title: Effect of severity of meningitis on fungicidal activity of flucytosine combined with fluconazole in a murine model of cryptococcal meningitis.
abstract: We studied the effect of the severity of meningitis on the response to therapy with fluconazole and flucytosine in a murine model of cryptococcal meningitis. Meningitis was established by intracerebral injection of Cryptococcus neoformans. The severity of meningitis was varied by delaying the onset of treatment from 3 to 7 days. Animals were sacrificed after 14 days of treatment, and the numbers of C. neoformans per gram of brain tissue were quantified. The range of effective dose combinations of fluconazole and flucytosine became progressively reduced as the severity of meningitis increased. The magnitude of treatment effect, as measured by the numbers of CFU/gram of brain tissue, was also reduced with increasing severity of meningitis. In this model, as the severity of meningitis increases, higher doses of fluconazole are required to achieve equivalent levels of activity. The combination of fluconazole and flucytosine appears to have the most-potent antifungal effects. This is most readily observed in animals with more-severe meningitis.
authors.affiliation: Department of Medicine (Infectious Diseases), University of Southern California, Los Angeles 90033, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Ding
authors.forename: M
authors.initials: M
authors.lastname: Bauer
authors.forename: D M
authors.initials: DM
authors.lastname: Diamond
authors.forename: M A
authors.initials: MA
authors.lastname: Leal
authors.forename: D
authors.initials: D
authors.lastname: Johnson
authors.forename: B K
authors.initials: BK
authors.lastname: Williams
authors.forename: A M
authors.initials: AM
authors.lastname: Thomas
authors.forename: L
authors.initials: L
authors.lastname: Najvar
authors.forename: J R
authors.initials: JR
authors.lastname: Graybill
authors.forename: R A
authors.initials: RA
authors.lastname: Larsen
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000254:growth & development; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D015725:Fluconazole / Q000627:therapeutic use; D005437:Flucytosine / Q000627:therapeutic use; D008297:Male; D016919:Meningitis, Cryptococcal / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D015996:Survival Rate
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole; D005437:Flucytosine