bs_bs_banner

EDITORIAL

The evidence base for non-CF bronchiectasis is finally evolving

Key words: azithromycin, bacterial drug resistance, bronchiectasis, erythromycin, macrolide.

Abbreviation: CF, cystic fibrosis.

A meaningful meta-analysis demonstrating consistent positive outcomes for a single therapeutic

approach in non-cystic fibrosis (CF) bronchiectasis
would have been unthinkable less than 2 years ago.
The meta-analysis of macrolides in this issue of
Respirology1 therefore represents a watershed in the
evolution of the therapeutic evidence base for this
condition. It was little more than 12 months ago that
Conroy Wong and colleagues published the results of
the Effectiveness of Macrolides in patients with Bronchiectasis using Azithromycin to Control Exacerbations (EMBRACE) study, arguably the first data to
prove the efficacy of any therapy for non-CF bronchiectasis.2 This dearth of high-quality evidence to
support management strategies in non-CF bronchiectasis is particularly striking when considered
against the extensive and high-quality evidence base
that exists for its more fashionable cousin, CF.
The relative paucity of high-quality evidence means
that therapies and management principles for nonCF bronchiectasis are largely empiric and often
simply extrapolated from those of proven efficacy in
CF. Ironically, however, where randomized controlled
trials of proven CF therapies have been performed in
the non-CF bronchiectasis population, they have
been generally negative or even overtly deleterious.
Inhaled recombinant deoxyribonuclease (dornase
alfa) significantly increases exacerbations and accelerates decline in lung function3 while inhaled
tobramycin solution for inhalation increases respiratory adverse events in non-CF bronchiectasis.4
Patients with non-CF bronchiectasis appear particularly susceptible to respiratory adverse events with
inhaled therapies and the poor tolerability seen with
tobramycin solution for inhalation4 has been replicated in other studies of inhaled antibiotics, most
recently with aztreonam lysine for inhalation.5 Hence,
in spite of demonstrating impressive microbiological
efficacy, neither tobramycin solution for inhalation
nor aztreonam lysine for inhalation improves clinical
outcomes.
Increased research activity in the past few years has
started to turn this tide however, typified by the development of dual-release ciprofloxacin for inhalation
(Pulmaquin), an inhaled antibiotic formulation containing liposomal ciprofloxacin which was shown to
be not only microbiologically effective, but also welltolerated in a recent phase 2 study.6 In addition to
2014 The Author
Respirology 2014 Asian Pacific Society of Respirology

increasing pharmaceutical interest, mounting academic research activity in non-CF bronchiectasis

is also growing the therapeutic evidence base. The
Bronchiectasis and Low-dose Erythromycin Study
(BLESS) study has recently confirmed the benefits of
macrolide antibiotics, using the short-acting agent
erythromycin rather than the more ecologically
costly, long-acting azithromycin.7,8 Macrolide therapy
has also recently been shown effective in an indigenous Australasian paediatric population.9 New
research is also shedding new light on underlying
pathophysiology. Recent publications have improved
our understanding of the airway inflammatory and
microbiological milieu associated with non-CF bronchiectasis, providing evidence to link airway bacterial
community composition (microbiota) to inflammation and clinical markers of disease severity.10
In the context of this evolving evidence base,
Wu and colleagues meta-analysis1 provides further
confirmatory evidence of the benefits of long-term
macrolide therapy in non-CF bronchiectasis. Consistent, clinically significant benefits were demonstrated
for nearly all assessed clinical outcome measures. Pulmonary exacerbation rates, quality of life, symptoms,
sputum production and lung function were all significantly improved compared with placebo. Furthermore, while there was an increase in mild, self-limiting
gastrointestinal side-effects with macrolides, this did
not lead to subject withdrawal and side-effects did
not differ overall. Given the breadth, magnitude and
clinical importance of these benefits and the lack of
treatment-limiting side-effects, should we be routinely considering macrolide therapy for all subjects
with non-CF bronchiectasis? Definitely not.
The use of any antibacterial agent is associated
with the development of bacterial resistance in
exposed microorganisms (in both target and innocent
bystander bacteria). For CF and other ultimately fatal
conditions with low prevalence (e.g. diffuse panbronchiolitis and transplant-associated bronchiolitis obliterans), macrolides can have a large net benefit, given
the low risk of significantly influencing population
antimicrobial resistance rates. However, for the more
indolent (and collectively very common) inflammatory airways diseases including chronic obstructive
pulmonary disease and non-CF bronchiectasis, the
benefits are much smaller and the antimicrobial
resistance risks are substantial. The widespread use of
these agents for non-CF inflammatory airways diseases poses a high likelihood of inducing substantial
population-level antibiotic resistance in a range of
microorganisms (reviewed in Serisier11). In particular,
the long-acting agent azithromycin rapidly induces
Respirology (2014) 19, 295297
doi: 10.1111/resp.12247

296

Editorial

practical application of this therapy in a manner that

optimises benefits to individuals while minimizing
the macrolide resistance risk to the broader community. For non-CF inflammatory airways diseases,
restricting the use of macrolides to more severe subgroups, combined with the preferential use of erythromycin, represents an approach that attempts to
balance the risk of resistance against the demonstrated clinical efficacy of these agents.

Figure 1 US rates of macrolide resistance in S. pneumoniae

isolates and global Pfizer azithromycin annual sales data.
, Azithromycin sales;
, macrolide resistance. (Reproduced from Serisier11 with permission from Elsevier).

sustained macrolide resistance, and its introduction

in the USA in 1992 was temporally associated with
substantial increases in rates of macrolide resistance
in pneumococcal isolates (see Fig. 1). Furthermore,
data suggest that azithromycin impairs host intracellular killing of mycobacteria,12 an issue of particular concern given the frequent co-colonization of
non-tuberculous mycobacteria in subjects with
chronic airway disease. Hence, the routine introduction
of long-term macrolide therapy, particularly azithromycin, for subjects with inflammatory airways diseases including non-CF bronchiectasis risks significant
negative impacts on community microbial ecology; in
the setting of little new research and development of
novel antibiotics, it is imperative that we do not render
an entire existing antibiotic class obsolete.
Macrolide therapy, particularly azithromycin, should
be limited to an appropriate, selected subgroup of subjects with non-CF bronchiectasis with either high
disease burden or at greatest risk of adverse outcomes.
While recent studies have not been adequately powered
to convincingly assess subgroups, data from the BLESS7
study suggest that subjects with chronic Pseudomonas
aeruginosa airway infection or those with a history of
frequent infective exacerbations (with a breakpoint at
5 exacerbations per year in that study) are likely to
derive the greatest benefits on exacerbation reduction
from erythromycinthese simply identified clinical
markers are also among the strongest predictors of
mortality and morbidity13 and hence represent a logical
target group for macrolide therapy. Future studies of
macrolides in bronchiectasis should aim to prospectively evaluate these specific subgroups. Furthermore,
concurrent airway infection with non-tuberculous
mycobacteria must be excluded, and any potentially
reversible risk factors for recurrent exacerbations
(e.g. current smoking, aspiration, sinus disease and
postnasal drip, etc.) need to be reversed or optimally
managed. Finally, where macrolide therapy is indicated, erythromycin represents a more ecologically
responsible choice than azithromycin.
The meta-analysis of Wu et al.1 strengthens the evidence base for maintenance macrolide use in non-CF
bronchiectasis, although it is unable to guide the
Respirology (2014) 19, 295297

David J. Serisier, MBBS, DM, FRACP1,2

1
Department of Respiratory Medicine,
Mater Adult Hospital, South Brisbane, and
2
Immunity, Infection, and Inflammation Program,
Translational Research Institute,
Mater Research InstituteUniversity of Queensland,
Woolloongabba, Queensland, Australia

REFERENCES
1 Wu Q, Shen W, Cheng H, Zhou X. Long-term macrolides for
non-cystic fibrosis bronchiectasis: A systematic review and
meta-analysis. Respirology 2014; 19: 3219.
2 Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H,
Milne D, Fergusson W, Tuffery C, Sexton P et al. Azithromycin for
prevention of exacerbations in non-cystic fibrosis bronchiectasis
(EMBRACE): a randomised, double-blind, placebo-controlled
trial. Lancet 2012; 380: 6607.
3 ODonnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with aerosolised recombinant human
DNase 1. Chest 1998; 113: 132934.
4 Barker AF, Couch L, Fiel SB, Gotfried MH, Ilowite J, Meyer KC,
ODonnell A, Sahn SA, Smith LJ, Stewart JO et al. Tobramycin
solution for inhalation reduces sputum Pseudomonas
aeruginosa density in bronchiectasis. Am. J. Respir. Crit. Care
Med. 2000; 162: 4815.
5 Barker A, ODonnell AE, Thompson PJ, Flume P, Ruzi J, de Gracia
J, Boersma W, Polverino E, Shao L, Zhang J et al. Two phase 3
placebo-controlled trials of aztreonam lysine for inhalation
(AZLI) for non-CF bronchiectasis (NCFB). ERS Congress 2013,
Barcelona, P4136.
6 Serisier DJ, Bilton D, De Soyza A, Thompson PJ, Kolbe J, Greville
HW, Cipolla D, Bruinenberg P, Gonda I. Inhaled, dual-release
liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis
(ORBIT-2)a randomised, double-blind, placebo-controlled
trial. Thorax 2013; 68: 81217.
7 Serisier DJ, Martin M, McGuckin M, Lourie R, Chen A, Brain B,
Dash P, Schlebusch S, Biga S, Bowler SD. 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: 12607.
8 Serisier DJ, Martin M. Long-term, low-dose erythromycin in
bronchiectasis subjects with frequent infective exacerbations.
Respir. Med. 2011; 105: 9469.
9 Valery PC, Morris PS, Byrnes CA, Grimwood K, Torzillo PJ, Bauert
PA, Masters IB, Diaz A, McCallum GB, Mobberley C et al. Longterm azithromycin for indigenous children with non-cystic
fibrosis bronchiectasis or chronic suppurative lung disease
(bronchiectasis intervention study): a multicentre, double-blind,
randomised controlled trial. Lancet Respir. Med. 2013; 1: 61020.
10 Rogers GB, van der Gast CJ, Cuthbertson L, Thomson SK, Bruce
KD, Martin M, Serisier DJ. Clinical measures of disease in
non-CF bronchiectasis correlate with airway microbiota composition. Thorax 2013; 68: 7317.
11 Serisier DJ. Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. Lancet Respir. Med. 2013; 1: 26274.
2014 The Author
Respirology 2014 Asian Pacific Society of Respirology

Editorial
12 Renna M, Schaffner C, Brown K, Shang S, Tamayo MH,
Hegyi K, Grimsey NJ, Cusens D, Coulter S, Cooper J et al.
Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J. Clin. Invest. 2011; 121:
355463.

2014 The Author

Respirology 2014 Asian Pacific Society of Respirology

297
13 Chalmers JD, Goeminne P, Aliberti S, McDonnell MJ, Lonni S,
Davidson J, Poppelwell L, Salih W, Pesci A, Dupont LJ et al. The
bronchiectasis severity index: an international derivation and
validation study. Am. J. Respir. Crit. Care Med. 2013. (ePub ahead
of print).

Respirology (2014) 19, 295297