Clarithromycin reverses sepsis-induced immunoparalysis of monocytes

Introduction

In a recently published double-blind, randomized trial conducted by our study group, clarithromycin was intravenously administered in patients with ventilator-associated pneumonia (VAP) and sepsis for three consecutive days [1]. An earlier resolution of VAP and a fivefold decrease of the risk for death by septic shock and multiple organ failure (MODS) compared with placebo were shown.

Objective

To investigate the mode of action of clarithromycin.

Methods

Blood was sampled before administration of the investigational product and on six consecutive days. Peripheral blood mononuclear cells (PBMCs) were isolated after gradient centrifugation over Ficoll. PBMCs were incubated and adherent monocytes were harvested and stimulated for 24 hours with 10 ng/ml LPS of Escherichia coli O55:B5. Concentrations of TNFα and of IL-6 were estimated in supernatants by an enzyme immunoassay.

Results

One hundred patients were treated with placebo and another 100 patients with clarithromycin. Median concentrations of TNFα and of IL-6 in monocyte supernatants of all patients and separately of those with septic shock and MODS are shown in Figure 1.

Figure 1

*Statistically significant differences between groups at the indicated time intervals. Day 0 corresponds to time before start of the investigational drug.

Conclusion

Administration of clarithromycin was accompanied by a considerable improvement of the response of monocytes to ex vivo stimulation with the release of TNFα and IL-6. These results signify that clarithromycin effectively reverses sepsis-induced immunoparalysis of monocytes.