Efficacies of amphotericin B-desoxycholate (Fungizone), liposomal amphotericin B (AmBisome) and fluconazole in the treatment of systemic candidosis in immunocompetent and leucopenic mice.
The in-vitro activities of amphotericin B-desoxycholate (AmB-DOC), liposomal amphotericin B (L-AmB) and fluconazole were determined against a single strain of Candida albicans. In addition, the efficacies of these agents in the treatment of systematic candidosis in both immunocompetent and leucopenic mice were compared. The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of AmB-DOC and L-AmB were similar, but on the basis of time-kill studies, the fungicidal activity of L-AmB was significantly less than that of AmB-DOC. In immunocompetent mice, the dosage of AmB-DOC was limited by toxicity, resulting in a maximum tolerated dosage (MTD) of 0.4 mg/kg/day during treatment for 5 days; L-AMB was less toxic, the MTD being 7 mg/kg/day following a treatment period of the same duration. Both AmB-DOC and L-AmB led to significant reductions in the numbers of C. albicans in the kidneys of these mice and prevented relapse of infection after completion of treatment. Fluconazole in dosages of 0.4 and 64 mg/kg/day resulted in initial reductions in the numbers of cfu but failed to prevent relapse. In leucopenic mice, treatment for 5 days with AmB-DOC in a dosage of 0.3 mg/kg/day resulted in survival of the animals and a significant reduction in the numbers of cfu in the liver, spleen and lungs. However, there was no reduction in the number of cfu in the kidneys and this led to relapse of infection once therapy was terminated. Fluconazole in a dosage of 64 mg/kg/day produced effects which were similar to those of AmB-DOC; prolonged treatment with fluconazole for 18 days did not improve the efficacy of this agent. Only treatment with high-dosage (7 mg/kg/day) L-AmB was effective in significantly reducing the numbers of cfu of C. albicans in the kidneys and other organs of leucopenic mice, as well as preventing relapse, even in severely infected animals.
van Etten
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Department of Clinical Microbiology and Antimicrobial Therapy, Erasmus University, Rotterdam, The Netherlands.
van den Heuvel-de Groot
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Bakker-Woudenberg
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D000666:Amphotericin B / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D002177:Candidiasis / Q000188:drug therapy* / Q000276:immunology; D003840:Deoxycholic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D004337:Drug Carriers; D004338:Drug Combinations; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use*; D007121:Immunocompetence; D007970:Leukopenia / Q000150:complications*; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests
D004337:Drug Carriers; D004338:Drug Combinations; D008081:Liposomes; C068538:liposomal amphotericin B; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D015725:Fluconazole