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

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.

• Authors: L Joseph Wheat, Patricia Connolly, Melinda Smedema, Michelle Durkin, Edward Brizendine, Paul Mann, Reena Patel, Paul M McNicholas, Mitchell Goldman
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 57 Issue 6 Pg. 1235-9 (Jun 2006) ISSN: 0305-7453 [Print] England
• PMID: 16627592 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antifungal Agents
• Fungal Proteins
• Triazoles
• Fluconazole
• Cytochrome P-450 Enzyme System

Topics

• AIDS-Related Opportunistic Infections (drug therapy, microbiology)
• Acquired Immunodeficiency Syndrome (complications)
• Amino Acid Substitution
• Antifungal Agents (pharmacology)
• Binding Sites (genetics)
• Cytochrome P-450 Enzyme System (genetics)
• Drug Resistance, Fungal (genetics)
• Fluconazole (pharmacology)
• Fungal Proteins (genetics)
• Histoplasma (drug effects, genetics, isolation & purification)
• Histoplasmosis (drug therapy, microbiology)
• Humans
• Microbial Sensitivity Tests
• Mutation
• Triazoles (pharmacology)