title: Effects of fluconazole singly and in combination with 5-fluorocytosine or amphotericin B in the treatment of cryptococcal meningoencephalitis in an intracranial murine model.
abstract: In this study we developed a highly reproducible intracranial murine model of cryptococcosis. Mice (Balb/c, 5-7 weeks old) were challenged intracranially and treated with intermediate (30 mg/kg) or high (90 mg/kg) dose fluconazole, and amphotericin B (0.75 mg/kg), administered singly or in combination with flucytosine (100 mg/kg). Survival and brain CFU analyses were performed. Effect of fluconazole prophylaxis was also determined. Our data show that the developed model mimics clinical signs of cryptococcal meningitis. In single treatment, fluconazole (30 mg/kg) was more efficacious than amphotericin B or flucytosine (P < 0.0001). Combination treatment led to significantly increased anticryptococcal activity, which was highest for high dose fluconazole + flucytosine (P < 0.0001). However, no significant difference was observed between high dose fluconazole treatment with and without flucytosine (P >0.05). Fluconazole prophylaxis led to a significant decrease in brain CFU. In conclusion, high dose fluconazole administered post-infection, or as prophylaxis, may be highly efficacious in the treatment and prevention of meningoencephalitis.
authors.affiliation: Center for Medical Mycology, Department of Dermatology, University Hospitals of Cleveland, Case Western Reserve University, OH 44106-5028, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Hossain
authors.forename: P K
authors.initials: PK
authors.lastname: Mukherjee
authors.forename: G
authors.initials: G
authors.lastname: Reyes
authors.forename: L
authors.initials: L
authors.lastname: Long
authors.forename: M A
authors.initials: MA
authors.lastname: Ghannoum
mesh_terms: D000666:Amphotericin B / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001921:Brain / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000302:isolation & purification; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000627:therapeutic use*; D015725:Fluconazole / Q000627:therapeutic use*; D005437:Flucytosine / Q000627:therapeutic use*; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D015996:Survival Rate
chemical_list: D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole; D005437:Flucytosine