Combination Treatment of Posaconazole (POS) and Granulocyte Colony-Stimulating Factor (G-CSF) against Aspergillus in a Mouse Pulmonary Infection Model

F. MENZEL JR, C. JACKSON, A. PATERA, J. HALPERN, A. CACCIAPUOTI, R. HARE, D. LOEBENBERG

Author address: 

Schering-Plough Research Institute, Kenilworth, NJ.

Abstract: 

Background: POS (SCH 56592) is a triazole antifungal agent, currently in Phase III clinical trials. In a previous publication (AAC 42: 2467-2473, 1998) Graybill et al. reported antagonism between POS and G-CSF in corticosteroid-compromised mice infected intranasally with A. fumigatus. Methods: Corticosteroid-compromised mice were infected by exposure in inhalation flasks to conidia of 2 strains of A. fumigatus (each done 3 times) or 1 strain of A. flavus. Recombinant human G-CSF was administered intraperitoneally at 600 or 125 mg/kg, and POS was administered orally at 100, 25, 5 mg/kg for A. fumigatus and 10, 1, 0.2 mg/kg for A. flavus. Survival was followed for 10 days, and survivors were cultured to determine lung burdens. Results: POS monotherapy prolonged survival against all strains tested in a dose dependent manner relative to vehicle-treated controls, while G-CSF monotherapy was ineffective and similar to controls. All controls died within 7 days. Statistical analysis (Wilcoxon, Log-Rank tests) indicated no significant differences (p>0.05) between survival curves for POS + G-CSF and POS alone at any dose, against any of the strains, in any of the experiments. Lung burdens for survivors of high dose POS (100 or 10 mg/kg) + G-CSF (600 or 125 mg/kg) and POS (100 or 10 mg/kg) alone also showed no significant differences (p>0.05, parametric and non-parametric tests). Conclusion: In contrast to the earlier report, POS and G-CSF were not antagonistic in corticosteroid-compromised mice infected with A. fumigatus or A. flavus.
2002

abstract No: 

M-858

Full conference title: 

42nd Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 42nd