Amoxicillin–clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2)

a multicentre, double-blind, non-inferiority, randomised controlled trial

Vikas Goyal, Keith Grimwood, Catherine A. Byrnes, Peter S. Morris, I. Brent Masters, Robert S. Ware, Gabrielle B. McCallum, Michael J. Binks, Julie M. Marchant, Peter van Asperen, Kerry Ann F. O'Grady, Anita Champion, Helen M. Buntain, Helen Petsky, Paul J. Torzillo, Anne B. Chang

    Research output: Contribution to journalArticleResearchpeer-review

    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.
    Original languageEnglish
    Pages (from-to)1197-1206
    Number of pages10
    JournalThe Lancet
    Volume392
    Issue number10154
    Early online date18 Sep 2018
    DOIs
    Publication statusPublished - 6 Oct 2018

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    Azithromycin
    Bronchiectasis
    New Zealand
    Placebos
    Non-Randomized Controlled Trials
    Clavulanic Acid
    Amoxicillin
    Macrolides
    Random Allocation
    Microbiology
    Treatment Failure
    Cystic Fibrosis
    Penicillins
    Registries
    Suspensions
    Hypersensitivity
    Therapeutics
    Randomized Controlled Trials
    Quality of Life
    Anti-Bacterial Agents

    Cite this

    Goyal, Vikas ; Grimwood, Keith ; Byrnes, Catherine A. ; Morris, Peter S. ; Masters, I. Brent ; Ware, Robert S. ; McCallum, Gabrielle B. ; Binks, Michael J. ; Marchant, Julie M. ; van Asperen, Peter ; O'Grady, Kerry Ann F. ; Champion, Anita ; Buntain, Helen M. ; Petsky, Helen ; Torzillo, Paul J. ; Chang, Anne B. / Amoxicillin–clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2) : a multicentre, double-blind, non-inferiority, randomised controlled trial. In: The Lancet. 2018 ; Vol. 392, No. 10154. pp. 1197-1206.
    @article{9fb9a60f8b7847f4a060f11a9551f325,
    title = "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.",
    author = "Vikas Goyal and Keith Grimwood and Byrnes, {Catherine A.} and Morris, {Peter S.} and Masters, {I. Brent} and Ware, {Robert S.} and McCallum, {Gabrielle B.} and Binks, {Michael J.} and Marchant, {Julie M.} and {van Asperen}, Peter and O'Grady, {Kerry Ann F.} and Anita Champion and Buntain, {Helen M.} and Helen Petsky and Torzillo, {Paul J.} and Chang, {Anne B.}",
    year = "2018",
    month = "10",
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    language = "English",
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    pages = "1197--1206",
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    Goyal, V, Grimwood, K, Byrnes, CA, Morris, PS, Masters, IB, Ware, RS, McCallum, GB, Binks, MJ, Marchant, JM, van Asperen, P, O'Grady, KAF, Champion, A, Buntain, HM, Petsky, H, Torzillo, PJ & Chang, AB 2018, 'Amoxicillin–clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2): a multicentre, double-blind, non-inferiority, randomised controlled trial', The Lancet, vol. 392, no. 10154, pp. 1197-1206. https://doi.org/10.1016/S0140-6736(18)31723-9

    Amoxicillin–clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2) : a multicentre, double-blind, non-inferiority, randomised controlled trial. / Goyal, Vikas; Grimwood, Keith; Byrnes, Catherine A.; Morris, Peter S.; Masters, I. Brent; Ware, Robert S.; McCallum, Gabrielle B.; Binks, Michael J.; Marchant, Julie M.; van Asperen, Peter; O'Grady, Kerry Ann F.; Champion, Anita; Buntain, Helen M.; Petsky, Helen; Torzillo, Paul J.; Chang, Anne B.

    In: The Lancet, Vol. 392, No. 10154, 06.10.2018, p. 1197-1206.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Amoxicillin–clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2)

    T2 - a multicentre, double-blind, non-inferiority, randomised controlled trial

    AU - Goyal, Vikas

    AU - Grimwood, Keith

    AU - Byrnes, Catherine A.

    AU - Morris, Peter S.

    AU - Masters, I. Brent

    AU - Ware, Robert S.

    AU - McCallum, Gabrielle B.

    AU - Binks, Michael J.

    AU - Marchant, Julie M.

    AU - van Asperen, Peter

    AU - O'Grady, Kerry Ann F.

    AU - Champion, Anita

    AU - Buntain, Helen M.

    AU - Petsky, Helen

    AU - Torzillo, Paul J.

    AU - Chang, Anne B.

    PY - 2018/10/6

    Y1 - 2018/10/6

    N2 - 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.

    AB - 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.

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