Antibiotics are one of the main therapies used to treat bronchiectasis, both during acute pulmonary exacerbations, and in some patients as long-term maintenance treatment during the chronic stable phase. Based on Cole’s ‘vicious cycle’ model of the pathophysiology of bronchiectasis, [27
] antibiotic treatments are recommended to reduce the bacterial load, which then decrease lower airway inflammation. Brief antibiotic interventions significantly improve airway [28
] and systemic [28
] inflammatory profiles, as well as improving QoL measures [29
]. For the chronic stable phase, cohort studies [31
] support the use of prolonged antibiotics for reducing exacerbations and sputum purulence, but there are only very limited data from RCTs to justify this approach [33
The rationale for choosing azithromycin includes its recognised antimicrobial effects, its putative in-vivo
immuno-modulatory and anti-inflammatory actions, and its unique pharmacological properties, which suggest once weekly oral dosing (30–40 hours half-life in children) may be effective [34
]. In non-CF bronchiectasis, a cohort study [31
] and one short term RCT (6
months) described improvement in lung function and reduction in pulmonary exacerbations when azithromycin was given to adults with bronchiectasis. In both studies, [31
] the exacerbation frequency rate while taking regular azithromycin was significantly reduced (count ratio 0.5-0.7). However, to date there are no RCTs beyond 6
months and there are no studies of azithromycin in children with non-CF bronchiectasis.
The long half-life of azithromycin, allowing once weekly dosing is advantageous for adherence and even directly supervised administration, which is necessary for the feasibility and sustainability of long-term programmes involving maintenance antibiotic treatment in some settings. Any positive aspects of treatment must however be weighed against the possibility of increased antibiotic resistance amongst bacterial pathogens in the respiratory tract, particularly H. influenzae, S. pneumoniaeS. pyogenes
and S. aureus
]. The underlying mechanisms of macrolide resistance can confer either low or high-level resistance to individual members of this antibiotic class. Azithromycin is also associated with increased risk of resistance to other antibiotic classes, especially the beta-lactams, in respiratory bacterial flora [40
]. While resistance is problematic and treatment failure has been reported, [41
] macrolides still play an important role in managing many infectious diseases, including other respiratory infections, trachoma and sexually transmitted infections [44
]. The current study is carefully monitoring antibiotic resistance in potential respiratory bacterial pathogens colonising the nasopharynx.
The reason for choosing pulmonary exacerbations as our primary outcome is two-fold. Firstly, in chronic respiratory disease (e.g. asthma and chronic obstructive pulmonary disease), pulmonary exacerbations are an important end point in clinical studies and most treatment strategies aim to reduce their frequency. Secondly, in a longitudinal cohort study in children with non-CF bronchiectasis, the only significant predictor of FEV1
decline (over 3-yrs) was frequency of hospitalised exacerbations [17
]. With each exacerbation, the FEV1
% predicted decreased significantly by 1.95% adjusted for time. In adults with bronchiectasis, the determinants of accelerated lung function decline are frequency of hospitalised exacerbations, increased systemic inflammatory markers and colonisation with P. aeruginosa
]. Increased mortality risk is also associated with the degree of lung function impairment [47
]. Thus interventions that can reduce pulmonary exacerbations are likely to be important for preventing future adult lung dysfunction [48
] in addition to reducing the economic and social costs associated with each episode [49
]. Furthermore, recurrent exacerbations are one of the strongest predictors of poor QoL in adults with bronchiectasis [50
]. This is consistent with data for asthma describing pulmonary exacerbations in childhood and adult asthma associated with accelerated FEV1
decline in those not receiving preventative therapy [51
]. Thirdly, in children at this very young age respiratory exacerbations can be readily recorded, unlike some other outcome measures.
Strengths of our study include its randomised trial design, the inclusion of local community workers, and monitoring of adherence. This study is being undertaken in two very different settings: in Australia the study is being conducted mostly in remote, rural Indigenous communities with limited healthcare provision, while in New Zealand the study is being performed in a tertiary hospital in a large urban setting. The study design should help to reduce the potential limitation of heterogeneity in study settings by stratifying by site during randomisation and also by using standardised inclusion/exclusion criteria and data collection procedures and forms. Regular meetings between research personnel to discuss data collection issues and study progress should also help to ensure very good standardisation of the data collection procedures across study sites. The use of local community workers to aid recruitment, administer study medicine and address adherence directly will also assist in the successful conduct of the study. In Australia and New Zealand, study medication is administered to participants under direct supervision by either health clinic or study personnel, and the details about adherence and any issues around administration are carefully recorded on standard forms. This ensures good documentation of adherence with study medication.
A potential limitation of our study is that it is underpowered for small differences between groups. Nevertheless, even though our final enrolment of participants (n
89) was less than the calculated target (n
102), it still provides 90% power to detect statistically significant differences between the intervention and placebo groups.
Internationally, Indigenous children continue to have very high rates of chronic respiratory diseases, including bronchiectasis. If efficacious, a treatment regime of maintenance azithromycin to reduce the frequency of pulmonary exacerbations in Indigenous children with CSLD, including non-CF bronchiectasis is attractive as it is simple to administer It could substantially improve the prognosis of Indigenous children with bronchiectasis and would be a substantial advance in the treatment of these infants and children.