Although bronchiectasis is a major contributor to chronic respiratory morbidity and mortality globally, few randomised controlled trials (RCTs) have been done to guide management. [1] [2] [3] Bronchiectasis is characterised by acute respiratory exacerbations, which in children are associated with increased parental stress, impaired quality of life, and lung function decline in severe exacerbations requiring hospitalisation. 4 Bronchiectasis guidelines advise treating exacer bations with antibiotics for 10-14 days. [5] [6] [7] The predominant pathogens detected in the lower airways of children with bronchiectasis are Haemophilus influenzae, Strepto coccus pneumoniae, and Moraxella catarrhalis, whereas (unlike in cystic fibrosis) Pseudomonas aeruginosa is uncommon. 2, 8 Accordingly, the combined Australian and New Zealand guidelines for bronchiectasis in children and adults recommend amoxicillin-clavulanate as the empirical firstline oral antibiotic for nonsevere exacerbations. 5 The 2019 British Thoracic Society guidelines for bronchiectasis in adults also recommend using oral amoxicillin or amoxicillin-clavulanate for exacerbations in adults, while highlighting the absence of randomised placebo controlled trials. 7 Likewise, the latest European adult guidelines 6 refer to an earlier publication in which amoxicillin-clavulanate was recommended as the first option for acute exacerbations in patients without P aeruginosa infection. 9 Because young children are often unable to expectorate to provide reliable lower airway specimens, amoxicillinclavulanate is usually continued for the whole treatment course. Nevertheless, azithromycin, with its broad antimicrobial spectrum and convenient oncedaily dosing, has become a popular alternative to amoxicillinclavulanate. Indeed, in some regions of Australia, more than 50% of children undergoing bronchoscopy for chronic cough had received azithromycin in the preceding 2week period. 10 Our previous RCT showed that, after 21 days of treatment, oral azithromycin was noninferior (within a 20% margin) to amoxicillinclavulanate for managing nonsevere (nonhospitalised) exacerbations in children with bronchiectasis. 11 However, those receiving azithromycin took significantly longer (median difference 4 days) to achieve symptom resolution. Although azithromycin is noninferior to amoxicillin-clavulanate, no superiority RCTs comparing either of these antibiotics to placebo have been done to address the important clinical question of whether oral antibiotics are necessary to treat all nonsevere acute exacerbations of bronchiectasis.
The role of antibiotics in the management of exacer bations of any severity has also been questioned by some experts, who have suggested that exacerbations triggered by viruses might be selflimiting. 12 In children, almost half of acute exacerbations are associated with viruses. 11, 13 As antimicrobial resistance is of increasing global concern, it is important to determine the efficacy of antibiotics for treating exacerbations. 14 Thus, in the absence of any published randomised placebocontrolled trials of oral antibiotics in either children or adults with an acute exacerbation of bronchiectasis, we aimed to test whether two commonly used but different classes of oral antibiotics, namely amoxicillin-clavulanate and azithromycin, were superior to placebo in achieving resolution of nonsevere exacerbations by day 14 of treatment. As secondary aims, we assessed the effects of the antibiotics on exacerbation duration, time to next respiratory exacerbation, parent coughspecific qualityoflife (PCQOL) score, 15, 16 systemic inflammatory markers, spirometry, upper airway microbiology, and treatmentrelated adverse effects, as well as describing
Evidence before this study Before the start of this study, we searched PubMed and Cochrane databases for randomised controlled trials (RCTs) involving bronchiectasis published between inception and Jan 15, 2011, using the search terms "bronchiectasis", "placebo", and "controlled trials". We then searched using keywords "antibiotics", "bronchiectasis", "randomised", and "exacerbation" in the same databases. Our searches were restricted to reports in English. We identified six RCTs investigating antibiotic treatment of exacerbations in adults, of which only one (using inhaled gentamicin) was placebo-controlled. All had small sample sizes , three were open-label, and five compared either different antibiotics or different doses of the same agent. None involved macrolide antibiotics or children. During the study period, we published the results of our parallel study, which showed that, within a 20% margin, azithromycin was non-inferior to amoxicillin-clavulanate for achieving symptom resolution at 21 days when treating acute exacerbations of bronchiectasis, but that the episodes took significantly longer to resolve with azithromycin than with amoxicillin-clavulanate. Randomised placebo-controlled trials assessing treatments for exacerbations of bronchiectasis in children are still lacking.
To our knowledge, this is the first RCT comparing use of any oral antibiotics with placebo for treating exacerbations in patients with bronchiectasis unrelated to cystic fibrosis. In this three-arm RCT, amoxicillin-clavulanate showed benefit compared with placebo in achieving symptom resolution within 14 days in non-severe (non-hospitalised) acute exacerbations of bronchiectasis in children. Exacerbation resolution was slightly but non-significantly more frequent in the azithromycin group than in the placebo group. Compared with placebo, azithromycin treatment was associated with an increased proportion of azithromycin-resistant bacteria isolated from the nasopharynx.
Evidence from this study supports the recommendations for use of amoxicillin-clavulanate in the treatment of exacerbations of bronchiectasis in children. Taken together with our previously published non-inferiority RCT comparing amoxicillin-clavulanate and azithromycin, amoxicillin-clavulanate should remain the first-line antibiotic treatment for non-severe exacerbations of bronchiectasis in children. Azithromycin could be reserved for use in selected settings, such as in patients with genuine penicillin hypersensitivity or in situations in which less frequent, supervised dosing might overcome difficulties with adherence.
the point prevalence of respiratory viruses and atypical bacterial pathogens during exacerbations.
A threearm, parallelgroup, doubledummy, double blind, placebocontrolled interventional RCT was done in four paediatric centres in Australia (Brisbane, Darwin, and Perth) and New Zealand (Auckland).
Children aged 1-18 years who attended one of the four paediatric centres were eligible for enrolment if they had CTconfirmed bronchiectasis; had been diagnosed by a respiratory physician in the 5 years immediately before to study entry or, if diagnosed earlier, had been followed regularly by a respiratory physician for treatment of bronchiectasis; and had had at least two respiratory exacerbations in the 18 months before study entry. Exclusion criteria included cystic fibrosis, liver dys function, hypersensitivity to βlactam or macrolide antibiotics, or having been enrolled previously in this RCT. Patients were also excluded if, at the time of randomisation, they had had a severe exacerbation of bronchiectasis (dyspnoea, hypoxia [oxygen saturation <90% in air], or hospitalisation) within the preceding 8 weeks, had P aeruginosa detected within the previous 16 weeks, had ever had nontuberculous mycobacterial infection, had received βlactam or macrolide antibiotics within the previous 3 weeks, or were receiving treatment for cancer. Those taking oral nonmacrolide antibiotics on a longterm basis (for >4 weeks) for bronchiectasis were not excluded, but these antibiotics were ceased tempor arily while the patient received the study medications.
Written informed consent was obtained from parents or caregivers and written assent obtained from children older than 12 years. The human research ethics committee at each participating site approved the trial, which was monitored by an independent datamonitoring committee. The study protocol has been published previously. 17
Randomisation was stratified by centre, age (≤5 years or >5 years), and aetiology of bronchiectasis (patients with postinfectious or idiopathic disease, or those with disease related to immunodeficiency, aspiration, primary ciliary dyskinesia, or other causes). A computer generated, permutedblock (block size 2-8) random isation allocation sequence was prepared centrally by an independent statistician and used to allocate children (1:1:1) to one of three groups: an amoxicillin-clavulanate group, an azithromycin group, and a placebo group. Respiratory physicians and research assistants at each site were responsible for enrolment. At the time of an exacerbation, the child was allocated to the next number on the stratified randomisation list maintained by the local hospital pharmacist, who was external to the study. The statistician and the trial pharmacists were not involved in data collection or conduct of the study after sequence preparation and allocation. Allocation was concealed to all investigators and participants, and was done centrally in each country. The participants, caregivers, study coordinators at various sites, and investigators were masked to treatment assignment until data analysis was completed.
As this was a doubledummy trial, the participants received either one active study medication and equivalent volume of placebo for the other study medication, or placebo for both study medications. The placebo medications (Institute of Drug Technology, Melbourne, Australia) had indistinguishable appearance and taste to those of the respective active antibiotics. 11
The parents or caregivers of enrolled children were instructed to contact research staff when their child was having an exacerbation. Once an acute exacerbation was confirmed, children were randomly allocated to a study group.
All study medications were supplied as dry powders to be reconstituted at home, with identical instructions to prepare the active medication or its matched placebo by adding equal volumes of water to each of the study medications. Children in the amoxicillin-clavulanate group received oral suspensions of amoxicillin-clavulanate (45 mg/kg per day [maximum 880 mg], divided into twice daily doses) and placebo azithromycin (once daily); those in the azithromycin group received azithromycin (5 mg/kg per day [maximum 200 mg] as a oncedaily dose) and placebo amoxicillin-clavulanate (twice daily); and those in the placebo group received both placebo medications. All treatment courses lasted for 14 days, in alignment with local and international guidelines. [5] [6] [7] Following consultation with respiratory physician colleagues and feedback from parents, 14 days was the longest period deemed acceptable for treating an exacerbation with a placebo with a safety exit after 7 days (appendix p 3). Adherence was assessed by return of study medication bottles and review of cough score and adverse event diaries. 18 Exacerbations, including their resolution or failure to respond to the study medication, were predefined as per our previous study 19 and RCT. 11 The baseline state for each child was ascertained at enrolment with use of a validated cough diary card 18 and clinical examination. A nonsevere exacerbation was defined as an increase in cough frequency, a change in character of the cough (ie, from dry to wet, or an increase in sputum volume or purulence) for at least 3 consecutive days and without any accompanying dyspnoea, hypoxia (oxygen saturation <90% in air), or need for hospitalisation, according to the treating clinician. 11 An exacerbation was considered resolved when a cough score had returned to baseline for at least 2 consecutive days after randomisation and commencement of study medications, and when any other new symptoms associated with the episode (such as fever, See Online for appendix lethargy, or general malaise) had resolved. An exacerbation was considered resolved even if the child exited the study protocol for any reason after resolution. 11 Treatment was considered to have failed if a cough score had not returned to baseline for at least 2 consecutive days by day 14 after randomisation and commencement of study medications, and also if any associated new symptoms had not resolved. These children were then treated with openlabel amoxicillin-clavulanate unless judged by their respiratory physician to require intravenous antibiotics. Treatment failures were also recorded in children whose resolution status was unknown.
Exacerbations were confirmed after medical review in the clinic or outreach clinic, or at a home visit. On day 3 of treatment, families were telephoned by research staff to monitor progress and the children were reviewed clinically on days 7 and 14 and at the resolution of the exacerbation. The day of resolution was ascertained by examining cough and symptom diaries, and was then recorded prospectively. Those in remote and rural areas where a home visit was not always feasible had the study medication and PCQOL questionnaire 15,16 sent via express post. Parents or caregivers completed daily cough and symptom diaries while receiving the study medication. Children were then followed up with monthly phone calls from research staff for 6 months after the exacerbation or until the next exacerbation after finishing the study medication, whichever was earlier.
In addition to recording a cough diary card 18 at enrolment, a baseline PCQOL questionnaire was completed, oxygen saturation was measured, and blood was drawn to assess white blood cell count and Creactive protein concen trations. Children aged 6 years or older underwent spirometry and FEV 1 % predicted was recorded, according to current guidelines. 20 Where possible, as determined by the clinical setting, these tests were repeated on days 1 and 14 of treatment for an exacerbation.
Nasal swabs were collected on days 1 and 14 of treatment for an exacerbation. They were cultured for respiratory bacterial pathogens, which then underwent antibiotic susceptibility testing as described previously. 17 Day1 nasal swabs also underwent realtime PCR assays, using established methods, 17 to detect atypical bacteria (Mycoplasma pneumoniae and Chlamydia pneumoniae) and 18 different viruses: respiratory syncytial viruses (subtypes A and B), adenoviruses, influenza A and B viruses, human parainfluenza virus types 1-3, human metapneumovirus, human coronaviruses (types OC43, HK1, 229E, and NL63), picornaviruses (rhinovirus and enterovirus), human bocavirus 1, and human polyomaviruses (KI and WU).
Children allocated to receive amoxicillin-clavulanate or azithromycin were compared with those in the placebo group. The primary outcome was the proportion of children whose exacerbations resolved by day 14 in the intentiontotreat population. Prespecified secondary outcomes were exacerbation duration and time to next respiratory exacerbation (in days, from the date of resolution while receiving study medications until the beginning of the next exacerbation), both calculated in children whose exacerbations resolved by day 14; changes in PCQOL score; biomarkers of systemic inflammation (white blood cell count and Creactive protein concentration); FEV 1 % predicted; nasal carriage of respiratory bacterial pathogens (including antibiotic resistance) between treatment days 1 and 14, and respiratory viruses or atypical bacteria on treatment day 1; and treatmentrelated adverse effects. The time to next respiratory exacerbation (in days) for each patient was calculated from the day their exacerbation resolved while receiving the study medications. All secondary analyses were done in the intentionto treat population, and perprotocol analyses were also done. We did a post hoc analysis based on age group (≤5 years or >5 years) and virus identified on day 1 of treatment for the exacerbation (present or absent) for both the primary and secondary outcomes.
The sample size was based on a pilot study comparing oral amoxicillin-clavulanate or azithromycin with placebo in terms of resolution at 14 days. 17 We assumed that exacerbations would resolve by day 14 in 60% of those receiving any antibiotic versus 30% in the placebo group. α was set at 0·0245 to account for the two twosided primary comparisons and an interim analysis. A sample size of 189 (63 per group) was estimated to provide 84% power to detect a difference in the primary outcome.
The statistical analysis plan was approved by the study investigators and the independent datamonitoring committee before the data were analysed. Data were also analysed before group allocations were revealed. An interim analysis was done by an independent researcher when 50% of the anticipated sample size was achieved. The independent datamonitoring committee deemed that the interim results did not meet the predetermined stopping criteria. 17 We used intentiontotreat and prespecified perprotocol analyses (appendix pp 6-8, 10-12). Site, age, and cause of bronchiectasis were not included in the analyses: these factors were not part of the protocol or the statistical analysis plan and, as in our previous study, 11 were only used for stratification during randomisation to allow for balance between the three groups.
We present summary statistics as median (IQR) for continuous data and as frequency (%) for categorical data. The association between treatment group and resolution of exacerbation was investigated with use of a generalised linear regression model with binomial family and log link, and reported as relative risk (RR) and 95% CI. Numberneededtotreat to benefit (NNT) was calculated with a generalised linear model with binomial family and identity link. For both models, treatment group was included as the main effect and no covariables were included. The associations between treatment group and exacerbation duration and between treatment group and time to next exacerbation were both investigated with use of median regression. Those children whose exacerbations had not resolved by day 14 received openlabel amoxicillin-clavulanate and were not included in these analyses. Children who did not have a further exacerbation were censored at day 180 (6 months), which was the total duration of followup.
The associations between treatment group and changes in secondary outcomes between treatment days 1 and 14 were also investigated with use of median regression. The association between treatment group and microbiological results was assessed with the χ² test. For bacteriological results, we also used a generalised linear model for the binomial family and identity link (estimating the risk difference) to control for baseline bacterial prevalence (appendix pp 13-14). Posthoc analyses based on age group and presence of viruses or atypical bacteria were also done and are reported in the appendix (pp 6-8).
All data were analysed with Stata version 15.1. Additional details of the study methods are described in the appendix (pp [3] [4] .
This study is registered as an international standard RCT with the Australian New Zealand Clinical Trials Registry (ACTRN12612000011886).
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. VG, ABC, MJB, and RSW had access to the raw data. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Between April 17, 2012, and March 1, 2017, 604 children were screened and 252 were enrolled. 197 children were All children who discontinued study medication and were not hospitalised were treated with oral amoxicillinclavulanate as per study protocol, except one child in the amoxicillin -clavulanate group (who was given sulfamethoxazole-trimethoprim by their respiratory physician) and one child in azithromycin group (who was prescribed roxithromycin by their respiratory physician). Characteristics at baseline ( [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] ). This higher rate of resolution in the amoxicillin-clavulanate group was formally statis tically significant (as per our apriori definition) 17 after accounting for use of the same placebo group in comparisons with the amoxicillin-clavulanate group and the azithromycin group, as well as for the interim analysis. In the azithromycin group, exacerbations had resolved by day 14 in 41 (61%) children (RR for resolution 1·41 [1·01-1·97] vs placebo, p=0·042; NNT 6 ), although this difference did not meet our predefined significance threshold. 17 The median duration of exacerbation in the placebo group (10 days [IQR [6] [7] [8] [9] [10] [11] [12] ) was longer than that in the amoxicillin-clavulanate group (7 days [6-10], p=0·018), but did not differ significantly from that in the azithromycin group (8 days [5] [6] [7] [8] [9] [10] [11] [12] , p=0·24). The median time to next exacerbation after resolution was similar in all three groups: 89 days (40-180) in the placebo group, 89 days (31-180, p=1·00 vs placebo) in the amoxicillinclavulanate group, and 83 days (51-180, p=0·86 vs placebo) in the azithromycin group (appendix p 15).
Changes in PCQOL scores, white blood cell counts, and Creactive protein concentrations did not differ significantly between the placebo group and either the (table 3) . Spirometry at the beginning of treatment was done in 44 (22%) participants in the study, as 93 (47%) participants were aged less than 6 years, 22 (11%) participants lived at a remote site, and in 38 (19%) children the research staff did not carry spirometry equipment when a home visit was required. Paired spirometry results (at days 1 and 14 of treatment) were available for only 28 (14%) children. FEV 1 % predicted values showed significantly greater improvement from day 1 to day 14 in the amoxicillin-clavulanate group than in the placebo group, although participant numbers providing these data were small (table 3) . Day 1-14 changes in FEV 1 % predicted values did not differ significantly between the azithromycin and placebo groups (table 3) .
Of the 128 paired nasal swabs available for analysis, no significant betweengroup differences were observed in the bacteria isolated at treatment day 1. However, by day 14, potentially pathogenic bacteria were isolated from the nasopharynx in significantly fewer patients in the amoxicillin-clavulanate (p<0·0001) and azithromycin (p<0·0001) groups than in the placebo group (table 4). In the azithromycin group, the proportion of azithromycin resistant bacterial isolates increased from day 1 (two [9%] of 22 patients with pathogenic bacterial isolates) to day 14 (five [63%] of eight), whereas these proportions of antibioticresistant bacteria did not change substantially between days 1 and 14 in the amoxicillin-clavulanate or placebo groups. 11 (92%) of the 12 children with azithromycinresistant bacterial pathogens on day 1 had been prescribed azithromycin previously by their respective respiratory physicians. 99 respiratory viruses were detected by PCR in 82 (53%) of 154 children with available nasal swabs on day 1 of treatment (table 2, appendix p 9). One (1%) child had three viruses identified, another 15 (10%) children had two viruses detected, and 66 (43%) had a single virus identified from their nasal swab specimens. C pneumoniae bacteria were detected by PCR in nasal swabs from five (3%) children (two of whom had viruses codetected), and M pneumoniae bacteria were detected in three (2%) children (one of whom also had a virus co detected). Rhinovirus was the most common virus, detected in 53 (65%) of 82 children with viruses identified (34% of children with available nasal swabs). Respiratory viruses were detected in a significantly higher proportion of participants on day 1 in both antibiotic treatment groups than in the placebo group: 31 (63%) of 49 nasal swabs in the amoxicillin-clavulanate group (p=0·0078 vs placebo), 31 (61%) of 51 in the azithromycin group (p=0·0149 vs placebo), and 20 (37%) of 54 in the placebo group. However, the relative distributions of virus types were similar across the three groups, although (with the exception of rhinoviruses) the numbers of individual virus types detected were small (appendix p 9). One (1%) child in the azithromycin group exited the study at day 2 of treatment and one (1%) in the placebo group exited at day 6 because of medication refusal. Eight (4%) children stopped the study medication and received openlabel antibiotics because of gastrointestinal adverse events (three [5%] in the amoxicillin-clavulanate group, three [4%] in the azithromycin group, and two [3%] in the placebo group). All eight, as well as the two who refused medication, received openlabel amoxicillinclavulanate as per the study protocol. One child in each of the three groups was hospitalised for worsening symptoms, and one other who was receiving azithromycin was hospitalised with seizures ( figure, table 5 ).
We did a perprotocol analysis for primary and secondary outcomes (appendix pp [6] [7] [8] [9] [10] [11] [12] 5) , as well as a posthoc analysis on the basis of age group (≤5 years or >5 years) and virus identified on day 1 of treatment for the exacerbation (present or absent) for the primary and secondary outcomes. Adjusted data for the minor imbalance between groups for nasal swab bacteria at baseline are also presented in the appendix (pp [13] [14] . The results of perprotocol analyses were similar to those of the intentiontotreat analyses for both primary and secondary outcomes. Data are median (IQR) or n/N (%). PC-QOL=parent cough-specific quality-of-life. *Some children were not seen by a study doctor on day 1 of treatment for their exacerbation, had incomplete information (including blood samples), or were unable to undergo spirometry. 
The results of this study show that use of oral amoxicillinclavulanate for 14 days for nonsevere exacerbations of bronchiectasis in children was superior to placebo in achieving exacerbation resolution by the end of treatment and in decreasing the duration of exacerbations. For both of these outcomes, azithromycin was associated with some improvements but did not meet our prespecified margin of statistical significance for superiority over placebo. Betweengroup differences were not observed for time to next exacerbation, PCQOL scores, or inflammatory markers (Creactive protein concentration or white blood cell count). Adherence was highest in the amoxicillin-clavulanate group, and both antibiotics were well tolerated. Although both antibiotics reduced the overall presence of bacterial pathogens in the nasopharynx at day 14 compared with placebo, the proportion of bacterial isolates with antibiotic resistance was significantly increased in the azithromycin group, but not in the amoxicillin-clavulanate group, compared with placebo at the end of treatment. Overall, 53% of participants with available nasal swabs had respiratory viruses detected at the beginning of an exacerbation.
In adults with bronchiectasis, antibiotic treatments can reduce airway and systemic inflammation, sputum volume, purulence, and bacterial density, and improve symptoms. 21, 22 Antibiotics are considered crucial inter ventions in the treatment of bronchiectasis. 3, [5] [6] [7] In the absence of other RCTlevel evidence in either children or adults, our placebocontrolled trial now provides evidence confirming recommendations for the use of oral amoxicillin-clavulanate to treat nonsevere exacerbations of bronchiectasis in children. 5 The superiority of amoxicillin-clavulanate over placebo in achieving cough resolution (NNT 5 [95% CI [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] ) and decreasing exacerbation duration is consistent with the results of a previous RCT, which also described the efficacy of amoxicillin-clavulanate compared with placebo for treating chronic wet cough in children with suspected protracted bacterial bronchitis. That study showed results at 2 weeks similar to our own with regard to achieving cough resolution (NNT 4 [95% ). 23 To the best of our knowledge, no other comparable paediatric studies have been done to date. An RCT in adults with moderate exacerbations of mildtomoderate chronic obstructive pulmonary disease (COPD) showed that 8 days of amoxicillinclavulanate was more effective than placebo, with an absolute difference in proportion cured of 14·2% (95% CI 3·7-24·3; NNT 7). 24 However, these NNT values suggest that, although amoxicillin-clavulanate is efficacious, antibiotics are not always needed to achieve resolution of an exacerbation in bronchiectasis-an observation reported previously in adults with COPD. 25 Thus, studies to identify those children with bronchiectasis exacerbations who are most likely to benefit from antibiotics are needed. In contrast to oral amoxicillin-clavulanate, azithromycin is not recommended as a firstline agent for treating non severe exacerbations of bronchiectasis. Nonetheless, we included this antibiotic in our RCT as it is commonly used in settings in which treatment adherence is problematic. 10, 26 Although both proportion of children with treatment resolution and median length of exacerbation were similar in the amoxicillin-clavulanate (resolution 65%, duration 7 days) and azithromycin (61%, 8 days) groups, the differences between azithromycin and placebo were not formally statistically significant. However, the duration of exacerbation could only be meaningfully calculated in those whose exacerbation had resolved by day 14 because the children who exited the study protocol or did not achieve resolution were given openlabel antibiotics per study protocol (and including them in the analysis would thus not reflect the true effect of intervention), and the number of children with resolution in placebo group was significantly lower than those in the antibiotic groups. Our previous RCT showed that, although 3 weeks of oral azithromycin treatment was noninferior (within a 20% margin) to 3 weeks of oral amoxicillin-clavulanate for achieving symptom resolution by day 21 in children with nonsevere exacerbations of bronchiectasis, 11 the episode duration was significantly shorter in children allocated to receive amoxicillin-clavulanate (median duration 10 days [IQR [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] ) compared with azithromycin (14 days [8] [9] [10] [11] [12] [13] [14] [15] [16] ). This difference in duration is clinically significant because of the stress, anxiety, and loss of work for parents associated with bronchiectasis exacerbations. 4 Never theless, in the current study, when compared with placebo, both antibiotics by day 14 had similar effect sizes with respect to symptom resolution and episode duration. Indeed, the p value comparing azithromycin to placebo was 0·042, suggesting that statistical significance might have been achieved in a twoarm comparison between azithromycin and placebo (ie, without the need to adjust for multiple comparisons). Furthermore, given the higher thananticipated proportion of participants who achieved resolution in the placebo group, it is possible that this study was insufficiently powered to show statistical superiority of azithromycin. Taken together, this and our previous RCT 11 support the empirical use of amoxicillinclavulanate treatment as the firstline antibiotic choice for nonsevere exacerbations of bronchiectasis in children. Furthermore, data from this study indicate that azithro mycin increased the proportion of azithromycinresistant bacteria in the nasopharynx, which is a recognised reser voir for the transmission of antibioticresistant organisms. 27 Our RCT has additional limitations. First, the doses of antibiotics might not be the optimum doses for use in clinical practice. We used 45 mg/kg per day of the 7:1 amoxicillin-clavulanate formulation. Although 80 mg/kg per day amoxicillin is recommended for treating childhood pneumonia in settings where 30 although higher daily doses of 12 mg/kg for 5 days have been used in preschoolaged children with acute wheezing illnesses. 31 Second, some data on secondary outcomes were not available for all children. Paired PCQOL data were available for only 160 (81%) of 197 children (53 in the amoxicillin-clavulanate, 53 in the azithromycin, and 54 in the placebo groups); however, paired PCQOL data from at least 51 children in each group, based on a betweengroup difference of 0·9 points (the minimum important difference), provides power of 99%. In addition, paired blood results and spirometry data were available for a small proportion of children in each group. Although the improvement in FEV 1 % predicted values differed significantly in the amoxicillin-clavulanate group (N=9) compared with the placebo group (N=6), the small samples mean that these results must be interpreted cautiously.
Third, the higherthanexpected proportion of children with spontaneous resolution in the placebo group might reflect a milder nature of exacerbations in this group versus the two antibiotic groups, or could be directly related to the lower prevalence of respiratory viruses at the beginning of an exacerbation in the placebo group (37%) compared with the other groups (63% and 61%) in this study. Virusassociated exacerbations are known to be more severe and more likely to necessitate intravenous antibiotics and hospitalisation than those in which respiratory viruses are not detected. 13 In the placebo group, the median duration of exacerbation was 11 days in the viruspositive group and 7 days in the virus negative group (appendix pp 7-8). Although we cannot explain the increased viral presence in both the antibiotic groups compared with the placebo group, the baseline parameters of the exacerbation were similar among all three groups (table 1). The role of viruses in nonsevere bronchiectasis exacerbations should be explored further, and more studies are needed to identify the subset of nonsevere exacerbations that might resolve without antibiotics. We plan to evaluate this further by exploring various clinical and microbiological factors associated with the resolution of exacerbations.
Finally, although deep nasal swabs do not directly reflect the lower airway microbiology, we used them to ascertain the effects of antibiotics on carriage and resistance in bacterial respiratory pathogens at this site, which is the principal reservoir for spreading antibiotic resistant respiratory bacteria within the community. 27 Paired nasal swabs for bacterial culture were available for less than 70% of children. Although numbers of children with macrolideresistant pathogens were similar in the placebo and azithromycin groups on day 14, the proportional increase in carriage of macrolideresistant pathogens in the azithromycin group was significant.
In conclusion, this randomised placebocontrolled trial showed that, for nonsevere exacerbations of bronchi ectasis in children, oral amoxicillin-clavulanate was superior to placebo after 14 days of treatment in terms of achieving symptom resolution and shortening the exacer bation duration. Azithromycin was associated with some improvements in exacerbation resolution and duration compared with placebo, but did not meet the threshold for significance defined in this threearm trial. Importantly, azithromycin was also associated with an increase in the proportion of bacteria with azithromycin resistance compared with placebo. The results suggest that amoxicillin-clavulanate should remain the firstline oral antibiotic for the treatment of nonsevere exacerbations of bronchiectasis in children, with oncedaily azithromycin reserved for those with genuine penicillin hypersensitivity or for situations in which directly observed therapy is feasible in settings of poor treatment adherence.
ABC conceived the study. ABC, PSM, KG, KAFO'G, PJT, and MC participated in study design. VG, ABC, PSM, CAB, IBM, HMB, and AS actively recruited participants. VG and GBM participated in coordination and data acquisition. AC randomly allocated patients in the pharmacy and dispensed medications. VG participated in coordination, followup, and statistical analysis. HSV developed the protocol for processing of nasal swabs for bacterial results. VG, ABC, MJB, and RSW had access to the raw data and RSW supervised the statistical analyses. VG drafted the initial manuscript, with substantial revisions undertaken by ABC and KG. All authors contributed to editing the manuscript and approved the final version.
We declare no competing interests.
The protocol for this study has been published previously. As per our institutions' policies involving Indigenous children from Australia and New Zealand, and in accordance with national guidelines, we are unable to share individual participant data with others as specific consent for this was not obtained. The statistical analysis plan will be made available upon individual request to the corresponding author.