Emergence of Resistance to Fluconazole as a Cause of Failure during Treatment of Histoplasmosis in Patients with Acquired Immunodeficiency Disease Syndrome [Wheat LJ et al. CID 2001;33:1910] This is a report from the Mycoses Study Group with further data from a prior report evaluating fluconazole vs. itraconazole for the treatment of disseminated histoplasmosis in patients with AIDS [Am J Med 1997;103:223]. The outcome of those infections was correlated with results of in vitro sensitivity tests of H. capsulatum using the NCCLS testing on the isolated strains. In comparing baseline susceptibility for 37 "responders" with 28 patients who were considered clinical failures or relapses, the baseline MICs exceeded 5 µg/mL in 3% of the 37 responders compared to 29% of the 28 who failed or relapsed. Further, there was a four-fold increase in fluconazole MICs from 10 of 17 patients (59%) who had failure or relapse. The median MIC to fluconazole at baseline was 1.25 µg/mL compared to 0.02 µg/mL for itraconazole. Resistance to fluconazole was not accompanied by resistance to itraconazole. The authors conclude that fluconazole is less active against H. capsulatum and may induce the development of resistance during therapy. Cross-resistance to itraconazole was not observed.
Comment: The authors claim that this is the first use of the NCCLS method correlating clinical outcome and in vitro sensitivity of a large number of H. capsulatum isolates. The procedure used seemed reproducible and there were good clinical correlations. These data also help confirm itraconazole as the preferred azole. The authors point out that the ratio of blood concentration: MIC with fluconazole at 800 mg/day is 35:1 and for itraconazole at 400 mg/day the ratio is 358:1. These observations, as well as the clinical trial, clearly established itraconazole as the preferred azole for histoplasmosis.
posted 12/10/2001

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