Macrolides and immunomodulation.

Macrolides are widely used antibiotics, but their clinical benefits in the setting of infection and sepsis span beyond their antimicrobial spectrum. They possess immunomodulatory properties, characterized, across preclinical models, by effects on macrophage M1/M2 polarization, autophagy, neutrophil extracellular trap formation, cytokine release, and bacterial virulence factors. In hospitalized CAP, macrolide and beta-lactam combination therapy confer survival benefit, as supported by observational studies and meta-analyses, and reinforced by a recent randomized trial. In non-CAP sepsis, three randomized trials using adjunctive clarithromycin demonstrated earlier resolution of infection, prevention of secondary sepsis episodes and a signal of improved survival, among the most severely ill patients. With a low risk of serious adverse events clarithromycin showed a cost-effective profile, compared to placebo. Mechanistic data, derived largely from biomarker analyses of these trials, point to a reversal of sepsis-induced immunoparalysis, including restored antigen presentation, monocyte reprogramming, and upregulation of cholesterol biosynthesis pathways, alongside. It is hypothesized that, depending on the timeline of infectioand on host response, macrolides have a role of immune "regulator" rather than purely anti-inflammatory properties.