Fluconazole, with or without dexamethasone for experimental cryptococcosis: impact of treatment timing

The time of initiation of fluconazole treatment with or without dexamethaso ne, and the impact on mycological outcome and drug pharmacokinetics were as sessed in a murine model of disseminated cryptococcosis. Non-infected mice and mice with disseminated cryptococcosis were given saline, dexamethasone, or fluconazole +/- dexamethasone, 1 or 8 days after infection. Cfus were c ounted in tissues, and fluconazole concentrations were determined in plasma and tissues by HPLC and a bioassay. Despite fluconazole tissue and plasma concentrations which were above the minimal inhibitory concentration, the n umbers of cfus in brain and lung tissues were reduced after early (P = 0.00 2 and 0.04, respectively), but not after late fluconazole treatment. The ad ministration of dexamethasone did not have a deleterious effect on the numb er of cfus, fluconazole pharmacokinetics or antifungal activity. In conclus ion, the size of the fungal burden influences the effective level of flucon azole activity in lung and brain. These results strongly suggest that poten tial antifungal agents should be studied following both early and late admi nistration in experimental cryptococcosis.