Treatment of murine pulmonary cryptococcosis with ketoconazole and amphotericin B

One hundred days postinfection there was a significant increase in the survival of immunosuppressed mice infected intranasally with C neoformans (P < 0.05- < 0.001) and a significant decrease in the incidence of C neoformans in both the lung and brain tissue (P < 0.02 to 0.001) of mice treated for 15 or 30 days with KTZ alone, AMB alone, or KTZ plus AMB compared with untreated mice. AMB was the most effective and KTZ the least effective therapy in the treatment of murine pulmonary cryptococcosis for both the 15- and the 30-days periods. Little difference was seen in either mortality or in the incidence of C neoformans in both the lung and brain tissue of mice treated with AMB alone for either the 15- or 30-days period. Although not statistically significant, there was a decrease in both mortality and the incidence of C neoformans in the lungs of mice when therapy with KTZ alone was extended from 15 to 30 days. It has previously been shown that prolonged therapy with KTZ is also more effective in the treatment of other systemic mycoses [1]. Treatment with KTZ plus AMB for 15 days was as effective as treatment with AMB alone in decreasing both mortality and decreasing the incidence of C neoformans in both lung and brain tissue, a trend also reported by other investigators who used KTZ plus AMB to treat cryptococcal disease in experimental animals [2, 3]; however, when treatment with KTZ plus AMB was extended to 30 days, there was an increase in both mortality and the percentage of C neoformans-positive cultures recovered from lung and brain tissue of infected mice, suggesting that antagonism may have occurred after prolonged treatment with the two drugs in combination. Since ketoconazole, an easily administered and relatively nontoxic drug, significantly decreased the mortality of infected mice by preventing dissemination of C neoformans from the lungs to the brain, it should be considered in the treatment of pulmonary cryptococcosis in the immunocompromised patient.