Clearance of fungal burden during treatment of disseminated histoplasmosis with liposomal amphotericin B versus itraconazole.

Animal studies have shown that fungal burden correlates with survival during treatment with new antifungal therapies for histoplasmosis. The purpose of this report is to compare the clearance of fungal burden in patients with histoplasmosis treated with liposomal amphotericin B versus itraconazole. In two separate closed clinical trials that evaluated the efficacy of liposomal amphotericin B and itraconazole treatment of disseminated histoplasmosis in patients with AIDS, blood was cultured for fungus and blood and urine were tested for Histoplasma antigen. The clinical response rates were similar; 86% with liposomal amphotericin B (n = 51) versus 85% with itraconazole (n = 59). Of the patients with positive blood cultures at enrollment, after 2 weeks of therapy cultures were negative in over 85% of the liposomal amphotericin B group versus 53% of the itraconazole group (P = 0.0008). Furthermore, after 2 weeks, median antigen levels in serum fell by 1.6 U in the liposomal amphotericin B group versus 0.1 U in the itraconazole group (P = 0.02), and those in urine fell by 2.1 U in the liposomal amphotericin B group and 0.2 U in the itraconazole group (P = 0.0005). The more rapid clearance of fungemia supports the use of liposomal amphotericin B rather than itraconazole for initial treatment of moderately severe or severe histoplasmosis.

DNA fingerprinting of serial Candida albicans isolates obtained during itraconazole prophylaxis in patients with AIDS.

During a randomized double-blind placebo-controlled study testing the efficacy of itraconazole for prophylaxis of systemic and mucosal fungal infections in patients with acquired immune deficiency syndrome, 298 patients were enrolled with 295 evaluable. Of those, 46 patients were considered prophylaxis failures because of recurrent oral or esophageal candidiasis. Oropharyngeal fungal cultures were taken at the time of suspected thrush or Candida esophagitis, but not at baseline. All of the Candida spp. isolates were cultured on CHROMagar Candida medium then identified using API 20 AUX strips. Antifungal susceptibility testing was performed following the National Committee for Clinical Laboratory Standards M-27A guidelines. Sequential isolates were genotyped using randomly amplified polymorphic DNA. Polymerase chain reaction fingerprints were generated using two repetitive sequence primers, (GGA)7 and (GACA)4. The study group consisted of 23 patients, nine from the itraconazole arm and 14 from the placebo arm, who were prophylaxis failures and had more than two C. albicans isolates. Five of 23 had isolates showing a > or =4-fold reduction in susceptibility; four of these patients were in the itraconazole prophylaxis arm and one was in the placebo arm. Three of the five had yeast isolations showing changes in banding patterns over time. Such changes may indicate genetic changes in the same strain that could be linked to acquired resistance to itraconazole, or acquisition of a new strain, or emergence of a previously minor component of the original population.

Hypothesis on the mechanism of resistance to fluconazole in Histoplasma capsulatum.

An AIDS patient with disseminated histoplasmosis who improved during treatment with fluconazole but remained fungemic and subsequently relapsed is described. Isolates obtained from blood during therapy showed a progressive increase in fluconazole MIC from 0.625 to 20 micrograms/ml. The pretreatment, or parent, isolate and the posttreatment, or relapse, isolate demonstrated identical genetic patterns by PCR fingerprinting with three different primers. Fluconazole was less potent inhibitor of the growth of the relapse isolate than of the pretreatment isolate (50% inhibitory concentration [IC50] = 11.7 microM), while itraconazole was more potent (relapse isolate IC50 = 0.0011 microM versus pretreatment isolate IC50 = 0.0064 microM). Neither the increased sensitivity to itraconazole nor the decreased activity of fluconazole on the growth of the relapse isolate results from changes in the intracellular content of these agents. To reach 50% inhibition of ergosterol synthesis in both the parent and relapse isolates, about 2 nM itraconazole was needed; with fluconazole, 50% inhibition was achieved at 20.9 microM and 55.5 microM, respectively. Resistance to fluconazole may develop during treatment and results from decreased sensitivity of ergosterol synthesis.