A high-dose-step-down strategy for
caspofungin treatment was evaluated in an experimental model of advanced-stage
invasive pulmonary aspergillosis. The therapeutic efficacy of
caspofungin in relation to the severity of invasive pulmonary
infection caused by Aspergillus fumigatus in transiently neutropenic rats was investigated by using rat survival and the decrease in the fungal burden as the parameters of efficacy. When treatment was started at either 16 h or 24 h after fungal inoculation,
caspofungin administered intraperitoneally at 4 mg/kg of
body weight/day for 10 days was highly effective (100% and 93% rat survival, respectively). However, only 27% rat survival was obtained when treatment was started at 72 h, when the rats had advanced-stage
infection. Increasing the dose from 4 to 10 mg/kg/day could compensate for the decrease in efficacy and resulted in 67% rat survival. The high dose of 10 mg/kg/day for 10 days did not appear to be necessary since a high-dose-step-down dosing schedule with 10 mg/kg/day for 3 days followed by 4 mg/kg/day for 7 days was equally effective.
At 10 days after the end of treatment with 10 mg/kg/day
caspofungin, the level of neither A. fumigatus
DNA nor A. fumigatus
galactomannan in the infected left lung was significantly decreased. In contrast, A. fumigatus
galactomannan concentrations in serum were significantly decreased. The levels of
creatinine, blood
urea nitrogen,
alanine aminotransferase, and asparate
aminotransferase were not elevated during treatment.
Caspofungin is effective for the treatment of
invasive pulmonary aspergillosis in transiently neutropenic rats and is even effective in rats with advanced-stage
infection. In this model, the administration of high-dose-step-down treatment was as effective as treatment with high doses for the whole treatment period.