1. Pharmacokinetics/pharmacodynamic correlations of fluconazole in murine model of cryptococcosis.
- Author
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Santos JR, César IC, Costa MC, Ribeiro NQ, Holanda RA, Ramos LH, Freitas GJ, Paixão TA, Pianetti GA, and Santos DA
- Subjects
- Amphotericin B therapeutic use, Animals, Brain metabolism, Brain microbiology, Chromatography, Liquid, Colony Count, Microbial, Disease Models, Animal, Lung metabolism, Lung microbiology, Male, Mice, Inbred C57BL, Microbial Sensitivity Tests, Models, Biological, Spectrometry, Mass, Electrospray Ionization, Antifungal Agents blood, Antifungal Agents pharmacokinetics, Antifungal Agents therapeutic use, Cryptococcosis drug therapy, Cryptococcosis metabolism, Cryptococcosis microbiology, Cryptococcus gattii drug effects, Cryptococcus gattii growth & development, Cryptococcus gattii isolation & purification, Drug Resistance, Fungal, Fluconazole blood, Fluconazole pharmacokinetics, Fluconazole therapeutic use
- Abstract
The emergence of fluconazole-resistant Cryptococcus gattii is a global concern, since this azole is the main antifungal used worldwide to treat patients with cryptococcosis. Although pharmacokinetic (PK) and pharmacodynamic (PD) indices are useful predictive factors for therapeutic outcomes, there is a scarcity of data regarding PK/PD analysis of antifungals in cryptococcosis caused by resistant strains. In this study, PK/PD parameters were determined in a murine model of cryptococcosis caused by resistant C. gattii. We developed and validated a suitable liquid chromatography-electrospray ionization tandem mass spectrometry method for PK studies of fluconazole in the serum, lungs, and brain of uninfected mice. Mice were infected with susceptible or resistant C. gattii, and the effects of different doses of fluconazole on the pulmonary and central nervous system fungal burden were determined. The peak levels in the serum, lungs, and brain were achieved within 0.5h. The AUC/MIC index (area under the curve/minimum inhibitory concentration) was associated with the outcome of anti-cryptococcal therapy. Interestingly, the maximum concentration of fluconazole in the brain was lower than the MIC for both strains. In addition, the treatment of mice infected with the resistant strain was ineffective even when high doses of fluconazole were used or when amphotericin B was tested, confirming the cross-resistance between these drugs. Altogether, our novel data provide the correlation of PK/PD parameters with antifungal therapy during cryptococcosis caused by resistant C. gattii., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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