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Dose-dependent antifungal activity and nephrotoxicity of amphotericin B colloidal dispersion in experimental
M C Allende1, J W Lee, P Francis
1Infectious Diseases Section, National Cancer Institute, Bethesda, Maryland 20892.
Abstract:
We investigated the safety and efficacy of amphotericin B colloidal dispersion (ABCD) for the treatment of invasive pulmonary aspergillosis in persistently granulocytopenic rabbits. Treatment groups included ABCD in dosages of 1, 5, and 10 mg/kg/day intravenously or conventional desoxycholate amphotericin B (DAmB) at 1 mg/kg/day intravenously. Antifungal activity was directly related to increasing dosage of ABCD as determined by the concentration of Aspergillus fumigatus organisms in lungs and the frequency of hemorrhagic pulmonary lesions. At 5 and 10 mg/kg/day, there was a significant reduction in the tissue burden of A. fumigatus as measured by percent culture-positive lobes and CFU per gram of tissue (P < or = 0.001), whereas at 1 mg/kg/day measured by percent culture-positive lobes and CFU per gram of tissue (P < or = 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 significantly greater at 1 mg of DAmB per kg per day than at 1 mg of ABCD per kg per day (P < or = 0.001). There was no difference in microbiological clearance of bronchoalveolar lavage fluid among the treatment groups as measured by CFU per milliliter. As determined by survival, ABCD at 5.0 mg/kg/day was more effective than DAmB at 1.0 mg/kg/day 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. Impairment of glomerular filtration developed as a direct function increasing the ABCD dosage (r = 0.77; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Amphotericin B colloidal dispersion (ABCD) shows dose-dependent efficacy against invasive pulmonary aspergillosis in rabbits. Higher ABCD doses improved fungal clearance but increased nephrotoxicity and mortality.
Area of Science:
- Mycology
- Pharmacology
- Infectious Diseases
Background:
- Invasive pulmonary aspergillosis is a serious fungal infection.
- Granulocytopenic patients are at high risk for invasive aspergillosis.
- Novel antifungal treatments are needed to improve outcomes.
Purpose of the Study:
- To evaluate the safety and efficacy of amphotericin B colloidal dispersion (ABCD) for treating invasive pulmonary aspergillosis.
- To compare ABCD with conventional desoxycholate amphotericin B (DAmB) in a rabbit model.
Main Methods:
- Rabbits with persistent granulocytopenia were infected with Aspergillus fumigatus.
- Treatment groups received varying doses of ABCD intravenously or DAmB intravenously.
- Efficacy was assessed by fungal burden in lungs, lesion frequency, and survival.
- Nephrotoxicity was evaluated by glomerular filtration impairment.
Main Results:
- ABCD efficacy was dose-dependent, with significant fungal burden reduction at 5 and 10 mg/kg/day.
- DAmB at 1 mg/kg/day showed greater microbiological clearance than ABCD at the same dose.
- ABCD at 5 mg/kg/day improved survival compared to DAmB.
- Higher ABCD doses (10 mg/kg/day) led to increased nephrotoxicity and mortality.
Conclusions:
- ABCD demonstrates promising efficacy for invasive pulmonary aspergillosis in a dose-dependent manner.
- Balancing efficacy and toxicity is crucial when selecting ABCD dosage.
- Further research is warranted to optimize ABCD use in clinical settings.