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

J Antimicrob Chemother. 2006 Jun;57(6):1235-9. doi: 10.1093/jac/dkl133. Epub 2006 Apr 20.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS-Related Opportunistic Infections / drug therapy
  • AIDS-Related Opportunistic Infections / 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*
  • Histoplasma / genetics
  • Histoplasma / isolation & purification
  • Histoplasmosis / drug therapy
  • Histoplasmosis / microbiology*
  • Humans
  • Microbial Sensitivity Tests
  • Mutation
  • Triazoles / pharmacology*

Substances

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