Changing azole resistance: A secondary analysis of the MUTT I randomized clinical trial

Abstract

IMPORTANCE: The development of multiple triazole resistance in pathogenic filamentous fungi has become an increasing clinical concern and has been shown to increase the risk for treatment failure. OBJECTIVE: To determine whether antifungal resistance increased during the Mycotic Ulcer Treatment Trial I (MUTT I), as measured by minimum inhibitory concentrations (MICs) in baseline cultures. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a double-masked, multicenter, randomized clinical trial included patients with culture- or smear-positive filamentous fungal corneal ulcer and a baseline visual acuity of 20/40 to 20/400. Culture-positive samples with susceptibility testing were included in this analysis. The patients were treated at multiple locations of the Aravind Eye Care Hospital system in South India. Data were collected from April 3, 2010, to December 31, 2011, and analyzed from July 15 to September 1, 2015. INTERVENTIONS: Corneal smears and cultures were obtained from all study participants at baseline. Susceptibility testing was performed for each culture-positive specimen. MAINOUTCOMESAND MEASURES: Minimum inhibitory concentration of voriconazole and natamycin in baseline cultures. RESULTS: Of 323 participants with smear-positive specimens (183 men [56.7%]; 140 women [43.3%]; median [interquartile range] age, 47 [38-56] years), fungal-positive cultures were obtained for 256 (79.3%). The MIC data were available for 221 of 323 participants (68.4%), because 35 samples had no growth during susceptibility testing. A 2.14-fold increase per year (95% CI, 1.13-4.56; P =.02) in voriconazole MICs after controlling for the infectious organism was found. This association was not found when looking at natamycin MICs of baseline cultures after controlling for the infectious organism (1.26; 95% CI, 0.13-12.55; P =.85). CONCLUSIONS AND RELEVANCE: Susceptibility to voriconazole appeared to decrease during the relatively short enrollment period of the clinical trial. This decrease may be more related to increased resistance of environmental fungi rather than previous treatment with azoles, because presenting with azole treatment was not a risk factor for resistance.