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In vitro pharmacodynamic model (PDM) simulation of serum antifungal concentrations may predict the value of combination antifungal regimens against Candida sp. endocarditis. We investigated the effects of combinations of flucytosine (5FC), micafungin (Mica), and voriconazole (Vor) against Candida-infected human platelet-fibrin clots, used as simulated endocardial vegetations (SEVs). Single clinical bloodstream isolates of Candida albicans, Candida glabrata, Candida parapsilosis, and Candida tropicalis were used. All four isolates were susceptible to 5FC, while C. glabrata was resistant to Vor and C. tropicalis had a paradoxical resistance phenotype to Mica. The SEVs were prepared with an initial inoculum of 1 x 10(6) CFU/g of SEV and added to a PDM, which utilized yeast nitrogen broth-2% glucose and incubation at 35 degrees C and simulated antifungal pharmacokinetic profiles. Fungal densities in the SEVs were determined in quadruplicate over 72 h. Scanning electron microscopy (SEM) was used to evaluate treatment and control SEVs. Vor was the least active single agent against all Candida spp. except for C. parapsilosis, where it was comparable to Mica. In contrast, 5FC was the most active against all Candida spp. except for C. tropicalis, where it was comparable to Mica. The combination of 5FC plus Vor was superior to either agent alone against C. parapsilosis. The combination of Vor plus Mica was inferior to the use of Mica alone against C. tropicalis. The triple combination of 5FC plus Vor plus Mica was no better than single or dual agents against any of the Candida spp. The ultrastructural features of infected SEVs were unique for each Candida sp., with C. parapsilosis in particular manifesting friable biofilm clusters. In general, 5FC and Mica were superior in their rates and extents of fungal burden reduction compared to Vor against Candida-infected SEVs. Evaluation of 5FC and Mica in animal models of Candida endocarditis is warranted.