Macrolide also ‘amazes’ in uncontrolled paediatric asthma

Improvements in uncontrolled asthma previously seen with low-dose macrolides in adults have been replicated in children aged five to fifteen.

Published in 2017, the reduction in exacerbations seen with azithromycin in the Australian AMAZES trial led to guideline recommendations for low-dose macrolides to be used as add-on therapy in adults whose asthma is not controlled despite optimum use of inhaled corticosteroids (ICS).

Now a randomised controlled trial published in Chest has extended the evidence of benefit to children.

Researchers in India evaluated the efficacy of low-dose (10 mg/kg, three times per week) azithromycin in asthma control for three months in 120 children with uncontrolled asthma.

The children were predominantly male (74%), had a mean age of 10 years and had poorly-controlled asthma as defined by scores of 19 or less on the Asthma Control Test (ACT) and Childhood Asthma Control Test (CACT), despite treatment with ICSs and/or long-acting beta-agonists in combination with good adherence and techniques.

After three months of azithromycin treatment, children in the macrolide group showed significant improvement in asthma control compared with the control group (change in CACT/ACT score: 7 ± 11 vs 3 ± 12, respectively, P < 0.001).

Despite the CACT/ACT score being lower in the azithromycin group at baseline, it improved substantially and became significantly higher than the control group score at 12 weeks of follow-up (21.7 ± 2.2 vs 18.3 ± 2.2, respectively; P < 0.001).

Azithromycin treatment also improved secondary outcomes, such as proportions of patients achieving asthma control as per GINA guidelines (41 of 56 vs 10 of 56, P < 0.001). The number of acute asthma exacerbations leading to ED visit or requiring steroid use were significantly reduced in the azithromycin group compared to the control group.

There were no differences in other outcomes such as change in spirometry parameters, fractional exhaled nitric oxide (FeNO), and neutrophil percentage in the sputum.

The study investigators noted that the improvements in asthma control were seen in all age groups and — as with the AMAZES study — in eosinophilic asthma and children with non-eosinophilic asthma. Unlike in adults, there appeared to be no tolerability issues with low-dose azithromycin such as diarrhoea, which mirrored experience with use of azithromycin in children with cystic fibrosis.

The study authors acknowledged there may be concerns about antibiotic resistance with long-term use of azithromycin, and said their three-month study did not find any azithromycin-resistant organisms in the throat samples processed.

“Management of poorly-controlled asthma in children is challenging. Although emphasis on personalised asthma management exists that includes biologicals, it is limited by high cost and unavailability,” the authors wrote.

“Hence, a cheaper, safe, effective, and readily available drug like azithromycin can help in management of children with poorly controlled asthma. It can be used in clinical conditions when the asthma is not controlled by routine medications before moving to biologics,” they suggested.

An accompanying commentary co-authored by AMAZES study investigator Professor Peter Gibson noted that two previous trials of low-dose azithromycin in children with uncontrolled asthma had produced mixed findings, but had been limited by their short duration and low patient numbers.

They described the findings of the latest study as “encouraging”, but cautioned that there were still many unanswered questions such as the optimum dose and duration of treatment and longer term safety with macrolides.

“Although the authors administered therapy for 12 weeks in the current study, it is unclear whether the asthma control achieved during the treatment was sustained over time after discontinuing the therapy,” they said.

“Nevertheless, the positive effect observed in this study provides a promising treatment option in managing difficult-to-treat asthma in children, who have demonstrated adequate use of controller medications and optimal inhaler techniques. Further research is required to identify the most effective macrolide, the ideal therapeutic regimen, the duration of the treatment, long-term consequences of long-term use of these antibiotics, and their mechanism of action,” they concluded.

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