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

Abstract

Background Bronchiectasis guidelines recommend antibiotics for the treatment of acute respiratory exacerbations, but randomised placebo-controlled trials in children are lacking. We hypothesised that oral amoxicillin-clavulanate and azithromycin would each be superior to placebo in achieving symptom resolution of non-severe exacerbations in children by day 14 of treatment.Methods In this multicentre, three-arm, parallel, double-dummy, double-blind, randomised placebo-controlled trial at four paediatric centres in Australia and New Zealand, we enrolled children aged 1-18 years with CTconfirmed bronchiectasis unrelated to cystic fibrosis, who were under the care of a respiratory physician and who had had at least two respiratory exacerbations in the 18 months before study entry. Participants were allocated (1:1:1) at exacerbation onset to receive oral suspensions of amoxicillin-clavulanate (45 mg/kg per day) plus placebo azithromycin, azithromycin (5 mg/kg per day) plus placebo amoxicillin-clavulanate, or both placebos for 14 days. An independent statistician prepared a computer-generated, permuted-block (size 2-8) randomisation sequence, stratified by centre, age, and cause. Participants, caregivers, study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was the proportion of children with exacerbation resolution by day 14 in the intention-to-treat population. Treatment groups were compared using generalised linear models. Statistical significance was set at p<0·0245 to account for multiple comparisons. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000011886) and is completed.Findings Between April 17, 2012, and March 1, 2017, 604 children were screened and 252 were enrolled. Between July 31, 2012, and June 26, 2017, 197 children were allocated at the start of an exacerbation (63 to the amoxicillinclavulanate group, 67 to the azithromycin group, and 67 to the placebo group). Respiratory viruses were identified in 82 (53%) of 154 children with available nasal swabs on day 1 of treatment. Primary outcome data were available for 196 (99%) children (one child with missing data [placebo group] was recorded as non-resolved according to criteria defined a priori). By day 14, exacerbations had resolved in 41 (65%) children in the amoxicillin-clavulanate group, 41 (61%) in the azithromycin group, and 29 (43%) in the placebo group. Compared with placebo, relative risk for resolution by day 14 was 1·50 (95% CI 1·08-2·09, p=0·015; number-needed-to-treat [NNT] 5 [95% CI 3-20]) in the amoxicillin-clavulanate group and 1·41 (1·01-1·97, p=0·042; NNT 6 [3-79]) in the azithromycin group. Adverse events were recorded in 19 (30%) children in the amoxicillin-clavulanate group, 20 (30%) in the azithromycin group, and 14 (21%) in the placebo group, but no events were severe or life-threatening.Interpretation Amoxicillin-clavulanate treatment is beneficial in terms of resolution of non-severe exacerbations of bronchiec...

Twenty‐five years of Respirology: Advances in bronchiectasis

“…The ORBIT RCT showed efficacy of once‐daily inhaled liposome‐encapsulated/free ciprofloxacin (ARD‐3150) in chronically infected adult patients with Pseudomonas aeruginosa (Pa) in reducing exacerbation frequency and severity compared to placebo . The recent BEST RCT assessed the role of oral antibiotics for treating non‐severe exacerbations of bronchiectasis in children . BEST‐1, the first placebo‐controlled RCT for exacerbations, showed the efficacy of amoxicillin‐clavulanate and azithromycin over placebo (relative risk of bronchiectasis resolution by day 14 was 1.50 (95% CI: 1.08–2.09; P = 0.015) and 1.41 (95% CI: 1.01–1.97; P = 0.042), respectively) .…”

“…7 The recent BEST RCT assessed the role of oral antibiotics for treating non-severe exacerbations of bronchiectasis in children. 8 BEST-1, the first placebocontrolled RCT for exacerbations, showed the efficacy of amoxicillin-clavulanate and azithromycin over placebo (relative risk of bronchiectasis resolution by day 14 was 1.50 (95% CI: 1.08-2.09; P = 0.015) and 1.41 (95% CI: 1.01-1.97; P = 0.042), respectively). 8 BEST-2 described that although azithromycin was non-inferior (within a 20% margin) to amoxicillin-clavulanate for resolving exacerbations in children with non-severe bronchiectasis, children on azithromycin had a longer exacerbation duration and increased risk of inducing macrolide resistance.…”

“…8 BEST-1, the first placebocontrolled RCT for exacerbations, showed the efficacy of amoxicillin-clavulanate and azithromycin over placebo (relative risk of bronchiectasis resolution by day 14 was 1.50 (95% CI: 1.08-2.09; P = 0.015) and 1.41 (95% CI: 1.01-1.97; P = 0.042), respectively). 8 BEST-2 described that although azithromycin was non-inferior (within a 20% margin) to amoxicillin-clavulanate for resolving exacerbations in children with non-severe bronchiectasis, children on azithromycin had a longer exacerbation duration and increased risk of inducing macrolide resistance. 9 Data over the last decade have shown that bronchiectasis exacerbations can be successfully reduced by 40-50% (using long-term oral azithromycin for 6-26 months in children and adults) by using inhaled fluoroquinolones (rate ratio = 0.74, 95% CI: 0.62-0.87).…”

Advancing the knowledge, understanding and management of respiratory exacerbations of bronchiectasis in children

“…306 Recently we conducted a RCT that found after 21-days treatment, oral azithromycin was non-inferior (within a 20% margin) to amoxicillin-clavulanate for managing non-severe (non-hospitalised) exacerbations in children with bronchiectasis. 307 However, those receiving azithromycin took significantly longer (4-days median difference) to achieve symptom resolution. Although azithromycin is non-inferior to amoxicillinclavulanate, there are no superiority RCTs comparing either antibiotic to placebo to address the important clinical question of whether oral antibiotics are necessary to treat all non-severe acute exacerbation of bronchiectasis.…”

“…252 In children, almost half of acute exacerbations are associated with viruses. 144,307 As antimicrobial resistance is of increasing global concern, it is important to determine antibiotic efficacy for treating exacerbations. 308…”