Amoxycillin-clavulanate vs azithromycin for respiratory exacerbations of bronchiectasis in children-a multi-centre double blind non-inferiority randomised controlled trial

Abstract

Rationale: Based on limited available data, current guidelines recommended amoxycillinclavulanate as the first-line empirical oral-antibiotic therapy for non-severe exacerbations of bronchiectasis in children. However, amoxycillin-clavulanate requires multiple dosing per day and causes gastrointestinal symptoms in many children. Oral azithromycin is attractive alternative firstline therapy because of its long half-life, markedly reduced dosing schedule, and good tolerance. Our primary question was “Is daily oral azithromycin non-inferior (within a 20% margin) to oral amoxycillin-clavulanate at achieving resolution of exacerbations by day-21 of treatment?” Methods: We conducted a multicentre, parallel group, double-dummy, double-blind placebo RCT with concealed allocation between April 2012 to August 2016 at 4 centres (Brisbane, Sydney, Darwin and Auckland). Primary outcome was resolution of exacerbation (defined as 'return to baseline') by 21-days. Secondary outcomes were cough-specific quality of life (PC-QoL), duration and time to next exacerbation, and microbiological data from deep nasal swabs. A lower limit of the 95%CI for relative difference in percentage cured between amoxycillin-clavulanate and azithromycin above 0.8 provided non-inferiority. When possible, bloods and spirometry were also obtained. Results: Baseline characteristics of the groups (amoxycillin-clavulanate, n=97 and azithromycin, n=82) were similar. By day-21, exacerbation resolution was comparable between the 2 groups, (relative risk 0.99 CI 0.84, 1.17,) falling within the non-inferiority margin. Betweengroup difference for duration of exacerbation (2-days 95%CI -1.7, 5.3) and PC-QoL at day-21 (0.42, 95%CI -0.06, 0.89) compared to beginning of exacerbation was also similar. Median duration to next exacerbation was similar: amoxycillin-clavulanate (84 days) azithromycin (81 days, p=0.78). Number of children exiting study protocol to start open label antibiotics because of severe adverse effects was higher in children in the azithromycin group (12/82, 14.6%), compared to amoxycillin-clavulanate (9/95, 9.5%) but the difference was not significant (RR 1.55, 95%CI 0.69, 3.48). Of the 147 children where virus data were available, 67 (45.6%) had a virus identified (34/77 in amoxycillin-clavulanate group and 33/70 in azithromycin group. Rhinovirus was the most common (50/67) followed by parainfluenza (n=8). Conclusion: This is the first to provide data that azithromycin is non-inferior to amoxicillin-clavulanate for treating non-severe exacerbations of bronchiectasis in children. Azithromycin may be preferred to amoxicillin-clavulanate in selected settings e.g. adherence. However, its use needs to be balanced with risk of treatment failure (within 20% compared to amoxicillin-clavulanate) and inducing macrolide resistance. Before azithromycin can substitute amoxycillin-clavulanate for exacerbations, a larger study with a smaller non-inferiority margin is required. (Table Presented) .L6229649382018-07-16 <br />