Does long-term itraconazole prophylaxis result in in vitro azole resistance in mucosal Candida albicans isolates from persons with advanced human immunodeficiency virus infection?

The effects of prolonged itraconazole exposure on the susceptibility of Can dida albicans isolates to itraconazole and fluconazole have not been well c haracterized. A recent placebo-controlled study of long-term itraconazole a ntifungal prophylaxis in persons with advanced human immunodeficiency virus infection afforded the opportunity to address this question, Mucosal Candi da sp, isolates were obtained from subjects who developed oropharyngeal or esophageal candidiasis, and in vitro susceptibilities of the last isolate o btained at removal from the study as a prophylaxis failure were compared in itraconazole and placebo recipients, More subjects in the placebo group (7 4 of 146 [51%]) than in the itraconazole group (51 of 149 [34%]) developed mucosal candidiasis (P = 0.001). A total of 112 isolates were recovered fro m 56 of the 74 (76%) subjects with mucosal candidiasis assigned to the plac ebo group, compared to 97 isolates from 45 of the 51 (88%) subjects in the itraconazole group. C. albicans accounted for 98% of isolates in the placeb o group and 89% of isolates in the itraconazole group. The itraconazole MIC at which 50% of the isolates tested were inhibited (MIC50) for last-episod e isolates from the itraconazole group was 0.125 mu g/ml compared to 0.015 mu g/ml for the placebo group subjects, P = 0.0001. The MIC50 of fluconazol e for the last isolates from the itraconazole group was 1.5 mu g/ml compare d to 0.5 mu g/ml for the placebo subjects (P = 0.005), A lower proportion o f isolates recovered from subjects on itraconazole therapy were classified as susceptible to itraconazole (63%) compared to isolates from the placebo group (96%) (P = 0.001). Similarly, a lower proportion of C, albicans isola tes from subjects on itraconazole therapy were susceptible to fluconazole ( 78%) compared to isolates from the placebo group (96%) (P = 0.01), Also, th e proportion of isolates that were not fully susceptible to itraconazole or fluconazole was greater in patients assigned to the itraconazole group tha n the placebo group (itraconazole susceptibility, 37 and 4%, respectively ( P = 0.001); fluconazole susceptibility, 23 and 4%, respectively (P = 0.01), In conclusion, long-term itraconazole prophylaxis in patients with AIDS is associated with reduction in susceptibility to itraconazole and cross-resi stance to fluconazole.