Anidulafungin Is Fungicidal and Exerts a Variety of Postantifungal Effects against Candida albicans , C. glabrata , C. parapsilosis , and C. krusei isolates

Abstract

Anidulafungin targets the cell walls of Candida species by inhibiting beta-1,3-glucan synthase, thereby killing isolates and exerting prolonged postantifungal effects (PAFEs). We performed time-kill and PAFE experiments on Candida albicans (n = 4), C. glabrata (n = 3), C. parapsilosis (n = 3), and C. krusei (n = 2) isolates and characterized the PAFEs in greater detail. MICs were 0.008 to 0.125 microg/ml against C. albicans, C. glabrata, and C. krusei and 1.0 to 2.0 microg/ml against C. parapsilosis. During time-kill experiments, anidulafungin caused significant kills at 16x MIC (range, log 2.68 to 3.89) and 4x MIC (log 1.87 to 3.19), achieving fungicidal levels (>or=log 3) against nine isolates. A 1-hour drug exposure during PAFE experiments resulted in kills ranging from log 1.55 to 3.47 and log 1.18 to 2.89 (16x and 4x MIC, respectively), achieving fungicidal levels against four isolates. Regrowth of all 12 isolates was inhibited for >or=12 h after drug washout. Isolates of each species collected 8 h after a 1-hour exposure to anidulafungin (16x and 4x MIC) were hypersusceptible to sodium dodecyl sulfate (0.01 to 0.04%) and calcofluor white (40 microg/ml). Moreover, PAFEs were associated with major cell wall disturbances, as evident in electron micrographs of viable cells, and significant reductions in adherence to buccal epithelial cells (P <or= 0.01). Finally, three of four PAFE isolates tested were hypersusceptible to killing by J774 macrophages (P <or= 0.007). Our data suggest that the efficacy of anidulafungin in the treatment of candidiasis might stem from both direct fungicidal activity and indirect PAFEs that lessen the ability of Candida cells to establish invasive disease and to persist within infected hosts.