Combination therapy in a model of pulmonary aspergillosis

The current treatment for pulmonary aspergillosis, amphotericin B, is toxic and not always effective. This study was done to evaluate combinations of amphotericin B with other agents in an animal model of pulmonary aspergillosis. Sprague-Dawley rats were treated with cortisone acetate, infected intratracheally with 10(6) spores of Aspergillus fumigatus, and followed daily for survival. Mortality among controls started on day 2, and it was 80% by day seven, whereas therapy with amphotericin B resulted in survival of all animals. When given alone, ketoconazole, 5-fluorocytosine and rifampin did not improve survival. The combination of ketoconazole with amphotericin B resulted in complete antagonism. When animals received a combination of aerosol amphotericin B prophylaxis two days prior to infection followed by treatments with SCH39304 or itraconazole seven days after infection, survival rates were superior as compared to animals that had received aerosol prophylaxis only. The combinations of either 5-fluorocytosine or rifampin with amphotericin B were not better than amphotericin B alone. While combinations with 5-fluorocytosine or rifampin appear not to offer any advantage over therapy with amphotericin B alone, additional studies to further evaluate the role of azoles in combination therapy are needed.