What do we know about Macrolides Immunomodulatory Therapeutic Potential in Respiratory Disease in 2023

Abstract

The broad antibacterial activities of macrolides have led to their widespread use on infections, particularly for respiratory infections. Many of the macrolide-susceptible microorganisms are respiratory pathogens known to be associated with exacerbations of asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis (BE) and cystic fibrosis (CF). Macrolides have been widely used to treat respiratory diseases, often beyond its acute antimicrobial use (Table 1), and they have long been accepted to show effects on inflammatory and immune cells, mucus secretion, and epithelial cell differentiation. Anti-inflammatory and immuno-modulatory actions, independent of their actions on bacteria, add to their therapeutic benefit in infectious and chronic inflammatory disorders, recognition that dates to the 1960s [1]. Long-term treatment improves clinical outcomes in several respiratory diseases, such as in symptoms, lung function, quality of life (QoL) and a significant exacerbations frequency reduction in COPD (30 to 60%), asthma, CF and BE, despite diversity in pathophysiology between these conditions, suggesting a degree of shared biology [2]. Thus, as macrolides show a positive effect in diseases where macrolide-resistant organisms are prevailing, and at dosages below the antibacterial threshold, this suggests that this effect may not be a result of antibacterial activity. This is further highlighted by reports that airway bacterial load remains unchanged [1]. However, until today, there has been limited success in defining the essential molecular mechanisms underlying these activities. By understanding them, it might be possible to enhance their non-antibiotic functions, apply them to other inflammatory diseases, avoid side effects, and limit bacterial resistance. Clinical studies exploring the long-term effects of macrolides in chronic lung diseases have reported adverse events including hearing impairment, gastrointestinal disarrangement and, althought rare, cardiotoxicity – extension of QT interval (reported in several COVID-19 trials of azithromycin (AZM) and inhibition of proarrhythmogenic drugs metabolism, leading to syncope and sudden death. The long-term use is also limited by the induction of bacterial resistance, and there is a concern about the length of low-dose macrolide therapy that starts to increase bacterial resistance. Thus, there is a need for new nonantibacterial macrolides that have similar effective disease-modifying properties without the risk of resistance [1].