title: Changing Azole Resistance: A Secondary Analysis of the MUTT I Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Corneal smears and cultures were obtained from all study participants at baseline. Susceptibility testing was performed for each culture-positive specimen.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00996736.
authors.affiliation: Aravind Eye Care System at Madurai, Pondicherry, and Coimbatore, India.
authors.forename: N Venkatesh
authors.initials: NV
authors.lastname: Prajna
authors.affiliation: Aravind Eye Care System at Madurai, Pondicherry, and Coimbatore, India.
authors.forename: Prajna
authors.initials: P
authors.lastname: Lalitha
authors.affiliation: Aravind Eye Care System at Madurai, Pondicherry, and Coimbatore, India.
authors.forename: Revathi
authors.initials: R
authors.lastname: Rajaraman
authors.affiliation: Aravind Eye Care System at Madurai, Pondicherry, and Coimbatore, India.
authors.forename: Tiruvengada
authors.initials: T
authors.lastname: Krishnan
authors.affiliation: Aravind Eye Care System at Madurai, Pondicherry, and Coimbatore, India.
authors.forename: Anita
authors.initials: A
authors.lastname: Raghavan
authors.affiliation: Aravind Eye Care System at Madurai, Pondicherry, and Coimbatore, India.
authors.forename: Muthiah
authors.initials: M
authors.lastname: Srinivasan
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco.
authors.forename: Kieran S
authors.initials: KS
authors.lastname: O'Brien
authors.affiliation: Department of Ophthalmology, Dartmouth Medical School, Hanover, New Hampshire.
authors.forename: Michael
authors.initials: M
authors.lastname: Zegans
authors.affiliation: Department of Ophthalmology, University of California, San Francisco.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: McLeod
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco4Department of Ophthalmology, University of California, San Francisco5Department of Epidemiology and Biostatistics, University of California, San Francisco.
authors.forename: Nisha R
authors.initials: NR
authors.lastname: Acharya
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco4Department of Ophthalmology, University of California, San Francisco.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Keenan
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco4Department of Ophthalmology, University of California, San Francisco5Department of Epidemiology and Biostatistics, University of California, San Francisco.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Lietman
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco4Department of Ophthalmology, University of California, San Francisco6Department of Optometry, University of California, Berkeley.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rose-Nussbaumer
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D003320:Corneal Ulcer / Q000188:drug therapy / Q000382:microbiology*; D004311:Double-Blind Method; D026141:Drug Resistance, Multiple, Fungal; D015821:Eye Infections, Fungal / Q000188:drug therapy / Q000382:microbiology*; D005260:Female; D005658:Fungi / Q000187:drug effects / Q000302:isolation & purification*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy / Q000382:microbiology*; D010866:Natamycin / Q000494:pharmacology; D014792:Visual Acuity / Q000502:physiology; D065819:Voriconazole / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D010866:Natamycin; D065819:Voriconazole