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

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,...

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Bibliographic Details
Published in:Journal of antimicrobial chemotherapy 1999-06, Vol.43 (6), p.817-824
Main Authors: LORTHOLARY, O, NICOLAS, M, SOREDA, S, IMPROVISI, L, RONIN, O, PETITJEAN, O, DUPONT, B, TOD, M, DROMER, F
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents - pharmacology
Anti-Inflammatory Agents - therapeutic use
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antifungal agents
Antifungal Agents - blood
Antifungal Agents - pharmacokinetics
Antifungal Agents - therapeutic use
Biological and medical sciences
Biological Assay
Chromatography, High Pressure Liquid
Cryptococcosis - drug therapy
Cryptococcus
Cryptococcus neoformans - drug effects
Dexamethasone - pharmacology
Dexamethasone - therapeutic use
Disease Models, Animal
Drug Therapy, Combination
Fluconazole - blood
Fluconazole - pharmacokinetics
Fluconazole - therapeutic use
Male
Medical sciences
Mice
Pharmacology. Drug treatments
Time Factors
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Summary: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.
ISSN:0305-7453
1460-2091
DOI:10.1093/jac/43.6.817