Patricia C Valery1, Peter S Morris2, Catherine A Byrnes3, Keith Grimwood4, Paul J Torzillo5, Paul A Bauert6, I Brent Masters7, Abbey Diaz8, Gabrielle B McCallum8, Charmaine Mobberley9, Irene Tjhung10, Kim M Hare8, Robert S Ware11, Anne B Chang12. 1. Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia. Electronic address: patricia.valery@menzies.edu.au. 2. Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia; Department of Paediatrics, Royal Darwin Hospital, Darwin, NT, Australia. 3. Department of Paediatrics, University of Auckland, Auckland, New Zealand; Paediatric Respiratory Medicine, Starship Children's Health, Auckland, New Zealand. 4. 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. 5. University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia. 6. Department of Paediatrics, Royal Darwin Hospital, Darwin, NT, Australia. 7. 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. 8. Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia. 9. Department of Paediatrics, University of Auckland, Auckland, New Zealand. 10. Torres Strait-Northern Peninsula Hospital and Health Service, Thursday Island, QLD, Australia. 11. Queensland Children's Medical Research Institute, The University of Queensland, Brisbane, QLD, Australia; School of Population Health, The University of Queensland, Brisbane, QLD, Australia. 12. 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.
Abstract
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. FINDINGS: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. INTERPRETATION: 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. FUNDING: National Health and Medical Research Council (Australia) and Health Research Council (New Zealand).
RCT Entities:
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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: National Health and Medical Research Council (Australia) and Health Research Council (New Zealand).
Authors: Kerry-Ann F O'Grady; Anne B Chang; Allan Cripps; Edward K Mulholland; Heidi Smith-Vaughan; Nicholas Wood; Margaret Danchin; Ruth Thornton; Andrew Wilson; Paul J Torzillo; Peter M Morris; Peter Richmond; Sheree Rablin; Daniel Arnold; Ann Connor; Vikas Goyal; Tanya Stoney; Kirsten Perrett; Keith Grimwood Journal: Hum Vaccin Immunother Date: 2018-07-12 Impact factor: 3.452
Authors: K M Hare; K Grimwood; A B Chang; M D Chatfield; P C Valery; A J Leach; H C Smith-Vaughan; P S Morris; C A Byrnes; P J Torzillo; A C Cheng Journal: Eur J Clin Microbiol Infect Dis Date: 2015-09-12 Impact factor: 3.267
Authors: Ahmad Kantar; Anne B Chang; Mike D Shields; Julie M Marchant; Keith Grimwood; Jonathan Grigg; Kostas N Priftis; Renato Cutrera; Fabio Midulla; Paul L P Brand; Mark L Everard Journal: Eur Respir J Date: 2017-08-24 Impact factor: 16.671