The role of macrolides in asthma: current evidence and future directions

Summary

Macrolides, such as clarithromycin and azithromycin, possess antimicrobial, immunomodulatory, and potential antiviral properties. They represent a potential therapeutic option for asthma, a chronic inflammatory disorder characterised by airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. Results from clinical trials, however, have been contentious. The findings could be confounded by many factors, including the heterogeneity of asthma, treatment duration, dose, and differing outcome measures. Recent evidence suggests improved effectiveness of macrolides in patients with sub-optimally controlled severe neutrophilic asthma and in asthma exacerbations. We examine the evidence from clinical trials and discuss macrolide properties and their relevance to the pathophysiology of asthma. At present, the use of macrolides in chronic asthma or acute exacerbations is not justified. Further work, including proteomic, genomic, and microbiome studies, will advance our knowledge of asthma phenotypes, and help to identify a macrolide-responsive subgroup. Future clinical trials should target this subgroup and place emphasis on clinically relevant outcomes such as asthma exacerbations.

Introduction

In 1949, erythromycin (the first macrolide) was isolated from metabolites of the bacterium Streptomyces erythrae (now called Saccharopolyspora erythrae of the Actinobacteria phylum) in a soil sample from the Philippines.¹ Macrolides are one of the most widely used antibiotic groups and have an expanding role in the treatment of a broad range of chronic respiratory diseases, including cystic fibrosis, non-cystic fibrosis bronchiectasis, and chronic obstructive pulmonary disease (COPD).2, 3, 4 Macrolides could also represent an attractive therapeutic option for asthma, which is characterised by chronic airway inflammation and bronchial hyper-responsiveness. Chronic asthma is often complicated by acute exacerbations, of which a major proportion is triggered by viral respiratory infections.⁵ In view of the immunomodulatory and potential antiviral properties of macrolides, they could have a beneficial effect in asthma. Furthermore, macrolides are effective against a broad range of respiratory bacterial pathogens, including the atypical bacteria Chlamydophila pneumoniae and Mycoplasma pneumoniae, both of which are implicated in chronic asthma and asthma exacerbations.⁶

Macrolides have a macrocyclic lactone ring of at least 12 elements whose size and features can be modified to derive agents with different properties. For example, erythromycin, clarithromycin, roxithromycin, and troleandomycin consist of a 14-membered ring, whereas azithromycin has a 15-membered ring. These subtle changes in structure give the advanced-generation macrolides, particularly azithromycin, improved bioavailability, acid stability, and half-life (40–68 h for azithromycin).⁷ Ketolides, such as telithromycin, are derived from erythromycin and are structurally related to macrolides; they have two bacterial ribosomal binding sites that confer better effectiveness against macrolide-resistant organisms than other macrolides.⁸

Whereas the scientific rationale for the use of macrolides in asthma might be persuasive, their efficacy in clinical trials has been variable, which is possibly related to many underpowered studies. A Cochrane database systematic review in 2005 was inconclusive,⁹ although a recent meta-analysis concluded that macrolide use for 3 weeks or more showed improvement in peak expiratory flow, clinical symptoms, quality of life, and airway hyper-reactivity.¹⁰ However, the substantial risk of antimicrobial resistance and concerns about adverse effects associated with long-term macrolide use must be considered.11, 12, 13

Although the use of macrolides in asthma is difficult to justify at present, there might be reason for cautious optimism. Asthma is widely recognised as a heterogeneous syndrome with distinct phenotypes and endotypes.¹⁴ Macrolides could be effective in certain phenotypes but not others. In a recent study, azithromycin therapy significantly reduced the rate of exacerbation in a subgroup of patients with severe neutrophilic asthma, although the mechanism of benefit was unclear.¹⁵ However, the primary endpoint in this study was the rate of severe exacerbation during the 26-week treatment period. Classically, forced expiratory volume in 1 s (FEV₁) is deemed the primary outcome measurement but exacerbation frequency might be a more clinically and economically meaningful outcome.¹⁶

Key messages

• Macrolides such as azithromycin and clarithromycin have antimicrobial, immunomodulatory, and potential antiviral properties

• Macrolides are effective in a broad range of chronic respiratory disorders, such as cystic fibrosis, non-cystic fibrosis bronchiectasis, and diffuse panbronchiolitis, in which neutrophilic inflammation is central

• Evidence to support the widespread use of macrolides for asthma is inadequate; however, macrolides might be effective in patients with severe neutrophilic asthma in whom symptoms are poorly controlled. Further mechanistic investigations and clinical trials are needed to validate this hypothesis

• Long-term use of macrolides could be associated with the emergence of antimicrobial-resistant organisms and adverse cardiovascular events in at-risk populations, thus their prescription should be rationalised

• Future clinical trials of macrolides in chronic asthma should use a range of clinically relevant outcome measures, with emphasis on frequency of asthma exacerbations

In this Review, we examine the evidence from clinical trials in chronic asthma and acute exacerbations, and discuss the scientific merits of macrolides (ie, their immunomodulatory, antiviral, and antibacterial properties) and their relevance to the pathophysiology of asthma. Finally, we discuss the potential hazards of macrolide therapy, future research, and the clinical directions of possible macrolide use in asthma.