Comparative in vivo dose-dependent activity of caspofungin and anidulafungin against echinocandin-susceptible and -resistant Aspergillus fumigatus

Abstract

Echinocandin resistance in Aspergillus species is rare. We examined if mutations in FKS1 would result in a complete loss of echinocandin activity in vivo in an experimental model of aspergillosis. Neutropenic mice were infected with either an echinocandin-susceptible Aspergillus fumigatus (AF 293) or an echinocandin-resistant A. fumigatus laboratory strain harbouring 'hot-spot' substitution in Fks1p (AF Ser678Pro). Mice then received daily treatment with either anidulafungin or caspofungin at varying dosages (0.25-16 mg/kg/day) for 5 days and Aspergillus lung fungal burden was assessed by quantitative real-time PCR. Both strains produced histological evidence of progressive invasive pulmonary aspergillosis, but AF Ser678Pro was less virulent than AF 293, as evidenced by lower lung fungal burden and longer median survival time. At > 0.5 mg/kg/day, both anidulafungin and caspofungin reduced the lung fungal burden in neutropenic animals infected with AF 293, but had mixed efficacy against the resistant AF Ser678Pro strain. For caspofungin, the fungal burden was reduced only at doses <1 mg/kg/day. Anidulafungin also modestly reduced AF Ser678Pro lung fungal burden, but only at > 4 mg/kg/day. Despite a lack of appreciable antifungal activity in vitro, both anidulafungin and caspofungin were still modestly effective in vivo against a laboratory-generated A. fumigatus mutant harbouring the Ser678Pro mutation in Fks1p. This persistent activity, combined with impaired fitness of the isolate in vivo, could partially explain why microbiologically documented echinocandin-resistance in Aspergillus species remains a rare clinical occurrence.