Antifungal activity of amphotericin B-lipid admixtures in experimental systemic candidosis in naive mice.
We have shown previously that admixtures of amphotericin B (AMB) and Intralipid (AMB-IL) obtained by vigorous and prolonged agitation are stable and can be standardized. These preparations exhibited in-vitro activity against various Candida spp., and had significantly lower toxicity. The present study was undertaken to evaluate the activity of AMB-IL admixtures in vivo in comparison with the conventional formulation of AMB (Fungizone), using a murine model of experimental systemic candidosis. ICR female mice (4-6 weeks old) were injected iv with 5 x 10(4) Candida albicans CBS 562. The animals developed a lethal infection (100%) within 10 days. Systemic candidosis was demonstrated by the presence of fungal elements in kidneys and spleen tissue, and by enumeration of cfu of Candida in the tissue homogenates. AMB-IL or AMB was administered iv 48 h post-Candida inoculation for 5 consecutive days. Four experiments with 108 mice treated with AMB 5 x 0.4 mg/kg and followed up for 6 weeks, showed that the mean survival percentages at the end of the experiment were 0, 24.9 and 52.5% for the untreated group, conventional AMB-treated and AMB-IL-treated groups, respectively. The mean survival time (MST) was 7.4, 25 and 30 days for the untreated, conventional AMB-treated and AMB-IL-treated groups, respectively. Use of increased doses of AMB showed that conventional AMB at doses greater than 5 x 1 mg/kg caused immediate animal death. AMB-IL was used at doses of AMB up to 5 x 2 mg/kg. Experiments with 104 mice revealed that the mean survival percentage at the end of the experiment was 0, 34.5, 58.6 and 97% for the untreated, conventional AMB-treated (5 x 1 mg/kg), AMB-IL-1-treated (5 x 1 mg/kg) and AMB-IL-2-treated (5 x 2 mg/kg) groups, respectively. The MST was 7, 27.8, 34.8 and 41.4 days for the untreated, conventional AMB-treated, AMB-IL-1-treated and AMB-IL-2-treated groups, respectively. The results of this study reveal that AMB-IL is significantly more effective in treating systemic murine candidosis than conventional AMB.
Shadkchan
Y
Y
Department of Human Microbiology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Segal
E
E
D000666:Amphotericin B / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002176:Candida albicans / Q000302:isolation & purification; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR
D000935:Antifungal Agents; D005217:Fat Emulsions, Intravenous; D000666:Amphotericin B