Immunomodulators and Fungal Infections: Use of Antifungal Drugs in Combination with G-CSF

Abstract

It is widely accepted that one of the most important host-defense mechanisms against invading microorganisms is phagocytosis, followed by intracellular killing and digestion of the microorganism by phagocytic cells. Recently it was found that survival, growth and differentiation of progenitor phagocytic cells are controlled by hemopoietic colony-stimulating factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF) or multi colony-stimulating factor (IL-3) (1). G-CSF induces hemopoietic precursor cells to proliferate and differentiate into neutrophils, which are one of the most important first defense lines to microbial infections (2). Recently our studies have shown that G-CSF activates the antimicrobial activity of peripheral neutrophils against pathogenic yeast such as Candida albicans in vitro (3). Furthermore, it has also been demonstrated that G-CSF treatment of neutropenic mice can protect following infection with fungi (3). These previous results suggest that G-CSF might be a useful cytokine for treatment of neutropenic patients to protect from secondary fungal infections. To treat fungal infections of neutropenic patients, antifungal drugs must often be used as a therapeutic agent. However, there is little information about the usefulness of G-CSF in combination with antifungal drugs against fungal infections. The present studies were designed to investigate the therapeutic efficacy of four antifungal drugs, i.e., amphotericin B (AMPH), flucytosine (5-FC), fluconazole (FCZ) and itraconazole (ICZ) in combination with recombinant human G-CSF against C. albicans infection in neutropenic mice induced with cyclophosphamide. The administration of G-CSF in combination with either FCZ or ICZ markedly enhanced the therapeutic effect of antifungal drugs against Candida infection. However, G-CSF administered to mice in combination with either 5-FC or AMPH resulted in no significant enhancement. These results indicate that effectiveness is dependent upon the kind of antifungal drugs used.