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JAC Advance Access published online on April 20, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl133
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received November 25, 2005
Revised February 1, 2006
Accepted March 21, 2006

Brief report

Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed fluconazole

L. Joseph Wheat 1 *, Patricia Connolly 1, Melinda Smedema 1, Michelle Durkin 1, Edward Brizendine 2, Paul Mann 3, Reena Patel 3, Paul M. McNicholas 3, and Mitchell Goldman 2

1 MiraVista Diagnostics/MiraBella Technologies, 4444 Decatur Boulevard, Indianapolis, IN 46241, USA
2 Indiana University School of Medicine, 1100 West Michigan Street, Indianapolis, IN 46202, USA
3 Schering-Plough Research Institute, 2015 Galloping Hill Road, K15-4-4700, Kenilworth, NJ 07033, USA

* To whom correspondence should be addressed.
L. Joseph Wheat, E-mail: jwheat{at}miravistalabs.com


  Abstract

Objectives: To determine the activity of newer triazoles against strains of Histoplasma capsulatum resistant to fluconazole.

Methods: Susceptibility testing was performed on 17 paired pre- and post-treatment H. capsulatum isolates from patients with AIDS who failed fluconazole.

Results: The median MICs of fluconazole, voriconazole, and posaconazole and ravuconazole for the pre-treatment isolates were 1 mg/L, 0.015 mg/L and <0.007 mg/L, respectively. A 4-fold or greater increase in the MIC of fluconazole and voriconazole was observed in 12 and 7 of the post-treatment isolates, respectively; the median fold increases in MIC were 8 and 2.1, respectively. No MIC increases were observed for posaconazole and ravuconazole. One pair of isolates exhibiting reduced susceptibility was examined in more detail. A single amino acid substitution (at tyrosine 136) was identified in the active site of the CYP51 protein from the post-treatment isolate, which is presumed to be responsible for reduced susceptibility to voriconazole and fluconazole, analogous to recent observations in Candida albicans.

Conclusions: These findings support careful monitoring for relapse in patients receiving voriconazole treatment for histoplasmosis, particularly in those who were previously treated with fluconazole.

Keywords: voriconazole; posaconazole; ravuconazole; susceptibility; resistance.
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