DOSE-DEPENDENT ANTIFUNGAL ACTIVITY AND NEPHROTOXICITY OF AMPHOTERICIN-B COLLOIDAL DISPERSION IN EXPERIMENTAL PULMONARY ASPERGILLOSIS

We investigated the safety and efficacy of amphotericin B colloidal di spersion (ABCD) for the treatment of invasive pulmonary aspergillosis in persistently granulocytopenic rabbits. Treatment groups included AB CD in dosages of 1, 5, and 10 mg/kg/day intravenously or conventional desoxycholate amphotericin B (DAmB) at 1 mg/kg/day intravenously. Anti fungal activity was directly related to increasing dosage of ABCD as d etermined by the concentration of Aspergillus fumigatus organisms in l ungs and the frequency of hemorrhagic pulmonary lesions. At 5 and 10 m g/kg/day, there was a significant reduction in the tissue burden of A. fumigatus as measured by percent culture-positive lobes and CFU per g ram of tissue (P less than or equal to 0.001), whereas at 1 mg/kg/day the tissue burden of A. fumigatus was not significantly different from that in untreated controls. Microbiological clearance was significant ly greater at 1 mg of DAmB per kg per day than at 1 mg of ABCD per kg per day (P less than or equal to 0.001). There was no difference in mi crobiological clearance of bronchoalveolar lavage fluid among the trea tment groups as measured by CFU per milliliter. As determined by survi val, ABCD at 5.0 mg/kg/day was more effective than DAmB at 1.0 mg/kg/d ay and ABCD at 10 mg/kg/day. ABCD at 10 mg/kg/day was more nephrotoxic than the lower dosages of ABCD and resulted in higher mortality. Impa irment of glomerular filtration developed as a direct function increas ing the ABCD dosage (r = 0.77; P < 0.001). In summary, this study foun d dose-dependent antifungal activity and nephrotoxicity of ABCD agains t invasive pulmonary aspergillosis in persistently granulocytopenic ra bbits and showed that the optimal dosage of ABCD for antifungal activi ty and safety was 5 mg/kg/day.