Efficacy of recombinant human granulocyte-colony stimulating factor alone and in combination with antifungal agents against disseminated trichosporonosis in neutropenic mice

Abstract

The ability of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to protect and potentiate the activity of antifungal agents against a lethal Trichosporon beigelii infection in myelosuppressed mice was evaluated in this study. Mice were rendered neutropenic by 2 consecutive-day intraperitoneal injections of cyclophosphamide (200mg/kg). Recombinant hG-CSF, given subcutaneously at daily doses of 15, 60, and 120μg/kg for 6 days, shortened the period of neutropenia and increased the number of circulating neutrophils in a dose-dependent manner. When rhG-CSF was administered to neutropenic mice before challenge with T. beigelii (5×106 CFU), it protected against the lethal infection, resulting in improved survival and decreased numbers of fungal cells in the lung, liver, spleen and kidney. However, when the inoculum size increased to 7×106 CFU, a poorer result was obtained using a dose of 60μg/kg of rhG-CSF, suggesting that the activity of rhG-CSF is dependent on the severity of the T. beigelii infection. Combined with fluconazole (10 mg/kg) or amphotericin B (1mg/kg), rhG-CSF improved the median survival time from 16 days with fluconazole (59%) and 12 days with amphotericin B (41%) alone to 20 days (93%) and 16 days (55%) in neutropenic mice treated with rhG-CSF plus fluconazole or amphotericin B, respectively. However, the combination of rhG-CSF and itraconazole did not produce significant improvement in survival or clearance of fungal cells from the organs of neutropenic mice. These findings show that rhG-CSF may be a useful immunomodulator against Trichosporon infections in neutropenic mice and the therapeutic outcome improves when used in combination with fluconazole or amphotericin B.