title: Pharmacokinetics/pharmacodynamic correlations of fluconazole in murine model of cryptococcosis.
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.
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Micologia, Universidade Ceuma (UNICEUMA), São Luís, Maranhão, Brazil.
authors.forename: Julliana Ribeiro Alves
authors.initials: JR
authors.lastname: Santos
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Isabela Costa
authors.initials: IC
authors.lastname: César
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Marliete Carvalho
authors.initials: MC
authors.lastname: Costa
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Noelly Queiroz
authors.initials: NQ
authors.lastname: Ribeiro
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Rodrigo Assunção
authors.initials: RA
authors.lastname: Holanda
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Lais Hott
authors.initials: LH
authors.lastname: Ramos
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Gustavo José Cota
authors.initials: GJ
authors.lastname: Freitas
authors.affiliation: Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Tatiane Alves
authors.initials: TA
authors.lastname: Paixão
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Gerson Antônio
authors.initials: GA
authors.lastname: Pianetti
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. Electronic address: das@ufmg.br.
authors.forename: Daniel Assis
authors.initials: DA
authors.lastname: Santos
mesh_terms: D000666:Amphotericin B / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism / Q000382:microbiology; D002853:Chromatography, Liquid; D015169:Colony Count, Microbial; D003453:Cryptococcosis / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D056285:Cryptococcus gattii / Q000187:drug effects / Q000254:growth & development / Q000302:isolation & purification; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole
keywords: Cryptococcus gattii; Fluconazole; Pharmacodynamics; Pharmacokinetics; Resistance