The effect of long-term macrolide treatment on respiratory microbiota composition in non-cystic fibrosis bronchiectasis: an analysis from the randomised, double-blind, placebo-controlled BLESS trial

doi:10.1016/S2213-2600(14)70213-9

The Lancet Respiratory Medicine

Volume 2, Issue 12, December 2014, Pages 988-996

https://doi.org/10.1016/S2213-2600(14)70213-9 Get rights and content

Summary

Background

Long-term macrolide treatment has proven benefit in inflammatory airways diseases, but whether it leads to changes in the composition of respiratory microbiota is unknown. We aimed to assess whether long-term, low-dose erythromycin treatment changes the composition of respiratory microbiota in people with non-cystic fibrosis bronchiectasis.

Methods

Microbiota composition was determined by 16S rRNA gene sequencing of sputum samples from participants in the BLESS trial, a 12-month, double-blind, placebo-controlled trial of twice-daily erythromycin ethylsuccinate (400 mg) in adult patients with non-cystic fibrosis bronchiectasis and at least two infective exacerbations in the preceding year. The primary outcome was within-patient change in respiratory microbiota composition (assessed by Bray-Curtis index) between baseline and week 48, comparing erythromycin with placebo. The BLESS trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12608000460303.

Findings

The BLESS trial took place between Oct 15, 2008, and Dec 14, 2011. Paired sputum samples were available from 86 randomly assigned patients, 42 in the placebo group and 44 in the erythromycin group. The change in microbiota composition between baseline and week 48 was significantly greater with erythromycin than with placebo (median Bray-Curtis score 0·52 [IQR 0·14–0·78] vs 0·68 [0·46–0·93]; median difference 0·16, 95% CI 0·01–0·33; p=0·03). In patients with baseline airway infection dominated by Pseudomonas aeruginosa, erythromycin did not change microbiota composition significantly. In those with infection dominated by organisms other than P aeruginosa, erythromycin caused a significant change in microbiota composition (p=0·03 [by analysis of similarity]), representing a reduced relative abundance of Haemophilus influenzae (35·3% [5·5–91·6] vs 6·7% [0·8–74·8]; median difference 12·6%, 95% CI 0·4–28·3; p=0·04; interaction p=0·02) and an increased relative abundance of P aeruginosa (0·02% [0·00–0·33] vs 0·13% [0·01–39·58]; median difference 6·6%, 95% CI 0·1–37·1; p=0·002; interaction p=0·45). Compared with placebo, erythromycin reduced the rate of pulmonary exacerbations over the 48 weeks of the study in patients with P aeruginosa-dominated infection (median 1 [IQR 0–3] vs 3 [2–5]; median difference −2, 95% CI −4 to –1; p=0·01), but not in those without P aeruginosa-dominated infection (1 [0–2] vs 1 [0–3]; median difference 0, –1 to 0; p=0·41; interaction p=0·04).

Interpretation

Long-term erythromycin treatment changes the composition of respiratory microbiota in patients with bronchiectasis. In patients without P aeruginosa airway infection, erythromycin did not significantly reduce exacerbations and promoted displacement of H influenzae by more macrolide-tolerant pathogens including P aeruginosa. These findings argue for a cautious approach to chronic macrolide use in patients without P aeruginosa airway infection.

Funding

Mater Adult Respiratory Research Trust Fund.

Introduction

Macrolide antibiotics have been shown to be clinically effective in several chronic respiratory diseases, most recently in non-cystic fibrosis bronchiectasis,1, 2, 3 although the mechanisms by which they work are unclear. Researchers believe that the effect is probably anti-inflammatory or immunomodulatory,⁴ but clinical studies have not provided convincing evidence to support this belief. Conversely, clinical data do not support the alternative hypothesis of a traditional antibacterial mechanism for clinical efficacy, and the inherent in-vitro resistance of Pseudomonas aeruginosa (a common pathogen in chronic airway disease) to macrolide antibiotics⁵ argues against this explanation. Indeed, data suggest that patients with airway infection by P aeruginosa derive the greatest clinical benefit from macrolide treatment.1, 6

However, macrolide antibiotics also represent a substantial selective pressure on microbial communities, evidenced most simply by the emergence of bacterial resistance that results from their use.7, 8 The increasingly widespread use of these drugs, particularly azithromycin, therefore poses a risk of inducing substantial population-level antibiotic resistance in a range of microorganisms.8, 9 Furthermore, exposure to long-term macrolide antibiotics is likely to change the composition of bacterial communities in the airways (and other niches); such shifts in the composition of respiratory microbiota are likely to involve the displacement of macrolide-susceptible organisms by those with inherent tolerance. Such an effect would provide further important direct evidence to link macrolide use with adverse microbiological consequences in individuals with chronic airway disease, strengthening the argument for limiting the long-term prescription of macrolides.¹⁰ Furthermore, such an effect will be greatest in respiratory bacterial communities dominated by macrolide-sensitive organisms, which could be relevant to the relatively smaller clinical benefit of macrolides seen in people without P aeruginosa infection.1, 6

The results of previous non-randomised studies that have used next-generation sequencing methods have shown profound effects of antibiotic consumption on the composition of human faecal microbiota.11, 12 Furthermore, antibiotic-induced shifts in the composition of gut microbiota promote both body fat acquisition¹³ and severity of asthma¹⁴ in animal models. Although results from studies of the respiratory tract have shown links between microbiota composition and disease severity in chronic airway infections,15, 16, 17, 18, 19, 20 no randomised studies have been done to investigate the effect of any antibiotic, including macrolides, on the composition of respiratory microbiota, as assessed by deep sequencing.

In this analysis from the Bronchiectasis and Low-dose Erythromycin Study (BLESS) study, we aimed to assess whether long-term, low-dose erythromycin treatment changes the composition of respiratory microbiota in people with non-cystic fibrosis bronchiectasis. Additionally, we sought to assess whether this effect was associated with changes in the key clinical outcome measure of pulmonary exacerbations, and whether it might result in changes in airway microbiology that promote the ascendancy of pathogenic species.

Section snippets

Study design and participants

BLESS was a 12-month, double-blind, randomised, placebo-controlled trial to compare low-dose erythromycin ethylsuccinate (400 mg twice daily; equivalent to 250 mg twice daily of erythromycin base) in patients with non-cystic fibrosis bronchiectasis.¹ Adult patients aged 20–85 years with high-resolution CT scan-proven bronchiectasis, at least two separate pulmonary exacerbations requiring supplemental systemic antibiotic treatment in the preceding 12 months, and daily sputum production were

Results

The BLESS study took place between Oct 15, 2008, and Dec 14, 2011.¹ Of the original 117 participants randomly assigned, ten (five in each group) did not complete the study (appendix)¹ and 21 (11 in the erythromycin group and ten in the placebo group) did not have sputum available from both visits for molecular analyses. Of the remaining participants, 44 were assigned to the erythromycin group and 42 to placebo. Baseline demographic and disease characteristics were generally well balanced

Discussion

Low-dose erythromycin given for 48 weeks to patients with non-cystic fibrosis bronchiectasis substantially changed airway bacterial community composition compared with placebo. These changes in microbiota composition were most substantial in patients with airway infection dominated by organisms other than P aeruginosa and primarily reflected reductions in the relative abundance of H influenzae and increases in intrinsically macrolide-tolerant organisms including P aeruginosa. By contrast with

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ArticlesThe effect of long-term macrolide treatment on respiratory microbiota composition in non-cystic fibrosis bronchiectasis: an analysis from the randomised, double-blind, placebo-controlled BLESS trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Lancet

Lancet

Lancet Respir Med

Infect Genet Evol

J Hepatol

J Cyst Fibros

Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial

JAMA

Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial

JAMA

Mechanisms of action and clinical application of macrolides as immunomodulatory medications

Clin Microbiol Rev

Macrolides for the treatment of Pseudomonas aeruginosa infections?

J Antimicrob Chemother

Effectiveness and safety of macrolides in cystic fibrosis patients: a meta-analysis and systematic review

J Antimicrob Chemother

The evidence base for non-CF bronchiectasis is finally evolving

Respirology

Macrolides for bronchiectasis and COPD—should we worry about antimicrobial resistance?

Clin Invest

Incomplete recovery and individualised responses of the human distal gut microbiota to repeated antibiotic perturbation

Proc Natl Acad USA

Short-term antibiotics treatment has differing long-term impacts on the human throat and gut microbiome

PLoS One

Antibiotics in early life alter the murine colonic microbiome and adiposity

Nature

Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma

EMBO Rep

Clinical measures of disease in non-CF bronchiectasis correlate with airway microbiota composition

Thorax

A novel microbiota stratification system predicts future exacerbations in bronchiectasis

Ann Am Thorac Soc

Articles
The effect of long-term macrolide treatment on respiratory microbiota composition in non-cystic fibrosis bronchiectasis: an analysis from the randomised, double-blind, placebo-controlled BLESS trial