Erythromycin in Septic Patients: Immunomodulatory Role and Clinical Impact

Overview

In sepsis and septic shock, the host response is characterized by a complex of immune-inflammatory reactions; triggered and activated by microbial components. These reactions are controlled by a balance of pro-inflammatory cytokines and anti-inflammatory cytokines. The imbalance of this immune response is a source of organ dysfunction; major prognostic factor during septic condition. This pretext has created the need for therapies aimed to modulate the overstated of host response. During the past 2 decades, macrolide molecules proved interest to be immunomodulatory agents; due beyond their antibacterial activity. Their regulatory role in the production of cytokines was demonstrated in the management of severe acute community pneumonia. The investigators hypothesize that the adjunction of macrolides to standard therapy in patients with sepsis or septic shock is associated to a favorable immunomodulatory and clinical effects.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It is considered as the main cause of death in critically ill patients ranging from 20 to 50%. These alarming death rates have prompted several intense research efforts to better understand the mechanisms underlying the pathogenesis of sepsis. Currently, sepsis is recognized as a complex entity created by an immuno-inflammatory reaction of the infected host; triggered and activated by microbial components. This reaction brings together the cellular and humoral immunity defense systems. Activation of the cellular system involves macrophages, polymorphonuclear cells, lymphocytes and endothelial cells. Therefore, pro-inflammatory cytokines are secreted in order to control the infection (IL-1, IL-6, IL-8, and TNF-alpha). Simultaneously, anti-inflammatory cytokines (IL-4, IL-10) are also released, allowing a local and systemic regulation of the inflammatory cascade. The imbalance of this immune response is a source of organ dysfunction aggravated by the lack of tissue oxygenation. Understanding that sepsis results from a disproportionate immune-inflammatory response have created the need for therapies aimed to modulate the overstated host response. The agents tested were: anti-endotoxin antibodies, tumor necrosis factor (TNF), anti-TNF-alpha, recombinant human activated protein C (rhAPC), stress-dose hydrocortisone and statins. Most of these clinical trials showed no obvious clinical impact or a limited clinical efficacy. During the past 2 decades, macrolides molecules were revealed to be immune-modulator agents; beyond their antibacterial activity. Their immune-modulator properties result from their ability to induce the activity of various immune cells and their regulatory role in the production of cytokines. Several cellular targets and mechanisms have been described to explain the immune-modulator effects of macrolides: Respiratory epithelial cells and innate immunity cells. Overall, macrolides decrease the production of pro-inflammatory cytokines by innate and adaptive immunity cells. In this clinical trial, the investigators are focusing on the effects of macrolides on the pro-inflammatory / anti-inflammatory balance by assaying cytokines and other immune-inflammatory markers during sepsis and septic shock. The main hypothesis is that the use of macrolides in addition to standard therapy in critically septic patients has a favorable immune-modulator and clinical effects compared to critically septic patients not receiving macrolide.