Azithromycin Has Some Benefits for CF Infants, Study Shows
Treatment with the antibiotic azithromycin did not prevent the development of lung damage in infants with cystic fibrosis (CF), but was safe and lowered inflammation, hospital stays and antibiotic usage, according to data from a Phase 3 clinical trial.
“Azithromycin treatment from diagnosis of cystic fibrosis after newborn screening did not reduce the extent of structural lung disease at age 36 months; however, it did reduce airway inflammation, and improved some clinical outcomes associated with cystic fibrosis lung disease,” the researchers wrote.
The study, “The effect of azithromycin on structural lung disease in infants with cystic fibrosis (COMBAT CF): a phase 3, randomised, double-blind, placebo-controlled clinical trial,” was published in the journal The Lancet Respiratory Medicine.
Lung damage begins to emerge early in infants with CF and progressively worsens, leading to increased respiratory symptoms, hospital admissions, and lower life quality. Airway inflammation is thought to be a significant contributor to these declines.
But the only recommended anti-inflammatory medication for CF — high-dose ibuprofen — is not recommended for young children. Azithromycin is an antibiotic sometimes used to treat infections in CF patients. Data show it has anti-inflammatory properties, and thus could represent an approach to stopping inflammation and preserving the lungs of infants with CF.
The Phase 3 trial COMBAT CF (NCT01270074) evaluated whether azithromycin was safe in infants with CF and could prevent the worsening of lung damage in the first three years of life.
Included in the study’s final analysis were 107 infants with CF who were seen at any of eight CF clinics in Australia and New Zealand. The infants were assigned randomly to receive oral liquid azithromycin (10 mg/kg) or a placebo three times weekly until they were 3 years old.
The study’s primary goal was to assess whether azithromycin could lower the severity of airway disease and the proportion of children who developed bronchiectasis — a condition in which the airways are damaged, usually as a result of inflammation, becoming scarred and thickened over time. Both were measured with a chest CT scan in 104 of the children.
Data showed the trial failed to meet those goals. Specifically, the proportion of treated patients who developed bronchiectasis — 50 children (88%) — did not differ significantly from the proportion of infants in the placebo group who developed it — 44 children (94%).
The severity of total airway disease was low in both groups, the researchers said, with no change in overall CT scores observed between scans taken at ages 1 and 3.
Technical limitations to the CT scan protocol used could have prevented true differences in lung disease from being discerned in children this young, the researchers noted.
“The COMBAT CF cohort will be followed to establish whether early intervention with azithromycin has an effect on structural lung disease and lung function in later childhood,” the researchers wrote.
But other secondary outcomes improved significantly with azithromycin treatment.
Children who received azithromycin spent significantly less time in the hospital — 6.3 days less — due to respiratory symptoms (pulmonary exacerbations) each year compared with those in the placebo group. These children also needed fewer into-the-vein antibiotics.
Azithromycin did not lead to overall improvements in life quality, but did lead to gains in physical well-being compared with the placebo group.
Bronchoalveolar lavage was used to collect lung fluid in order to analyze which bacteria were present in the children’s lungs. The most common bacteria observed in the children at age 3 were Haemophilus influenzae, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus species. The prevalence of these bacteria did not differ significantly between treated and untreated infants.
An exploratory analysis was performed to evaluate levels of two proteins in lung fluid — neutrophil elastase and IL-8, which are markers of inflammation that have been linked to lung damage in CF. While no significant differences were observed at age 1, levels of both were significantly lower in children on azithromycin at age 3, suggesting the treatment has anti-inflammatory effects.
The use of other treatments, including hypertonic saline, Pulmozyme (dornase alfa), and anti-Staphylococcus preventative treatments, did not have a significant influence on outcomes in children in either group.
The treatment was generally safe, with few adverse side effects reported in either group.
Overall, the findings suggest that azithromycin is safe and may have clinical benefit for infants with CF, particularly those without access to CFTR modulator therapies, the team noted.
“Although the mechanisms of action of azithromycin in this age group are beyond the scope of this study, the unique and extensive COMBAT CF biobank, database, and image archive are available for further research,” the team concluded.