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Journal of Antimicrobial Chemotherapy (1999) 43, 817-824
© 1999 The British Society for Antimicrobial Chemotherapy

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

Olivier Lortholarya, Marlène Nicolasa, Stephan Soredab, Luce Improvisia, Olivier Ronina, Olivier Petitjeanb, Bertrand Duponta, Michel Todb and Françoise Dromera,*

a Unité de Mycologie, Institut Pasteur, 25, rue du Dr Roux, 75724 Paris Cedex 15; b Service de Pharmaco-Toxicologie, Centre de Recherches en Pathologie Infectieuse et Tropicale, CREPIT 93, Hôpital Avicenne, Université Paris-Nord, 125, route de Stalingrad, 93009 Bobigny-Cedex, France

The time of initiation of fluconazole treatment with or without dexamethasone, and the impact on mycological outcome and drug pharmacokinetics were assessed 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 counted 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 numbers of cfus in brain and lung tissues were reduced after early (P= 0.002 and 0.04, respectively), but not after late fluconazole treatment. The administration of dexamethasone did not have a deleterious effect on the number of cfus, fluconazole pharmacokinetics or antifungal activity. In conclusion, the size of the fungal burden influences the effective level of fluconazole activity in lung and brain. These results strongly suggest that potential antifungal agents should be studied following both early and late administration in experimental cryptococcosis.

* Corresponding author. Tel: +33-1-40-61-33-89; Fax: +33-1-45-68-84-20; E-mail: dromer{at}pasteur.fr


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