In vitro interaction between dirithromycin or its metabolite, erythromycylamine, and oxidative polymorphonuclear metabolism

Abstract

The direct stimulation by neutrophil-infectious bacteria induces an increase in the production of reactive oxygen species which is an important host defense mechanism. Antibiotics that enter rapidly and are concentrated in neutrophils, can stimulate or damage this function. In this study, an in vitro evaluation has been made of the macrolide, dirithromycin, and its active metabolite, erythromycylamine, on the superoxide anion generation by neutrophils in three systems of stimulation: the oligopeptide fMLP, an analogue of bacterial chemotactic factors; the phorbol ester PMA, a direct activator of protein kinase C; and a bacteria strain, Staphylococcus aureus. It has been demonstrated that dirithromycin, at therapeutic plasma concentrations, and its active metabolite have a significant pro-oxidant effect on the two systems: fMLP and bacteria. This effect is greater for dirithromycin than that for erythromycylamine. At higher non-therapeutic concentrations, these substances decrease superoxide generation in the three systems. The effects of these two agents seem to be the result of an intracellular mechanism resulting in the intervention of the oxidative metabolism of neutrophils since no effect was found in the cell-free systems. Therefore, this in vitro study suggests that at therapeutic concentrations, dirithromycin and erythromycylamine could benefit therapy by stimulation of the oxidative metabolism of neutrophils.