Combination effects between KW-2228 and antibiotics against systemic infections in normal and neutropenic mice

KW-2228, a mutationally modified recombinant human granulocyte colony-stimulating factor (rhG-CSF), possesses some excellent properties such as high specific activity in stimulating granulocyte colony-formation in vitro, great biological stability in plasma, good pharmacokinetic profile and high potency in granulopoiesis in normal mice in vivo. Recently, the application of G-CSF against infectious diseases has been considered, and some animal experiments have been carried out to support such an application on human infectious deseases. In this paper, we examined combination effects of KW-2228 with various chemotherapeutic drugs in experimental infections in mice. A combination effect of KW-2228 with ceftazidime (CAZ) was evaluated in a systemic infection with Pseudomonas aeruginosa in normal mice. Combination effects of KW-2228 with CAZ, astromicin and amphotericin B were also evaluated in experimental systemic infections caused by P. aeruginosa, Serratia marcescens and Candida albicans in immunosuppressed mice treated with cyclophosphamide. Synergistic effects were generally observed at KW-2228 doses from 1 to 5 μg per mouse with all combinations. We concluded that combination therapies of KW-2228 with various chemotherapeutic drugs in experimental infections in mice showed that it should be effective in normal and immunosuppresed host. These results of our laboratory studies suggest that KW-2228 in combination with anitibiotics would be useful in the clinical treatment of microbial infections. Recently, clinical efficacy studies of KW-2228 have been initiated in Japan.