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

Abstract

ABSTRACTIt has been argued that thein vitroactivity of caspofungin (CSP) is not a good predictor of the outcome of echinocandin treatmentin vivo. We evaluated thein vitroactivity of CSP and the presence ofFKSmutations in the hot spot 1 (HS1) region of theFKS1andFKS2genes 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 theFKS1gene and five in theFKS2gene. 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 theFKS2gene of six strains with different MICs, but their presence did not influence drug efficacy. Thein 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 theFKS1andFKS2genes, are predictive of outcome.