title: Dynamic interaction between fluconazole and amphotericin B against Cryptococcus gattii.
abstract: Cryptococcus gattii is the main pathogen of cryptococcosis in healthy patients and is treated mainly with fluconazole and amphotericin B. The combination of these drugs has been questioned because the mechanisms of action could lead to a theoretical antagonistic interaction. We evaluated distinct parameters involved in the in vitro combination of fluconazole and amphotericin B against Cryptococcus gattii. Fourteen strains of C. gattii were used for the determination of MIC, fractional inhibitory concentration, time-kill curve, and postantifungal effect (PAFE). Ergosterol quantification was performed to evaluate the influence of ergosterol content on the interaction between these antifungals. Interaction between the drugs varied from synergistic to antagonistic depending on the strain and concentration tested. Increasing fluconazole levels were correlated with an antagonistic interaction. A total of 48 h was necessary for reducing the fungal viability in the presence of fluconazole, while 12 h were required for amphotericin B. When these antifungals were tested in combination, fluconazole impaired the amphotericin B activity. The ergosterol content decreased with the increase of fluconazole levels and it was correlated with the lower activity of amphotericin B. The PAFE found varied from 1 to 4 h for fluconazole and from 1 to 3 h for amphotericin B. The interaction of fluconazole and amphotericin B was concentration-dependent and special attention should be directed when these drugs are used in combination against C. gattii.
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
authors.forename: Julliana Ribeiro Alves
authors.initials: JR
authors.lastname: Santos
authors.forename: Ludmila Ferreira
authors.initials: LF
authors.lastname: Gouveia
authors.forename: Erika Linzi Silva
authors.initials: EL
authors.lastname: Taylor
authors.forename: Maria Aparecida
authors.initials: MA
authors.lastname: Resende-Stoianoff
authors.forename: Gerson Antônio
authors.initials: GA
authors.lastname: Pianetti
authors.forename: Isabela Costa
authors.initials: IC
authors.lastname: César
authors.forename: Daniel Assis
authors.initials: DA
authors.lastname: Santos
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D056285:Cryptococcus gattii / Q000187:drug effects* / Q000254:growth & development; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004357:Drug Synergism; D004875:Ergosterol / Q000378:metabolism; D015725:Fluconazole / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D013045:Species Specificity; D013053:Spectrophotometry
chemical_list: D000935:Antifungal Agents; D003470:Culture Media; D000666:Amphotericin B; D015725:Fluconazole; D004875:Ergosterol