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Brief Report
June 2016

Changing Azole ResistanceA Secondary Analysis of the MUTT I Randomized Clinical Trial

Author Affiliations
  • 1Aravind Eye Care System at Madurai, Pondicherry, and Coimbatore, India
  • 2Francis I. Proctor Foundation, University of California, San Francisco
  • 3Department of Ophthalmology, Dartmouth Medical School, Hanover, New Hampshire
  • 4Department of Ophthalmology, University of California, San Francisco
  • 5Department of Epidemiology and Biostatistics, University of California, San Francisco
  • 6Department of Optometry, University of California, Berkeley
JAMA Ophthalmol. 2016;134(6):693-696. doi:10.1001/jamaophthalmol.2016.0530

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.

Main Outcomes and 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.

Trial Registration  clinicaltrials.gov Identifier: NCT00996736