Acute lower respiratory infections (ALRI) remain a leading cause of recurrent hospitalisation, particularly among young Indigenous children from Australia and New Zealand. Early and repeated ALRI in young children increase the risk for poor future lung outcomes, such impaired lung function and chronic lung diseases (i.e. bronchiectasis and non-smoking related chronic obstructive pulmonary disease) which are highly prevalent among Indigenous populations.

Despite the high burden and long-term consequences of severe ARLI, clinically feasible strategies to prevent recurrent ALRI in early childhood are limited. Evidence-based strategies to reduce ALRIs, prevent bronchiectasis, and preserve lung function are required. While addressing housing and socio-economic inequalities of Indigenous children should ultimately help reduce the incidence of ALRI, a systematic review found limited evidence for these current public health interventions. Thus, additional approaches that are achievable within a short timeframe are needed.

There is a need to reduce the high burden of recurrent ALRI and its future consequences on lung health. A small body of evidence has shown that early and intermittent azithromycin treatment improves respiratory outcomes, but this has not been tested in an at-risk population such as Indigenous children. Despite these being limited studies, clinicians in some settings, e.g. the Northern Territory (NT), currently prescribe long-term azithromycin in children with recurrent ALRI, but who are without underlying bronchiectasis. While this might be clinically useful, the associated increased antimicrobial resistance, safety, and health-care costs have not been examined. Thus, the efficacy, safety, and microbiological and economic impacts of azithromycin in children at high-risk of recurrent ALRI and future bronchiectasis to be determined.

This multi-centre placebo-controlled randomised trial (RCT) has been funded by the National Health and Medical Research Council of Australia, and is designed to answer the below questions.

Primary question: Does 12-months of weekly azithromycin (compared to placebo) improve clinical outcomes of Indigenous children (aged <2-years) hospitalised with an ALRI?
Primary hypothesis is that children receiving long-term azithromycin will have fewer medically-treated episodes of ALRI within the first 12 months.
Secondary aims are to determine the effect of 12-months of weekly azithromycin (compared to placebo) on:
(i) Rates of ALRI-hospitalisations in 12 months;
(ii) Chronic respiratory symptoms/signs of bronchiectasis (at 24-months);
(iii) Serious adverse events (at 12-months);
(iv) Antimicrobial resistance in the upper airway respiratory bacteria;
(v) The upper airway microbiota and gut microbiota; and
(vi) Cost-effectiveness.