The trial’s findings were reported in the study, “Efficacy of oral amoxicillin-clavulanate or azithromycin for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1): a multicentre, three-arm, double-blind, randomised placebo-controlled trial,” published in The Lancet Respiratory Medicine.
Patients with bronchiectasis may experience acute respiratory exacerbations, or flare-ups, associated with aggravated symptoms, and deteriorated lung function. Such acute exacerbations in children can increase stress for parents and lower quality of life.
Current guidelines recommend treating flare-ups with antibiotics for 10–14 days. Amoxicillin-clavulanate — a combination of a penicillin antibiotic (amoxicillin) with a beta-lactamase inhibitor (clavulanate) that’s used to prevent bacterial resistance — is often given longer for young children. Azithromycin, an antibiotic with broad antimicrobial spectrum and a convenient once-daily dosing, is a common alternative.
BEST-1 was a double-blind Phase 4 trial (ACTRN12612000011886) designed to address the lack of evidence comparing oral antibiotics to placebo in children with non-severe flare-ups of bronchiectasis.
The study enrolled 252 children from four pediatric clinical centers in Australia and New Zealand. Using computed tomography scans, all participants had a confirmed diagnosis of bronchiectasis unrelated to cystic fibrosis (another lung disorder that is associated with bronchiectasis in some cases).
To be eligible, the children must have had experienced at least two disease flare-ups in the 18 months before the beginning of the trial. A total of 197 children (median age of 6 years) were randomly assigned to one of three different 14-day treatments for flare-ups — amoxicillin-clavulanate, azithromycin, or a placebo.
In total, 63 children received oral suspensions of amoxicillin-clavulanate (45 mg/kg per day), divided into two daily doses, and a placebo of azithromycin once-a-day. Sixty seven other children received a daily dose of azithromycin (5 mg/kg per day) and a placebo of amoxicillin-clavulanate twice-a-day. The remaining 67 children received both placebos.
The trial’s primary objective was to assess the percentage of children whose flare-ups were resolved at the end of treatment. All but one child was eligible for the analysis.
After 14 days of treatment, flare-ups had resolved in 41 children (65%) in the amoxicillin-clavulanate group, in 41 children (61%) in the azithromycin group, and in 29 children (43%) in the placebo group.
A subsequent statistical analysis found that, compared with the placebo, the higher rate of flare-up resolution with antibiotics was significantly higher with amoxicillin-clavulanate.
A similar difference favoring amoxicillin-clavulanate, but not azithromycin, was found in the shorter median duration of flare-ups. However, the median time to next flare-up after resolution was 83 to 89 days, which was similar across the three groups.
Significant improvements in lung function were found throughout treatment with amoxicillin–clavulanate but not with azithromycin, although the researchers cautioned that the analysis was done in a limited number of children (28 children).
By day 14, potentially harmful bacteria were isolated less often from the airways of children who were treated with antibiotics than from those in the placebo group. Patients on azithromycin, but not those on amoxicillin–clavulanate, showed an increase in the proportion of antibiotic-resistant bacteria compared to the placebo group.
The incidence of adverse events was 30%, which was similar in the two antibiotic treatment groups, and 21% in children on placebo. Yet, no severe (grade 3) or life-threatening (grade 4) adverse events were reported.
Eight children discontinued treatment due to gastrointestinal adverse events: three (5%) in the amoxicillin–clavulanate group, three (4%) in the azithromycin group, and two (3%) in the placebo group.
Overall, “the results suggest that amoxicillin-clavulanate should remain the first-line oral antibiotic for the treatment of non-severe exacerbations of bronchiectasis in children, with once-daily azithromycin reserved for those with genuine penicillin hypersensitivity or for situations in which directly observed therapy is feasible in settings of poor treatment adherence,” the scientists wrote.