Macrolides for Acute Lung Injury

In this issue of CHEST (see page 1153), Walkey and Wiener¹ examine the association between receipt of a macrolide antibiotic and mortality in patients with acute lung injury (ALI). The authors used existing, publicly available data from the Acute Respiratory Distress Network (ARDSNet) Lisofylline and Respiratory Management of Acute Lung Injury (LARMA) trial in which 235 patients were randomized in a two-by-two fashion to receive low tidal volume vs standard tidal volume ventilation and either lisofylline or placebo.² The exposure of interest in this study was receipt of a macrolide antibiotic within 24 h of enrollment (47 of 235 patients studied received a macrolide). After adjustment for confounding variables, patients who received a macrolide antibiotic had a significant reduction in mortality and shorter time to discontinuation of mechanical ventilation. By contrast, patients who received a fluoroquinolone or cephalosporin, compared with patients who did not, had no survival advantage, suggesting that this benefit was due to macrolides.

The antibacterial property of macrolides arises from their interaction with the bacterial ribosome and resultant inhibition of protein synthesis. However, there is growing evidence that macrolides have beneficial effects in patients with inflammatory lung diseases in addition to their ability to inhibit the replication of pathogenic bacteria. Numerous in vitro and in vivo studies have shown that macrolides mitigate inflammation and otherwise modulate the immune system. Specifically, macrolides have been shown to cause downregulation of cell surface adhesion molecules, decreased production of proinflammatory cytokines, stimulation of phagocytosis by alveolar macrophages, decreased production of reactive oxygen species, and inhibition of neutrophil activation and mobilization. In addition, macrolides reduce mucous production and bronchial hyperresponsiveness.³ The mechanism by which macrolides exert these antiinflammatory and immunomodulatory effects is not well understood.

Macrolides have proven beneficial in a number of inflammatory lung diseases, presumably because of their ability to modulate the immune response. The addition of a macrolide to a β-lactam antibiotic was associated with higher rates of survival in patients with bacteremic pneumococcal pneumonia,⁴ and macrolides, but not fluoroquinolones or tetracyclines, were associated with improved outcomes in bacteremic pneumonia.⁵ The lack of improvement with the addition of a fluoroquinolone or tetracycline suggests that the benefit observed with macrolides is not due to an enhanced antibacterial spectrum. In a randomized controlled trial, clarithromycin improved the time to resolution of ventilator-associated pneumonia and decreased the time on mechanical ventilation but did not have an impact on mortality.⁶ Azithromycin improved lung function and reduced the frequency of exacerbations in patients with cystic fibrosis.⁷ A randomized controlled trial recently demonstrated that chronic treatment with azithromycin reduced the frequency of acute exacerbations of COPD.⁸ Treatment with macrolides slowed the progression and improved symptoms in patients with diffuse panbronchiolitis.⁹ Macrolide treatment of patients with asthma yielded mixed results, and there are small studies demonstrating a benefit of macrolides in the treatment of post-lung transplant bronchiolitis obliterans.¹⁰ The benefit of macrolides in these conditions, all of which are marked by inflammation, may portend a role for macrolides in the treatment of other inflammatory diseases affecting the lungs.

ALI is an inflammatory syndrome, responding to direct or indirect lung damage, that manifests clinically with the acute onset of severe hypoxemia and bilateral pulmonary infiltrates. The early, or exudative, phase of ALI is marked by diffuse neutrophilic alveolar infiltrates and accumulation of protein-rich pulmonary edema. A multitude of cytokines perpetuate the inflammation, which results in damage to the alveolar epithelium and capillary endothelium.¹¹ It is reasonable to hypothesize that the antiinflammatory and immune modulatory effects of macrolides may benefit patients with ALI. In support of this theory, treatment with macrolides leads to reduced histopathologic evidence of inflammation and lung damage as well as decreased levels of proinflammatory cytokines in animal models of lipopolysaccharide-induced ALI.¹²

The results of the current study are intriguing because they demonstrate a clear association between receiving a macrolide antibiotic during ALI and higher rates of survival. The authors also demonstrate the utility of ARDSNet data for exploratory studies. The study is limited by its observational design and the small number of patients who received macrolides in the LARMA trial. Patients who received a macrolide were more likely to have pneumonia, less likely to have sepsis, and spent less time in the ICU and in the hospital prior to enrollment. Although the authors adjust for these differences between the groups, the potential for confounding remains. Currently, only mechanical ventilation with low tidal volumes improves survival in patients with ALI, and no known pharmacologic therapies exist. ALI is not a rare condition and carries a high rate of mortality; hence safe, effective pharmacologic treatments would be welcomed. The results of this study are promising and call for a prospective, randomized controlled clinical trial to definitively address the impact of macrolides on outcomes in patients with ALI.