Several antimicrobial agents have already been investigated relating to their influence on neutrophil ROS generation. Azithromycin provides, a dose-related anti-oxidant effect, after 15 min incubation, with the stimulating agent FMLP, as well with PMA or S. aureus. This finding was however obtained with concentrations not considered in therapeutics. Since short incubation times are not representative of the physiological situation, and since azithromycin is characterized by prolonged high concentrations within phagocytes, the same experiments were performed over 2 and 4 h exposures. A time-dependent anti-oxidant effect was then reported. The maximum effect was obtained with PMA (IC50 were 856 and 30 micrograms/ml for 15 min and 4 h incubation times respectively). Time-dependent modifications of neutrophil oxidative metabolism seem to be correlated with intracellular concentrations. Depressed oxidative metabolism might be related neither to azithromycin cellular toxicity, nor to superoxide scavenging properties. By increasing exposure periods, therapeutic concentrations could therefore lead to an anti-inflammatory effect, potentially of clinical interest since associated with bacteriostatic activity.

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 damagethis function. In this study, an in vitro evaluation has been madeof 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: fMLPand 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. Polymorphonuclear neutrophils (PMN) play a prominent role in the host response to infectious diseases. An important bactericidal mechanism employed by these cells is the production of reactive compoundsof oxygen during the oxidative burst1}. These compounds are

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