title: Amphotericin B colloidal dispersion combined with flucytosine with or without fluconazole for treatment of murine cryptococcal meningitis.
abstract: Studies with animals and in vitro studies have demonstrated that flucytosine plus amphotericin B or fluconazole has significantly improved mycologic activity against meningitis caused by Cryptococcus neoformans compared to the activity of amphotericin B or fluconazole used alone. However, few doses have been tested in combination. This study evaluated the antifungal efficacy of amphotericin B colloidal dispersion (ABCD) combined with flucytosine with and without fluconazole in a murine model of cryptococcal meningitis. The following dosages were tested: ABCD at 0 to 12.5 mg/kg of body weight given intravenously 3 days/week, flucytosine at 0 to 110 mg/kg/day, and fluconazole at 0 to 50 mg/kg/day. Meningitis was established in male BALB/c mice by intracerebral injection of C. neoformans. Treatment with flucytosine with or without fluconazole dissolved in the sole source of drinking water was started on day 2; animals were sacrificed at 16 days, and the numbers of fungal colonies in the brain were quantified. A survival rate of 100% was achieved with ABCD plus flucytosine without fluconazole; however, the addition of fluconazole was required to prevent weight loss (P < 0.00001) and to achieve the maximum antifungal effect (P < 0.00001). The only region of dose combinations for which the 99% confidence intervals were less than 100 CFU/g of brain was defined by ABCD at 5.0 to 7.5 mg/kg combined with flucytosine at 20 to 60 mg/kg/day and fluconazole at 30 to 40 mg/kg/day. The triple combination of ABCD plus flucytosine and fluconazole was necessary to achieve the greatest antifungal activity.
authors.affiliation: Department of Medicine (Infectious Diseases), University of Southern California, Los Angeles 90033, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Diamond
authors.forename: M
authors.initials: M
authors.lastname: Bauer
authors.forename: B E
authors.initials: BE
authors.lastname: Daniel
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: J C
authors.initials: JC
authors.lastname: Ding
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: D000666:Amphotericin B / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000382:microbiology; D004359:Drug Therapy, Combination / Q000008:administration & dosage / Q000627:therapeutic use*; D015725:Fluconazole / Q000008:administration & dosage; D005437:Flucytosine / Q000627:therapeutic use*; D008297:Male; D016919:Meningitis, Cryptococcal / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D013047:Specific Pathogen-Free Organisms; D016019:Survival Analysis
chemical_list: D000666:Amphotericin B; D015725:Fluconazole; D005437:Flucytosine