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

Steven Taylor, Lex E.X. Leong, Fredrick Mobegi, Jocelyn Choo, Steven 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 Rogers, Jodie L. Simpson

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

LanguageEnglish
Pages309-317
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume200
Issue number3
DOIs
Publication statusPublished - 1 Aug 2019

Keywords

  • Antibiotic resistance
  • Asthma
  • Haemophilus influenzae
  • Macrolides

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Taylor, Steven ; Leong, Lex E.X. ; Mobegi, Fredrick ; Choo, Jocelyn ; Wesselingh, Steven ; Yang, Ian A. ; Upham, John W. ; Reynolds, Paul N. ; Hodge, Sandra ; James, Alan L. ; Jenkins, Christine ; Peters, Matthew J. ; Baraket, Melissa ; Marks, Guy B. ; Gibson, Peter G. ; Rogers, Geraint ; Simpson, Jodie L. / Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma. In: American journal of respiratory and critical care medicine. 2019 ; Vol. 200, No. 3. pp. 309-317.
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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.",
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author = "Steven Taylor and Leong, {Lex E.X.} and Fredrick Mobegi and Jocelyn Choo and Steven Wesselingh and Yang, {Ian A.} and Upham, {John W.} and Reynolds, {Paul N.} and Sandra Hodge and James, {Alan L.} and Christine Jenkins and Peters, {Matthew J.} and Melissa Baraket and Marks, {Guy B.} and Gibson, {Peter G.} and Geraint Rogers and Simpson, {Jodie L.}",
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Taylor, S, Leong, LEX, Mobegi, F, Choo, J, Wesselingh, S, Yang, IA, Upham, JW, Reynolds, PN, Hodge, S, James, AL, Jenkins, C, Peters, MJ, Baraket, M, Marks, GB, Gibson, PG, Rogers, G & Simpson, JL 2019, 'Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma', American journal of respiratory and critical care medicine, vol. 200, no. 3, pp. 309-317. https://doi.org/10.1164/rccm.201809-1739OC

Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma. / Taylor, Steven; Leong, Lex E.X.; Mobegi, Fredrick; Choo, Jocelyn; Wesselingh, Steven; Yang, Ian A.; Upham, John W.; Reynolds, Paul N.; Hodge, Sandra; James, Alan L.; Jenkins, Christine; Peters, Matthew J.; Baraket, Melissa; Marks, Guy B.; Gibson, Peter G.; Rogers, Geraint; Simpson, Jodie L.

In: American journal of respiratory and critical care medicine, Vol. 200, No. 3, 01.08.2019, p. 309-317.

Research output: Contribution to journalArticle

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T1 - Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma

AU - Taylor, Steven

AU - Leong, Lex E.X.

AU - Mobegi, Fredrick

AU - Choo, Jocelyn

AU - Wesselingh, Steven

AU - Yang, Ian A.

AU - Upham, John W.

AU - Reynolds, Paul N.

AU - Hodge, Sandra

AU - James, Alan L.

AU - Jenkins, Christine

AU - Peters, Matthew J.

AU - Baraket, Melissa

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N2 - 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.

AB - 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.

KW - Antibiotic resistance

KW - Asthma

KW - Haemophilus influenzae

KW - Macrolides

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