title: Comparison of D0870 and fluconazole in the treatment of murine cryptococcal meningitis.
abstract: Cryptococcal meningitis is a common infection in patients with AIDS. Using a murine cryptococcosis model, we compared treatment with a new triazole, D0870, and fluconazole. Groups of ICR (Institute for Cancer Research) mice were infected intracerebrally with eight different isolates of Cryptococcus neoformans variety neoformans with different in vitro susceptibilities to fluconazole. For survival studies mice were challenged with two to four times LD(50) or six to nine times LD(50). Treatment was given for 10 days. Mice were observed through to day 30. To assess the effect of treatment on fungal tissue burden, mice received a three to five times LD(50) inoculum and treatment for 10 days. They were sacrificed on day 12 and serial dilutions of brain homogenates were cultured. Fluconazole prolonged survival primarily in isolates which were susceptible in vitro. D0870 prolonged survival in all isolates except one, which was also resistant in vitro to D0870 and fluconazole. Both drugs reduced colony counts of all isolates. D0870 warrants further development for use in cryptococcosis, and appears effective for isolates relatively resistant to fluconazole. There is a relative correlation of in vivo and in vitro susceptibility to D0870 as well as fluconazole.
authors.affiliation: Department of Medicine University of Texas Health Science Center, San Antonio, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Correa
authors.forename: G
authors.initials: G
authors.lastname: Velez
authors.forename: M
authors.initials: M
authors.lastname: Albert
authors.forename: M
authors.initials: M
authors.lastname: Luther
authors.forename: M G
authors.initials: MG
authors.lastname: Rinaldi
authors.forename: J R
authors.initials: JR
authors.lastname: Graybill
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D003455:Cryptococcus neoformans; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial; D015725:Fluconazole / Q000627:therapeutic use*; D008297:Male; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D015996:Survival Rate; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C058219:ICI 195739; D015725:Fluconazole