Efficacy of Oral Antibiotics for Non-Severe Exacerbations of Bronchiectasis in Children (BEST 1): A Multi-Centre, Double-Blind, Double-Dummy, Randomised Placebo-Controlled Trial

Abstract

Background: Bronchiectasis guidelines recommend antibiotics for treating acute respiratory exacerbations, but placebo-controlled, randomised-controlled trials (RCTs) are lacking in children. Since many exacerbations are virus-triggered, antibiotics may be unnecessary for non-severe (non-hospitalised) episodes. We hypothesised that oral amoxicillin-clavulanate and azithromycin are both superior to placebo for achieving symptom resolution by day-14 when treating non-severe exacerbations in children. Methods: In this multicentre (n=4), parallel, double-dummy, double-blind, placebo-controlled three-arm RCT, children aged 1-19 years were randomised at exacerbation onset to receive: (a) amoxicillin-clavulanate (45mg/kg/day)/azithromycin-placebo, (b) azithromycin (5mg/kg/day)/amoxicillin-clavulanate-placebo, or (c) placebo/placebo for 14-days (Australian-New Zealand Registry, ACTRN12612000011886). The primary outcome was exacerbation resolution by day-14. Secondary outcomes included exacerbation duration, time-to-next exacerbation, parent cough-specific quality-of-life, laboratory and spirometry assessments and nasopharyngeal microbiology. Treatment arms were compared using generalised-linear-models. Statistical significance was set at p<0·0245. Findings: Between April 2012 and December 2017, 197 children were randomised (amoxicillin-clavulanate n=63, azithromycin n=67, placebo n=67). By day-14, exacerbations had resolved in 41 (65%), 41 (61%) and 29 (43%) children in the respective groups. Compared to placebo, the relative risk of resolution by day-14 for amoxicillin-clavulanate was 1·50 (95% confidence interval [CI] 1·08-2·09; p=0·02, number needed-to-treat-for-benefit=5, 95%CI 3-20) and for azithromycin 1·41 (95%CI 1·01-1·97; p=0·04). Compared to placebo, the median exacerbation duration was significantly shorter in the amoxicillin-clavulanate (7 versus 10-days, p=0·02), but not the azithromycin group (8 vs 10-days, p=0·24). Other secondary between-group outcomes were not significantly different. Azithromycin was associated with increased nasopharyngeal carriage of macrolide-resistant-bacteria, while respiratory viruses were identified in 53% of exacerbations. Interpretation: Amoxicillin-clavulanate and azithromycin both showed benefit compared to placebo for treating non-severe exacerbations of bronchiectasis in children. However, azithromycin was associated with increased carriage of antibiotic-resistant bacteria. Consequently, amoxicillin-clavulanate should remain the first-line oral antibiotic for treating non-severe exacerbations of bronchiectasis in children. Funding: This work was supported by the Australian National Health and Medical Research Council (NHMRC; project grant number 1019834,) the NHMRC Centre for Research Excellence in Lung Health of Aboriginal and Torres Strait Islander Children (1040830), and Cure Kids, Auckland, New Zealand (3702764/3539). VG was supported by an NHMRC post-graduate scholarship (1075119). ABC is supported by an NHMRC practitioner fellowship (1058213). KFO and HSV were supported by NHMRC CRE in Children’s Indigenous Lung Health fellowships (10450830). MB is supported by a NHMRC Hot North Fellowship (1131932). Declaration of Interest: We declare that we have no conflicts of interest. Ethical Approval: The protocol has received ethical approval from the respective Human Research Ethics Committees of all the participating institutions (Darwin: Department of Health and Families and Menzies School of Health Research; Brisbane: Children’s Health Services (Royal Children’s Hospital) and University of Queensland; Perth: Princess Margaret Hospital; Melbourne: Royal Children’s Hospital; Auckland: Northern Ethics Committee, Ministry of Health and Starship Children’s Health local ethics committee). The study is being conducted under Australia’s Therapeutic Goods Administration Clinical Trial Notification scheme.