and baseline organism, but this was not statistically significant (95% CI 0.32-4.87; P = .74). Those who underwent TPK for lack of response to medical therapy were 10.64-fold more likely to be culture positive than if the indication for surgery was perforation and this was statistically significant (95% CI 2.16-51.70; P = .003).ConclusionsThere appears to be no benefit to adding oral voriconazole to topical antifungal agents in the treatment of severe filamentous fungal ulcers. Infection rather than inflammation appears to be the reason for the worsening clinical picture in many of these patients.
| S-EPMC6584760 | biostudies-literature
Project description:Background/aimsThe Mycotic Ulcer Treatment Trial I (MUTT I) was a double-masked, multicentre, randomised controlled trial, which found that topical natamycin is superior to voriconazole for the treatment of filamentous fungal corneal ulcers. In this study, we determine risk factors for low vision-related quality of life in patients with fungal keratitis.MethodsThe Indian visual function questionnaire (IND-VFQ) was administered to MUTT I study participants at 3 months. Associations between patient and ulcer characteristics and IND-VFQ subscale score were assessed using generalised estimating equations.Results323 patients were enrolled in the trial, and 292 (90.4%) completed the IND-VFQ at 3 months. Out of a total possible score of 100, the average VFQ score for all participants was 81.3 (range 0-100, SD 23.6). After correcting for treatment arm, each logMAR line of worse baseline visual acuity in the affected eye resulted in an average 1.2 points decrease on VFQ at 3 months (95% CI -1.8 to 0.6, p<0.001). Those who required therapeutic penetrating keratoplasty had an average of 25.2 points decrease on VFQ after correcting for treatment arm (95% CI -31.8 to -18.5, p<0.001). Study participants who were unemployed had on average 28.5 points decrease on VFQ (95% CI -46.9 to -10.2, p=0.002) after correcting for treatment arm.ConclusionsMonocular vision loss from corneal opacity due to fungal keratitis reduced vision-related quality of life. Given the relatively high worldwide burden of corneal opacity, improving treatment outcomes of corneal infections should be a public health priority.Trial registration numberClinicaltrials.gov Identifier: NCT00996736.
| S-EPMC4965324 | biostudies-literature
Project description:BackgroundTo determine if pretreatment with antifungal agents is predictive of worse clinical outcome in a fungal keratitis clinical trial.DesignNon-pre-specified subgroup analysis of a randomized controlled trial in a tertiary hospital.ParticipantsThree hundred twenty-three fungal ulcer cases with an enrolment visual acuity of 20/40 to 20/400.MethodsThe Mycotic Ulcer Treatment Trial I was a randomized, double-masked trial to determine the optimal treatment for filamentous fungal keratitis at the Aravind Eye Care System, India. Enrolled cases were randomized to receive topical natamycin or voriconazole. Prior antifungal medication use, dose and duration were collected at enrolment. A subgroup analysis was performed to determine if patients using natamycin or azoles at presentation have worse clinical outcomes compared with those who were not pretreated.Main outcome measuresThree-month visual acuity (primary), 3-month infiltrate or scar size, corneal perforation and/or transplant and re-epithelialization time.ResultsOf the 323 patients enrolled, 44% presented on an antifungal agent. Pretreated patients had larger mean baseline infiltrate size (P < 0.001) and epithelial defect size (P = 0.02). Multivariate regression analysis demonstrated that pretreatment was associated with significantly worse 3-month visual acuity (P = 0.006), larger 3-month scar size (P < 0.001) and increased odds of corneal perforation and/or transplant (P = 0.001).ConclusionsFungal keratitis that is smear-positive despite being pretreated with appropriate antifungal agents appears to be a risk factor for worse outcomes, likely a result of initial ulcer severity and treatment failure. These patients may benefit from more aggressive multimodal therapy at a tertiary centre.
| S-EPMC5177485 | biostudies-literature