title: Comparison of a new triazole, posaconazole, with itraconazole and amphotericin B for treatment of histoplasmosis following pulmonary challenge in immunocompromised mice.
abstract: A murine model of intratracheally induced histoplasmosis in immunocompromised B6C3F(1) mice was used to evaluate a new triazole antifungal agent, posaconazole. This compound was previously shown to be comparable to amphotericin B and superior to itraconazole for the treatment of histoplasmosis in immunocompetent mice. The current study used mice that were depleted of T lymphocytes by intraperitoneal injection of anti-CD4 and anti-CD8 monoclonal antibodies beginning 2 days before infection and continuing at 5-day intervals until completion of the study. Groups of B6C3F(1) mice that were depleted of CD4 and CD8 T cells were infected with an inoculum of 10(4) Histoplasma capsulatum yeasts. All mice receiving posaconazole at 1 or 0.1 mg/kg of body weight/day, amphotericin B at 2 mg/kg every other day (qod), or itraconazole at 75 mg/kg/day survived to day 29. Only 60% of mice receiving itraconazole at 10 mg/kg/day and none receiving amphotericin B at 0.2 mg/kg qod survived to that date. Fungal burdens were determined at day 14 of infection, 1 day after discontinuation of therapy. Quantitative colony counts and Histoplasma antigen levels in lung and spleen tissues declined following treatment with amphotericin B at 2 mg/kg qod, posaconazole at 5 and 1 mg/kg/day, and itraconazole at 75 mg/kg/day but not in mice treated with amphotericin B at 0.2 mg/kg qod or itraconazole at 10 mg/kg/day. Posaconazole at 0.1 mg/kg/day reduced fungal colony counts and antigen levels in spleens but not in lungs. This study shows posaconazole activity for the treatment of histoplasmosis in immunosuppressed animals.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. paconnol@iupui.edu
authors.forename: P
authors.initials: P
authors.lastname: Connolly
authors.forename: L J
authors.initials: LJ
authors.lastname: Wheat
authors.forename: C
authors.initials: C
authors.lastname: Schnizlein-Bick
authors.forename: M
authors.initials: M
authors.lastname: Durkin
authors.forename: S
authors.initials: S
authors.lastname: Kohler
authors.forename: M
authors.initials: M
authors.lastname: Smedema
authors.forename: J
authors.initials: J
authors.lastname: Goldberg
authors.forename: E
authors.initials: E
authors.lastname: Brizendine
authors.forename: D
authors.initials: D
authors.lastname: Loebenberg
mesh_terms: D000666:Amphotericin B / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D006658:Histoplasma / Q000187:drug effects / Q000276:immunology; D006660:Histoplasmosis / Q000188:drug therapy* / Q000382:microbiology; D016867:Immunocompromised Host / Q000502:physiology*; D007165:Immunosuppression Therapy; D017964:Itraconazole / Q000627:therapeutic use*; D008168:Lung / Q000382:microbiology*; D051379:Mice; D008815:Mice, Inbred Strains; D013154:Spleen / Q000382:microbiology; D016019:Survival Analysis; D013997:Time Factors; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; D017964:Itraconazole; C101425:posaconazole; D000666:Amphotericin B