Immunomodulatory therapies for sepsis: unexpected effects with macrolides

Despite intensive efforts to increase our knowledge of the inflammatory pathways involved in the pathogenesis of sepsis, several clinical trials of agents aimed at modulating the immune response of the host, such as anti-endotoxin antibodies, anti-tumour necrosis factor (TNF) antibodies and soluble TNF receptors, have failed to disclose any definite clinical benefit. The same applies to the administration of low-dose hydrocortisone as well as intense glucose control by continuous insulin infusion. Macrolides are a traditional class of antimicrobials proven to act as modulators of the host's response in chronic lung disorders such as diffuse panbronchiolitis and cystic fibrosis. The favourable outcome of community-acquired pneumonia treated with the combination of a beta-lactam and a macrolide is partly attributed to their immunomodulatory properties. Based on favourable responses to intravenous administration of clarithromycin in experimental models of sepsis by susceptible and multidrug-resistant Gram-negative isolates, a randomised clinical trial was conducted in 200 patients with ventilator-associated pneumonia (VAP) and sepsis (http://www.clinicaltrials.gov; NCT00297674). Clarithromycin was administered at a dose of 1g within 1h of infusion for three consecutive days. Analysis revealed a considerable benefit of clarithromycin in shortening the time to resolution of VAP and to de-intubation from mechanical ventilation. The relative risk of death by septic shock and multiple organ dysfunction was 19.00 among placebo-treated patients; it was reduced to 3.78 among clarithromycin-treated patients. These results render new perspectives for the future application of clarithromycin as an immunomodulatory therapy of sepsis.