The effect of macrolides in reducing exacerbations in obstructive airways disease is probably less to do with their anti-inflammatory effects or direct antimicrobial action and more to do with their ability to modify macrophage function.
That’s the message from Professor Peter Gibson, recipient of the 2018 ERS Gold Medal in Asthma, who told the ERS International Congress the drugs could improve the ability of macrophages to clear apoptotic cells and bacteria.
“Are macrolides working through lung dysbiosis to reduce exacerbations? I think the data is suggestive but not conclusive and we need to design some studies to answer those questions.”
Professor Gibson, from the Centre of Excellence in Severe Asthma at the University of Newcastle, said asthma and COPD had recently been added to the list of obstructive airway diseases where macrolides appeared to be effective.
His 2017 AMAZES trial found add-on therapy with azithromycin could reduce exacerbations in adults with asthma and persistent symptoms despite bronchodilator and corticosteroid therapy.
As expected, the effect was seen in non-eosinophilic asthma but also, surprisingly, in eosinophilic asthma.
“So the drug is effective in both inflammatory subtypes of asthma and we’re left puzzling about how the drug is working.”
“Overall there was a 40% reduction in exacerbations in the study as a whole. That increased slightly in the mucous hypersecretion group and even further to 60% in those with positive bacteriology.”
In a very small number of patients with a highly responsive phenotype and bacteria pathogens in their sputum at baseline, there was as much as an 80% reduction in exacerbation rate.
Professor Gibson said a sub-study had looked at the lung microbiome using 16S rRNA gene sequencing.
The study found Moraxella and Haemophilus species were a highly abundant taxa and particularly in the neutrophilic disease.
Azithromycin treatment resulted in less microbial diversity and changes in community structure.
“In virtually every case there is a reduction in copies of H. influenza with azithromycin treatment compared to placebo.”
He added there were other studies with similar results showing that effect of macrolides on the microbiome was not a reduction in total microbial number but a reduction in diversity.
“You aren’t getting rid of bacteria from the airway, there is reduction in diversity and along with that a change in the community structure with some species over-represented and the pathogenic taxa reduced by azithromycin treatment.”
While there was more work to do, he said the clinical message was that adults with persistently active obstructive airways disease despite conventional therapy could experience a 40% reduction in exacerbations when treated with azithromycin three times a week for up to 12 months.
However care should be taken to limit adverse effects by excluding patients with long QTc or hearing loss and actively managing the potential for interactions between the statins that are metabolised by CYP3A4 (simvastatin and atorvastatin) and the macrolides that inhibit the enzyme (erythromycin and clarithromycin).