Long-term azithromycin for Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease (Bronchiectasis Intervention Study): a multicentre, double-blind, randomised controlled trial.
BACKGROUND
Indigenous children in high-income countries have a heavy burden of bronchiectasis unrelated to cystic fibrosis. We aimed to establish whether long-term azithromycin reduced pulmonary exacerbations in Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease.


METHODS
Between Nov 12, 2008, and Dec 23, 2010, we enrolled Indigenous Australian, Maori, and Pacific Island children aged 1-8 years with either bronchiectasis or chronic suppurative lung disease into a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial. Eligible children had had at least one pulmonary exacerbation in the previous 12 months. Children were randomised (1:1 ratio, by computer-generated sequence with permuted block design, stratified by study site and exacerbation frequency [1-2 vs ≥3 episodes in the preceding 12 months]) to receive either azithromycin (30 mg/kg) or placebo once a week for up to 24 months. Allocation concealment was achieved by double-sealed, opaque envelopes; participants, caregivers, and study personnel were masked to assignment until after data analysis. The primary outcome was exacerbation (respiratory episodes treated with antibiotics) rate. Analysis of the primary endpoint was by intention to treat. At enrolment and at their final clinic visits, children had deep nasal swabs collected, which we analysed for antibiotic-resistant bacteria. This study is registered with the Australian New Zealand Clinical Trials Registry; ACTRN12610000383066.


RESULTS
45 children were assigned to azithromycin and 44 to placebo. The study was stopped early for feasibility reasons on Dec 31, 2011, thus children received the intervention for 12-24 months. The mean treatment duration was 20·7 months (SD 5·7), with a total of 902 child-months in the azithromycin group and 875 child-months in the placebo group. Compared with the placebo group, children receiving azithromycin had significantly lower exacerbation rates (incidence rate ratio 0·50; 95% CI 0·35-0·71; p<0·0001). However, children in the azithromycin group developed significantly higher carriage of azithromycin-resistant bacteria (19 of 41, 46%) than those receiving placebo (four of 37, 11%; p=0·002). The most common adverse events were non-pulmonary infections (71 of 112 events in the azithromycin group vs 132 of 209 events in the placebo group) and bronchiectasis-related events (episodes or investigations; 22 of 112 events in the azithromycin group vs 48 of 209 events in the placebo group); however, study drugs were well tolerated with no serious adverse events being attributed to the intervention.


CONCLUSIONS
Once-weekly azithromycin for up to 24 months decreased pulmonary exacerbations in Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease. However, this strategy was also accompanied by increased carriage of azithromycin-resistant bacteria, the clinical consequences of which are uncertain, and will need careful monitoring and further study.


BACKGROUND
National Health and Medical Research Council (Australia) and Health Research Council (New Zealand).
Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia. Electronic address: patricia.valery@menzies.edu.au.
Patricia C
PC
Valery
Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia; Department of Paediatrics, Royal Darwin Hospital, Darwin, NT, Australia.
Peter S
PS
Morris
Department of Paediatrics, University of Auckland, Auckland, New Zealand; Paediatric Respiratory Medicine, Starship Children's Health, Auckland, New Zealand.
Catherine A
CA
Byrnes
Queensland Children's Medical Research Institute, The University of Queensland, Brisbane, QLD, Australia; Queensland Paediatric Infectious Diseases Laboratory, Royal Children's Hospital, Brisbane, QLD, Australia.
Keith
K
Grimwood
University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia.
Paul J
PJ
Torzillo
Department of Paediatrics, Royal Darwin Hospital, Darwin, NT, Australia.
Paul A
PA
Bauert
Queensland Children's Medical Research Institute, The University of Queensland, Brisbane, QLD, Australia; Queensland Children's Respiratory Centre, Royal Children's Hospital, Brisbane, QLD, Australia.
I Brent
IB
Masters
Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia.
Abbey
A
Diaz
Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia.
Gabrielle B
GB
McCallum
Department of Paediatrics, University of Auckland, Auckland, New Zealand.
Charmaine
C
Mobberley
Torres Strait-Northern Peninsula Hospital and Health Service, Thursday Island, QLD, Australia.
Irene
I
Tjhung
Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia.
Kim M
KM
Hare
Queensland Children's Medical Research Institute, The University of Queensland, Brisbane, QLD, Australia; School of Population Health, The University of Queensland, Brisbane, QLD, Australia.
Robert S
RS
Ware
Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia; Queensland Children's Respiratory Centre, Royal Children's Hospital, Brisbane, QLD, Australia; Queensland Children's Medical Research Institute, Queensland University of Technology, Brisbane, QLD, Australia.
Anne B
AB
Chang
D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001315:Australia; D017963:Azithromycin / Q000008:administration & dosage* / Q000009:adverse effects; D001987:Bronchiectasis / Q000188:drug therapy* / Q000208:ethnology; D002353:Carrier State / Q000382:microbiology*; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D018450:Disease Progression; D004311:Double-Blind Method; D024881:Drug Resistance, Bacterial; D057239:Early Termination of Clinical Trials; D017050:Episode of Care; D005260:Female; D006193:Haemophilus influenzae / Q000187:drug effects; D006801:Humans; D007223:Infant; D057194:Intention to Treat Analysis; D007902:Length of Stay; D008171:Lung Diseases / Q000188:drug therapy* / Q000208:ethnology / Q000473:pathology; D008297:Male; D008826:Microbial Sensitivity Tests; D001936:Moraxella catarrhalis / Q000187:drug effects; D009666:Nose / Q000382:microbiology; D012720:Severity of Illness Index; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013492:Suppuration; D013997:Time Factors
D000900:Anti-Bacterial Agents; D017963:Azithromycin