Comparison of the dose-dependent activity and paradoxical effect of caspofungin and micafungin in a neutropenic murine model of invasive pulmonary aspergillosis

The safety and concentration-dependent pharmacodynamic characteristics of the echinocandins make them ideal candidates for dosage escalation in the treatment of aspergillosis. However, paradoxical attenuation of antifungal activity with increasing doses has been reported for some echinocandins in experimental models of invasive pulmonary aspergillosis (IPA). We compared the activity of micafungin and caspofungin administered over a wide dosing range that encompasses clinical exposures (0.25–10 mg/kg) in a neutropenic murine model of IPA. Both echinocandins exhibited dose-dependent reductions in fungal burden; however, caspofungin displayed a relatively steeper dose–response curve with a modest paradoxical increase in fungal burden that was not seen in micafungin-treated animals. Equivalent activity was observed with both echinocandins at daily doses ranging from 4 to 10 mg/kg. Both micafungin and caspofungin exhibit dose-dependent pharmacodynamic activity in vivo in the treatment of neutropenic IPA. Both echinocandins were equivalent at dosages ≥4 mg/kg day. Invasive aspergillosis (IA) is a common mould infection in patients with haematological malignancies undergoing chemotherapy and/or haematopoietic stem cell transplantation. Pneumonia, with or without sinusitis, is the most common manifestation of aspergillosis in this population.1 Although IA mortality rates have improved somewhat over the last decade due to changes in transplantation practices, earlier diagnosis and availability of new treatment options such as voriconazole and the echinocandins,2 crude mortality rates still exceed 50%.3 Consequently, improved strategies for the management of IA are still required.