title: Nasopharyngeal carriage and macrolide resistance in Indigenous children with bronchiectasis randomized to long-term azithromycin or placebo.
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.
authors.affiliation: Child Health Division, Menzies School of Health Research, Darwin, Australia. Kim.Hare@menzies.edu.au.
authors.forename: K M
authors.initials: KM
authors.lastname: Hare
authors.affiliation: Menzies Health Institute Queensland, Griffith University, Gold Coast Health, Gold Coast, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Grimwood
authors.affiliation: Child Health Division, Menzies School of Health Research, Darwin, Australia.|Department of Respiratory and Sleep Medicine, Queensland Children's Medical Research Institute, Children's Health, Queensland University of Technology, Brisbane, Australia.
authors.forename: A B
authors.initials: AB
authors.lastname: Chang
authors.affiliation: Menzies School of Health Research, Darwin, Australia.
authors.forename: M D
authors.initials: MD
authors.lastname: Chatfield
authors.affiliation: Menzies School of Health Research, Darwin, Australia.|Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: P C
authors.initials: PC
authors.lastname: Valery
authors.affiliation: Child Health Division, Menzies School of Health Research, Darwin, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Leach
authors.affiliation: Child Health Division, Menzies School of Health Research, Darwin, Australia.|School of Medicine, Griffith University, Gold Coast, Australia.
authors.forename: H C
authors.initials: HC
authors.lastname: Smith-Vaughan
authors.affiliation: Child Health Division, Menzies School of Health Research, Darwin, Australia.|Department of Paediatrics, Royal Darwin Hospital, Darwin, Australia.
authors.forename: P S
authors.initials: PS
authors.lastname: Morris
authors.affiliation: Department of Paediatrics, University of Auckland, Auckland, New Zealand.|Paediatric Respiratory Medicine, Starship Children's Health, Auckland, New Zealand.
authors.forename: C A
authors.initials: CA
authors.lastname: Byrnes
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, Australia.|Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Torzillo
authors.affiliation: Infectious Disease Epidemiology Unit, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.|Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, Australia.
authors.forename: A C
authors.initials: AC
authors.lastname: Cheng
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001315:Australia; D017963:Azithromycin / Q000627:therapeutic use*; D001419:Bacteria / Q000187:drug effects* / Q000302:isolation & purification; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology*; D001987:Bronchiectasis / Q000150:complications; D002353:Carrier State / Q000382:microbiology; D002648:Child; D002675:Child, Preschool; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D007223:Infant; D018942:Macrolides / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009305:Nasopharynx / Q000382:microbiology*; D009520:New Zealand; D010139:Pacific Islands; D010919:Placebos / Q000008:administration & dosage; D044382:Population Groups
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; D010919:Placebos; D017963:Azithromycin