IN-VITRO INTERACTION BETWEEN DIRITHROMYCIN OR ITS METABOLITE, ERYTHROMYCYLAMINE, AND OXIDATIVE POLYMORPHONUCLEAR METABOLISM

The direct stimulation by neutrophil infectious bacteria induces an in crease in the production of reactive oxygen species which is an import ant host defense mechanism. Antibiotics that enter rapidly and are con centrated in neutrophils, can stimulate or damage this function. In th is study, an in vitro evaluation has been made of the macrolide, dirit hromycin, and its active metabolite, erythromycylamine, on the superox ide anion generation by neutrophils in three systems of stimulation: t he oligopeptide fMLP, an analogue of bacterial chemotactic factors; th e phorbol ester PMA, a direct activator of protein kinase C; and a bac teria strain, Staphylococcus aureus. It has been demonstrated that dir ithromycin, at therapeutic plasma concentrations, and its active metab olite have a significant pro-oxidant effect on the two systems: fMLP a nd bacteria. This effect is greater for dirithromycin than that for er ythromycylamine. At higher non-therapeutic concentrations, these subst ances decrease superoxide generation in the three systems. The effects of these two agents seem to be the result of an intracellular mechani sm resulting in the intervention of the oxidative me tabolism of neutr ophils since no effect was found in the cell-free systems. Therefore, this in vitro study suggests that at therapeutic concentrations, dirit hromycin and erythromycylamine could benefit therapy by stimulation of the oxidative metabolism of neutrophils.