Goyal V

Grimwood K

Ware RS

Byrnes CA

Morris, Peter

Masters IB

McCallum GB

Binks MJ

Smith-Vaughan H

O'Grady K-AF

Champion A

Buntain HM

Schultz A

Chatfield M

Torzillo PJ

Chang AB

2019-08-16

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. 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 CT-confirmed 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. 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 amoxicillin-clavulanate 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. Amoxicillin-clavulanate treatment is beneficial in terms of resolution of non-severe exacerbations of bronchiectasis in children, and should remain the first-line oral antibiotic in this setting. National Health and Medical Research Council (Australia), Cure Kids (New Zealand).

Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, QLD, Australia; Department of Paediatrics, Gold Coast Health, Gold Coast, QLD, Australia; School of Medicine, The University of Queensland Brisbane, QLD, Australia; Centre for Children's Health Research, Queensland University of Technology, Brisbane, QLD, Australia. Electronic address: drvikasgoyal@gmail.com..

Department of Paediatrics, Gold Coast Health, Gold Coast, QLD, Australia; Department of Infectious Diseases, Gold Coast Health, Gold Coast, QLD, Australia; School of Medicine, Griffith University, Gold Coast, QLD, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia..

Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia..

Department of Paediatrics, University of Auckland, Auckland, New Zealand; Respiratory Department, Starship Children's Hospital, Auckland, New Zealand..

Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia; Department of Paediatrics, Royal Darwin Hospital, Darwin, NT, Australia..

Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, QLD, Australia; Centre for Children's Health Research, Queensland University of Technology, Brisbane, QLD, Australia..

Child Health Division, Charles Darwin University, Darwin, NT, Australia..

Child Health Division, Charles Darwin University, Darwin, NT, Australia..

School of Medicine, Griffith University, Gold Coast, QLD, Australia; Child Health Division, Charles Darwin University, Darwin, NT, Australia..

Centre for Children's Health Research, Queensland University of Technology, Brisbane, QLD, Australia..

Pharmacy Department, Queensland Children's Hospital, Brisbane, QLD, Australia..

Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, QLD, Australia..

Telethon Kids Institute, Perth, WA, Australia; Division of Paediatrics, School of Medicine, University of Western Australia, Perth, WA, Australia; Department of Respiratory and Sleep Medicine, Perth Children's Hospital, Perth, WA, Australia..

Centre for Health Services Research, Faculty of Medicine, The University of Queensland Brisbane, QLD, Australia..

Central Clinical School, University of Sydney, Sydney, NSW, Australia; Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, NSW, Australia..

Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, QLD, Australia; Centre for Children's Health Research, Queensland University of Technology, Brisbane, QLD, Australia; Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia..

Lancet Respir Med . 2019 Sep;7(9):791-801. doi: 10.1016/S2213-2600(19)30254-1. Epub 2019 Aug 16.

https://pubmed.ncbi.nlm.nih.gov/31427252/?otool=iaurydwlib

https://hdl.handle.net/10137/7745

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.

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