HYPOTHESIS ON THE MECHANISM OF RESISTANCE TO FLUCONAZOLE IN HISTOPLASMA-CAPSULATUM

An AIDS patient,vith disseminated histoplasmosis who improved during t reatment with fluconazole but remained fungemic and subsequently relap sed is described. Isolates obtained from blood during therapy showed a progressive increase in fluconazole MIC from 0.625 to 20 mu g/ml. The pretreatment, or parent, isolate and the posttreatment, or relapse, i solate demonstrated identical genetic patterns by PCR fingerprinting w ith three different primers, Fluconazole was a less potent inhibitor o f the growth of the relapse isolate than of the pretreatment isolate ( 50% inhibitory concentration [IC50] = 11.7 mu M versus 30.6 mu M), whi le itraconazole was more potent (relapse isolate IC50 = 0.0011 mu M ve rsus pretreatment isolate IC50 = 0.0064 mu M), Neither the increased s ensitivity to itraconazole nor the decreased activity of fluconazole o n the growth of the relapse isolate results from changes in the intrac ellular content of these agents. To reach 50% inhibition of ergosterol synthesis in both the parent and relapse isolates, about 2 nM itracon azole was needed; with fluconazole, 50% inhibition was achieved at 20. 9 mu M and 55.5 mu M respectively, Resistance to fluconazole may devel op during treatment and results from decreased sensitivity of ergoster ol synthesis.