Macrolide antibiotics as immunomodulatory medications: Proposed mechanisms of action

Abstract

Macrolide antibiotics administered in sub-antimicrobial doses improve pulmonary function and decrease exacerbation frequency for persons with diffuse panbronchiolitis or cystic fibrosis. Data also suggest a beneficial effect of macrolide antibiotics in the treatment of steroid dependent asthma. Many potential immunomodulatory effects of macrolide antibiotics have been reported including the ability to down-regulate prolonged inflammation, decreasing airway mucus secretion, inhibiting bacterial biofilm, decreasing the production of reactive oxygen species, inhibiting neutrophil activation and mobilization, accelerating neutrophil apoptosis, and blocking the activation of nuclear transcription factors. Macrolides initially decrease, then increase, and have finally a sustained suppression of cytokine secretions from normal human bronchial epithelial cells through inhibition and activation of extracellular signal-regulated kinases (ERK) and then reversibly retard cell proliferation probably through ERK. Consistent with this, macrolide antibiotics possibly reduce mucin production as well as neutrophil migration by interfering with ERK signal transduction.

Introduction

The term “macrolide” encompasses a diverse family of unrelated compounds with large macrolactam rings. The macrolide antibiotics consist of 14-, 15-, and 16- member macrolactam ring antimicrobials. Erythromycin A, the prototype macrolide antibiotic was isolated from a Philippine soil sample in the 1940s and was first marketed in 1952 as an alternative therapy to beta lactam agents for the treatment of infections with Gram positive cocci. During the 1990's clarithromycin, roxithromycin, and azithromycin were introduced. Macrolide antibiotics (henceforth referred to in this manuscript as “macrolides”) inhibit RNA-dependent protein synthesis by reversibly binding to the 50S ribosomal subunit of a susceptible microorganism.

Interest in the immunomodulatory effects of macrolides began in the 1960s with the observation that the 14-member antibiotic, troleandomycin, was an effective “steroid-sparing” agent when used to treat patients with severe asthma (Spector et al., 1974). It has been more than 20 years since the immunomodulatory effects of macrolides were accepted as a standard of care for the treatment of diffuse panbronchiolitis (DPB) in Japan (Kudoh et al., 1987). Erythromycin and clarithromycin are also widely used in Japan for the therapy of sinusitis and chronic obstructive pulmonary disease (COPD) (Tamaoki et al., 1995b). In more recent years, azithromycin has been widely adopted as immunomodulatory agents for the treatment of cystic fibrosis (CF) and bronchiectasis. In this paper, we review the clinical use and proposed mechanisms of action for macrolide immunomodulation (Labro & Abdelghaffar, 2001).