Amoxicillin-clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2): a multicentre, double-blind, non-inferiority, randomised controlled trial

Abstract

Background: Although amoxicillin-clavulanate is the recommended first-line empirical oral antibiotic treatment for non-severe exacerbations in children with bronchiectasis, azithromycin is also often prescribed for its convenient once-daily dosing. No randomised controlled trials involving acute exacerbations in children with bronchiectasis have been published to our knowledge. We hypothesised that azithromycin is non-inferior to amoxicillin-clavulanate for resolving exacerbations in children with bronchiectasis.; Methods: We did this parallel-group, double-dummy, double-blind, non-inferiority randomised controlled trial in three Australian and one New Zealand hospital between April, 2012, and August, 2016. We enrolled children aged 1-19 years with radiographically proven bronchiectasis unrelated to cystic fibrosis. At the start of an exacerbation, children were randomly assigned to oral suspensions of either amoxicillin-clavulanate (22·5 mg/kg, twice daily) and placebo or azithromycin (5 mg/kg per day) and placebo for 21 days. We used permuted block randomisation (stratified by age, site, and cause) with concealed allocation. The primary outcome was resolution of exacerbation (defined as a return to baseline) by 21 days in the per-protocol population, with a non-inferiority margin of -20%. We assessed several secondary outcomes including duration of exacerbation, time to next exacerbation, laboratory, respiratory, and quality-of-life measurements, and microbiology. This trial was registered with the Australian/New Zealand Registry (ACTRN12612000010897).; Findings: We screened 604 children and enrolled 236. 179 children had an exacerbation and were assigned to treatment: 97 to amoxicillin-clavulanate, 82 to azithromycin). By day 21, 61 (84%) of 73 exacerbations had resolved in the azithromycin group versus 73 (84%) of 87 in the amoxicillin-clavulanate group. The risk difference showed non-inferiority (-0·3%, 95% CI -11·8 to 11·1). Exacerbations were significantly shorter in the amoxicillin-clavulanate group than in the azithromycin group (median 10 days [IQR 6-15] vs 14 days [8-16]; p=0·014). Adverse events were attributed to the trial medication in 17 (21%) of 82 children in the azithromycin group versus 23 (24%) of 97 in the amoxicillin-clavulanate group (relative risk 0·9, 95% CI 0·5 to 1·5).; Interpretation: By 21 days of treatment, azithromycin is non-inferior to amoxicillin-clavulanate for resolving exacerbations in children with non-severe bronchiectasis. In some patients, such as those with penicillin hypersensitivity or those likely to have poor adherence, azithromycin provides another option for treating exacerbations, but must be balanced with risk of treatment failure (within a 20% margin), longer exacerbation duration, and the risk of inducing macrolide resistance.; Funding: Australian National Health and Medical Research Council. (Copyright © 2018 Elsevier Ltd. All rights reserved.)Expert Rev Anti Infect Ther. 2014 Oct;12(10):1277-96. (PMID: 25156239); Front Pediatr. 2017 Feb 20;5:27. (PMID: 28265556); Chest. 2010 Jul;138(1):158-64. (PMID: 20173055); Eur Respir J. 2017 Sep 9;50(3):. (PMID: 28889110); Pediatr Pulmonol. 2011 Feb;46(2):131-8. (PMID: 20717910); Respir Med. 1993 Aug;87(6):449-54. (PMID: 8210615); Antimicrob Agents Chemother. 2003 Mar;47(3):997-1001. (PMID: 12604533); Int J Antimicrob Agents. 2012 Oct;40(4):365-9. (PMID: 22819151); Chest. 2011 Mar;139(3):576-580. (PMID: 20947650); Lancet Respir Med. 2013 May;1(3):262-74. (PMID: 24429132); Thorax. 2012 Aug;67(8):689-93. (PMID: 22628120); Cochrane Database Syst Rev. 2015 Mar 08;(3):CD001954. (PMID: 25749735); Rev Recent Clin Trials. 2012 Feb;7(1):24-30. (PMID: 22023177); Am J Respir Crit Care Med. 2012 Oct 1;186(7):657-65. (PMID: 22744718); Med J Aust. 2015 Jan 19;202(1):21-3. (PMID: 25588439); Pediatr Pulmonol. 2012 Jan;47(1):68-75. (PMID: 21830316); Lancet Respir Med. 2013 Oct;1(8):610-620. (PMID: 24461664); Breathe (Sheff). 2016 Sep;12(3):222-235. (PMID: 28210295); Trials. 2013 Feb 20;14:53. (PMID: 23421781); Clin Microbiol Infect. 2011 Nov;17 Suppl 6:E1-59. (PMID: 21951385); JAMA. 2006 Mar 8;295(10):1172-4. (PMID: 16522840); JAMA. 2012 Dec 26;308(24):2594-604. (PMID: 23268518); Eur J Clin Microbiol Infect Dis. 2015 Nov;34(11):2275-85. (PMID: 26363637); Arch Dis Child. 2014 Jun;99(6):522-5. (PMID: 24521788); Chest. 2012 Apr;141(4):1018-1024. (PMID: 21885727); Pediatr Pulmonol. 2016 May;51(5):450-69. (PMID: 26840008); Pediatr Pulmonol. 2018 Apr;53(4):467-474. (PMID: 29405664); Eur Respir J. 1998 Feb;11(2):462-6. (PMID: 9551755); JAMA Pediatr. 2016 Oct 1;170(10):979-986. (PMID: 27533601). Linking ISSN: 01406736. Subset: MEDLINE; Date of Electronic Publication: 2018 Sep 18. Current Imprints: Publication: 2004- : London : Elsevier; Original Imprints: Publication: London : J. Onwhyn <br />