title: Emergence of resistance to fluconazole as a cause of failure during treatment of histoplasmosis in patients with acquired immunodeficiency disease syndrome.
abstract: In sequential clinical trials of treatment for histoplasmosis in patients with acquired immunodeficiency syndrome, therapy with fluconazole failed in a higher proportion of patients than did therapy with itraconazole. To determine the cause for failure with fluconazole, antifungal susceptibility testing that used modified National Committee on Clinical Laboratory Standards procedures was performed on all baseline and failure isolates. Failure occurred more frequently in patients with baseline isolates with fluconazole minimum inhibitory concentrations (MICs) > or =5 microg/mL versus lower MICs; 29% versus 3%, respectively. There was at least a 4-fold increase in fluconazole MIC in the isolates from 10 (59%) of 17 patients for whom paired pretreatment and failure or relapse isolates were available. Cross-resistance to itraconazole was not seen. In conclusion, fluconazole is less active than itraconazole for Histoplasma capsulatum and induces resistance during therapy, which accounted for treatment failure in some patients.
authors.affiliation: Indiana University School of Medicine, Histoplasmosis Reference Laboratory, and Veterans' Affairs Medical Center, Indianapolis, IN 46202, USA. lwheat@iupui.edu
authors.forename: L J
authors.initials: LJ
authors.lastname: Wheat
authors.forename: P
authors.initials: P
authors.lastname: Connolly
authors.forename: M
authors.initials: M
authors.lastname: Smedema
authors.forename: E
authors.initials: E
authors.lastname: Brizendine
authors.forename: R
authors.initials: R
authors.lastname: Hafner
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004198:Disease Susceptibility; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000494:pharmacology / Q000627:therapeutic use*; D006658:Histoplasma / Q000187:drug effects / Q000302:isolation & purification; D006660:Histoplasmosis / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D012008:Recurrence; D017211:Treatment Failure
chemical_list: D000935:Antifungal Agents; D017964:Itraconazole; D015725:Fluconazole