In VitroAntifungal Susceptibility of Candida glabratato Caspofungin and the Presence of FKSMutations Correlate with Treatment Response in an Immunocompromised Murine Model of Invasive Infection

ABSTRACTIt has been argued that the in vitroactivity of caspofungin (CSP) is not a good predictor of the outcome of echinocandin treatment in vivo. We evaluated the in vitroactivity of CSP and the presence of FKSmutations in the hot spot 1 (HS1) region of the FKS1and FKS2genes in 17 Candida glabratastrains with a wide range of MICs. The efficacy of CSP against systemic infections from each of the 17 strains was evaluated in a murine model. No HS1 mutations were found in the eight strains showing MICs for CSP of ≤0.5 μg/ml, but they were present in eight of the nine strains with MICs of ≥1 μg/ml, i.e., three in the FKS1gene and five in the FKS2gene. CSP was effective for treating mice infected with strains with MICs of ≤0.5 μg/ml, showed variable efficacy in animals challenged with strains with MICs of 1 μg/ml, and did not work in those with strains with MICs of >1 μg/ml. In addition, mutations, including one reported for the first time, were found outside the HS1 region in the FKS2gene of six strains with different MICs, but their presence did not influence drug efficacy. The in vitroactivity of CSP was compared with that of another echinocandin, anidulafungin, suggesting that the MICs of both drugs, as well as mutations in the HS1 regions of the FKS1and FKS2genes, are predictive of outcome.