Common antibiotic halves exacerbations in rare lung disease

Maintenance therapy with the common macrolide antibiotic azithromycin halves the rate of respiratory events in patients with primary ciliary dyskinesia (PCD) – otherwise known as immotile-cilia syndrome – in the first multicentre randomized controlled clinical trial of azithromycin in PCD.

At 6 months, azithromycin given thrice weekly significantly reduced the rate of respiratory exacerbations in paediatric and adult patients (n=90) enrolled in the BESTCILIA programme compared to placebo (rate ratio [RR], 0.45; 95 percent confidence interval [CI], 0.26 –0.78; p=0.004), reported primary investigator Dr Helene Kobbernagel of the Copenhagen University Hospital in Copenhagen, Denmark. [ERS 2019, abstract 5102]

In addition, patients on azithromycin also had a longer time to first exacerbation than those on placebo. “This is an important step towards evidence-based therapy for this rare, lifelong disease,” said Kobbernagel. “Maintenance therapy [with azithromycin] should then be considered for PCD patients with frequent exacerbations.”

Patients with PCD may have to live with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function, resulting in incompetent mucociliary clearance and mucus-bacteria retention in the respiratory tract, which can lead to chronic otosinopulmonary disease. The condition affects one in 20,000 individuals. Currently, therapies are merely empiric. There is also very little evidence to support the use of specific therapeutics in PCD, hence patients are treated in different ways.

Despite concerns about resistance with frequent or chronic antibiotic use, there were no significant differences between groups in terms of emergence of macrolide-resistant bacteria in BESTCILIA, but Kobbernagel said this has to be confirmed in trials with a larger sample size.

“I can’t say for now if azithromycin will not increase the risk of macrolide resistance as the numbers in this study are too small. But if you put patients on maintenance therapy, you should survey whether they develop resistance.”

The take-home message

“PCD is a serious condition that begins early in life and tends to deteriorate over time,” said Kobbernagel. “Because it is a rare disease, there is a lack of good evidence on how to treat children and adults to relieve symptoms and prevent long-term damage.”

“We’ve demonstrated [azithromycin] is safe and can reduce illness episodes interfering with everyday activities as well as reduce the need for full dose antibiotic courses and potentially irreversible lung damage,” Kobbernagel said.

Discussant Dr Tobias Welte from Hannover University in Germany and current ERS president commented: “we now have the first proof-of-concept study that azithromycin could help reduce symptoms. We hope research continues to help us find the best way to preserve health in the long term for all children and adults with PCD.”

Patients enrolled in the study had confirmed PCD and forced expiratory volume in 1 second (FEV₁) values of >40 percent of predicted and were randomized to azithromycin (250 mg if <40 kg, 500 mg if >40 kg) or placebo. Mean age of the patients was 19 years (range 7–50 years), FEV₁ was about 77 percent at baseline, with mean lung clearance index of 10 and 11 in the azithromycin and placebo arms, respectively.

There were reductions in bacterial species with azithromycin vs placebo in 224 sputum cultures available for testing (RR, 0.34, 95 percent CI, 0.24-0.64; p=0.0002), Kobbernagel said. But there were no differences in quality of life, hearing impairment, inflammatory markers, or lung function, between groups, she added.  

Overall, mild gastrointestinal events were more common with azithromycin than with placebo, particularly loose stools or diarrhoea (22.4 percent vs 4.9 percent). Serious events were one and three for azithromycin and placebo, respectively.

“Azithromycin could offer an effective maintenance therapy for PCD, reducing ill-health and helping children and adults get on with their daily lives,” Kobbernagel said. The next step is to find out if taking azithromycin longer than 6 months is safe and can prevent irreversible lung damage, she concluded.