Children who took azithromycin three times a week had less airway inflammation and needed fewer courses of antibiotics.
Children with cystic fibrosis who took the antibiotic azithromycin three times a week had less airway inflammation, respiratory symptoms requiring antibiotics, and days spent in hospital, an Australian study has shown.
The study of 130 children set out to determine whether azithromycin given to children from diagnosis at birth up to age three could reduce the structural lung damage that occurs from cystic fibrosis lung disease.
Azithromycin is a broad-spectrum macrolide antibiotic. When used in combination with hypertonic saline, azithromycin could help manage cystic fibrosis until children are old enough to access the highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, the researchers said.
While the study found no evidence that azithromycin prevented structural airway disease by the age of three, treatment with the antibiotic reduced airway inflammation and improved clinical outcomes commonly associated with cystic fibrosis.
“For secondary outcomes, children who received azithromycin spent less time in hospital for pulmonary exacerbations each year (mean difference 6·3 days, 95% CI 10·5 to 2·1; p=0·0037), had fewer days of intravenous antibiotics each year (0·2 for azithromycin group vs 6·7 for placebo group per year; median difference 6·7, 95% CI 12·2 to 1·2; p=0·018), and fewer courses of inhaled or oral antibiotics each year (incidence rate ratio 0·88, 95% CI 0·81 to 0·97; p=0·0088),” the study said.
The phase three, randomised, double-blind, placebo-controlled trial was conducted in eight paediatric cystic fibrosis clinics in Australia and New Zealand.
Children diagnosed with cystic fibrosis after newborn screening were given either azithromycin or a placebo three times a week from diagnosis to age three.
Children in the azithromycin group had fewer inflammatory markers – neutrophil elastase and IL-8 – in the lower respiratory system at 36 months than children in the placebo group.
“Given the strong association between neutrophilic inflammation and lung disease in all age groups and the particular role of neutrophil elastase in the progression of lung damage in early life, azithromycin could be used as a safe and effective anti-inflammatory agent for continuous use in young children,” the authors wrote.
However, chest CT scans at age 12 months and 36 months showed that lung disease progressed to a similar extent in both groups. The researchers said an explanation could be the insensitivity of the algorithm to detect tiny differences in lung structure between individuals.
“These include the low number of airways captured due to their small size in relation to the resolution of the CT scans, low resolution for imaging the peripheral airways where early disease is most evident, and the diffuse and heterogenous lung disease in very young children.”
Children in the azithromycin group also scored higher when their physical wellbeing was assessed at 36 months.
Lead author Professor Stephen Stick from the University of WA said some cystic fibrosis research centres have the technology to detect neutrophil elastase, a protein enzyme that causes destruction in the lungs.
Ideally, the highest risk infants would be identified via those biomarkers in the lungs and started on routine azithromycin, said Professor Stick, director of the Wal-yan Respiratory Research Centre in Perth.
“However, until that is the case, azithromycin should be considered in combination with hypertonic saline for any child who cannot access the new class of modulator therapy that is proving to be transformational for many individuals.”
If that technology isn’t available, other high-risk factors may indicate those children who would benefit from azithromycin.
“If a child has had a couple of admissions in the first year of life, and there’s evidence of inflammatory changes on a CT scan, then they might be the ones that could benefit the most, but they’re the sorts of questions that we really don’t have answers to at the moment,” Professor Stick said.
Children are usually diagnosed with cystic fibrosis through the “heel prick” neonatal screening test, which is routinely done on all babies born in Australia when they’re three days old.
“Until recently, there were no proven interventions that address the basic pathological triggers for lung disease, such as airway dehydration and inflammation,” Professor Stick said.
“There are now two options, hypertonic saline which stops progression of structural damage, and azithromycin that reduces inflammation.”
Professor Stick said some CFTR modulators are approved for young children with specific CF gene mutations. However, access is limited for most other families, and most countries including Australia do not reimburse the cost for children under six, which can add up to about $200,000-$300,000 a year.
Associate Professor Jim Manos, head of the bacterial pathogens group at the University of Sydney, said a followup study would confirm whether there was indeed no difference between the groups when it came to lung disease progression.
“While less inflammation is a positive outcome, it’s only a small part of the cystic fibrosis story,” Professor Manos told TMR.
“The larger story is whether this treatment is going to make a decisive difference to the infection cycle that cystic fibrosis patients go through.
“The lack of a reduction in structural lung disease, if upheld in a subsequent study, would mean the treatment is unlikely to reduce infections. If structural disease is reduced, then there is hope for better outcomes for infection.”
Professor Manos said azithromycin had a number of side effects, and some of them – such as anaphylaxis and irregular heartbeat – could be difficult to identify in infants. “While macrolide hypersensitivity is mentioned as an exclusion, I can’t see it as covering all angles in the potential side effects.”
This is the first randomised controlled study to see whether anti-inflammatory therapy could prevent progressive lung damage in children diagnosed at birth. The study also provided further evidence of its safety in young children, the authors said.
The mechanisms of action of azithromycin in children were beyond the scope of this study, the researchers said.
Researchers will continue following the study cohort to see whether early management with azithromycin reduces structural lung disease as the children get older.
