title: Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed fluconazole.
abstract: OBJECTIVE
  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.affiliation: MiraVista Diagnostics/MiraBella Technologies, 4444 Decatur Boulevard, Indianapolis, IN 46241, USA. jwheat@miravistalabs.com
authors.forename: L Joseph
authors.initials: LJ
authors.lastname: Wheat
authors.forename: Patricia
authors.initials: P
authors.lastname: Connolly
authors.forename: Melinda
authors.initials: M
authors.lastname: Smedema
authors.forename: Michelle
authors.initials: M
authors.lastname: Durkin
authors.forename: Edward
authors.initials: E
authors.lastname: Brizendine
authors.forename: Paul
authors.initials: P
authors.lastname: Mann
authors.forename: Reena
authors.initials: R
authors.lastname: Patel
authors.forename: Paul M
authors.initials: PM
authors.lastname: McNicholas
authors.forename: Mitchell
authors.initials: M
authors.lastname: Goldman
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000382:microbiology*; D000163:Acquired Immunodeficiency Syndrome / Q000150:complications; D019943:Amino Acid Substitution; D000935:Antifungal Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D025141:Drug Resistance, Fungal / Q000235:genetics*; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics; D006658:Histoplasma / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006660:Histoplasmosis / Q000188:drug therapy / Q000382:microbiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D014230:Triazoles; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System