JAC Advance Access originally published online on April 20, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1235-1239; doi:10.1093/jac/dkl133
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Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed fluconazole
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
Received 25 November 2005; returned 24 January 2006; revised 1 February 2006; accepted 21 March 2006
*Corresponding author. Tel: +1-317-856-2681; Fax: +1-317-856-3685; E-mail: jwheat{at}miravistalabs.com
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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