title: Correlation of the in vitro antifungal drug susceptibility with the in vivo activity of fluconazole in a murine model of cerebral infection caused by Cryptococcus gattii.
abstract: Forty Cryptococcus gattii strains were submitted to antifungal susceptibility testing with fluconazole, itraconazole, amphotericin B and terbinafine. The minimum inhibitory concentration (MIC) ranges were 0.5-64.0 for fluconazole, <0.015-0.25 for itraconazole, 0.015-0.5 for amphotericin B and 0.062-2.0 for terbinafine. A bioassay for the quantitation of fluconazole in murine brain tissue was developed. Swiss mice received daily injections of the antifungal, and their brains were withdrawn at different times over the 14-day study period. The drug concentrations varied from 12.98 to 44.60 μg/mL. This assay was used to evaluate the therapy with fluconazole in a model of infection caused by C. gattii. Swiss mice were infected intracranially and treated with fluconazole for 7, 10 or 14 days. The treatment reduced the fungal burden, but an increase in fungal growth was observed on day 14. The MIC for fluconazole against sequential isolates was 16 μg/mL, except for the isolates obtained from animals treated for 14 days (MIC = 64 μg/mL). The quantitation of cytokines revealed a predominance of IFN-γ and IL-12 in the non-treated group and elevation of IL-4 and IL-10 in the treated group. Our data revealed the possibility of acquired resistance during the antifungal drug therapy.
authors.affiliation: Faculdade de Ciências da Saúde, Universidade Vale do Rio Doce, Rua Israel Pinheiro, 2000, Bairro Universitário, 35020-220 Governador Valadares, Minas Gerais, Brazil.
authors.forename: F E S
authors.initials: FE
authors.lastname: Mendes
authors.forename: L V N
authors.initials: LV
authors.lastname: Oliveira
authors.forename: E S
authors.initials: ES
authors.lastname: Faria
authors.forename: D G
authors.initials: DG
authors.lastname: Alvarenga
authors.forename: M R
authors.initials: MR
authors.lastname: Pinto
authors.forename: C P
authors.initials: CP
authors.lastname: Taborda
authors.forename: B M
authors.initials: BM
authors.lastname: Soares
authors.forename: P S
authors.initials: PS
authors.lastname: Cisalpino
authors.forename: D A
authors.initials: DA
authors.lastname: Santos
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000382:microbiology*; D020314:Central Nervous System Fungal Infections / Q000188:drug therapy* / Q000382:microbiology; D003453:Cryptococcosis / Q000188:drug therapy* / Q000382:microbiology; D056285:Cryptococcus gattii / Q000187:drug effects*; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole
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