Nasopharyngeal Carriage and Macrolide Resistance in Indigenous Children with Bronchiectasis Randomized to Long-term Azithromycin or Placebo

Overview

Journal Eur J Clin Microbiol Infect Dis

Publisher Springer

Specialties Infectious Diseases
Microbiology

Date 2015 Sep 14

PMID 26363637

Citations 24

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

Affiliations

Soon will be listed here.

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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References

Nielsen K, Pedersen T, Udekwu K, Petersen A, Skov R, Hansen L . Fitness cost: a bacteriological explanation for the demise of the first international methicillin-resistant Staphylococcus aureus epidemic. J Antimicrob Chemother. 2012; 67(6):1325-32. DOI: 10.1093/jac/dks051. View

Phaff S, Tiddens H, Verbrugh H, Ott A . Macrolide resistance of Staphylococcus aureus and Haemophilus species associated with long-term azithromycin use in cystic fibrosis. J Antimicrob Chemother. 2006; 57(4):741-6. DOI: 10.1093/jac/dkl014. View

Satzke C, Turner P, Virolainen-Julkunen A, Adrian P, Antonio M, Hare K . Standard method for detecting upper respiratory carriage of Streptococcus pneumoniae: updated recommendations from the World Health Organization Pneumococcal Carriage Working Group. Vaccine. 2013; 32(1):165-79. DOI: 10.1016/j.vaccine.2013.08.062. View

Flanagan P, Paull A . Carbon dioxide requirements of Streptococcus pneumoniae and Haemophilus influenzae. J Antimicrob Chemother. 1998; 42(5):669-70. DOI: 10.1093/jac/42.5.669. View

Hare K, Grimwood K, Leach A, Smith-Vaughan H, Torzillo P, Morris P . Respiratory bacterial pathogens in the nasopharynx and lower airways of Australian indigenous children with bronchiectasis. J Pediatr. 2010; 157(6):1001-5. DOI: 10.1016/j.jpeds.2010.06.002. View

Steinfort D, Brady S, Weisinger H, Einsiedel L . Bronchiectasis in Central Australia: a young face to an old disease. Respir Med. 2007; 102(4):574-8. DOI: 10.1016/j.rmed.2007.11.007. View

Tu Y, Gunnell D, Gilthorpe M . Simpson's Paradox, Lord's Paradox, and Suppression Effects are the same phenomenon--the reversal paradox. Emerg Themes Epidemiol. 2008; 5:2. PMC: 2254615. DOI: 10.1186/1742-7622-5-2. View

Singleton R, Valery P, Morris P, Byrnes C, Grimwood K, Redding G . Indigenous children from three countries with non-cystic fibrosis chronic suppurative lung disease/bronchiectasis. Pediatr Pulmonol. 2013; 49(2):189-200. DOI: 10.1002/ppul.22763. View

BAUER A, KIRBY W, SHERRIS J, Turck M . Antibiotic susceptibility testing by a standardized single disk method. Tech Bull Regist Med Technol. 1966; 36(3):49-52. View

10.

Peric M, Bozdogan B, Jacobs M, Appelbaum P . Effects of an efflux mechanism and ribosomal mutations on macrolide susceptibility of Haemophilus influenzae clinical isolates. Antimicrob Agents Chemother. 2003; 47(3):1017-22. PMC: 149331. DOI: 10.1128/AAC.47.3.1017-1022.2003. View

11.

Serisier D, Martin M, McGuckin M, Lourie R, Chen A, Brain B . Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial. JAMA. 2013; 309(12):1260-7. DOI: 10.1001/jama.2013.2290. View

12.

Assmann S, Pocock S, Enos L, Kasten L . Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet. 2000; 355(9209):1064-9. DOI: 10.1016/S0140-6736(00)02039-0. View

13.

Valery P, Morris P, Grimwood K, Torzillo P, Byrnes C, Masters I . Azithromycin for Indigenous children with bronchiectasis: study protocol for a multi-centre randomized controlled trial. BMC Pediatr. 2012; 12:122. PMC: 3445847. DOI: 10.1186/1471-2431-12-122. View

14.

Hare K, Smith-Vaughan H, Leach A . Viability of respiratory pathogens cultured from nasopharyngeal swabs stored for up to 12 years at -70°C in skim milk tryptone glucose glycerol broth. J Microbiol Methods. 2011; 86(3):364-7. DOI: 10.1016/j.mimet.2011.06.016. View

15.

Edwards E, Asher M, Byrnes C . Paediatric bronchiectasis in the twenty-first century: experience of a tertiary children's hospital in New Zealand. J Paediatr Child Health. 2003; 39(2):111-7. DOI: 10.1046/j.1440-1754.2003.00101.x. View

16.

Altenburg J, de Graaff C, Stienstra Y, Sloos J, van Haren E, Koppers R . Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA. 2013; 309(12):1251-9. DOI: 10.1001/jama.2013.1937. View

17.

Horvath A, Dobay O, Kardos S, Ghidan A, Toth A, Paszti J . Varying fitness cost associated with resistance to fluoroquinolones governs clonal dynamic of methicillin-resistant Staphylococcus aureus. Eur J Clin Microbiol Infect Dis. 2012; 31(8):2029-36. DOI: 10.1007/s10096-011-1536-z. View

18.

Bowden F, Fethers K . "Let's not talk about sex": reconsidering the public health approach to sexually transmissible infections in remote Indigenous populations in Australia. Med J Aust. 2008; 188(3):182-4. DOI: 10.5694/j.1326-5377.2008.tb01569.x. View

19.

Coles C, Mabula K, Seidman J, Levens J, Mkocha H, Munoz B . Mass distribution of azithromycin for trachoma control is associated with increased risk of azithromycin-resistant Streptococcus pneumoniae carriage in young children 6 months after treatment. Clin Infect Dis. 2013; 56(11):1519-26. DOI: 10.1093/cid/cit137. View

20.

Hare K, Leach A, Morris P, Smith-Vaughan H, Torzillo P, Bauert P . Impact of recent antibiotics on nasopharyngeal carriage and lower airway infection in Indigenous Australian children with non-cystic fibrosis bronchiectasis. Int J Antimicrob Agents. 2012; 40(4):365-9. DOI: 10.1016/j.ijantimicag.2012.05.018. View