Emergence of resistance to fluconazole as a cause of failure during treatment of histoplasmosis in patients with acquired immunodeficiency disease syndrome

In sequential clinical trials of treatment for histoplasmosis in patients w ith acquired immunodeficiency syndrome, therapy with fluconazole failed in a higher proportion of patients than did therapy with itraconazole. To dete rmine the cause for failure with fluconazole, antifungal susceptibility tes ting that used modified National Committee on Clinical Laboratory Standards procedures was performed on all baseline and failure isolates. Failure occ urred more frequently in patients with baseline isolates with fluconazole m inimum inhibitory concentrations (MICs) greater than or equal to5 mug/mL ve rsus lower MICs; 29% versus 3%, respectively. There was at least a 4-fold i ncrease in fluconazole MIC in the isolates from 10 (59%) of 17 patients for whom paired pretreatment and failure or relapse isolates were available. C ross-resistance to itraconazole was not seen. In conclusion, fluconazole is less active than itraconazole for Histoplasma capsulatum and induces resis tance during therapy, which accounted for treatment failure in some patient s.