Macrolide antibiotics for bronchiectasis

Carol Kelly; James D Chalmers; Iain Crossingham; Nicola Relph; Lambert M Felix; David J Evans; Stephen J Milan; Sally Spencer

doi:10.1002/14651858.CD012406.pub2

. 2018 Mar 15;2018(3):CD012406. doi: 10.1002/14651858.CD012406.pub2

Macrolide antibiotics for bronchiectasis

Carol Kelly ^1,², James D Chalmers ³, Iain Crossingham ⁴, Nicola Relph ^1,², Lambert M Felix ⁵, David J Evans ⁶, Stephen J Milan ⁷, Sally Spencer ^1,^2,^✉

Editor: Cochrane Airways Group

PMCID: PMC6494352 PMID: 29543980

Abstract

Background

Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation and distortion of the smaller airways. Bacterial colonisation of the damaged airways leads to chronic cough and sputum production, often with breathlessness and further structural damage to the airways. Long‐term macrolide antibiotic therapy may suppress bacterial infection and reduce inflammation, leading to fewer exacerbations, fewer symptoms, improved lung function, and improved quality of life. Further evidence is required on the efficacy of macrolides in terms of specific bacterial eradication and the extent of antibiotic resistance.

Objectives

To determine the impact of macrolide antibiotics in the treatment of adults and children with bronchiectasis.

Search methods

We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted all searches on 18 January 2018.

Selection criteria

We included randomised controlled trials (RCTs) of at least four weeks' duration that compared macrolide antibiotics with placebo or no intervention for the long‐term management of stable bronchiectasis in adults or children with a diagnosis of bronchiectasis by bronchography, plain film chest radiograph, or high‐resolution computed tomography. We excluded studies in which participants had received continuous or high‐dose antibiotics immediately before enrolment or before a diagnosis of cystic fibrosis, sarcoidosis, or allergic bronchopulmonary aspergillosis. Our primary outcomes were exacerbation, hospitalisation, and serious adverse events.

Data collection and analysis

Two review authors independently screened the titles and abstracts of 103 records. We independently screened the full text of 40 study reports and included 15 trials from 30 reports. Two review authors independently extracted outcome data and assessed risk of bias for each study. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures as expected by Cochrane.

Main results

We included 14 parallel‐group RCTs and one cross‐over RCT with interventions lasting from 8 weeks to 24 months. Of 11 adult studies with 690 participants, six used azithromycin, four roxithromycin, and one erythromycin. Four studies with 190 children used either azithromycin, clarithromycin, erythromycin, or roxithromycin.

We included nine adult studies in our comparison between macrolides and placebo and two in our comparison with no intervention. We included one study with children in our comparison between macrolides and placebo and one in our comparison with no intervention.

In adults, macrolides reduced exacerbation frequency to a greater extent than placebo (OR 0.34, 95% confidence interval (CI) 0.22 to 0.54; 341 participants; three studies; I² = 65%; moderate‐quality evidence). This translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 8). Data show no differences in exacerbation frequency between use of macrolides (OR 0.31, 95% CI 0.08 to 1.15; 43 participants; one study; moderate‐quality evidence) and no intervention. Macrolides were also associated with a significantly better quality of life compared with placebo (MD ‐8.90, 95% CI ‐13.13 to ‐4.67; 68 participants; one study; moderate‐quality evidence). We found no evidence of a reduction in hospitalisations (OR 0.56, 95% CI 0.19 to 1.62; 151 participants; two studies; I² = 0%; low‐quality evidence), in the number of participants with serious adverse events, including pneumonia, respiratory and non‐respiratory infections, haemoptysis, and gastroenteritis (OR 0.49, 95% CI 0.20 to 1.23; 326 participants; three studies; I² = 0%; low‐quality evidence), or in the number experiencing adverse events (OR 0.83, 95% CI 0.51 to 1.35; 435 participants; five studies; I² = 28%) in adults with macrolides compared with placebo.

In children, exacerbation frequency was reduced more with macrolides than with placebo (IRR 0.50, 95% CI 0.35 to 0.71; 89 children; one study; low‐quality evidence). However there was no significant difference in this age group with regard to: hospitalisations (OR 0.28, 95% CI 0.07 to 1.11; 89 children; one study; low‐quality evidence), serious adverse events, defined within the study as exacerbations of bronchiectasis or investigations related to bronchiectasis (OR 0.43, 95% CI 0.17 to 1.05; 89 children; one study; low‐quality evidence), or adverse events (OR 0.78, 95% CI 0.33 to 1.83; 89 children; one study), in those receiving macrolides compared to placebo. The same study reported an increase in macrolide‐resistant bacteria (OR 7.13, 95% CI 2.13 to 23.79; 89 children; one study), an increase in resistance to Streptococcus pneumoniae (OR 13.20, 95% CI 1.61 to 108.19; 89 children; one study), and an increase in resistance to Staphylococcus aureus (OR 4.16, 95% CI 1.06 to 16.32; 89 children; one study) with macrolides compared with placebo. Quality of life was not reported in the studies with children.

Authors' conclusions

Long‐term macrolide therapy may reduce the frequency of exacerbations and improve quality of life, although supporting evidence is derived mainly from studies of azithromycin, rather than other macrolides, and predominantly among adults rather than children. However, macrolides should be used with caution, as limited data indicate an associated increase in microbial resistance. Macrolides are associated with increased risk of cardiovascular death and other serious adverse events in other populations, and available data cannot exclude a similar risk among patients with bronchiectasis.

Plain language summary

Macrolide antibiotics for bronchiectasis

Background to the question

Bronchiectasis is a long‐term respiratory condition. The airways in the lungs are damaged, and people are prone to infection. Symptoms are chronic cough and the production of sputum (coughed‐up material (phlegm) from the lower airways). Moreover, bronchiectasis is associated with a mortality rate more than twice that of the general population.

Long‐term antibiotic therapy with macrolides (such as azithromycin, roxithromycin, erythromycin, and clarithromycin) may reduce the cycle of reinfection, reduce symptoms, and improve quality of life. We wanted to do this review to look at the evidence on use of macrolides in people with bronchiectasis. This review is intended to help people such as guideline producers, doctors, and patients make decisions about whether to use or recommend macrolides.

Study characteristics

We found 15 studies that compared macrolides with placebo (a substance or treatment with no benefit) or no intervention. Eleven studies involved 690 adults (aged 18 years and older) and four studies involved 190 children. Among adults, six used azithromycin, four roxithromycin, and one erythromycin. The four studies with children used azithromycin, clarithromycin, erythromycin, or roxithromycin. This review is current to January 2018.

Main results

The studies on azithromycin reported improved quality of life in adults. We do not have sufficient evidence from other macrolides to make a robust judgement on their use, and we similarly have insufficient evidence from children to draw clear conclusions.

Although we found only a few trials, they do show a possible increase in antibiotic resistance. Antibiotic resistance is seen when an antibiotic becomes less effective at killing the bacteria causing the chest infection.

We know that macrolides are associated with higher risk of cardiovascular death and other serious adverse events when they are used to treat other conditions. The data in our review suggest it is possible that people with bronchiectasis are at risk for these adverse effects when taking macrolides.

Quality of the evidence

Generally the limited number of studies evaluating macrolides and the variation among them indicate that we cannot be sure of the overall effect of their use in bronchiectasis. Further high‐quality studies are needed to examine the role of long‐term macrolide antibiotics in the treatment of adults and children with bronchiectasis.

Summary of findings

Background

Description of the condition

Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation and distortion of the airways (Pasteur 2010). Bacterial colonisation of the damaged airways leads to chronic cough and sputum production, often with breathlessness and further structural damage to the airways. Diagnosis is made by computed tomography (CT) scanning of the chest when appropriate clinical symptoms are identified (Chang 2010), but asymptomatic radiological evidence of bronchiectasis may be noted (Kwak 2010).

Bronchiectasis has many causes, generally involving major or repeated insults to the lungs. Severe infections including pneumonia, tuberculosis, and pertussis may cause bronchiectasis, particularly if they occur during childhood while the lungs are still developing. Connective tissue disorders and defects in the immune system are other common causes of bronchiectasis, but many cases are idiopathic. Cystic fibrosis leads to severe, progressive bronchiectasis and usually is considered a separate entity from 'non‐cystic fibrosis' bronchiectasis. This review will exclude bronchiectasis secondary to cystic fibrosis.

Prevalence estimates are unclear owing to variable diagnostic strategies (Weycker 2005), a well as higher prevalence rates in developing countries (Habesoglu 2011), but the global disease burden is increasing, with mortality rising by 3% per year between 2001 and 2007, in England and in Wales (Roberts 2010), and hospitalisations by 3% per year in the United States (Seitz 2010). Prevalence is higher in women and those over 60 years of age (Roberts 2010; Seitz 2012). However, prevalence rates may be increasing more rapidly than was previously estimated, with 67 cases per 100,000 general population reported in Germany (Ringshausen 2015), and with UK prevalence rising from 350.5 to 566.1 in women and from 301.2 to 485.5 in men, affecting around 262,900 adults (Quint 2016). Similarly, UK incidence rates increased by 63% over nine years to 2013, rising from 21.2 to 35.2 in women and 8.2 to 26.9 in men, per 100,000 person‐years (Quint 2016). In paediatric populations, younger children and more frequent exacerbations are associated with worse quality of life (Kapur 2012). A higher prevalence of bronchiectasis has been reported among indigenous children in Australia (15:1000) and Alaska (16:1000) (Chang 2002). Incidence rates of 3.7 per 10,000 per year in children under 15 years of age have been reported in New Zealand (Twiss 2005). This equates to a prevalence of 1:3000 children overall and 1:625 children of Pacific Island descent (Twiss 2005). However, these increases may be due to improved diagnosis resulting from easier access to high‐quality CT scanners, rather than reflecting a true rise in prevalence (Goeminne 2016).

Estimated European mortality rates are 0.3 per 100,000 general population in EU countries (ranging from 0.01 in Germany to 1.18 in the UK) and 0.2 per 100,000 in non‐EU countries (ranging from 0.01 in Azerbaijan to 0.67 in Kyrgyzstan), based on data to 2009 (European Lung White Book 2013). Recent age‐adjusted mortality rates in the UK are estimated to be 2.26 times higher in women and 2.14 times higher in men compared with the wider population (Quint 2016). This information is based on estimated mortality rates for bronchiectasis of 1437.7 per 100,000 and for the general population of 635.9 per 100,000 (Quint 2016).

Description of the intervention

Chronic airway infection with pathogens such as Pseudomonas aeruginosa and Haemophilus influenzae and neutrophil‐mediated airway inflammation are key drivers of disease progression and poor outcomes in bronchiectasis (Chalmers 2012; Chalmers 2014; Finch 2015). Long‐term antibiotic therapy therefore is often prescribed with the intention of suppressing bacterial load and reducing airway inflammation (Chalmers 2012). This in turn aims to reduce exacerbations, improve symptoms, and improve quality of life (Haworth 2014). Prolonged antibiotic treatment can be administered in the form of oral or inhaled antibiotics. Inhaled antibiotics offer the advantage of delivering a higher dose of the drug directly to the site of bronchiectasis infection, with less potential for collateral damage and resistance; however, they are often time consuming to administer (Brodt 2014). Oral antibiotics by contrast are typically cheaper and easier to administer than inhaled antibiotics.

Oral antibiotics may be given at lower doses than those used to treat acute infection, with the aims of reducing adverse effects and promoting compliance (Haworth 2014). Macrolide antibiotics are antibacterial agents with anti‐inflammatory and immunomodulatory properties (Haworth 2014). Long‐acting macrolide antibiotics such as azithromycin can be given intermittently rather than requiring daily dosing. Penicillins, tetracyclines, and macrolides have all been tested as prolonged therapy in bronchiectasis (Pasteur 2010). National guidelines for bronchiectasis, such as those provided by the British Thoracic Society, suggest that use of long‐term antibiotic treatment should be considered for patients with three or more exacerbations per year (Pasteur 2010).

Long‐term use of macrolides in bronchiectasis is supported by their ease of administration, their effectiveness in cystic fibrosis and other neutrophilic lung diseases, and their reported anti‐inflammatory properties (Saiman 2003). Balanced against these traits is the potential for macrolides to induce antibiotic resistance and produce antibiotic‐related adverse effects, hearing impairment, and cardiotoxicity (Serisier 2013a).

How the intervention might work

Exacerbations, symptoms, and quality of life are directly linked to bacterial infection and airway inflammation in bronchiectasis (Chalmers 2012; Chalmers 2014). Macrolides are given as both antibacterial and anti‐inflammatory drugs, although it is unclear which of these properties is primarily responsible for the clinical effect observed in cystic fibrosis or bronchiectasis. Macrolides bind reversibly to the 50s ribosomal subunit, preventing bacterial protein synthesis (Haworth 2014). They therefore have broad activity against Gram‐positive organisms such as staphylococci and streptococci and exhibit a degree of activity against Gram‐negative organisms such as Haemophilus bacteria. It is interesting to note that macrolides show no bacteriocidal activity against P aeruginosa but may modify virulence by interfering with quorum sensing and virulence factors (Kohler 2010).

The anti‐inflammatory effects of macrolides have been known for decades and are classically demonstrated in their effectiveness against diffuse panbronchiolitis (Amsden 2005). Macrolides contain a macrocytic lactone ring that is thought to be responsible for most anti‐inflammatory effects (Haworth 2014). Macrolides are classified according to the number of lactone rings as 14‐, 15‐, and 16‐member ring macrolides. Macrolides confer potentially beneficial effects at every level of the 'vicious cycle' of bronchiectasis. They reduce the secretion of pro‐inflammatory cytokines from epithelial cells, inhibit leucocyte recruitment to the airway, inhibit neutrophil activation, and reduce oxidative stress (Zarogoulidis 2012).

Thus potential benefits of macrolides include suppression of bacterial infection, leading to reduced exacerbations, reduced cough and sputum production, and improved lung function and quality of life.

Why it is important to do this review

Bronchiectasis is associated with a mortality rate more than twice that of the general population ‐ 2.26 times higher in women and 2.14 times higher in men (Quint 2016). Data on the economic burden of bronchiectasis are few; however a 2001 US study reported 2.0 more days in hospital, 6.1 more outpatient appointments, and 27.2 more days of antibiotic treatment (Weycker 2005). It is estimated that additional annual costs associated with bronchiectasis ranged from USD 5681 to USD 7827 during the period between 2001 and 2009 (Joish 2013; Seitz 2010; Weycker 2005).

Frequent exacerbations lead to impaired quality of life and progressive lung damage with permanent loss of lung function (Martínez‐García 2007). Therefore, drug interventions that are effective in reducing the frequency of exacerbations should offer both short‐term and long‐term benefit for patients with bronchiectasis. A Cochrane Review of short‐term antibiotics provided little evidence on which to base a recommendation, with one small trial showing evidence of global improvement and pathogen eradication in sputum (Wurzel 2011). Another Cochrane Review of long‐term antibiotic therapy included 18 trials of moderate quality and provided evidence of reduced exacerbation frequency and hospitalisation but increased drug resistance (Hnin 2015). Neither of these Cochrane Reviews examined effects by class of antibiotics, and neither specifically created subgroups by macrolide therapy. A Cochrane Overview concluded that further evidence is required on the efficacy of antibiotics in terms of eradication of specific bacterial colonisation and the extent of antibiotic resistance (Welsh 2015). Recent recommendations from the European Task Force on Bronchiectasis further reinforced the importance of this question by identifying research on macrolide therapy as one of the key priorities in bronchiectasis (Aliberti 2016). Macrolides may potentially reduce exacerbations of bronchiectasis. Given their drawbacks, particularly cardiac toxicity as described by Ray 2012 and the potential for selecting antibiotic‐resistant organisms as discussed by Leclercq 2002, robust evidence on the effectiveness of macrolides is needed if they are to be used with confidence for this indication.

This review is being conducted alongside two other, closely related reviews: "Dual antibiotics for bronchiectasis" and"Head to head trials of antibiotics for bronchiectasis".

Objectives

To determine the impact of macrolide antibiotics in the treatment of adults and children with bronchiectasis.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) of at least four weeks' duration. We included cross‐over studies but used only data from the first pre‐cross‐over phase to eliminate potentially irreversible carry‐over effects (e.g. antibiotic resistance). We included studies reported as full text, those published as abstract only, and unpublished data.

Types of participants

We included adults and children with a diagnosis of bronchiectasis by bronchography, plain film chest radiography, or high‐resolution computed tomography who reported daily sputum expectoration for at least three months. We did not exclude participants whose condition was diagnosed by radiography alone. When a study included participants with different respiratory conditions, we included the study only if investigators performed a separate subgroup analysis for participants with bronchiectasis. We excluded studies if participants had been receiving continuous or high‐dose antibiotics immediately before enrolment, or if they had received a diagnosis of cystic fibrosis, sarcoidosis, or allergic bronchopulmonary aspergillosis. We defined children as individuals from six months to 18 years of age.

Types of interventions

We included studies comparing macrolide antibiotics with placebo, no intervention, or non‐macrolide antibiotics for long‐term management of stable bronchiectasis and reporting these different comparisons separately. We excluded studies looking at short‐term macrolides for management (as opposed to prevention) of exacerbations of bronchiectasis.

Types of outcome measures

We used exacerbation and hospitalisation rates as reported by study authors. We collected outcome data at a range of follow‐up points that best reflected available evidence from included studies (e.g. end of study, end of follow‐up, change from baseline).

Primary outcomes

Exacerbations (defined by study authors' criteria)
Hospitalisation (defined by study authors' criteria)
Serious adverse events defined by Hansen 2015, as follows: adverse events that result in death or life‐threatening events, requirement for hospitalisation or prolongation of existing hospitalisation, persistent or significant disability, or congenital anomalies; or events that are considered medically important

Secondary outcomes

Sputum volume and purulence
Measures of lung function (e.g. forced expiratory volume in one second (FEV₁))
Systemic markers of infection (C‐reactive protein (CRP))
Adverse events (e.g. cardiac arrhythmias, gastrointestinal symptoms, hearing impairment)
Mortality (with this review indicating whether defined as all‐cause or bronchiectasis‐related in individual studies)
Emergence of resistance to antibiotics
Exercise capacity (e.g. the Six‐Minute Walk Distance test (6MWD))
Health‐related quality of life (e.g. St. George's Respiratory Questionnaire (SGRQ))

Reporting in the study one or more of the outcomes listed here was not an inclusion criterion for this review.

Search methods for identification of studies

Electronic searches

We identified studies from the Cochrane Airways Trials Register, which is maintained by the Information Specialist for the Group. The Cochrane Airways Trials Register contains studies identified from the following sources.

Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL), through the Cochrane Register of Studies Online (crso.cochrane.org).
Weekly searches of MEDLINE Ovid SP 1946 to date.
Weekly searches of Embase Ovid SP 1974 to date.
Monthly searches of PsycINFO Ovid SP 1967 to date.
Monthly searches of Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO 1937 to date.
Monthly searches of Allied and Complementary Medicine (AMED) EBSCO.
Handsearches of the proceedings of major respiratory conferences.

Studies contained in the Cochrane Airways Trials Register are identified through search strategies based on the scope of Cochrane Airways. We have provided details of these strategies, as well as a list of handsearched conference proceedings, in Appendix 1. See Appendix 2 for search terms used to identify studies for this review.

We also conducted a search of the US National Institutes of Health Ongoing Trials Register, ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch).

We searched all databases from their inception to January 2018 and imposed no restrictions on language of publication.

Searching other resources

We checked the reference lists of all primary studies and review articles for additional references and searched relevant manufacturers' websites for study information. We searched PubMed (www.ncbi.nlm.nih.gov/pubmed) for errata or retractions from included studies published in full text and reported within the review the date this was done.

Data collection and analysis

Selection of studies

Two review authors (DE and LF) independently screened titles and abstracts for inclusion of all potential studies identified as a result of the search and coded them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We retrieved full‐text study reports/publications, and two review authors (CK and LF) independently screened the full texts, identified studies for inclusion, and identified and recorded reasons for exclusion of ineligible studies. We encountered no disagreements, so the need to consult a third review author (SS or SJM) did not arise. We identified and excluded duplicates and collated multiple reports of the same trial, so that each trial rather than each report was the unit of interest in the review. We recorded the selection process in detail in the PRISMA flow diagram and the Characteristics of excluded studies table (Moher 2009).

Data extraction and management

We used a data collection form that was piloted on at least one study in the review to extract study characteristics and outcome data. One review author (LF) extracted the following characteristics from included studies.

Methods: study design, total duration, details of 'run‐in' period, number of centres and their locations, settings, withdrawals, and dates the study was carried out.
Participants: number, mean age and range, gender, bronchiectasis severity, diagnostic criteria, baseline lung function, smoking history, inclusion and exclusion criteria.
Interventions and comparisons: intervention, comparison, concomitant medications, and excluded medications.
Outcomes: primary and secondary outcomes reported and follow‐up time points.
Notes: funding source and notable conflicts of interest of study authors.

Two review authors (LF and NR) independently extracted outcome data from the included studies. When investigators did not report outcome data in a usable way, we noted this in the Characteristics of included studies table. We resolved disagreements by reaching consensus or by involving a third review author (SS or SJM). One review author (LF) transferred data into the Review Manager 5 file (RevMan 2014), and a second review author (SS) verified and validated the information. One review author (CK) spot‐checked study characteristics for accuracy against the trial reports.

Assessment of risk of bias in included studies

Two review authors (NR and LF) independently assessed the risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), according to the domains below. We resolved disagreements by discussion or by consultation with another review author (SS or SJM).

Random sequence generation.
Allocation concealment.
Blinding of participants and personnel.
Blinding of outcome assessment.
Incomplete outcome data.
Selective outcome reporting.
Other bias.

We graded each potential source of bias as bringing high, low, or unclear risk, provided a quote from the study report, and recorded our judgement in the 'Risk of bias' table. We summarised risk of bias judgements across different studies for each of the domains listed and reported these in a 'Risk of bias summary table' and a 'Risk of bias graph'. We considered blinding separately for different key outcomes when necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a patient‐reported pain scale). When information on risk of bias was related to unpublished data or correspondence with a study author, we noted this in the 'Risk of bias' table.

When considering treatment effects, we took into account the risk of bias for studies that contributed to that outcome.

Assessment of bias in conducting the systematic review

We conducted the review according to the previously published protocol and have reported deviations from it in the Differences between protocol and review section.

Measures of treatment effect

We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We analysed hospitalisation and exacerbation rates as rate ratios when possible. We entered data as a scale with a consistent direction of effect. We undertook meta‐analyses only when these were meaningful (i.e. when treatments, participants, and the underlying clinical question were similar enough for pooling to make sense). We narratively described skewed data reported as medians and interquartile ranges, as well as data not suitable for meta‐analysis (e.g. data from mixed methods regression). Our review did not include trials with multiple intervention arms, but if future updates of the review should identify this type of trial, we will include only the intervention arms relevant to this review. When we combined two comparisons (e.g. drug A vs placebo and drug B vs placebo) in the same meta‐analysis, we halved the control group to avoid double‐counting.

Unit of analysis issues

The study participant was the unit of analysis in all included studies. For exacerbation and admission rates, we focused on the number of events experienced by the participant during the trial. For cross‐over trials, we used only data from the first pre‐cross‐over phase to minimise potential bias from carry‐over effects.

Dealing with missing data

We contacted investigators or study sponsors to verify key study characteristics and to obtain missing numerical outcome data when possible (e.g. only abstract available). When this was not possible and we thought that missing data might introduce serious bias, we explored the impact of including such studies in the overall assessment of results by performing a sensitivity analysis.

Assessment of heterogeneity

We used the I² statistic to measure heterogeneity among the studies in each analysis. When we identified substantial heterogeneity (> 50%), we reported this in the text and explored possible causes by conducting prespecified subgroup analyses (e.g. adults vs children).

Assessment of reporting biases

We were not able to pool more than 10 studies for any comparison; therefore, we were unable to explore small‐study effects and publication biases by using a funnel plot.

Data synthesis

We included outcomes in meta‐analyses when we considered study designs, interventions, and outcomes as sufficiently similar. When we identified substantial heterogeneity (> 50%), we reported outcomes in the text, revealing the direction and size of the effect, along with the strength of the evidence (risk of bias). Antibiotic studies varied by population, design, and outcomes. However, we identified few studies for each comparison, and estimates from a random‐effects model therefore may have been unreliable, we used a fixed‐effect model, reported data with 95% confidence intervals (CIs), and evaluated the impact of model choice by performing a sensitivity analysis, when appropriate. We synthesised and reported dichotomous and continuous data separately for each outcome (e.g. exacerbation/no exacerbation or exacerbation duration), and when study authors reported both end‐of‐study point estimates and change from baseline scores, we analysed these separately.

'Summary of findings' tables

We created 'Summary of findings' tables by using the following primary and secondary outcomes: exacerbations, hospitalisations, serious adverse events, deaths, and quality of life. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of evidence from studies contributing data to meta‐analyses for these outcomes. We used methods and recommendations as described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and we used GRADEproGDT software (GRADEproGDT). We justified all decisions to downgrade or upgrade the quality of evidence provided by studies by using footnotes and adding comments to aid understanding when necessary.

Subgroup analysis and investigation of heterogeneity

We planned to carry out the following subgroup analyses, although data were insufficient for comparisons of all subgroups. However, we chose to present the data for different macrolides as subgroups for all outcomes.

Macrolides versus other classes of long‐term antibiotics.
Types of macrolides.
Dose and frequency.
Duration.

We planned to use the following outcomes in conducting subgroup analyses.

Exacerbations.
Hospitalisations.
Serious adverse events.

We used the formal test for subgroup interactions provided in Review Manager 5 (RevMan 2014).

Sensitivity analysis

We evaluated effects of methodological study quality by removing studies at high or unclear risk of bias for the domains of random sequence generation and allocation concealment.

Results

Description of studies

Results of the search

A systematic search, conducted on 18 January 2018, identified 103 unique records of potentially relevant trials. Of these, we considered 63 records irrelevant following inspection of their titles and abstracts. We obtained and read full texts for the remaining 40 records and formally excluded eight records (documented in Excluded studies). We contacted the authors of one study (two records) awaiting classification (see Studies awaiting classification). A total of 15 trials, with 30 records, met our inclusion criteria for studies of macrolides for bronchiectasis. We have summarised the selection process in the study flow diagram (Figure 1).

Included studies

In 11 trials (Altenburg 2013; Asintam 2012; Cymbala 2005; Diego 2013; Juthong 2011; Liu 2012; Liu 2014; Lourdesamy 2014; Sadigov 2013; Serisier 2013; Wong 2012), study participants were adults, and in the remaining four trials (Koh 1997; Masekela 2013; Valery 2013; Yalcin 2006), participants were children. See Characteristics of included studies for further details. See Table 5 for an overview of study characteristics.

1. Study characteristics.

Study	Adults/ Children	No. of participants	Type of macrolide	Macrolide dose	Frequency	Delivery mode	Combined weekly dose	Comparison	Duration (months unless stated)
Altenburg 2013	Adults	83	Azithromycin	250 mg	Once daily	Oral	1750 mg	Placebo	12
Asintam 2012	Adults	30	Roxithromycin	300 mg	Once daily	Oral	2100 mg	Placebo	12 weeks
Cymbala 2005	Adults	12	Azithromycin	500 mg	3 days per week	Oral	1000 mg	No intervention	6
Diego 2013	Adults	36	Azithromycin	250 mg	3 days per week	Oral	750 mg	No intervention	3
Juthong 2011	Adults	26	Roxithromycin	300 mg	Once daily	Oral	2100 mg	Placebo	8 weeks
Koh 1997	Children	25	Roxithromycin	4 mg/kg	Twice daily	Oral	56 mg/kg	Placebo	12 weeks
Liu 2012	Adults	50	Roxithromycin, ambroxol hydrochloride	150 mg	Once daily	Oral	1050 mg	Ambroxol hydrochloride (no intervention)	6
Liu 2014	Adults	52	Roxithromycin	150 mg	Once daily	Oral	1050 mg	No intervention	6
Lourdesamy 2014	Adults	78	Azithromycin	1000 mg	Weekly		1000 mg	Placebo	3
Masekela 2013	Children	42	Erythromycin	125 mg for children weighing < 15 kg and 250 mg ≥ 15 kg	Daily	Oral	875 mg for children weighing < 15 kg and 1750 mg ≥ 15 kg	Placebo	12
Sadigov 2013	Adults	65	Azithromycin	500 mg	3 days per week	Oral	1500 mg	Placebo	6
Serisier 2013	Adults	117	Erythromycin	250 mg	Twice daily	Oral	3500 mg	Placebo	11
Valery 2013	Children	89	Azithromycin	30 mg/kg up to a maximum of 600 mg	Once a week	Oral	30 mg/kg up to a maximum of 600 mg	Placebo	24
Wong 2012	Adults	141	Azithromycin	500 mg	3 days per week	Oral	1500 mg	Placebo	6
Yalcin 2006	Children	34	Clarithromycin, supportive therapies	15 mg/kg	Daily	Oral	105 mg/kg	Supportive therapies (no intervention)	3

Macrolides compared with placebo for adults with bronchiectasis
Patient or population: adults with bronchiectasis  Setting: outpatient clinics in Australia, Azerbaijan, Malaysia, Netherlands, New Zealand, and Thailand  Intervention: macrolides  Comparison: placebo
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with placebo	Risk with macrolides	Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
≥ 1 exacerbation  Follow‐up: range 24 weeks to 52 weeks	714 per 1000	459 per 1000  (355 to 574)	OR 0.34  (0.22 to 0.54)	341  (3 RCTs)	⊕⊕⊕⊝  MODERATE^a	2 studies azithromycin (1750 mg/week for 52 weeks; 1500 mg/week for 6 months) 1 study erythromycin (3500 mg/week for 48 weeks)
Hospitalisation: all cause  Follow‐up: range 12 weeks to 52 weeks	133 per 1000	79 per 1000  (28 to 200)	OR 0.56  (0.19 to 1.62)	151  (2 RCTs)	⊕⊕⊝⊝  LOW^b,c	2 studies azithromycin (1000 mg/week for 12 weeks; 1750 mg/week for 52 weeks)
Serious adverse events  Follow‐up: range 24 weeks to 48 weeks	86 per 1000	44 per 1000  (18 to 104)	OR 0.49  (0.20 to 1.23)	326  (3 RCTs)	⊕⊕⊝⊝  LOW^b,d	2 studies azithromycin (1500 mg/week for 6 months; 1000 mg/week for 12 weeks) 1 study erythromycin (3500 mg/week for 48 weeks)
All‐cause mortality  Follow‐up: range 8 weeks to 52 weeks	0 per 1000	0 per 1000  (0 to 0)	not estimable	540  (7 RCTs)	⊕⊕⊝⊝  Low^e,f	4 studies azithromycin (1000 to 1750 mg/week for 12 to 52 weeks)  2 studies roxithromycin (2100 mg/week for 8 to 12 weeks)  1 study erythromycin (3500 mg/week for 48 weeks)
Quality of life: endpoint  assessed with SGRQ  Scale from 0 to 100  Follow‐up: 12 weeks	Mean SGRQ score at endpoint in placebo groups was 39.1 points.	MD 8.90 lower (13.13 lower to 4.67 lower)	‐	68  (1 RCTs)	⊕⊕⊕⊝  Moderate^b	1 study azithromycin (1000 mg/week for 12 weeks)
Quality of life: change  assessed with SGRQ  Scale from 0 to 100  Follow‐up: range 8 weeks to 48 weeks	Mean change in SGRQ score ranged from ‐1.3 to ‐8.9 points.	MD 2.86 lower  (5.67 lower to 0.04 lower)	‐	305  (4 RCTs)	⊕⊕⊝⊝  LOW^g,h	1 study azithromycin (1500 mg/week for 6 months)  1 study erythromycin (3500 mg/week for 48 weeks)  2 studies roxithromycin (2100 mg/week for 12 weeks; 2100 mg/week for 8 weeks)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio; SGRQ: St. George's Respiratory Questionnaire.
GRADE Working Group grades of evidence.  High quality: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Macrolides compared with no intervention for adults with bronchiectasis
Patient or population: adults with bronchiectasis  Setting: outpatient clinics in China and Spain  Intervention: macrolides  Comparison: no intervention
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with no intervention	Risk with macrolides
≥ 1 exacerbation  Follow‐up: 6 months	Study population		OR 0.31  (0.08 to 1.15)	43  (1 RCT)	⊕⊕⊕⊝  MODERATE^a	Roxithromycin (1050 mg/week for 6 months)
	762 per 1000	498 per 1000  (204 to 786)
Hospitalisations ‐ not reported	‐	‐	‐	‐	‐
Serious adverse events ‐ not reported	‐	‐	‐	‐	‐
Mortality  Follow‐up: range 3 months to 6 months	No deaths in two trials, although in 1 study (azithromycin), 6 participants were lost to follow‐up		not estimable	88  (2 RCTs)	⊕⊝⊝⊝  VERY LOW^a,b,c	1 study azithromycin (750 mg/week for 3 months)  1 study roxithromycin (1050 mg/week for 6 months)
QoL SGRQ: endpoint total score  Scale from 0 to 100  Follow‐up: 6 months	Mean SGRQ: endpoint total score of 51.7 points	MD 8.81 lower (14.33 lower to 3.28 lower)	‐	89  (2 RCT)	⊕⊕⊕⊝  MODERATE^a	1 study roxithromycin (1050 mg/week for 6 months)  1 study roxithromycin (1050 mg/week for 6 months)
QoL SGRQ: change in total score  Scale from 0 to 100  Follow‐up: 3 months	Mean SGRQ: change in total score of 4.1	MD 12 lower  (21.61 lower to 2.39 lower)	‐	30  (1 RCT)	⊕⊕⊕⊝  MODERATE^a	Azithromycin (750 mg/week for 3 months)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio; QoL: quality of life; SGRQ: St. George's Respiratory Questionnaire.
GRADE Working Group grades of evidence.  High quality: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Macrolides compared with placebo for children with bronchiectasis
Patient or population: children with bronchiectasis  Setting: outpatient clinics in Australia, New Zealand, and South Africa  Intervention: macrolides  Comparison: placebo
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with placebo	Risk with macrolides	Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Exacerbation frequency	Number of exacerbations 195 (median: 4 range 0‐14)	Number of exacerbations 104 (median: 2 range 0‐9)	IRR 0.50 95% CI 0.35 to 0.71	89  (1 RCT)	⊕⊕⊝⊝  LOW^a,b	Azithromycin (30 mg/kg/week for up to 24 months)
Hospitalisation: all‐cause  Follow‐up: 24 months	205 per 1000	67 per 1000  (18 to 222)	OR 0.28  (0.07 to 1.11)	89  (1 RCT)	⊕⊕⊝⊝  LOW^a,b	Azithromycin (30 mg/kg/week for 24 months)
Serious adverse events  Follow‐up: 24 months	432 per 1000	246 per 1000  (114 to 444)	OR 0.43  (0.17 to 1.05)	89  (1 RCT)	⊕⊕⊝⊝  LOW^a,b	Azithromycin (30 mg/kg/week for 24 months)
Mortality	1 child died but study group was not stated.		‐	42  (1 RCT)	⊕⊕⊝⊝  LOW^c,d	Erythromycin (875 to 1750 mg/kg/week for 52 weeks)
Quality of life not reported	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; IRR: incidence rate ratio; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence.  High quality: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Database	Frequency of search
CENTRAL (the Cochrane Library)	Monthly
MEDLINE (Ovid)	Weekly
Embase (Ovid)	Weekly
PsycINFO (Ovid)	Monthly
CINAHL (EBSCO)	Monthly
AMED (EBSCO)	Monthly

Conference	Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI)	2001 onwards
American Thoracic Society (ATS)	2001 onwards
Asia Pacific Society of Respirology (APSR)	2004 onwards
British Thoracic Society Winter Meeting (BTS)	2000 onwards
Chest Meeting	2003 onwards
European Respiratory Society (ERS)	1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)	2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)	1999 onwards

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ≥ 1 exacerbation	3	341	Odds Ratio (M‐H, Fixed, 95% CI)	0.34 [0.22, 0.54]
1.1 Azithromycin	2	224	Odds Ratio (M‐H, Fixed, 95% CI)	0.23 [0.13, 0.40]
1.2 Erythromycin	1	117	Odds Ratio (M‐H, Fixed, 95% CI)	0.74 [0.34, 1.63]
2 Hospitalisation: all‐cause	2	151	Odds Ratio (M‐H, Fixed, 95% CI)	0.56 [0.19, 1.62]
2.1 Azithromycin	2	151	Odds Ratio (M‐H, Fixed, 95% CI)	0.56 [0.19, 1.62]
3 Serious adverse events	3	326	Odds Ratio (M‐H, Fixed, 95% CI)	0.49 [0.20, 1.23]
3.1 Azithromycin	2	209	Odds Ratio (M‐H, Fixed, 95% CI)	0.51 [0.20, 1.34]
3.2 Erythromycin	1	117	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 8.07]
4 Sputum weight (g): endpoint	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.1 Azithromycin	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 FEV₁ (% predicted): endpoint	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.1 Azithromycin	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 FEV₁ (% predicted): change (post bronchodilator)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
6.1 Erythromycin	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 FEV₁ (L): endpoint	2	94	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.17, 0.22]
7.1 Azithromycin	1	68	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐0.23, 0.21]
7.2 Roxithromycin	1	26	Mean Difference (IV, Fixed, 95% CI)	0.15 [‐0.27, 0.57]
8 FEV₁ (L): change	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
8.1 Azithromycin	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 FVC (% predicted): endpoint	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
9.1 Azithromycin	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 FVC (L): endpoint	2	94	Mean Difference (IV, Fixed, 95% CI)	0.08 [‐0.19, 0.36]
10.1 Azithromycin	1	68	Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.34, 0.30]
10.2 Roxithromycin	1	26	Mean Difference (IV, Fixed, 95% CI)	0.38 [‐0.16, 0.92]
11 FVC (L): change	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
11.1 Azithromycin	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 FEV₁/FVC: endpoint	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
12.1 Azithromycin	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Adverse events	5	435	Odds Ratio (M‐H, Fixed, 95% CI)	0.83 [0.51, 1.35]
13.1 Azithromycin	3	292	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.41, 1.45]
13.2 Erythromycin	1	117	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [0.51, 2.62]
13.3 Roxithromycin	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	0.13 [0.01, 2.83]
14 Azithromycin‐resistant bacteria (any)	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
14.1 Azithromycin	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 6‐Minute walk test: change	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
15.1 Erythromycin	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Quality of life: endpoint	1	68	Mean Difference (IV, Fixed, 95% CI)	‐8.90 [‐13.13, ‐4.67]
16.1 Azithromycin	1	68	Mean Difference (IV, Fixed, 95% CI)	‐8.90 [‐13.13, ‐4.67]
17 Quality of life: change	4	305	Mean Difference (IV, Fixed, 95% CI)	‐2.86 [‐5.67, ‐0.04]
17.1 Azithromycin	1	141	Mean Difference (IV, Fixed, 95% CI)	‐3.25 [‐7.19, 0.69]
17.2 Erythromycin	1	117	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐7.12, 1.92]
17.3 Roxithromycin	2	47	Mean Difference (IV, Fixed, 95% CI)	‐1.86 [‐10.63, 6.91]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hospitalisation: all‐cause	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.1 Azithromycin	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Serious adverse events	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.1 Azithromycin	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Sputum purulence score: endpoint	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.1 Roxithromycin	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 FEV₁ (% predicted): endpoint	2	65	Mean Difference (IV, Fixed, 95% CI)	1.73 [‐3.32, 6.78]
4.1 Azithromycin	1	40	Mean Difference (IV, Fixed, 95% CI)	3.70 [‐5.99, 13.39]
4.2 Roxithromycin	1	25	Mean Difference (IV, Fixed, 95% CI)	1.0 [‐4.91, 6.91]
5 Adverse events	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.1 Azithromycin	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Azithromycin‐resistant bacteria (any)	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.1 Azithromycin	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Azithromycin‐resistant Streptococcus pneumoniae	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.1 Azithromycin	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Azithromycin‐resistant Staphylococcus aureus	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.1 Azithromycin	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Methods	Aims: to investigate whether 1 year of long‐term low‐dose macrolide treatment added to standard therapy is effective in reducing exacerbation frequency in patients with non‐CF bronchiectasis Design: randomised, double‐blind, placebo‐controlled trial Total study duration: 30 months Number of study centres and locations: 14, Netherlands Study setting: outpatient clinics Methods of recruitment: outpatient clinics at each study centre by the pulmonary physician or the study investigator Withdrawals: 1 in each group owing to adverse events Study start/end dates: April 2008/September 2010 Analysis by intent‐to‐treat: yes
Participants	83 adults randomised Inclusion criteria: individuals 18 years of age or older with non‐CF bronchiectasis diagnosed by plain bronchography or high‐resolution computed tomography, ≥ 3 lower respiratory tract infections (LRTIs) treated with oral or intravenous antibiotics in the preceding year, and ≥ 1 sputum culture yielding ≥ 1 bacterial respiratory pathogen in the preceding year Exclusion criteria: prolonged (> 4 weeks) macrolide therapy during the previous 3 months, oral or intravenous corticosteroids within 30 days of screening, or any antimicrobial treatment for an LRTI in the previous 2 weeks Mean age: intervention group: 59.9 years; control group: 64.6 years Gender: intervention group: 25 females, 18 males; control group: 28 females, 12 males Bronchiectasis diagnosis: plain bronchography or HRCT Severity of condition: not reported Baseline lung function: FEV₁ (% predicted): intervention group: 77.7, control group: 82.7; FVC (% predicted): intervention group: 91.9, control group: 98.5 Smoking history: 2% current, 44% former, 54% never Baseline imbalances: no statistically significant differences between groups
Interventions	Intervention group: azithromycin (n = 43) Dose: 250 mg; delivery mode: oral; frequency: 1/d; duration: 52 weeks Control group: placebo (n = 40) Placebo tablets indistinguishable from azithromycin were manufactured by a licensed trial pharmacy. Adherence: empty blister‐pack count: intervention group: 96.5%; control group: 98% Run‐in phase: following randomisation, participants observed for clinical stability for 2 weeks Run‐out phase: variable run‐out period of ≥ 90 days after 1 year of intervention
Outcomes	Primary: number of infectious exacerbations, defined as an increase in respiratory symptoms requiring antibiotic treatment. Two types of exacerbations ‐ a protocol‐defined exacerbation (PDE) and a non‐PDE Secondary: lung function, CRP level, WBC count, microbiological evaluation, LRTI, HRQoL, and adverse events Post hoc analysis: time to a first exacerbation
Notes	Power calculation: assuming that azithromycin would reduce the number of exacerbations by at least one‐third, a 1‐sided significance level of P = 0.05, with 80% power and estimated 20% dropout = total of 90 patients, for 36 per group Trial registration: clinicaltrials.gov Identifier: NCT00415350 Conflicts of interest: Dr. Boersma reported serving on an advisory board, and receiving payment from Pfizer, for an educational presentation. No other review authors reported COIs. Funders: Dr. Altenberg and Dr. Boersma were supported by a research grant from the Forest Medical School, an independent scientific institution based in the Alkmaar Medical Centre. The study was also supported by an unrestricted research grant from GlaxoSmithKline, and Teva Netherlands supplied the azithromycin tablets. Role of the sponsors: Funders had no role in the design and conduct of the study; collection, analysis, and interpretation of data; or preparation, review, or approval of the manuscript. Ethical approval: yes Conclusions: Macrolide maintenance therapy was effective in reducing exacerbations in patients with non‐CF bronchiectasis. In this trial, azithromycin treatment resulted in improved lung function and better quality of life but involved an increase in gastrointestinal adverse effects and high rates of macrolide resistance.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Permuted block randomisation was performed centrally with equally sized blocks of 10.
Allocation concealment (selection bias)	Low risk	Placebo and azithromycin tablets were provided in identical, individually numbered boxes, with each box containing a year's supply of study medication for 1 participant. Numbers on the boxes matched treatment allocation, in accordance with a computer‐generated allocation sequence that was kept in a safe place in the pharmacy providing the study medication.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	All participants were seen by the investigator and were sequentially assigned a subject identification code through double‐blinded allocation to azithromycin or placebo treatment. Placebo tablets were indistinguishable from azithromycin tablets with respect to appearance, feel, and taste.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Attending physicians reporting study outcomes were blinded to group allocation. It is unlikely that blinding was ineffective.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Balanced between groups with similar reasons for withdrawal
Selective reporting (reporting bias)	Low risk	Study protocol prepublished and all prespecified outcomes reported
Other bias	Low risk	None identified

Methods	Aims: to determine whether roxithromycin would alter clinical outcomes Design: randomised, double‐blind, placebo‐controlled trial Total study duration: 6 months Number of study centres and locations: 1, Thailand Study setting: outpatient department, Songklanagarind Hospital Methods of recruitment: unclear Withdrawals: intervention group: 4, control group: 5 Study start/end dates: March 2011/September 2011 Analysis by intent‐to‐treat: unclear
Participants	30 adults were randomised. Inclusion criteria: adults aged 15 to 75 years; symptomatic patients, with total symptoms score* ≥ 2 per day; stable clinical state; absence of deterioration in cough, dyspnoea, wheezing, fever, chest pain at least 2 weeks before randomisation Exclusion criteria: adverse drug reaction to macrolides; recent exacerbation within 2 weeks before randomisation; history of macrolide therapy within 2 weeks before randomisation; active malignancy and end‐stage disease, such as chronic heart failure, chronic renal failure, and cirrhosis; inability of patients to perform lung function tests due to haemoptysis, AFB positivity, aortic aneurysm, and unstable angina; women who were lactating Mean age: intervention group: 67 years; control group: 64 years Gender: intervention group: 9 women, 6 men; control group: 14 women, 1 man Bronchiectasis diagnosis: HRCT Severity of condition: intervention group: 13 (range 9‐19); control group: 12 (range 5‐19) (Bhalla) Baseline lung function: FEV₁ (% predicted): intervention group: 53.5 ± 13.9; control group: 61.7 ± 19.2; FVC (% predicted): intervention group: 65.4 ± 20; control group: 66.9 ± 14.3 Smoking history: 20% former, 80% never; smoking history in pack‐years: intervention group: 6.7 years; control group: 0.7 years Baseline imbalances: no statistically significant differences between groups
Interventions	Intervention group: roxithromycin (n = 15) Dose: 300 mg; delivery mode: oral; frequency: once daily; duration: 12 weeks Control group: placebo (n = 15) Co‐interventions: mucolytic drugs (93%), SABA (73%), theophylline (63%), and a combination of LABA/ICS (47%) Adherence: not reported Run‐in phase: not reported Run‐out phase: 12‐week wash
Outcomes	Primary: quality of life (SGRQ) Secondary: exacerbations, sputum volume, pulmonary function tests Post hoc analysis: not reported
Notes	Power calculation: estimated 61 patients needed to detect an increment in SGRQ scores of 12% with roxithromycin as compared with placebo with statistical power (1 minus the β value) of 80%, allowing for a type I (α) error of 0.05 Trial registration: not reported Conflicts of interest: not reported Funders: not reported Role of the sponsors: not reported Ethical approval: yes Conclusions: 12‐week roxithromycin 300 mg once daily in symptomatic stable bronchiectatic patients; did not show significant improvement in QoL by SGRQ scores, reduced sputum volume, or improved lung function
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Eligible subjects were randomized (1:1) into the treatment and control groups by block of four randomization method"; insufficient detail
Allocation concealment (selection bias)	Unclear risk	"30 patients were randomly allocated"; insufficient detail
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient detail
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient detail
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	9 patients withdrew (30%), but no further details were reported.
Selective reporting (reporting bias)	Unclear risk	The protocol was not prespecified.
Other bias	Unclear risk	Details of funding sources were not reported.

Methods	Aims: to determine whether long‐term, low‐dose azithromycin would improve pulmonary function and decrease incidences of infection and exacerbation Design: open‐label, cross‐over, randomised controlled (no intervention) trial Total study duration: 12 months Number of study centres and location: 1, USA Study setting: outpatient clinic Methods of recruitment: unclear Withdrawals: 1, who provided insufficient data for analysis Study start/end dates: January 2001/December 2001 Analysis by intent‐to‐treat: no
Participants	12 adults were randomised. Inclusion criteria: patients aged > 18 years with a clinical diagnosis of bronchiectasis confirmed by HRCT, demonstrating airways larger than accompanying vessels Exclusion criteria: patients with a history of serious intolerance, allergy, or sensitivity to azithromycin or macrolides. In addition, if the investigator believed that the patient may not be able to follow instructions, the patient was excluded. Mean age: 70.8; SD 9.7 years Gender: 6 women, 5 men Bronchiectasis diagnosis: HRCT Severity of condition: not reported Baseline lung function (intervention group, control group): FEV₁ (% predicted): 65.3, SD 15.1; FVC (% predicted): 48.5, SD 19.9 Smoking history: present or ex‐smoker: 8; never: 3 Baseline imbalances: not reported
Interventions	Intervention group: azithromycin plus usual medications (n = 8) Dose: 500 mg; delivery mode: oral; frequency: 2/week (Monday and Thursday); duration: 6 months If participants complained of intolerable adverse events from the azithromycin regimen but wanted to continue in the study, their azithromycin regimen was reduced to 250 mg orally every Monday, Wednesday, and Friday. Control group: usual medications alone (n = 3) Adherence: 85% to 108% on azithromycin (1 person took an additional dose) Run‐in phase: 1‐month washout in participants who received azithromycin first Run‐out phase: unclear
Outcomes	Primary: did not state which of the outcomes below was primary Secondary: pulmonary function tests (diary card), PF measurements, 24‐hour sputum volume Post‐hoc analysis: unclear
Notes	Power calculation: By a paired t‐lest power calculation, the original proposed sample size of 30 participants would have provided 92.5% power at an alpha of 0.1 to identify a 50% change in 24‐hour sputum volume. However, only 11 of the 12 enrolled participants completed the study; therefore, the power to identify the same extent of change in 24‐hour sputum volume fell to 56%. Trial registration: not reported Conflicts of interest: no conflicts of interest for 6 study authors. One had received payments from several pharmaceutical companies including Pfizer, Bayer, Abbott, and Bristol Myers Squibb. Funders: The first year of the study was unfunded, although investigators received donations of study medication from local sales representatives. In the second year, a small unrestricted stipend was received from the manufacturer of azithromycin that covered participant incidentals (i.e. travel expenses, extra pulmonary function tests only). Role of the sponsors: unclear Ethical approval: yes Conclusions: The results of this pilot study support past data regarding probable disease‐modifying benefits of long‐term macrolide use in the treatment of individuals with chronic inflammatory pulmonary disorders. Long‐ term therapy with twice‐weekly azithromycin was well tolerated and may provide added benefit for patients with bronchiectasis without the adverse effect of immunosuppression, which is demonstrated with corticosteroids. Given that significant findings were identified in a study with such a limited sample size, additional large‐scale trials are warranted.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Allocation concealment (selection bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Selective reporting (reporting bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Other bias	High risk	"Because of the randomization schedule and less than expected numbers at enrolment, the distribution of patients between the two study phases they received first was heavily biased, with 8 of II (73%) patients receiving the azithromycin phase first". The randomisation schedule was ineffective, with most receiving the active intervention in the first phase.

Study	Reason for exclusion
Chang 2013	Protocol
Kudo 1988	Not an RCT
Min 1988	Not an RCT; not exclusively bronchiectasis; duration of treatment < 4 weeks
Ming 2005	Not an RCT
Rikitomi 1988	Not an RCT
Saito 1988	Not an RCT
Tagaya 2002	Macrolide used for treatment as opposed to prevention; duration of treatment < 4 weeks
Unoura 1986	Not an RCT

Methods	Aims: to explore the effect of long‐term therapy with azithromycin on airway oxidative stress markers in exhaled breath condensate (EBC) Design: open‐label, randomised controlled (no intervention) trial Total study duration: 12 months Number of study centres and location: 1, Spain Study setting: outpatient clinic Methods of recruitment: invited patients with confirmed diagnosis of bronchiectasis attending clinic at University Hospital La Fe Withdrawals: 6. Numbers per study group not reported Study start/end date: 2005 Analysis by intent‐to‐treat: no
Participants	36 adults were randomised. Inclusion criteria: stable, without change in medication or symptoms, emergency department visits or hospitalisations in the previous 4 weeks Exclusion criteria: positive sweat test for CF, bronchiectasis secondary to CF, pulmonary surgical processes, immunodeficiency secondary to HIV, malignancy, common variable immunodeficiency, emphysema, allergic bronchopulmonary aspergillosis or diffuse interstitial pulmonary disease, intolerance to macrolides, severe liver disease Mean age: 58 years; intervention group: 57 years; control group: 61 years Gender: intervention group: 9 women, 7 men; control group: 7 women, 7 men Bronchiectasis diagnosis: clinical data and HRCT Severity of condition: intervention group: 22; control group: 31 (Bhalla) Baseline lung function: FEV₁ (% predicted): intervention group: 56, SD 6; control group: 58, SD 7 Smoking history: not reported Baseline imbalances: no statistically significant differences between groups
Interventions	Intervention group: azithromycin plus usual care (n = 16) Dose: 250 mg; delivery mode: oral; frequency: 3/week; duration: 3 months Control group: usual care alone (n = 14) Participants in both groups continued taking their habitual treatment to the same doses, including inhaled steroids, bronchodilators, mucolytic therapy, and physiotherapy. In cases of severe exacerbations, steroids or antibiotics were recommended. Adherence: not reported Run‐in phase: unclear Run‐out phase: unclear
Outcomes	Primary: changes in airway oxidative stress markers (FeNO, 8‐isoprostane, nitrites (NO₂), and nitrates (NO₃)) Secondary: changes in lung function (FVC, FEV₁ (pre‐ and post‐BD), FEV₁/FVC, total lung capacity, colour and volume of sputum, number of exacerbations, hospital admissions, functional capacity, health‐related quality of life Post hoc analysis: colonised vs not colonised with Pseudomonas aeruginosa
Notes	Power calculation: based on expected 10% difference in FeNO between groups with 90% power and 5% statistical significance Trial registration: clinicaltrials.gov: NTC01463371 Conflicts of interest: not reported Funders: Fundacion Valenciana de Neumologia Role of the sponsors: not reported Ethical approval: yes Conclusions: 3‐month treatment with azithromycin; clinical benefit in patients with non‐CF bronchiectasis but no effect on airway oxidative stress markers
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Allocation concealment (selection bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Study investigators were blinded to group allocation, but this was an open‐label study.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Six participants were lost to follow‐up. No reasons for missing data were provided.
Selective reporting (reporting bias)	Low risk	Study protocol was published and all prespecified (primary and secondary) outcomes were reported.
Other bias	Low risk	None identified

Methods	Aims: to investigate the efficacy of once‐daily roxithromycin for improving clinical outcomes Design: double‐blind, randomised, placebo‐controlled trial Total study duration: 6 months Number of study centres and location: 1, Thailand Study setting: outpatient department, Songklanagarind Hospital Methods of recruitment: not reported Withdrawals: none Study start/end dates: June 2010/November 2010 Analysis by intent‐to‐treat: yes
Participants	26 adults were randomised. Inclusion criteria: aged 18 years and above, diagnosis of bronchiectasis, symptomatic bronchiectasis Exclusion criteria: macrolides in previous year, exacerbation of bronchiectasis in previous 3 months, allergy to macrolides, active malignancy, active or recent pulmonary infection within 3 months, pregnancy Mean age: intervention group: 55 years; control group: 60 years Gender: intervention group: 4 women, 8 men; control group: 8 women, 6 men Bronchiectasis diagnosis: chest radiograph and HRCT; diagnosis confirmed by pulmonologist Severity of condition: described as "severe" Baseline lung function: FEV₁ (L): intervention group: 1.53 ± 0.62; control group: 1.31 ± 0.44; FVC (L): intervention group: 2.27 ± 0.79; control group: 1.98 ± 0.55 Smoking history: present 2 (8%),former: 6 (23%), never 18 (69%) Baseline imbalances: no statistically significant differences between groups
Interventions	Intervention group: roxithromycin (n = 12) Dose: 300 mg; delivery mode: oral; frequency: once daily; duration: 8 weeks Control group: placebo (n = 14) Adherence: not reported Run‐in phase: not reported Run‐out phase: not reported
Outcomes	Primary: symptoms scores, pulmonary function tests (FEV₁ L, FVC L) Secondary: safety, tolerability, drug resistance Post hoc analysis: not reported
Notes	Power calculation: not reported Trial registration: unclear Conflicts of interest: not stated Funders: Faculty and Hospital Fund for Research, Songklanagarind Hospital Role of the sponsors: not reported Ethical approval: not reported Conclusions: Once‐daily roxithromycin showed benefit for clinical outcomes as well as quality of life. Larger studies on the effects of macrolide in bronchiectasis treatment with longer follow‐up times should be done.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Allocation concealment (selection bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind effectiveness was confirmed by contact with trial authors.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No withdrawals were reported.
Selective reporting (reporting bias)	Unclear risk	Informaiton was insufficient to permit judgement of 'low risk' or 'high risk'.
Other bias	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.

Methods	Aims: to determine whether roxithromycin can reduce the degree of airway responsiveness in bronchiectasis Design: double‐blind, randomised, placebo‐controlled trial Total study duration: 12 weeks Number of study centres and location: 1, South Korea Study setting: outpatient clinic, Seoul National University Hospital Methods of recruitment: selected from the outpatient clinic list Withdrawals: 2 (1 in each group) removed by investigators owing to non‐compliance Study start/end dates: October 1995/February 1996 Analysis by intent‐to‐treat: no
Participants	25 children were randomised. Inclusion criteria: increased airway responsiveness (defined as a provocative concentration of methacholine causing a 20% fall in FEV₁ (PC20) < 25 mg/mL evaluated by the dosimeter method Exclusion criteria: not explicitly stated but patients with cystic fibrosis, humoral immune deficiency, bronchopulmonary aspergillosis, excluded; also, those who had taken antibiotics or corticosteroids or who had an upper respiratory tract infection in the past month Mean age: intervention group: 13.3 years; control group: 12.9 years Gender: intervention group: 6 girls, 7 boys; control group: 5 girls, 7 boys Bronchiectasis diagnosis: clinical features; confirmed by computed tomography, with bronchography when necessary Baseline lung function: FEV₁ (% predicted): intervention group: 83 ± 6; control group: 84 ± 7 Smoking history: not applicable Severity of condition: not reported Baseline imbalances: 3 asthmatic patients in the intervention group and 4 in the control group. In the initial methacholine challenge test, 3 participants in the intervention group and 2 in the control group did not attain a maximal response plateau. No other significant differences were noted at baseline.
Interventions	Intervention group: roxithromycin (n = 13) Dose: 4 mg/kg; delivery mode: oral; frequency: 2/d; duration: 12 weeks Control group: placebo (n = 12) Adherence: used packets or drug sachets monitored for compliance; 2 participants withdrew owing to non‐compliance Run‐in phase: not reported Run‐out phase: not reported
Outcomes	Primary: unclear which of the outcomes below were primary Secondary: FEV₁, sputum colour (sputum purulence score), sputum ‐ polymorphonuclear leucocyte (PMN) (sputum leucocyte score) Post hoc analysis: unclear
Notes	Power calculation: not reported Trial registration: not reported Conflicts of interest: not reported Funders: Seoul National University Hospital Research Fund Role of the sponsors: not reported Ethical approval: yes Conclusions: Roxithromycin may decrease the degree of airway responsiveness in patients with bronchiectasis and increased airway responsiveness.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"The study was conducted in a double‐blind, randomized, placebo‐controlled fashion after the preliminary methacholine challenge test". Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Allocation concealment (selection bias)	Unclear risk	"A doctor (not responsible for follow‐up or data analysis) was assigned the task of dividing the patients into two groups". Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	"The study was conducted in a double‐blind, randomized, placebo‐controlled fashion after the preliminary methacholine challenge test". Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Two participants (1 in each group) were withdrawn from the study because of non‐compliance with medication or regular check‐up. Missing outcome data were balanced in numbers across intervention groups, and reasons for missing data were similar across groups.
Selective reporting (reporting bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Other bias	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.

Methods	Aims: to assess the effect of roxithromycin on inflammation media in induced sputum, dilated bronchial wall thickness, SGRQ scores, and exacerbation rates Design: open‐label, randomised controlled trial Total study duration: 6 months Number of study centres and location: 1, Qinzhou City, Guangxi Province, China Study setting: hospital Methods of recruitment: not reported Withdrawals: 4, number per group not reported; reasons for withdrawal not reported Study start/end dates: June 2007/June 2010 Analysis by intent‐to‐treat: no
Participants	50 adults were randomised. Inclusion criteria: aged 18 to 65 years with bronchiectasis diagnosed by HRCT Exclusion criteria: allergy to macrolide, cirrhosis, liver dysfunction and exacerbation. Bronchiectasis exacerbation was defined as abnormalities in 4 of the following 9 symptoms, signs, or laboratory findings: change in sputum production (consistency, colour, volume, or hemoptysis); increased dyspnoea (chest congestion or shortness of breath); increased cough; fever (38° C); increased wheezing; decreased exercise tolerance, malaise, fatigue, or lethargy; FEV₁ or FVC decreased 10% from a previously recorded value; radiographic changes indicative of a new pulmonary process; or changes in chest sounds. Concomitant medications unclear Mean age: intervention group: 47, SD 8; control group: 49, SD 9 (range 29‐67) Gender: intervention group: 12 male, 13 female; control group: 14 male, 11 female Bronchiectasis criteria: HRCT Severity of condition: not reported Baseline lung function (intervention group, control group): not reported Smoking history: intervention group, control group, pack‐years: not reported Baseline imbalances: not reported
Interventions	Intervention group: roxithromycin + ambroxol hydrochloride (n = 25) Dose (Rox): 15 g (150 mg); delivery mode: oral; frequency: 1/d; duration: 6 months+ Dose (AH): 30 mg; delivery mode: oral; frequency: 3/d; duration: 6 months Control group: oral ambroxol hydrochloride (n = 25) Dose: 30 mg; delivery mode: oral; frequency: 3/d; duration: 6 months Adherence: not reported Run‐in phase: not reported Run‐out phase: not reported
Outcomes	Primary: unclear Secondary: SGRQ and MRC Breathlessness Scale Time points: baseline, 6 months Post hoc analysis: unclear
Notes	Power calculation: not reported Trial registration: not reported Conflicts of interest: unclear Funders: Chinese Medical Association Chronic Pulmonary Disease Fund (07010150023), Guangxi Province Department of Science Youth Fund (0991019), Guangxi Province Health Department Self‐funded Research Project (Z2007047) Role of the sponsors: unclear Ethical approval: unclear Conclusions: Scores for bronchial wall thickening of bronchiectasis were increased in participants with stable bronchiectasis. Low‐dose roxithromycin combined with ambroxol hydrochloride significantly improved degree of dyspnoea and reduced scores for extent of bronchiectasis, scores for bronchial wall thickening of bronchiectasis, and global CT scores as compared with treatment with ambroxol hydrochloride alone in participants with bronchiectasis who were in stable condition.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"random number table"
Allocation concealment (selection bias)	Unclear risk	Information in study report was insufficient.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Reporting was unclear, but this was an open‐label study.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Outcome assessors were blinded to group allocation.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	4 withdrawals were reported, but numbers for each group were not given.
Selective reporting (reporting bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Other bias	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.

Methods	Aims: to assess effects of roxithromycin on inflammation media in induced sputum, dilated bronchial wall thickness, SGRQ scores, and exacerbation of bronchiectasis in patients in stable condition Design: open‐label, randomised controlled trial Total study duration: 26 months Number of study centres and location: 1, China Study setting: Tenth Affiliated Hospital of Guangxi Medical University Methods of recruitment: unclear Withdrawals: intervention group: 4; control group: 5 Study start/end dates: May 2009/July 2011 Analysis by intent‐to‐treat: no
Participants	52 adults randomised; 43 completed Inclusion criteria: between 18 and 65 years of age and hospitalised at the Tenth Affiliated Hospital of Guangxi Medical University directed by First Affiliated Hospital of Guangxi Medical University, Qinzhou, China, from May 2009 to July 2011 Exclusion criteria: protocol‐defined exacerbation (PDE) of bronchiectasis. PDE was prospectively defined as abnormalities in 4 of the following 9 symptoms, signs, or laboratory findings: change in sputum production (consistency, colour, volume, or haemoptysis); increased dyspnoea (chest congestion or shortness of breath); increased cough; fever (> 38° C); increased wheezing; decreased exercise tolerance, malaise, fatigue, or lethargy; FEV₁ or FVC decreasing 10% from a previously recorded value; radiographic changes indicative of a new pulmonary process; or changes in chest sounds. Patients with CF who had documented clinical, radiological, and genotypic features and abnormal sweat test results (sweat sodium and chloride > 60 mmol/L) were excluded. Patients who were allergic to macrolides and patients with impaired hepatic disease or diabetes mellitus were also excluded. Mean age: intervention group: 47.1 years; control group: 49.2 years Gender: intervention group: 11 women, 11 men; control group: 9 women, 12 men Bronchiectasis diagnosis: standard chest radiograph compatible with bronchiectasis, for instance, fusiform infiltrates of mucoid impaction, "signet ring", or "tram tracks"; chest CT showing ectasia of peripheral bronchi, fluid‐filled airways, or thickening of the mucosa; daily chronic sputum production or haemoptysis ‐ all confirmed at baseline by HRCT Severity of condition: global CT score: intervention group: 9.47; control group: 9.54 Baseline lung function (intervention group, control group): FEV₁ (L) 1.59, 1.63; FEV₁ (% predicted): 66.8, 67.4; FVC (L) 2.27, 2.34; FVC (% predicted): not reported; FEV₁/FVC: 70, 69.6 Smoking history: intervention group: 4.7 pack‐years; control group: 4.3 pack‐years Baseline imbalances: no significant differences between study groups at baseline
Interventions	Intervention group: roxithromycin (n = 22) Dose: 150 mg; delivery mode: oral; frequency: 1/d; duration: 6 months Control group: no treatment (n = 21) Adherence: Treatment adherence was encouraged by telephone calls from the study co‐ordinator and by measurement of pill counts. Run‐in phase: 1‐month run‐in period free of exacerbation symptoms before baseline sampling Run‐out phase: not reported
Outcomes	Primary: not specified Secondary: sputum production, lung function, inflammatory markers (including IL‐8, neutrophil elastase (NE), MMP‐9, tissue inhibitor of metalloproteinases‐1 (TIMP‐1), hyaluronidase (HA), and type IV collagen concentration in induced sputum), total and differential sputum cell counts, quality of life (SGRQ), dyspnoea, CT evaluation of the thorax Time points: baseline, 6 months Post hoc analysis: NA
Notes	Power calculation: not reported Trial registration: not reported Conflicts of interest: none Funders: Trial authors acknowledge support from the Medical Experiment Center of Guangxi Medical University. The study was supported by grants from the Special Foundation for Chronic Respiratory Disease of Chinese Medical Association (no. 07010150023) and Youth Science Fund of Guangxi Zhuang Autonomous Region in China (no. 0991019). Role of the sponsors: not reported Ethical approval: yes Conclusions: Treatment with roxithromycin can decrease airway inflammation and reduce airway thickness of dilated bronchus, both of which are positively associated with chronic airway inflammation in steady‐state bronchiectasis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Eligible participants were randomly assigned to control and roxithromycin groups; information is insufficient to permit judgement of 'low risk' or 'high risk'.
Allocation concealment (selection bias)	Low risk	Study report information was insufficient.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Reporting was unclear but this was an open‐label study.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Withdrawal was balanced between groups.
Selective reporting (reporting bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Other bias	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.

Methods	Aims: to demonstrate effects of azithromycin on sputum volume, quality of life, and independence, and to estimate duration of effects of azithromycin after cessation of therapy Design: double‐blind, randomised, placebo‐controlled trial Total study duration: 26 weeks Number of study centres and location: single, Malaysia Study setting: Respiratory Clinic, Hospital Taiping, Taiping; unclear whether in‐patient or out‐patient setting Methods of recruitment: not reported Withdrawals: 10 adults lost to follow‐up (intervention group: 6; control group: 4) Study start/end dates: November 2011/December 2013 Analysis by intent‐to‐treat: no
Participants	78 adults were randomised. Inclusion criteria: over 18 years of age with diagnosis of bronchiectasis, reproducible spirometry and chronic sputum production documented in second week of the run‐in period; stable for 6 weeks before study entry Exclusion criteria: pregnant and lactating, active tuberculosis, malignancy Mean age: intervention group: 65.94 years; control group: 59.74 years Gender: intervention group: 24 women, 15 men; control group: 26 women, 13 men Bronchiectasis diagnosis: HRCT Severity of condition: not reported Baseline lung function (intervention group, control group): FEV₁ (L): 1.09, 1.17; FVC (L): 1.56, 1.69; FEV₁/FVC: 72.6, 70.90 Smoking history: intervention group: 11 current smokers, 28 non‐smokers; control group: 11 current smokers, 28 non‐smokers Baseline imbalances: no significant differences between treatment groups at baseline with respect to age, gender, weight, height, smoking status, serum albumin and creatinine levels, SGRQ scores, and lung function. Baseline sputum volume was significantly higher in the azithromycin group.
Interventions	Intervention group: azithromycin (n = 39) Dose: 1000 mg; delivery mode: oral; frequency: weekly; duration: 12 weeks Control group: placebo (n = 39) Identical to Zithromax tablets Adherence: not reported Run‐in phase: 2 weeks Run‐out phase: 12 weeks; both groups received placebo
Outcomes	Primary: 24‐hour sputum volume (percentage change from baseline) Secondary: SGRQ score, SGRQ (change in score from baseline) and spirometric assessment of FVC and FEV₁, adverse events, serious adverse events Post hoc analysis: unclear
Notes	Power calculation: "The study was powered to detect differences in sputum volume, quality of life and spirometry values with azithromycin treatment". Trial registration: clinicaltrials.gov: NCT02107274 Conflicts of interest: See role of sponsors below; conflicts of interest for individual trial authors not stated Funders: grant approved by the Ministry of Health of Malaysia. Study medications were manufactured and provided by Pfizer Inc. (Ann Arbor, Ml, USA). Role of the sponsors: Pfizer Ltd. (Sandwich, Kent, UK) was not involved in study design, data collection, or data interpretation. Ethical approval: yes (local institutional ethics committee) Conclusions: 12‐Week administration of 1000 mg azithromycin weekly in pulmonary bronchiectasis significantly reduced mean sputum volume, improved health status, and stabilised lung function. Azithromycin had a 'carryover effect' on sputum volume and health status for 12 weeks after cessation of therapy.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random number sequence in a 1:1 ratio
Allocation concealment (selection bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Patients were randomised to receive 12 weeks of placebo or azithromycin in a 1:1 ratio in a double‐blinded fashion.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Blinding was maintained from randomisation until database lock unless any patient emergencies arose.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Ten participants did not complete the study and were excluded from analyses. Four participants were lost to follow‐up for logistic reasons. Another 4 had gastrointestinal (GI) disturbances, which consisted predominantly of diarrhoea. Two deaths were recorded in the treatment arm. Both participants passed away owing to severe pneumonia. Missing outcome data were balanced in numbers across intervention groups, and reasons for missing data were similar across groups.
Selective reporting (reporting bias)	Low risk	The study protocol is available, and all of the study's prespecified (primary and secondary) outcomes of interest in the review have been reported in the prespecified way.
Other bias	High risk	Groups were not balanced at baseline with regard to the primary outcome – sputum volume.

Methods	Aims: to evaluate the efficacy of erythromycin compared with placebo in reducing the number of pulmonary exacerbations among children with HIV‐related bronchiectasis over a period of 52 weeks Design: randomised, double‐blind, placebo‐controlled trial Total study duration: not reported Number of study centres and location: single, South Africa Study setting: Paediatric Chest Clinic, Steve Biko Academic Hospital, Pretoria Methods of recruitment: not reported Withdrawals: 1 child died after randomisation, but group allocation was not stated, and 10 were lost to follow‐up (intervention group: 6; control group: 4) Study start/end dates: January 2009/June 2012 Analysis by intent‐to‐treat: no
Participants	42 children were randomised. Inclusion criteria: children aged 6 to 18 years with confirmed HIV infection. The presence of bronchiectasis was confirmed on HRCT scanning, with exclusion of other causes of bronchiectasis, including a sweat test to rule out CF. All children had to be able to perform reliable pulmonary function tests. Exclusion criteria: abnormal liver function tests (ALT/AST > 2.5 times normal); abnormal urea/creatinine; use of carbamazepine, warfarin, cyclosporine, or long‐term midazolam Mean age: intervention group: 8.4 years; control group: 9.1 years Gender: intervention group: 4 girls, 13 boys; control group: 9 girls, 5 boys Bronchiectasis diagnosis: HRCT scanning Severity of condition: Bhalla score: intervention group: 15; control group: 11.5 Baseline lung function (intervention group, control group): FEV₁ (% predicted): 56, 53.6; FVC (% predicted): 49, 45 Baseline imbalances: Characteristics of the 2 study arms were generally balanced, with the exception of gender distribution, with more males (76%) in the erythromycin arm and more females in the placebo arm (64%). CD4 count (%) and CD4 (total × 10⁶) were significantly lower and Bhalla score significantly higher in the intervention group than in the control group (worse).
Interventions	Intervention group: erythromycin (n = 17) Dose: 125 mg per oral suspension if < 15 kg body weight, or 250 mg per oral suspension if ≥ 15 kg body weight; delivery mode: oral; frequency: daily; duration: 52 weeks Control group: placebo (n = 14) Adherence: Compliance was assessed with use of a medication diary and verbal interviews. 90% of participants in each arm took their medication. Run‐in phase: unclear Run‐out phase: unclear
Outcomes	Primary: exacerbations (protocol defined as the presence of ≥ 2 of the following: increased tachypnoea or dyspnoea, change in frequency of cough, increase in sputum productivity, fever, chest pain, new infiltrates on chest x‐ray) Secondary: pulmonary function parameters (FEV₁, FVC, FEF), BMI z‐score, CD4 count (%), CD4 (total* 10⁸), proinflammatory and anti‐inflammatory chemokines and cytokines, Bhalla score Post hoc analysis: unclear
Notes	Power calculation: Sample size calculation was based on the number of pulmonary exacerbations requiring antibiotic therapy, estimated at 3 per year. A sample size of 20 participants per study arm was determined to have 90% power to detect a clinically relevant reduction in exacerbations of 30%, when a mean of 2 and a standard deviation of 1 exacerbation were assumed; and with a presumed dropout rate of 10% when testing was 1sided at the 0.05 level of significance. Trial registration: not reported Conflicts of interest: not declared Funders: unrestricted grant from the Research Development Program of the University of Pretoria. Adcock Ingram South Africa donated erythromycin. Role of the funders/sponsors: not reported Ethical approval: yes Conclusions: Administration of HAART and adjunctive care, which includes airway clearance and treatment of exacerbations, in children with HIV‐related bronchiectasis is associated with significant improvement in pulmonary function tests and IL‐8, with no additional benefit derived from the use of erythromycin.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Participants were randomly assigned (1:1) to the erythromycin group (55%) or to the placebo group (45%).
Allocation concealment (selection bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	All study personnel performing clinical evaluations were blinded to treatment assignment.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Two blinded radiologists carried out the CT scan. Additional details on outcome blinding were not reported.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	10 participants were lost to follow‐up ‐ 4 in the placebo group and 6 in the intervention group; no reasons were provided.
Selective reporting (reporting bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Other bias	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.

Methods	Aims: to test the hypothesis that azithromycin would decrease the frequency of exacerbations, increase lung function, and decrease the severity of symptoms Design: randomised placebo‐controlled trial Total study duration: 12 months Number of study centres and location: single, Azerbaijan Study setting: hospital clinic Methods of recruitment: not reported Withdrawals: unclear Study start/end dates: February 2011/February 2012 Analysis by intent‐to‐treat: unclear
Participants	65 adults were randomised. Inclusion criteria: not reported Exclusion criteria: not reported Mean age: not reported Gender: not reported Bronchiectasis diagnosis: not reported Severity of condition: not reported Baseline lung function: not reported Smoking history: not reported Baseline imbalances: not reported
Interventions	Intervention group: azithromycin (n = 35) Dose: 500 mg; delivery mode: oral; frequency: 3 days per week; duration: 6 months Control group: placebo (n = 30) Adherence: unclear Run‐in phase: unclear Run‐out phase: unclear
Outcomes	Primary: event‐based exacerbations, times of first exacerbation, adverse events, serious adverse events Secondary: sputum volume and purulence, FEV₁, systemic and local markers of infection (leucocyte count, CRP, neutrophil count of induced sputum, interleukin‐6 (IL‐6) in induced sputum), adverse events (e.g. cardiac arrhythmias, gastrointestinal symptoms, hearing impairment)
Notes	Conference abstract only. Additional information provided by personal communication
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Allocation concealment (selection bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Selective reporting (reporting bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Other bias	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk' as only data from the conference abstract were available.

Methods	Aims: to test the hypothesis that low‐dose erythromycin would reduce pulmonary exacerbations in patients with non‐CF bronchiectasis with a history of frequent exacerbations Design: randomised, double‐blind, placebo‐controlled study Total study duration: 26 months Number of study centres and location: single, Australia Study setting: regional adult CF centre, respiratory medicine department, Australian University Teaching Hospital; out‐patient setting Methods of recruitment: patients attending the centre, referral from respiratory physicians at other centres, and public radio advertisements Withdrawals: 10; intervention group: 5 (2 lost to follow‐up, 1 lost for possible QTc prolongation, 1 moved, 1 unable to continue); control group: 5 (2 lost to follow‐up, 1 with nausea, 1 withdrawn by physician, 1 unable to continue) Study start/end dates: October 2008/December 2011 Analysis by intent‐to‐treat: yes, using LOCF for missing data
Participants	117 adults were randomised. Inclusion criteria: confirmed diagnosis of bronchiectasis and clinically stable for at least 4 weeks before enrolment (defined as no symptoms of exacerbation, no requirement for supplemental antibiotic therapy, and FEV₁ within 10% of best recently recorded value when available) Exclusion criteria: CF, current mycobacterial disease or bronchopulmonary aspergillosis, any reversible cause for exacerbations, maintenance oral antibiotic prophylaxis, prior macrolide use except short‐term use, changes to medications in the preceding 4 weeks, cigarette smoking within 6 months, medications or comorbidities with the potential for important interactions with erythromycin Mean age: intervention group: 61.1 years; control group: 63.5 years Gender: intervention group: 38 women, 21 men; control group: 33 women, 25 men Bronchiectasis diagnosis: HRCT scan and clinical diagnosis (≥ 2 separate pulmonary exacerbations requiring supplemental systemic antibiotic therapy in the preceding 12 months, and daily sputum production) Severity of condition: 35% of adults had more than 5 exacerbations in the previous year. Bhalla score was not reported. Baseline lung function (intervention group, control group): FEV₁ (postbronch % predicted): 70.2, 73.6 Smoking history: intervention group: ex‐smokers: 10, 2.3 pack‐years: non‐smokers: 49; control group: ex‐smokers: 15, 2.9 pack‐years: non‐smokers: 44 Baseline imbalances: no significant between‐group differences
Interventions	Intervention group: erythromycin ethylsuccinate (n = 59) Dose: 400 mg (equivalent to 250 mg erythromycin base); delivery mode: oral; frequency: 2/d; duration: 48 weeks Control group: placebo (n = 58) spray‐dried lactose/magnesium stearate tablets Adherence: assessed at each visit by pill counts (intervention group: 95.6%; control group: 96.5%) Run‐in phase: unclear Run‐out phase: 4‐week washout period Erythromycin and placebo tablets were manufactured and supplied by Alpha Pharm and were identical in shape, appearance, and taste.
Outcomes	Primary: mean rate of protocol‐defined pulmonary exacerbation (PDPE) per patient per year (required antibiotic administration for a sustained (> 24‐hour) increase in sputum volume or purulence accompanied by new deteriorations in ≥ 2 additional symptoms: sputum volume, sputum purulence, cough, dyspnoea, chest pain, or hemoptysis Secondary: rate of all pulmonary events (i.e. PDPEs plus non‐PDPEs) for which participants commenced antibiotics, total days of antibiotics, change in the proportion of commensal oropharyngeal streptococci resistant to macrolides, symptoms (LCQ), quality of life (SGRQ), 24‐hour sputum weight, FEV₁ percent predicted, CRP level, exercise capacity (6MWT), sputum bacteriology, and sputum inflammatory cell counts. Safety endpoints included adverse events, liver function test results, and electrocardiogram findings. Post hoc analysis: unclear
Notes	Power calculation: Assuming a baseline (SD) annual rate of exacerbations in the control group of 2.9 (1.2), 98 participants gave 90% power at the 5% significance level to show a 28% reduction in exacerbation rate with erythromycin ‐ a much more conservative estimate of efficacy than the 50% reduction seen in our uncontrolled pilot data. Assuming 20% attrition, the required sample size was increased to 118. Trial registration: anzctr.org.au Identifier: ACTRN12609000578202 Conflicts of interest: Dr. Serisier received honoraria, speakers' fees, and travel support from a range of pharmaceutical companies including GSK, Boehringer‐Ingelheim, AstraZeneca, Phebra, and Pharmaxis. Dr. Bowler received honoraria, speakers' fees, and travel support from a range of pharmaceutical companies including GSK, Boehringer‐Ingelheim, AstraZeneca, and Novartis. Other trial authors reported no conflicts of interest. Funders: Mater Adult Respiratory Research Trust Fund. No pharmaceutical company or other agency (including medical writers) had any role in this study. Role of the sponsors: The funding source had no role in design and conduct of the study; collection, analysis, and interpretation of data; or preparation, review, or approval of the manuscript. Ethical approval: yes Conclusions: Among patients with non‐CF bronchiectasis, 12‐ month use of erythromycin compared with placebo resulted in a modest decrease in the rate of pulmonary exacerbations and an increased rate of macrolide resistance.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation sequences, blocked in random groups of 2, 4, and 8 and stratified for the presence of sputum Pseudomonas aeruginosa at screening, were held by the Department of Pharmacy.
Allocation concealment (selection bias)	Low risk	The independent trial pharmacist dispensed blinded study drug according to the randomisation sequence.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Trial participants, trial supervisors, and all trial staff directly involved in participant care were unaware of treatment assignment at all times.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	All participants and study personnel were masked to treatment assignment, including all investigators involved in sample processing and data entry.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Loss of follow‐up was similar in both groups.
Selective reporting (reporting bias)	Low risk	All measurements stated in the methods were reported in the results section. Extended methods were available online (http://www.jama.com).
Other bias	Low risk	Trial authors used LOCF methods to impute missing data for ITT analyses, but robustness was confirmed via multiple imputation techniques to assess sensitivity.

Methods	Aims: to establish whether long‐term (12 to 24 months) antibiotic treatment with azithromycin would reduce the rate of pulmonary exacerbations in indigenous children with non‐cystic fibrosis bronchiectasis; also to monitor for serious adverse events associated with azithromycin and examine its effect on nasopharyngeal carriage of bacterial pathogens. Design: double‐blind, randomised, placebo‐controlled trial Total study duration: 25 months Number of study centres and location: multi‐centre, Australia and New Zealand Study setting: community clinics in central and northern Australia and urban Maori and Pacific Island children from a tertiary paediatric hospital in Auckland Methods of recruitment: Children entered the study when they were clinically stable (≥ 8 weeks after their last exacerbation) as decided by clinic staff. Withdrawals: intervention group: 4 (1 was withdrawn by physician, 1 was withdrawn by parent, 1 refused meds, 1 fulfilled exit criteria); control group: 4 (2 withdrawn by physician, 1 moved out of study, 1 fulfilled exit criteria) Study start/end dates: November 2008/December 2010 Analysis by intent‐to‐treat: Analysis of the primary endpoint was by intention‐to‐treat. Analysis of secondary endpoints was by modified intention‐to‐treat, excluding participants with missing data, except for analysis of nasal swabs, which was done only for participants with swabs available from baseline and last clinic visits.
Participants	89 children were randomised. Inclusion criteria: aged 1 to 8 years, living within the study area, had bronchiectasis confirmed radiographically by HRCT scans or chronic suppurative lung disease (bronchiectasis suspected clinically when HRCT scans were unavailable), and had ≥ 1 pulmonary exacerbation in the past 12 months Exclusion criteria: receiving chemotherapy, immunosuppressive treatment, or long‐term antibiotics; had an underlying cause for their bronchiectasis (e.g. cystic fibrosis, primary immunodeficiency), other chronic disorders (e.g. cardiac, neurological, renal, or hepatic abnormality), or macrolide hypersensitivity Mean age: intervention group: 3.99 years; control group: 4.22 years Gender: intervention group: 19 girls, 26 boys; control group: 23 girls, 21 boys Bronchiectasis diagnosis: HRCT scans or chronic suppurative lung disease (bronchiectasis suspected clinically when HRCT scans were unavailable) Severity of condition: Bhalla score not reported Baseline lung function: not reported Baseline imbalances: The most substantial difference was mechanical ventilation, with more children in the placebo group needing ventilation as neonates compared with those in the azithromycin group (22% vs 5%). However, participants in the azithromycin group were less likely to be premature (29% vs 39%), fewer had proven bronchiectasis (76% vs 89%), and their first admission to hospital for respiratory disease occurred later in life (mean of 6.5 vs 4.2 months).
Interventions	Intervention group: azithromycin (n = 45) Dose: 30 mg/kg, maximum 600 mg; delivery mode: oral; frequency: once a week; duration: 24 months Study drug was administered under direct supervision at the community clinic (Australia) or at the child's home, preschool, or school (New Zealand). Control group: placebo (n = 44) Placebo medication was similar in appearance, taste, smell, and packaging to the active medication and had no active ingredients. Adherence: Research nurses contacted the community clinic and the child's caregiver, preschool, or school weekly to record drug adherence (children receiving medication and, if any, children who were absent from the community) and any issues with administration, such as the child spitting out the medication. These data were recorded in a participant medication logbook. Study personnel completed a medical review every 3 to 4 months. Intervention group: 88%; control group: 84% Run‐in phase: Children who were already receiving azithromycin (4 in each treatment group) had the antibiotic discontinued and underwent a 3‐month washout period before commencing the study. Run‐out phase: unclear Both azithromycin and placebo were provided in powder format and were reconstituted with 9 mL of sterile water to syrup for oral use (40 mg/mL).
Outcomes	Primary: pulmonary exacerbation rate (treatment by clinic or hospital staff with antibiotics for any of the following (as recorded in the medical chart): increased cough, dyspnoea, increased sputum volume or colour intensity, new chest examination or radiographic findings, deterioration in predicted FEV₁ percentage > 10%, or haemoptysis) Secondary: time to first pulmonary exacerbation, duration of exacerbation episode (discharge date minus admission date plus 1 day), severity (admission to hospital, oxygen supplementation), weight‐for‐age z‐scores (z‐score at last study clinic minus its value at baseline), respiratory signs and symptoms (assessed by study personnel on history and physical examination), sputum characteristics, school absenteeism, FEV₁ % predicted in those aged 6 years and older, serious adverse events, and antibiotic resistance in bacterial pathogens cultured from deep nasal swabs Post hoc analysis: post hoc subgroup analyses for participants taking ≥ 70% of their expected doses, those who received the intervention for 23 to 24 months, children with HRCT‐proven bronchiectasis, children with ≥ 2 hospital‐managed pulmonary exacerbations before enrolment, children with ≥ 10 pulmonary exacerbations before enrolment, those without a history of mechanical ventilation, and those carrying any respiratory bacterial pathogens at baseline
Notes	Power calculation: Sample size and power calculations were based on previous data; we anticipated that participants in the placebo group would have 4 episodes during the 24‐month trial period. Guided by results from an earlier randomised trial of azithromycin in patients with CF, we assumed pulmonary exacerbations would be reduced by 50% in the intervention group and by 15% in the placebo group. 51 participants per group would give 90% power to detect an average difference of 1.4 respiratory exacerbations per participant over a 2‐year period at the 5% level of significance. Trial registration: Australian New Zealand Clinical Trials Registry, number ACTRN12610000383066 Conflicts of interest: Trial authors declared they had no conflicts of interest. Funders: National Health and Medical Research Council (NHMRC) of Australia (project grant numbers 389837 (clinical component), 545223 (microbiology component), and CRE for lung health 1040830 (feedback)); Telstra Foundation (seeding grant ‐ Telstra Community Development Grant, 2004); Health Research Council of New Zealand (grant number 08/158); and Auckland Medical Research Foundation (grant number 81542) Role of the sponsors: Sponsors of the study had no role in study design, data collection, data analysis, or data interpretation, nor in writing of the report. Ethical approval: yes Conclusions: Once‐weekly azithromycin for up to 24 months decreased pulmonary exacerbations among indigenous children with non‐cystic fibrosis bronchiectasis or chronic suppurative lung disease. However, this strategy was accompanied by increased carriage of azithromycin‐resistant bacteria, the clinical consequences of which are uncertain, and will need careful monitoring and further study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	An independent statistician used a computer‐generated permuted‐block design to provide the randomisation sequences. Children were allocated in a 1:1 ratio (stratified by study site and exacerbation frequency in the preceding 12 months (1‐2 vs > 3 episodes)) to azithromycin or placebo.
Allocation concealment (selection bias)	Low risk	Allocation concealment was achieved by use of sequentially numbered, double‐sealed, opaque envelopes. An independent person at the Queensland Institute of Medical Research (Brisbane, QLD, Australia) prepared the individual envelopes labelled with a randomisation number that contained the treatment code inside.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Study drugs (powder for reconstitution to suspension) were provided in identical packaging, and the placebo (Institute of Drug Technology, Melbourne, VIC, Australia) was much the same in appearance, taste, and smell to azithromycin (Pfizer Australia, West Ryde, NSW, Australia). Participants, families, health professionals, and study personnel were unaware of treatment assignment until data analysis was completed.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Investigators collecting data were unaware of the treatment assigned to each child.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Eight children (4 per group) ceased the intervention early, mainly after they were withdrawn by their treating physician or because they experienced treatment failure (2 in the azithromycin group, 3 in the placebo group).
Selective reporting (reporting bias)	Low risk	The study protocol is available, and all of the study's prespecified (primary and secondary) outcomes of interest to the review were reported in the prespecified way.
Other bias	Low risk	Baseline imbalances were tested in post hoc subgroup analyses and showed increased efficacy for the intervention group, although as the trial authors note, analyses were not hypothesis driven and results should therefore be interpreted with caution.

PERMALINK

Macrolide antibiotics for bronchiectasis

Carol Kelly

James D Chalmers

Iain Crossingham

Nicola Relph

Lambert M Felix

David J Evans

Stephen J Milan

Sally Spencer

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Assessment of bias in conducting the systematic review

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

'Summary of findings' tables

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

1. Study characteristics.

Methods

2.

Participants

Adults

Children

Interventions

Adults

Outcomes

Subgroup analysis

Excluded studies

Risk of bias in included studies

3.

4.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Macrolides compared with placebo for adults with bronchiectasis.

Summary of findings 2. Macrolides compared with no intervention for adults with bronchiectasis.

Summary of findings 3. Macrolides compared with placebo for children with bronchiectasis.

Summary of findings 4. Macrolides compared with no intervention for children with bronchiectasis.

Forced expiratory volume in one second (FEV₁)

FEV₁/FVC ratio

Forced expiratory volume in one second (FEV₁)

Methods	Aims: to test whether azithromycin decreases the frequency of exacerbations, increases lung function, and improves HRQoL in patients with non‐CF bronchiectasis Design: randomised, double‐blind, placebo‐controlled trial Total study duration: 18 months Number of study centres and location: 3, New Zealand Study setting: health centres Methods of recruitment: not reported Withdrawals: 4 withdrew from the azithromycin group (1 had adverse events, 2 were lost to follow‐up, 1 withdrew consent); 10 withdrew from the placebo group (2 had adverse events, 3 were lost to follow‐up, 4 withdrew consent, 1 had cultured Mycobacterium avium intracellulare in sputum). Study start/end dates: February 2008/October 2009 Analysis by intent‐to‐treat: yes
Participants	141 adults were randomised. Inclusion criteria: ≥ 18 years of age, ≥ 1 pulmonary exacerbation requiring antibiotic treatment in the past year, and diagnosis of bronchiectasis defined by HRCT scan Exclusion criteria: history of CF; hypo‐gammaglobulinaemia; allergic bronchopulmonary aspergillosis; positive culture of non‐tuberculous mycobacteria in the past 2 years or at screening; macrolide treatment for more than 3 months in the past 6 months; or unstable arrhythmia Mean age: intervention group: 60.9 years; control group: 59 years Gender: intervention group: 48 women, 23 men; control group: 50 women, 20 men Bronchiectasis diagnosis: HRCT scan Severity of condition: Bhalla score not reported Baseline lung function (intervention group, control group): FEV₁ (% predicted): 67.1, 67.3; FVC (% predicted): 77.7, 78.5; FEV1/FVC: 65.4%, 64.7% Smoking history: not reported Baseline imbalances: unclear
Interventions	Intervention group: azithromycin (n = 71) Dose: 500 mg; delivery mode: oral; frequency: 3/week (Monday, Wednesday, and Friday); duration: 6 months Control group: placebo (n = 70) Adherence: intervention group: 97.9%; control group: 98.3%, assessed by pill counts Run‐in phase: not reported Run‐out phase: followed up for another 6 months without treatment
Outcomes	Primary: rate of event‐based exacerbations in the first 6 months (increase in or new onset of ≥ 1 pulmonary symptom (sputum volume, sputum purulence, or dyspnoea) requiring treatment with antibiotics), FEV₁ before bronchodilation, and SGRQ total score at the end of the treatment period Secondary: time to first exacerbation, rate of symptom‐based exacerbations (increase in or new onset of ≥ 1 pulmonary symptom reported on the daily diary card and mean of 3 symptom scores from the daily diary card on 2 consecutive days had to increase by ≥ 1 point (on a 5‐point scale) compared with the same calculation 1 week earlier), prebronchodilator and postbronchodilator FVC, postbronchodilator FEV₁, exercise capacity (as measured by the 6MWT), SGRQ total score at 12 months, concentration of CRP (assessed only at 6 months), sputum cell counts and microbiology, and adverse events Post hoc analysis: unclear
Notes	Power calculation: We estimated that about 134 patients would need to be enrolled for the study to have 80% power to detect a 33% difference between the 2 groups in the Poisson frequency of exacerbations during the 6‐month treatment period, assuming a 2‐sided level of 0 to 5 and a 10% dropout rate. With the assumption of normality, the study had power of 89% to detect a difference of 0 to 16 L in the prebronchodilator FEV₁ and power of 87% to detect a difference of 8 units in SGRQ total score. Trial registration: Australian New Zealand Clinical Trials Registry, number ACTRN12607000641493 Conflicts of interest: Trial authors declared they had no conflicts of interest. Funders: Health Research Council of New Zealand and Auckland District Health Board Charitable Trust Role of the sponsors: The sponsor had no role in study design, data collection, data analysis, or data interpretation. The data monitoring committee of the sponsor provided feedback on the completed report. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. Ethical approval: yes Conclusions: Azithromycin, taken 3 times a week for 6 months, decreased the frequency of event‐based exacerbations and increased the time to first exacerbation in patients with non‐cystic fibrosis bronchiectasis. A treatment effect on exacerbations was evident 6 months after completion of treatment.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐ generated random number list. Patients were randomly assigned in a 1:1 ratio with a permuted block size of 6 and sequential assignment, stratified by centre.
Allocation concealment (selection bias)	Low risk	Randomly assigned to receive azithromycin or placebo by a statistician independent of the reporting statistician
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Participants, research assistants, and investigators were masked to treatment allocation.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Participants, research assistants, and investigators were masked to treatment allocation.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	4 withdrew from the intervention group and 10 from the placebo group for similar reasons.
Selective reporting (reporting bias)	Low risk	All outcomes specified in the protocol were reported.
Other bias	Low risk	None identified

Methods	Aims: to evaluate effects of macrolide antibiotics on the process of inflammation (by measuring IL‐8, TNF‐a, IL‐10 levels and cell profiles in BAL fluid), pulmonary function, and sputum production in children with steady‐state bronchiectasis, secondary to causes other than CF or primary immunodeficiencies Design: randomised controlled trial (open‐label, as no placebo) Total study duration: 12 months Number of study centres and location: single, Turkey Study setting: Department of Paediatric Chest Diseases at Hecettepe University Faculty of Medicine Methods of recruitment: unclear Withdrawals: none Study start/end dates: April 1999/March 2000 Analysis by intent‐to‐treat: yes
Participants	34 children were randomised. Inclusion criteria: diagnosis of bronchiectasis not due to CF or primary immunodeficiencies, clinically stable with no evidence of acute pulmonary exacerbations; no history of upper or lower respiratory tract infection for at least 4 weeks before start of the study. No patients had received antibiotics within 4 months of study entry. None had taken oral or inhaled corticosteroids before or during the study. Exclusion criteria: not reported Mean age: intervention group: 13.1 years; control group: 11.9 years Gender: intervention group: 9 girls, 8 boys; control group: 6 girls, 11 boys Bronchiectasis diagnosis: clinical and high‐resolution computed tomography Severity of condition: not reported Baseline lung function (intervention group, control group): FEV₁ (% predicted): 74, 79 Baseline imbalances: Data show no statistically significant differences between study and control groups in age, sex, FEV₁, or oxygen saturation. But among inflammatory parameters, IL‐8 and TNF‐a levels in BAL fluid were significantly higher at the beginning of the study in the treatment group than in the control group (P = 0.02 and P = 0.02, respectively).
Interventions	Intervention group: clarithromycin (CAM) + supportive therapies (n = 17) Dose: 15 mg/kg; delivery mode: oral; frequency: daily; duration: 3 months plus supportive therapies (mucolytic and expectorant medications and postural drainage) Control group: supportive therapies alone (mucolytic and expectorant medications and postural drainage) (NB: no placebo) (n = 17) Adherence: not reported Run‐in phase: unclear Run‐out phase: unclear
Outcomes	Primary: unclear Secondary: unclear BAL cytokine levels (IL‐8, IL‐10, TNF‐alpha); BAL cell profiles (cell number, neutrophils, macrophages); culture test (aerobic and anaerobic bacteria, fungi, and mycobacteria); pulmonary function test (FEV₁, FEF); oxygen saturation; sputum volume Post hoc analysis: unclear
Notes	Power calculation: not reported Trial registration: not reported Conflicts of interest: not reported Funders: SANOVEL Pharmaceuticals Inc., supplied cytokine kits. Role of the sponsors: not reported Ethical approval: not reported Conclusions: Use of CAM in children with steady‐state bronchiectasis results in laboratory improvement by reducing inflammatory processes in the lungs. No corresponding clinical improvement could be shown, and although this is possible with long‐term use, trial validation is necessary.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information about the sequence generation process was insufficient to permit judgement of 'low risk' or 'high risk'.
Allocation concealment (selection bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Participants and personnel were not blinded as trial was not placebo‐controlled.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Treatment protocols for all participants were completed without interruption, as none experienced acute infection during follow‐up.
Selective reporting (reporting bias)	Unclear risk	Information was insufficient to permit judgement of 'low risk' or 'high risk'.
Other bias	High risk	Inflammatory markers were significantly higher in the intervention group at baseline; it is unclear whether this was controlled for in the change analysis.

Methods	Aims: to evaluate effects of low‐dose erythromycin on sputum volume and lung function indices in steady‐state bronchiectasis Design: double‐blind placebo‐controlled trial (trial authors contacted to determine whether randomised) Total study duration: 6 months Number of study centres and location: single, Hong Kong Study setting: outpatient clinics at the University of Hong Kong Methods of recruitment: not reported Withdrawals: intervention group: 3 withdrawals ‐ 2 were unreliable attenders, 1 developed a maculopapular rash 5 days after erythromycin therapy; control group: 0 withdrawals Study start/end dates: October 1996/April 1997 Analysis by intent‐to‐treat: no
Participants	24 adults were randomised. Inclusion criteria: 24‐hour sputum volume > 10 mL; absence of unstable systemic disease; and "steady‐state" bronchiectasis (< 10% alteration of 24‐hour sputum volume, forced expiratory volume in 1 second (FEV₁), and forced vital capacity (FVC); in the absence of deterioration in cough, dyspnoea, wheezing, fever, or chest pain at baseline visits) Exclusion criteria: unreliable clinic attendance, adverse reaction to macrolides, women who were lactating Mean age: intervention group: 50 years; control group: 59 years Gender: intervention group: 8 women, 3 men; control group; 8 women, 2 men Bronchiectasis diagnosis: high‐resolution computed tomography (HRCT) Severity of condition: not reported Baseline lung function: not reported Smoking history: intervention group: never: 10, ex‐smoker: 1; control group: never: 8, ex‐smoker: 2 Baseline imbalances: no significant differences between groups
Interventions	Intervention group: erythromycin (n = 11) Dose: 500 mg; delivery mode: oral; frequency: 2/d; duration: 8 weeks Control group: placebo (n = 10) Adherence: not reported Run‐in phase: unclear Run‐out phase: unclear
Outcomes	Primary: unclear which is the primary outcome Secondary: unclear 24‐Hour sputum volume; sputum leucocyte density (per mL); sputum pathogenic density (colony‐forming unit (cfu) ‐ mL˜); sputum (sol phase) IL‐la, TNF‐a, and LTB₄; pulmonary function test (FEV₁, FVC) Post hoc analysis: unclear
Notes	Power calculation: Based on trial authors' experience, daily sputum volume might vary by as much as 10% between days in patients with stable bronchiectasis. With acceptance of a type I error of 0.05 and a type II error of 0.20 (power 0.80), study size for a randomised placebo‐controlled study of 20 participants (10 in each treatment group) would allow detection of 12% change in sputum volume. Trial registration: not reported Conflicts of interest: not declared Funders: CRCG grant from the University of Hong Kong Role of the sponsors: not reported Ethical approval: yes Conclusions: Results of this preliminary study, which is the first controlled study on the effects of erythromycin in chronic bronchial sepsis, show the efficacy of low‐dose and moderately long‐term erythromycin in steady‐state bronchiectasis. Low‐dose and long‐term erythromycin therapy might be a disease‐modifying treatment for idiopathic bronchiectasis. Additional studies should be performed to establish dose response, appropriate duration of therapy, and criteria for patient selection.