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Nasopharyngeal carriage and macrolide resistance in Indigenous children with bronchiectasis randomized to long-term azithromycin or placebo

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Abstract

Although long-term azithromycin decreases exacerbation frequency in bronchiectasis, increased macrolide resistance is concerning. We investigated macrolide resistance determinants in a secondary analysis of a multicenter randomized controlled trial. Indigenous Australian children living in remote regions and urban New Zealand Māori and Pacific Islander children with bronchiectasis were randomized to weekly azithromycin (30 mg/kg) or placebo for up to 24 months and followed post-intervention for up to 12 months. Nurses administered and recorded medications given and collected nasopharyngeal swabs 3–6 monthly for culture and antimicrobial susceptibility testing. Nasopharyngeal carriage of Haemophilus influenzae and Moraxella catarrhalis was significantly lower in azithromycin compared to placebo groups, while macrolide-resistant Streptococcus pneumoniae and Staphylococcus aureus carriage was significantly higher. Australian children, compared to New Zealand children, had higher carriage overall, significantly higher carriage of macrolide-resistant bacteria at baseline (16/38 versus 2/40 children) and during the intervention (69/152 versus 22/239 swabs), and lower mean adherence to study medication (63 % versus 92 %). Adherence ≥70 % (versus <70 %) in the Australian azithromycin group was associated with lower carriage of any pathogen [odds ratio (OR) 0.19, 95 % confidence interval (CI) 0.07–0.53] and fewer macrolide-resistant pathogens (OR 0.34, 95 % CI 0.14–0.81). Post-intervention (median 6 months), macrolide resistance in S. pneumoniae declined significantly in the azithromycin group, from 79 % (11/14) to 7 % (1/14) of positive swabs, but S. aureus strains remained 100 % macrolide resistant. Azithromycin treatment, the Australian remote setting, and adherence <70 % were significant independent determinants of macrolide resistance in children with bronchiectasis. Adherence to treatment may limit macrolide resistance by suppressing carriage.

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Acknowledgments

We sincerely thank the children and their families for participating in this study, and research nurses Gabrielle McCallum and Charmaine Mobberley for project management, data collection, and data management in Australia and NZ, respectively. We also thank the Menzies School of Health Research personnel: research nurses Clare Mckay, Kobi Schutz, and Lesley Versteegh for assistance with data collection, Vanya Hampton and Joanna Bugg for assistance with processing the Australian specimens, and Valerie Logan and Hayley Williams for their help with data management and data cleaning.

Funding

This work was supported by Australia’s National Health and Medical Research Council (grant numbers 389837, 545223, 1020561 to A.J.L., 1024175 to H.C.S.-V., 1058213 to A.B.C., 1068732 to A.C.C., 1072870 to K.M.H., 1083090 to P.C.V.); New Zealand’s Health Research Council (grant number 08/158); and the Auckland Medical Research Foundation (grant number 81542).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Child Health Division, Menzies School of Health Research, Darwin, Australia

    K. M. Hare, A. B. Chang, A. J. Leach, H. C. Smith-Vaughan & P. S. Morris

  2. Menzies Health Institute Queensland, Griffith University, Gold Coast Health, Gold Coast, Australia

    K. Grimwood

  3. Department of Respiratory and Sleep Medicine, Queensland Children’s Medical Research Institute, Children’s Health, Queensland University of Technology, Brisbane, Australia

    A. B. Chang

  4. Menzies School of Health Research, Darwin, Australia

    M. D. Chatfield & P. C. Valery

  5. Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia

    P. C. Valery

  6. School of Medicine, Griffith University, Gold Coast, Australia

    H. C. Smith-Vaughan

  7. Department of Paediatrics, Royal Darwin Hospital, Darwin, Australia

    P. S. Morris

  8. Department of Paediatrics, University of Auckland, Auckland, New Zealand

    C. A. Byrnes

  9. Paediatric Respiratory Medicine, Starship Children’s Health, Auckland, New Zealand

    C. A. Byrnes

  10. Sydney Medical School, University of Sydney, Sydney, Australia

    P. J. Torzillo

  11. Royal Prince Alfred Hospital, Sydney, Australia

    P. J. Torzillo

  12. Infectious Disease Epidemiology Unit, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia

    A. C. Cheng

  13. Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, Australia

    A. C. Cheng

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  1. K. M. Hare
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  2. K. Grimwood
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  3. A. B. Chang
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  4. M. D. Chatfield
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  5. P. C. Valery
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  7. H. C. Smith-Vaughan
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  8. P. S. Morris
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  9. C. A. Byrnes
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  10. P. J. Torzillo
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  11. A. C. Cheng
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Corresponding author

Correspondence to K. M. Hare.

Electronic supplementary material

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Online Resource 1

CLSI versus EUCAST antibiotic susceptibility criteria (PDF 52 kb)

Online Resource 2

Carriage and resistance at baseline and end-of-study, by country (Tables S1 and S2) (PDF 52 kb)

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Hare, K.M., Grimwood, K., Chang, A.B. et al. Nasopharyngeal carriage and macrolide resistance in Indigenous children with bronchiectasis randomized to long-term azithromycin or placebo. Eur J Clin Microbiol Infect Dis 34, 2275–2285 (2015). https://doi.org/10.1007/s10096-015-2480-0

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  • DOI: https://doi.org/10.1007/s10096-015-2480-0

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