Fluconazole has been used for treatment of histoplasmosis in patients with AIDS but appears to be less effective than amphotericin B or itraconazole. Treatment failure or relapse occurred in nearly half of patients during a prospective trial (ACTG 174). The patient reviewed here improved initially but remained fungemic and subsequently relapsed. Isolates at week 8, 12 and 16 of therapy showed progressive increase in fluconazole MIC from 0.625 micrograms/ml initially to 20 micrograms/ml at relapse. Inhibition of ergosterol synthesis and accumulation of the sterol intermediaries obtusifolione and eburicol during incubation with fluconazole were reduced in the relapse isolate. The relapse isolate remained fully susceptible to itraconazole. These findings indicate that H. capssulatum may develop resistance to fluconazole and suggest that its 14 alpha-demethylase and/or ketosteroid reductase changed fluconazole treatment. Patients receiving fluconazole for histoplasmosis are at risk for failure because of development of resistance.

Acquired Immunodeficiency Syndrome/*COMPLICATIONS Antifungal Agents/*PHARMACOLOGY/THERAPEUTIC USE Fluconazole/*PHARMACOLOGY/THERAPEUTIC USE Histoplasma/*DRUG EFFECTS/ENZYMOLOGY Histoplasmosis/COMPLICATIONS/*DRUG THERAPY Human Microbial Sensitivity Tests Treatment Failure ABSTRACT

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