Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma

Steven L Taylor; Lex E X Leong; Fredrick M Mobegi; Jocelyn M Choo; Steve Wesselingh; Ian A Yang; John W Upham; Paul N Reynolds; Sandra Hodge; Alan L James; Christine Jenkins; Matthew J Peters; Melissa Baraket; Guy B Marks; Peter G Gibson; Geraint B Rogers; Jodie L Simpson

doi:10.1164/rccm.201809-1739OC

Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma

Am J Respir Crit Care Med. 2019 Aug 1;200(3):309-317. doi: 10.1164/rccm.201809-1739OC.

Authors

Steven L Taylor^{1

2}, Lex E X Leong^{1

2}, Fredrick M Mobegi^{1

2}, Jocelyn M Choo^{1

2}, Steve Wesselingh^{1

2}, Ian A Yang^{3

4}, John W Upham^{3

5}, Paul N Reynolds^{6

7}, Sandra Hodge^{6

7}, Alan L James^{8

9}, Christine Jenkins^{10

11}, Matthew J Peters^{11

12}, Melissa Baraket^{13

14}, Guy B Marks^{13

14

15}, Peter G Gibson^{15

16}, Geraint B Rogers^{1

2}, Jodie L Simpson¹⁶

Affiliations

¹ 1South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
² 2South Australian Health and Medical Research Institute Microbiome Research Laboratory, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia.
³ 3Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia.
⁴ 4Department of Thoracic Medicine, The Prince Charles Hospital, Chermside, Queensland, Australia.
⁵ 5Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.
⁶ 6Department of Thoracic Medicine, Lung Research Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
⁷ 7School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
⁸ 8Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
⁹ 9School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.
¹⁰ 10Respiratory Trials, The George Institute for Global Health, New South Wales, Australia.
¹¹ 11Department of Thoracic Medicine, Concord General Hospital, New South Wales, Australia.
¹² 12Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia.
¹³ 13Respiratory Medicine Department and Ingham Institute, Liverpool Hospital, New South Wales, Australia.
¹⁴ 14South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales Australia.
¹⁵ 15Woolcock Institute of Medical Research, Glebe, New South Wales, Australia; and.
¹⁶ 16Respiratory and Sleep Medicine, Priority Research Centre for Healthy Lungs, The University of Newcastle, Callaghan, New South Wales, Australia.

PMID: 30875247
DOI: 10.1164/rccm.201809-1739OC

Abstract

Rationale: The macrolide antibiotic azithromycin reduces exacerbations in adults with persistent symptomatic asthma. However, owing to the pleotropic properties of macrolides, unintended bacteriological consequences such as augmented pathogen colonization or dissemination of antibiotic-resistant organisms can occur, calling into question the long-term safety of azithromycin maintenance therapy.Objectives: To assess the effects of azithromycin on the airway microbiota, pathogen abundance, and carriage of antibiotic resistance genes.Methods: 16S rRNA sequencing and quantitative PCR were performed to assess the effect of azithromycin on sputum microbiology from participants of the AMAZES (Asthma and Macrolides: The Azithromycin Efficacy and Safety) trial: a 48-week, double-blind, placebo-controlled trial of thrice-weekly 500 mg oral azithromycin in adults with persistent uncontrolled asthma. Pooled-template shotgun metagenomic sequencing, quantitative PCR, and isolate whole-genome sequencing were performed to assess antibiotic resistance.Measurements and Main Results: Paired sputum samples were available from 61 patients (n = 34 placebo, n = 27 azithromycin). Azithromycin did not affect bacterial load (P = 0.37) but did significantly decrease Faith's phylogenetic diversity (P = 0.026) and Haemophilus influenzae load (P < 0.0001). Azithromycin did not significantly affect levels of Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, or Moraxella catarrhalis. Of the 89 antibiotic resistance genes detected, five macrolide resistance genes and two tetracycline resistance genes were increased significantly.Conclusions: In patients with persistent uncontrolled asthma, azithromycin reduced airway H. influenzae load compared with placebo but did not change total bacterial load. Macrolide resistance increased, reflecting previous studies. These results highlight the need for studies assessing the efficacy of nonantibiotic macrolides as a long-term therapy for patients with persistent uncontrolled asthma.

Keywords: antibiotic resistance; asthma; macrolides.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Anti-Bacterial Agents / administration & dosage*
Asthma / microbiology*
Azithromycin / administration & dosage*
Bacterial Load
Double-Blind Method
Drug Administration Schedule
Drug Resistance, Bacterial / drug effects*
Female
Haemophilus influenzae / isolation & purification*
Humans
Male
Middle Aged
Moraxella catarrhalis / isolation & purification
Pseudomonas aeruginosa / isolation & purification
Sputum / microbiology
Staphylococcus aureus / isolation & purification
Streptococcus pneumoniae / isolation & purification

Substances

Anti-Bacterial Agents
Azithromycin