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2015 OMIG Abstract 17

Changing Azole Susceptibility in the Mycotic Ulcer Treatment Trial I
N. Venkatesh Prajna MD1, Lalitha Prajna MD1, Revathi Rajaraman MD1, Tiruvengada Krishnan MD1, Anita Raghavan MD1, Muthiah Srinivasan MD1, Kieran S. O’Brien MPH2, Michael Zegans6, Stephen D. McLeod3, Nisha R. Acharya, MD2,3,4, Thomas M. Lietman MD2,3,4, Jennifer Rose-Nussbaumer, MD2,3,5 for the Mycotic Ulcer Treatment Trial Group
1Aravind Eye Care System at Madurai, Pondicherry and Coimbatore, India
2Francis I. Proctor Foundation, San Francisco, USA
3Department of Ophthalmology, University of California San Francisco, USA
4Department of Epidemiology and Biostatistics, University of California San Francisco, USA 
5Department of Optometry, University of California Berkeley, USA
6Department of Ophthalmology, Dartmouth Medical School, Hanover NH USA

Introduction: The development of multiple-triazole resistance in pathogenic filamentous fungi has become an increasing clinical concern and has been shown to increase the risk of treatment failure. The Mycotic Ulcer Treatment Trial I, was a NIH-funded double-masked, randomized controlled trial that found natamycin to be superior to voriconazole in the treatment of filamentous fungal ulcers, and in particular those infected with Fusarium species. In this non-pre-specified subgroup analysis, we will investigate how azole resistance patterns changed over the duration of the MUTT I clinical trial.

Methods: Smear-positive filamentous fungal corneal ulcers patients with visual acuity between 20/40 and 20/400 enrolled at Aravind Eye Care System, were randomized to receive 5% topical natamycin or 1% topical voriconazole. Baseline scrapping and cultures were obtained from all study participants. Using the standards set by the Clinical and Laboratory Standards Institute, speciation and analysis of minimum inhibitory concentration (MIC) to natamycin and voriconazole were performed on all positive fungal samples collected. Multiple linear regression was performed to analyze the association between the date enrolled in the study, as our primary predictor of interest and baseline MIC, adjusting for infectious organism. In order to get fold change in MIC per year, the antilog was taken of the coefficient multiplied by 365.

Results: Between April 3, 2010 and December 31st, 2011 positive fungal cultures were obtained on 256/323 (79%) of study participants. MIC data were available for 221/323 (68.4%), as 35 samples did not grow during susceptibility testing. The average voriconazole MIC for all organisms over the entire duration of the study was 3.19 (SD 3.62). Mean Log2-transformed voriconazole MICs were 4.69 (SD 3.79) for Fusarium, 0.99 (SD 1.24) for Aspergillus and1.47 (SD 2.83) for all other organisms. There was a 2.14-fold increase in voriconazole MIC per year after controlling for infectious organism (95% CI1.13 to 4.56, P = 0.02). This association was not found when looking at natamycin MICs from baseline cultures after controlling for infectious organism (1.26, 95% CI 0.13 to 12.55, P = 0.852).

Discussion: Susceptibility to voriconazole apparently decreased even over the relatively short enrollment period of a clinical trial. This may be more related to increased resistance of environmental fungi rather than previous treatment with azoles, as presenting on an azole was not itself a risk factor for resistance. These microbiological findings highlight the primary clinical trial result that natamycin is superior to voriconazole in the treatment of filamentous fungal keratitis. A trend of increasing azole resistance could impact treatment of human mycoses. 

2015 Agenda and Abstracts | < Previous | Next >