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New therapeutic options for noncystic fibrosis bronchiectasis

Yap, Vanessa L.; Metersky, Mark L.

Current Opinion in Infectious Diseases: April 2015 - Volume 28 - Issue 2 - p 171–176
doi: 10.1097/QCO.0000000000000147
RESPIRATORY INFECTIONS: Edited by Michael S. Niederman
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Purpose of review Patients with noncystic fibrosis bronchiectasis (NCFB) share many of the respiratory symptoms of cystic fibrosis and often are provided therapies effective in cystic fibrosis, often without clear evidence of benefit. There are currently no approved therapies for NCFB, but in recent years, there has been increased interest in developing new therapies due to the increasing prevalence and perceived unmet needs. This review is meant to provide the most recent information to clinicians about currently available and pipeline therapies for NCFB.

Recent findings Inhaled antibiotics may provide effective bacterial suppressive therapy with an acceptable safety profile in adults with NCFB, although evidence of improved outcomes is limited. Inhaled hyperosmolar agents such as hypertonic saline and mannitol are promising but study results have been mixed. Macrolide antibiotics have anti-inflammatory properties and, in several randomized controlled trials, demonstrated the benefit of chronic low-dose treatment. Other anti-inflammatory agents that have shown promising preliminary results include statins and neutrophil elastase inhibitors.

Summary There is high-quality evidence supporting chronic low-dose macrolide therapy in patients with NCFB. There is limited evidence of benefit of other therapies, including inhaled antibiotics and pharmacologic agents to enhance mucus clearance.

Division of Pulmonary and Critical Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA

Correspondence to Mark L. Metersky, MD, Division of Pulmonary and Critical Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1321, USA. Tel: +1 860 679 3582; fax: +1 860 679 1103; e-mail: Metersky@nso.uchc.edu

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INTRODUCTION

Bronchiectasis is a chronic lung disease characterized by permanent dilatation of bronchi [1], due to repeated cycles of airway infection and inflammation. It results in chronic airway infection and loss of lung function and may contribute to premature mortality [2]. Symptoms include chronic cough, often with daily mucopurulent sputum production, dyspnea and fatigue; and acute exacerbations are common [3].

The vicious cycle hypothesis of bronchiectasis argues that bacterial colonization of the respiratory tract perpetuates neutrophil-mediated airway inflammation, leading to structural damage. This causes further impairment of the mucociliary escalator and increased bacterial load. Bronchiectasis can be caused by postinfectious damage, abnormal host defenses, genetic defects, congenital malformations, mechanical obstruction, chronic inflammatory conditions and autoimmune disease [4]; in approximately 50% of patients, the disease is idiopathic.

Noncystic fibrosis bronchiectasis (NCFB) remains an important cause of chronic respiratory morbidity with a considerable healthcare burden in both developed and developing countries [5]. In the United States, the estimated prevalence is over 100 000 [6]. The airways of almost all patients with bronchiectasis are chronically infected with pathogenic bacteria, even among those who are clinically stable [7,8]. The most common infecting pathogens are Haemophilus influenzae (47–55%) and Pseudomonas aeruginosa (12–26%).

There are currently no medications approved by the US Food and Drug Administration (FDA) for the treatment of bronchiectasis in the United States [9]. However, recently, pharmaceutical companies have become increasingly interested in developing new therapies, likely due to increased prevalence (or detection) of the disease and the perceived unmet needs in therapy [10]. Here, we discuss new therapies for NCFB, some of which are increasingly being used off-label for bronchiectasis, while others are still in development and are not yet available.

Box 1

Box 1

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INHALED ANTIBIOTICS

The utility of chronic maintenance antibiotic therapy in NCFB is unknown, although patients with frequent exacerbations and debilitating symptoms are often started on such therapy [11]. The theoretical advantages of inhaled over systemic antibiotics include the high concentration of antibiotic delivered into the airway and the reduced systemic absorption and systemic side-effects [11,12▪▪]. There has been particular interest in the use of anti-pseudomonal antibiotics, as a chronic P. aeruginosa infection is associated with worse quality of life, increased exacerbation frequency and more rapid decline in lung function [13]. The proven efficacy of this approach in cystic fibrosis (CF) provides an appealing blueprint [14].

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Liposomal ciprofloxacin

Liposomal encapsulation of inhaled antibiotics may improve tolerability without sacrificing microbiological efficacy by minimizing the amount of free antibiotic in direct contact with the airway during inhalation and yet still releasing adequate drug dose to the lower airways. Dual-release ciprofloxacin for inhalation (DRCFI, Pulmaquin; Aradigm Corporation, Hayward, California, USA) is a mixture of liposomal and free ciprofloxacin, facilitating once-daily dosing. ORBIT-2 (Once Daily Respiratory Bronchiectasis Inhalation Treatment), a phase II, 24-week Australian/New Zealand multicenter, randomized, double-blind, placebo controlled trial, enrolled 42 adult bronchiectasis patients with at least two pulmonary exacerbations in the prior 12 months and ciprofloxacin-sensitive P. aeruginosa at screening. Twenty patients received liposomal ciprofloxacin in three treatment cycles of 28 days on/28 days off, which resulted in a mean [standard deviation (SD)] 4.2 (3.7) log10 colony forming units/g reduction in P. aeruginosa bacterial density at day 28 [vs. −0.08 (3.8) with placebo, P = 0.002]. There was also delayed time to first pulmonary exacerbation (median 134 vs. 58 days, P = 0.057). Liposomal ciprofloxacin had a similar incidence of systemic adverse events to the placebo group, but fewer pulmonary adverse events [14]. A phase III study of this drug is currently enrolling patients.

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Dry powder ciprofloxacin

Ciprofloxacin has also been formulated into a dry powder for inhalation (DPI) using PulmoSphere technology (Novartis Pharma AG, Basel, Switzerland) for use with the small, portable, breath-actuated T-326 inhalers. A phase II, randomized, double-blind, multicenter study investigated the safety and efficacy of ciprofloxacin DPI in patients with NCFB. Adults culture positive for predefined potential respiratory pathogens were randomized to ciprofloxacin DPI 32.5 mg or placebo twice daily for 28 days (with 56 days of follow-up). Patients on ciprofloxacin DPI had a significant reduction (P < 0.001) in total sputum bacterial load (primary endpoint) at the end of treatment compared with placebo. In the ciprofloxacin DPI group, 14 out of 40 (35%) patients had pathogen eradication at the end of treatment vs. four out of 49 (8%) in the placebo group (P = 0.001). No safety issues were reported and rates of bronchospasm were low [15].

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Colistin

Nebulized colistin is commonly prescribed for patients with bronchiectasis in Europe, but has only recently been evaluated in a randomized, double-blind, placebo-controlled study administered through the I-neb adaptive aerosol delivery device (Philips Respironics, Chichester, UK) in patients with bronchiectasis and chronic P. aeruginosa infection [13]. One hundred and forty-four patients were randomized to receive either 1 million international unit (IU) of colistin or placebo twice a day within 21 days of anti-pseudomonal treatment for an exacerbation, for up to 6 months. The primary endpoint of time to exacerbation was not met. Median time to exacerbation was 165 vs. 111 days in the placebo group (P = 0.11). Thirty-six of 73 patients (49%) in the colistin group and 42 of 71 patients in the placebo group (59%) experienced an exacerbation. Among the most adherent of patients (adherence >81%), 27 of 54 (50%) of colistin patients had an exacerbation, whereas the adherent placebo group had an exacerbation rate of 39 of 54 (72%). There was no significant change in forced expiratory volume in 1 s (FEV1), consistent with other studies of inhaled antibiotics in bronchiectasis [13,16].

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Aztreonam

Aztreonam is an anti-pseudomonal antibiotic formulated for inhalation, which decreases symptoms, delays time to pulmonary exacerbation and improves lung function in patients with CF and chronic P. aeruginosa infection [3]. AIR-BX1 (aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis) and AIR-BX2 were identical double-blind, multicenter, randomized, placebo-controlled, phase III trials using aztreonam 75 mg or placebo given three times a day, two cycles, with each cycle consisting of 4 weeks on treatment, followed by 4 weeks off-treatment. Aztreonam did not improve respiratory symptoms or delay the time to exacerbation in patients with NCFB. Moreover, those receiving aztreonam had increased incidence of study discontinuations due to safety or tolerability, for reasons that are unclear [3].

A systematic review of 12 randomized trials involving 1264 participants and a meta-analysis of eight trials with 590 participants show that in adult patients with clinically stable non-CF bronchiectasis and chronic bronchial infection, inhaled antibiotics were more effective than placebo or symptomatic treatment in reducing sputum bacterial load, eradicating the bacteria from sputum and reducing the risk of acute exacerbations. However, there was no significant benefit of inhaled antibiotics in reducing the risk of unscheduled hospitalizations or in improving health-related quality of life [12▪▪]. Moreover, inhaled antibiotic use was associated with a small, but statistically significant, reduction in FEV1% predicted [12▪▪].

Among the agents discussed above, inhaled aztreonam and colistin are available in the United States, although not FDA approved for bronchiectasis, while neither formulation of ciprofloxacin is available. Gentamicin has been studied in NCFB [17] and is also available from some specialty pharmacies. Liposomal amikacin was studied in NCFB, with positive phase II results reported in 2009 [18], and is being studied in CF [19], and nontuberculous mycobacterial disease but is not currently being studied for NCFB [20].

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OTHER NOVEL ANTIBIOTIC STRATEGIES

A retrospective study assessed clinical and microbiological outcomes of eradication therapy following initial Pseudomonas infection in 30 patients with median follow-up time of 26.4 months. Eradication therapy involved intravenous (i.v.) antibiotics (n = 12), i.v. antibiotics followed by oral ciprofloxacin (n = 13) or ciprofloxacin alone (n = 5), combined with 3 months of nebulized colistin. Pseudomonas was eradicated in 24 patients (80%) and 13 out of 24 patients remained Pseudomonas-free whereas 11 out of 24 were reinfected (median time 6.2 months). Exacerbation frequency was significantly reduced. Two-thirds of the patients reported initial clinical improvement and at 1-year follow-up, 90% of the patients had further improved or remained stable [21].

Cyclical i.v. antibiotics for 14 days, 8 weeks apart, were initiated in 19 patients with severe bronchiectasis and recurrent exacerbations (≥5/year). Antibiotics were based on sputum microbiology results and patients were followed for 1 year. There was a significant reduction in the number of exacerbations [mean (SE): 9.3 (0.5) in the year before vs. 8.0 (0.4) in the year after, P = 0.02]. There was an improvement in the Leicester Cough Questionnaire (LCQ) and in St. George's Respiratory Questionnaire (SGRQ) with an increase in exercise capacity [22].

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HYPEROSMOLAR AGENTS

Hyperosmolar agents are used with the aim of reducing sputum viscosity in the hopes of easing clearance. When inhaled, they are deposited in the airway, and draw fluid from the airway epithelium onto the mucosal surface, which then favorably changes mucus properties, likely allowing more rapid and effective clearance [8,10,23▪▪,24].

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Hypertonic saline

Two recent studies [25,26] provided contrasting results on exacerbation rates, antibiotic use and hospitalizations in patients treated with hypertonic saline. One found that treatment with both isotonic and hypertonic saline resulted in a large drop in exacerbation frequency over the year of the study; there was no difference between the treatments in number of hospital admissions [26]. In contrast, Kellet 2011 reported a statistically significant and clinically important reduction in exacerbations in the hypertonic saline group (annualized exacerbation rate 2.1 for hypertonic saline, 4.9 for isotonic saline), with a comparable reduction in the use of antibiotics (annualized rate 2.4) vs. isotonic saline (5.4). No clear conclusions can be drawn regarding the effects of nebulized hypertonic saline in bronchiectasis [23▪▪], but in patients with difficulty clearing secretions, it is a reasonable option.

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Mannitol

Mannitol is a naturally occurring sugar alcohol and, when inhaled, causes improvement in mucus clearance both acutely and over 24 h in NCFB and improves mucus clearance and FEV1 in patients with CF [8]. Mannitol has the theoretical advantage that its half-life in the airways is much longer than that of hypertonic saline, with a potential of a more sustained effect [10]. In a recent randomized controlled trial (RCT), 461 patients with NCFB were randomized to 52 weeks of treatment with inhaled mannitol 400 mg or low-dose mannitol control twice a day. There was no difference in annual exacerbation rate between the two arms (the primary endpoint). Inhaled mannitol at a dose of 400 mg twice daily significantly extended the time to first exacerbation, increased the proportion of patients who remained exacerbation free, reduced the number of days of antibiotic therapy and improved quality of life [8]. A recent Cochrane review on inhaled mannitol for NCFB revealed that overall, inhaled mannitol increases time to infective exacerbation in patients with bronchiectasis, without improving respiratory quality of life. The authors concluded that it may have a role in reducing exacerbations and antibiotic use in those with normal or mild to moderately impaired spirometry [23▪▪].

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ANTI-INFLAMMATORY AGENTS

There is an amplified level of airway inflammation in patients with non-CF bronchiectasis, hence the interest in the efficacy of anti-inflammatory agents.

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Macrolides

Studies on long-term oral antibiotics in NCFB have recently focused on macrolide antibiotics, which may have immunomodulatory effects at concentrations lower than those required to kill the infecting or colonizing bacteria, thereby modulating persistent airway inflammation. There have been several RCTs published recently, all of which demonstrated benefit. The effectiveness of macrolides in patients with bronchiectasis using azithromycin to control exacerbations (EMBRACE) study enrolled 141 patients, randomized to azithromycin 500 mg or placebo three times a week [27]. The rate of event-based exacerbations was 0.59 vs. 1.57 per patient in the placebo group during the 6-month treatment period (rate ratio 0.38, 95% CI 0.26–0.54, P < 0.0001). There was no significant effect on FEV1. The change in SGRQ total score did not differ between the azithromycin (−5.17 units) and placebo groups (−1.92 units, difference −3.25, 95% CI −7.21 to 0.72, P = 0.108).

The bronchiectasis and long-term azithromycin treatment study enrolled patients (n = 83) with confirmed bronchiectasis who had at least three lower respiratory tract infections in the prior year, to receive azithromycin 250 mg/day or placebo for 12 months [28▪]. Azithromycin treatment significantly reduced the number of exacerbations compared with placebo, with a median of 0 vs. 2 during treatment (P < 0.001). The number of patients with at least one exacerbation during the study was 80% in the placebo group and 46.5% in the azithromycin group, corresponding to a number needed to treat (NNT) of three to prevent one exacerbation in 12 months. Azithromycin also significantly attenuated changes in FEV1 and forced vital capacity (P = 0.047 and 0.02 vs. placebo, respectively). In contrast to EMBRACE, azithromycin treatment was associated with significant improvements in the SGRQ score compared with placebo. Macrolide resistance developed during the study, at a rate of 88% in azithromycin-treated individuals, compared with 26% in the placebo group [28▪].

The bronchiectasis and low-dose erythromycin study enrolled patients with at least two pulmonary exacerbations during the previous 12 months and daily sputum production. One hundred and seventeen patients received oral erythromycin ethylsuccinate 400 mg twice daily (equivalent to 250 mg of base erythromycin) or placebo for 12 months. The number of protocol-defined pulmonary exacerbations was 76 and 114 in the erythromycin and placebo groups, respectively, corresponding to a mean of 1.29 and 1.97 per patient per year, incidence rate ratio 0.57 (P = 0.003). Erythromycin significantly prevented the decline in FEV1 during the study period but had no significant effect on cough or quality of life. The proportion of macrolide-resistant commensal oropharyngeal streptococci increased significantly in erythromycin, but not placebo, recipients [29].

A recent meta-analysis demonstrated that macrolides result in improved quality of life and decreased exacerbation rate in patients with NCFB. Patients being considered for chronic macrolide therapy should be screened for infection or colonization with nontuberculous mycobacteria as macrolide monotherapy can promote the selection of macrolide-resistant infection, which is almost impossible to cure. Furthermore, patients should be screened for risk factors for ventricular arrhythmias before commencing chronic macrolide therapy, due to the risk of QT prolongation associated with this class of antibiotics [30▪▪].

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Statins

Statins have pleiotropic effects, including modulation of the innate and adaptive immune systems and reduction of inflammation [31▪]. In a proof-of-concept randomized controlled trial (RCT), 60 patients were randomized to atorvastatin 80 mg or placebo for 6 months. The primary endpoint was reduction in cough, as measured by the Leicester cough questionnaire (LCQ), with a lower score indicating more severe cough. There was a statistically significant improvement of cough (mean difference 2.2, 95% CI 0.5–3.9, P = 0.01) [31▪]. Multicenter studies are needed to assess whether these findings translate to reducing exacerbations or improving quality of life.

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Neutrophil elastase inhibitor

Neutrophil elastase is a serine protease that is able to degrade extracellular matrix and proteins, damaging the lung parenchyma and airway walls. Neutrophil elastase also has proinflammatory effects, and stimulates mucus secretion as well as inhibiting mucociliary clearance. Neutrophil elastase activity is increased in bronchiectasis and its control may downregulate proteolytic lung destruction and slow disease progression. AZD9668 is a novel, orally active reversible inhibitor of human neutrophil elastase. Efficacy and safety of AZD9668 60 mg twice daily over 4 weeks were evaluated in a randomized, double-blind, placebo-controlled, phase II, signal-searching study in patients with bronchiectasis. Four weeks of AZD9668 improved lung function. Larger studies of longer duration would be needed to confirm the potential benefits of this agent in bronchiectasis [32▪].

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SUMMARY

Inhaled antibiotics may provide an effective suppressive antibiotic therapy with an acceptable safety profile in adults with NCFB. Macrolide antibiotics taken at lower than the usual therapeutic dosages between 6 and 12 months have led to significant reductions in exacerbation rate and, in some studies, improved quality of life and reduced the decline in lung function. Further multicenter randomized trials are still needed to better define the optimal regimen and duration of treatment of the different inhaled and systemic antibiotics and between inhaled vs. systemic antibiotics. No clear conclusions can be made regarding the role of hypertonic saline or inhaled mannitol.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

M.M. has participated as an investigator in clinical trials for bronchiectasis sponsored by Pharmaxis, Gilead and Aradigm. V.Y. has no conflicts of interest to report.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1. Barker AF. Bronchiectasis. N Engl J Med 2002; 346:1383–1393.
2. O’Donnell AE. Bronchiectasis. Chest 2008; 134:815–823.
3. Barker AF, O’Donnell AE, Flume P, et al. Aztreonam for inhalation solution in patients with noncystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials. Lancet Respir Med 2014; 2:738–749.
4. Metersky ML. The initial evaluation of adults with bronchiectasis. Clin Chest Med 2012; 33:219–231.
5. Twiss J, Metcalfe R, Edwards E, Byrnes C. New Zealand national incidence of bronchiectasis ‘too high’ for a developed country. Arch Dis Child 2005; 90:737–740.
6. Weycker D, Edelsberg J, Oster G. Prevalence and economic burden of bronchiectasis. Clin Pulm Med 2005; 12:205–209.
7. Haworth CS, Bilton D, Elborn JS. Long-term macrolide maintenance therapy in non-CF bronchiectasis: evidence and questions. Respir Med 2014; 108:1397–1398.
8. Bilton D, Tino G, Barker AF, et al. Inhaled mannitol for noncystic fibrosis bronchiectasis: a randomised, controlled trial. Thorax 2014; 12:1073–1079.
9. Rubin BK, Williams RW. Aerosolized antibiotics for noncystic fibrosis bronchiectasis. Respiration 2014; 88:177–184.
10. Metersky ML. New treatment options for bronchiectasis. Ther Adv Respir Dis 2010; 4:93–99.
11. O’Donnell AE. Antimicrobial therapy for bronchiectasis. Clin Chest Med 2012; 33:381–386.
12▪▪. Brodt AM, Stovold E, Zhang L. Inhaled antibiotics for stable noncystic fibrosis bronchiectasis: a systematic review. Eur Respir J 2014; 44:382–393.

Systematic review on 14 RCTs and meta-analysis on eight studies showing benefits of inhaled antibiotics in NCFB.

13. Haworth CS, Foweraker JE, Wilkinson P, et al. Inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. Am J Respir Crit Care Med 2014; 189:975–982.
14. Serisier DJ, Bilton D, De Soyza A, et al. Inhaled, dual release liposomal ciprofloxacin in noncystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial. Thorax 2013; 68:812–817.
15. Wilson R, Welte T, Polverino E, et al. Ciprofloxacin dry powder for inhalation in noncystic fibrosis bronchiectasis: a phase II randomised study. Eur Respir J 2013; 41:1107–1115.
16. Tabernero E, Gil P, Alkiza R, et al. Inhaled colistin in elderly patient with noncystic fibrosis bronchiectasis with chronic Pseudomonas aeruginosa bronchial infection. Chest 2014; 145 (3, Suppl):431A.
17. Murray MP, Govan JR, Doherty CJ, et al. A randomized controlled trial of nebulized gentamicin in noncystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2011; 183:491–499.
18. O’Donnell AE, Swarnakar R, Yahina L, et al. A placebo-controlled study of liposomal amikacin for inhalation nebulized once daily in the treatment of bronchiectatic patients with chronic Pseudomonas aeruginosa lung infection. Eur Respir J 2009; 34:231S.
19. Clancy JP, Dupont L, Konstan MW, et al. Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. Thorax 2013; 68:818–825.
20. Arikace® for Nontuberculous Mycobacteria. ClinicalTrials.gov; 2013 [cited 2014 11/14/2014]; Available from: http://clinicaltrials.gov/ct2/show/NCT01315236?term=liposomal+amikacin&rank=1 in press. [Accessed 4 November 2014]
21. White L, Mirrani G, Grover M, et al. Outcomes of Pseudomonas eradication therapy in patients with noncystic fibrosis bronchiectasis. Respir Med 2012; 106:356–360.
22. Mandal P, Sidhu MK, Donaldson LS, et al. Eight-weekly intravenous antibiotics is beneficial in severe bronchiectasis. QJM 2013; 106:27–33.
23▪▪. Hart A, Sugumar K, Milan SJ, et al. Inhaled hyperosmolar agents for bronchiectasis. Cochrane Database Syst Rev 2014; 5:CD002996.

Systematic review on hypertonic saline and mannitol with no clear conclusions on their utility in NCFB.

24. Nair GB, Ilowite JS. Pharmacologic agents for mucus clearance in bronchiectasis. Clin Chest Med 2012; 33:363–370.
25. Kellett F, Robert NM. Nebulised 7% hypertonic saline improves lung function and quality of life in bronchiectasis. Respir Med 2011; 105:1831–1835.
26. Nicolson CH, Stirling RG, Borg BM, et al. The long term effect of inhaled hypertonic saline 6% in noncystic fibrosis bronchiectasis. Respir Med 2012; 106:661–667.
27. Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations in noncystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 380:660–667.
28▪. Altenburg J, de Graaff CS, Stienstra Y, et al. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with noncystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA 2013; 309:1251–1259.

Another RCT showing improvement of SGQR in NCFB on azithromycin.

29. Serisier DJ, Martin ML, McGuckin MA, et al. Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with noncystic fibrosis bronchiectasis: the BLESS randomized controlled trial. JAMA 2013; 309:1260–1267.
30▪▪. Wu Q, Shen W, Cheng H, Zhou X. Long-term macrolides for noncystic fibrosis bronchiectasis: a systematic review and meta-analysis. Respirology 2014; 19:321–329.

Meta-analysis of nine RCTs on long-term macrolides in NCFB showing clinical benefit.

31▪. Mandal P, Chalmers JD, Graham C, et al. Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial. Lancet Respir Med 2014; 2:455–463.

Proof of concept of utility of statins as anti-inflammatory agents in bronchiectasis.

32▪. Stockley R, De Soyza A, Gunawardena K, et al. Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis. Respir Med 2013; 107:524–533.
Keywords:

aerosolized antibiotics; airway clearance; bronchiectasis; macrolides; Pseudomonas

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