In Vitro Antifungal Susceptibility of Candida glabrata to Caspofungin and the Presence of FKS Mutations Correlate with Treatment Response in an Immunocompromised Murine Model of Invasive Infection

Identifier:  PC:51

Handle: https://hdl.handle.net/20.500.11797/PC51

Authors:  Fabiola Fernández-Silva; Michaela Lackner; Javier Capilla; Emilio Mayayo; Deanna Sutton; Mariana Castanheira; Annette W Fothergill

Abstract:
It has been argued that in vitro activity of caspofungin (CSP) is not a good predictor of the in vivo outcome of echinocandins treatment. We evaluated the in vitro activity of CSP and the presence of FKS mutations in the hot spot 1 (HS1) region of FKS1 and FKS2 genes of 17 Candida glabrata strains with a wide MICs range. The efficacy of CSP against systemic infections by all those strains was evaluated in a murine model. No HS1 mutations were found in the eight strains showing MICs of CSP ≤ 0.5 μg/ml, but they were present in eight of the nine strains with MICs ≥ 1 μg/ml, i.e. three in the FKS1 and five in the FKS2 genes. CSP was effective to treat mice infected with strains with MICs ≤ 0.5μg/ml, showed variable efficacy in animals challenged with strains with MICs = 1μg/ml and did not work in those with strains with MICs > 1μg/ml. In addition, mutations outside the HS1 region were found in the FKS 2 gene of six strains with different MICs, including a first time reported mutation, but their presence did not influence the drug efficacy. In vitro activity of CSP was compared with other echinocandin i.e., anidulafungin suggesting that MICs of both drugs as well as mutations in the HS1 regions of FKS1 or FKS2 genes are predictive of the outcome.