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Macrolides for Clinically Significant Bronchiectasis in Adults: Who Should Receive This Treatment? FREE TO VIEW

Adam T. Hill, MD
Author and Funding Information

Department of Respiratory Medicine, Royal Infirmary and University of Edinburgh, Edinburgh, Scotland

CORRESPONDENCE TO: Adam T. Hill, MD, Department of Respiratory Medicine, Royal Infirmary and University of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, Scotland


Copyright 2016, . All Rights Reserved.


Chest. 2016;150(6):1187-1193. doi:10.1016/j.chest.2016.08.1451
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Long-term macrolide therapy offers an evidence-based treatment to reduce frequent exacerbations in stable adult patients with bronchiectasis. There is limited evidence that these agents also attenuate the decline in lung function and improve health-related quality of life. The benefits and risks of long-term macrolide use need to be clearly explored for individual patients. Further work is needed to understand the optimal drug, dose, and regimen, the mechanisms behind these benefits, appropriate patient selection, sustainability of efficacy, potential long-term risk for the lung microbiome; and their use with or without inhaled antibiotic treatment. We reviewed the current evidence on long-term macrolides in adults with bronchiectasis.

Patients with clinically significant bronchiectasis have daily symptoms and recurrent chest infections leading to impaired health-related quality of life. There is excessive neutrophilic airway inflammation, and, despite this, frequent infection of the airways with potential pathogenic organisms is observed. At high microbial loads, increased airway and systemic inflammation is evident. A vicious cycle of infection and inflammation ensues, and therapies attenuating this inflammatory cycle would be beneficial.,, There has been a lack of evidence-based therapies for bronchiectasis since it was first described by Laennec in 1819; however, three studies of macrolide administration in patients with bronchiectasis, as well as recent meta-analyses combining these and smaller studies, have been published. An evaluation of these data was undertaken to better understand the evidence supporting the use of macrolides to prevent exacerbations in patients with bronchiectasis, and a benefit-to-risk analysis was performed to help guide clinicians on important pretreatment considerations.

Recent systematic reviews and meta-analyses of randomized controlled trials confirm the benefit of long-term macrolide therapy in reducing the frequency of exacerbations in stable adult bronchiectasis, which is likely leading to their increased use in clinical practice., In practice, our UK audits show that about 20% of these patients are receiving long-term macrolides, while in a multinational cohort in Europe, approximately one-third of patients with bronchiectasis are treated with long-term macrolides.,, In the United States, the current rates are not known. As the use of macrolides increases, it is important to ensure that clinicians understand and weigh the benefits and risks before initiating therapy and subsequently monitor patients accordingly.

It is not known whether the beneficial effect of macrolides is due to their antiinflammatory properties or their antiinfective properties, or a combination. Data from the three largest adult studies, the Bronchiectasis and Low-Dose Erythromycin Study (BLESS), which used long-term erythromycin ethylsuccinate 400 mg twice daily for 48 weeks; the Bronchiectasis and Long-Term Azithromycin Treatment (BAT) trial, which used azithromycin 250 mg daily for 12 months; and the Effectiveness of Macrolides in Patients with Bronchiectasis Using Azithromycin to Control Exacerbations (EMBRACE) trial, which used azithromycin 500 mg three times weekly for 6 months, showed no consistent clinical benefit on markers of airway or systemic inflammation.,, Meta-analyses showed that there was a trend toward increased eradication of pathogens with macrolide therapy, but this did not reach statistical significance (P = .06 and P = .09, respectively)., There are no data on bacterial load in these macrolide studies. Overall, it is likely that the beneficial effects of macrolides are a combination of antiinfective and antiinflammatory properties.

Although pooling the long-term macrolide data has been useful, we have to be cautious with our interpretation. The recent meta-analyses of randomized controlled trials use varying macrolides (azithromycin, erythromycin, clarithromycin, and roxithromycin), different populations (pediatric and adult studies), treatment durations ranging from 8 weeks to 24 months, and overall a small number of patients for a meta-analysis (n = 530 and n = 601 patients, respectively)., More than 50% of the evidence is derived from the three largest studies: BLESS (n = 177), BAT (n = 89) and EMBRACE (n = 141). Given the importance of these studies, their design and population are summarized in Table 1, and their individual outcomes are shown in Table 2 for comparison purposes.

Table Graphic Jump Location
Table 1 Comparison of Design and Baseline Patient Demographics and Characteristics in the Three Largest Studies of Macrolide Therapy in Bronchiectasis

BAT = Bronchiectasis and Long-Term Azithromycin Treatment; BLESS = Bronchiectasis and Low-Dose Erythromycin Study; EMBRACE = Effectiveness of Macrolides in Patients with Bronchiectasis Using Azithromycin to Control Exacerbations.

Table Graphic Jump Location
Table 2 Comparison of Clinical Outcomes in the Three Largest Studies of Macrolide Therapy in Bronchiectasis
a Postbronchodilator FEV1 % predicted, mean (SD).
b Postbronchodilator FEV1 difference 0.07 L (95% CI, –0.03 to 0.15).
c Postbronchodilator FEV1 difference 0.07 L (95% CI, –0.01 to 0.15).

NR = not reported; NS = not significant; SGRQ = St. George’s Respiratory Questionnaire. See Table 1 legend for expansion of other abbreviations.

Reducing exacerbations is a key end point and has been a consistent finding between studies (Table 2). Wu et al concluded that long-term macrolide use significantly reduced the risk of exacerbations (number of participants with exacerbations: relative risk, 0.70; 95% CI, 0.60-0.82; P < .00001; reduced average exacerbations per participant: weighted mean difference, −1.01; 95% CI, −1.35 to −0.67; P < .00001). Fan et al showed that macrolides significantly reduced acute exacerbations in patients during follow-up treatment (relative risk, 0.55; 95% CI, 0.47-0.64; P < .001), increasing the number of patients free of exacerbations (OR, 2.81; 95% CI, 1.85-4.26; P < .001), and prolonged the time to a first exacerbation (hazard ratio, 0.38; 95% CI, 0.28-0.53; P < .001). The macrolide-treated arm had fewer patients with three or more exacerbations and more patients with no exacerbations. Three or more exacerbations have been shown to be a prognostic marker for poor outcomes in the bronchiectasis severity index scoring system and are associated with both hospitalization and mortality. Macrolides, when used long-term, are to date the only agents that have been proven in randomized double-blind, placebo-controlled trials to reduce exacerbations in bronchiectasis.

The meta-analysis reported that macrolide maintenance treatment was superior to placebo or usual medical care with respect to attenuating a decline in FEV1 (mean weighted difference, 0.02 L; 95% CI, 0.00-0.04; P = .01). Although statistically significant, the attenuation is unlikely to be clinically relevant, as a mean weighted difference of 0.02 L is very small and based on a heavily weighted (91.9%) open-label prospective study of 30 patients randomized to azithromycin 250 mg three times per week (n = 16) vs a control population (n = 14) for 3 months.

The meta-analysis showed improved health-related quality of life: the St. George's Respiratory Questionnaire total scores improved with a weighted mean difference of −5.39 points (95% CI, −9.89 to −0.88; P = .02)., A four-point improvement in bronchiectasis is clinically significant, so the mean difference of −5.39 is important. One caveat to this is that there was a wide CI around this improvement, which was likely attributable to the 12-point improvement observed at 3 months in the 30-patient study noted earlier. A statistically significant finding was not observed in EMBRACE at 6 months or 1 year nor in BLESS at 48 weeks; a statistically significant finding was observed in BAT at 1 year but not at 6 months. Additional research on the impact of long-term macrolide use on health-related quality of life is required.

The macrolide studies show clear evidence of reduced exacerbations, which is important to achieve in bronchiectasis. Nevertheless, before embarking on long-term macrolide therapy, the benefit-to-risk ratio needs careful consideration. A variety of risks, including adverse events (in particular ototoxicity, cardiovascular effects, and ecological impact on bacteria), and other considerations such as drug-drug interactions and the optimal drug dose and duration of therapy are all factors that need to be considered on an individualized basis for each patient before initiating therapy (Table 3).

Table Graphic Jump Location
Table 3 Long-Term Macrolide Therapy Risk Analysis and Pretreatment Considerations

ECG = electrocardiogram; NTM = mycobacterial infection; QTc = corrected Q-T interval.

The risk of adverse events, in particular diarrhea (OR,5.36; 95% CI, 2.06-13.98; P = .0006) was higher in the macrolide-treated group in the meta-analyses., There were no significant differences in nausea or vomiting, epigastric discomfort, headache, sinusitis, or drug rash. Participant withdrawal due to adverse events showed no significant differences between the two groups. Although there are increased gastrointestinal side effects, none of the studies to date show this leads to patients with bronchiectasis being unable to tolerate long-term treatment (6-12 months’ duration).

Hearing and balance are important to consider, as the majority of eligible patients will be middle-aged or elderly. Adverse events associated with auditory deficits have not been investigated in patients with bronchiectasis but have been studied to some depth in patients with COPD (azithromycin 250 mg daily for 1 year, with audiometry at baseline and 3 and 12 months). Hearing decrements were more common in the azithromycin-treated group than in the placebo-treated group (25% vs 20%, respectively; P = .04). Documentation of any pretreatment hearing decrements is therefore important, and if indicated, clinicians should consider ordering audiometric testing before starting therapy. All patients should be warned about possible hearing loss, and audiometry should be carried out if the patient reports deterioration in hearing.

Potential cardiovascular effects also exist. In a 2012 observational study involving Tennessee Medicaid patients, the authors found that the use of azithromycin vs amoxicillin increased all-cause and cardiovascular deaths in the 5 days of antibiotic treatment, with the highest risk of death seen in patients with the highest risk for cardiovascular disease. A second study found that patients who received clarithromycin for community-acquired pneumonia exacerbations in the hospital had increased cardiovascular events, but there was no effect on mortality at 1 year. The risk of cardiovascular events has not been studied in detail in patients with bronchiectasis, but there was no prolongation of the QTc interval in the BLESS trial. The potential cardiovascular impact of macrolide use should be evaluated and monitored. A baseline electrocardiogram (ECG) to exclude QTc prolongation is recommended prior to initiation of long-term macrolide therapy, and if QTc prolongation is present, macrolides should be used with caution. In addition, concomitant medication that is associated with prolongation of the QTc should be avoided. In practice, the ECG is not repeated unless clinically indicated.

The ecological impact of macrolides on the resistance of common respiratory pathogens such as Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and nontuberculous mycobacteria (NTM), as well as the overall impact on the microbiome, are important factors to consider when prescribing long-term macrolide treatment. An increased risk of the development of macrolide-resistant Streptococcus pneumoniae, Staphylococcus aureus, and H influenzae related to long-term macrolide use has been reported (OR, 16.83; 95% CI, 7.26-38.99; P < .001). Despite this, the studies to date show no negative consequences, for example, no increased exacerbations, increased use of IV antibiotics, or increased hospitalization. However, studies may be too small to detect these types of outcomes, and long-term studies addressing this issue are needed.

There is concern about the relationship of long-term macrolide monotherapy and environmental NTM infection and resistance. A meta-analysis revealed that about 9% of patients with bronchiectasis have NTM, but much higher figures (33%) have been identified from the American Bronchiectasis Registry.,An in vivo study showed that macrolides impair autophagy, which is essential in clearance of NTM. Therefore, long-term macrolide use may be a potential risk factor for the development of NTM, but further studies are needed to confirm or confute this theory. More importantly, macrolides as part of a multidrug regimen, remain one of the key therapies for treating established NTM infection; macrolide sensitivity is the only positive predictor of NTM treatment success. If NTM is present when macrolide monotherapy is initiated or is acquired during long-term treatment, there is a high likelihood that macrolide-resistant NTM would occur, making treatment of such infections more challenging. It is essential that NTM infection is excluded in patients being considered for long-term macrolide therapy, the minimum being one negative mycobacterial culture result before initiating macrolide therapy. At least one spontaneous sputum sample should be sent for culture, or if this is not possible, induced sputum (through 3%-7% hypertonic saline) or BAL should be used (Table 3).

There is also concern that macrolides may affect the normal microbiome and promote the development of colonization with Pseudomonas aeruginosa, but long-term studies are needed to explore this further. Such an effect was shown in the BLESS trial of 1-year therapy with erythromycin in patients with bronchiectasis., In patients with baseline airway infection dominated by P. 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, with a reduced median interquartile range relative abundance of H. 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 = .04) and an increased median interquartile range 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 = .002). More research to confirm or refute this finding is required.

Important considerations when initiating macrolide therapy are choice of drug, drug regimen, treatment duration, and whether the drug might interact with other concomitant medications. For example, in patients receiving concomitant statin drugs, it is important to prescribe a statin that macrolides do not interact with, for example, pravastatin, fluvastatin, or rosuvastatin.

The principal positive trials in adults have used azithromycin 500 mg three times weekly for 6 months, azithromycin 250 mg daily for 1 year, and erythromycin ethylsuccinate 400 mg twice daily for 1 year. UK Bronchiectasis National Audit data indicate that azithromycin seems to be the preferred agent,, the three times weekly regimen is popular with patients, and azithromycin has been traditionally known for less gastrointestinal intolerance compared with erythromycin.

The optimal length of macrolide therapy is not known, but treatment may be needed long-term for continued efficacy. Further research is needed to ascertain whether efficacy decreases over time. Depending on the individual patient’s needs, and if there is a seasonal element to exacerbation frequency, one strategy is to prescribe macrolides over the worst months for bronchiectasis exacerbations followed by a drug-free period for the months of the year with the lowest frequency of exacerbations.

Clear evidence on which to base decisions about which patients should be selected for macrolide therapy is lacking, but there is strong support for selecting patients with three or more exacerbations in the past year despite chest clearance., In the EMBRACE trial, patients had a mean of 3.34 to 3.93 exacerbations in the year prior to study entry, the BAT trial had a median of four to five exacerbations in the year prior to study entry, and in the BLESS trial, 34.5% to 37.3% of subjects had five or more exacerbations in the preceding year (Table 1).,, Efficacy was observed in patients with and those without pathogens at baseline as well as those infected with P. aeruginosa or other potential pathogenic organisms.

There remains controversy when instituting long-term antibiotics about whether a macrolide, an inhaled antibiotic, or a combination of both should be chosen to reduce the risk of exacerbations. Even though there are no inhaled antibiotics licensed for reducing exacerbations in patients with bronchiectasis, use in UK and European cohorts varies between 7% and 10% of patients (US rates have not been reported)., Inhaled antibiotic therapy has the benefit of targeting therapy to the site of infection. In addition, it allows higher concentrations of antibiotics in comparison with IV antibiotic therapy and may therefore work in patients with apparent resistance patterns seen from in vitro sensitivity testing.,, Two published studies of IV formulations prepared for inhalation support the hypothesis for their use and showed a reduction in exacerbations as well as improvements in other clinical end points., Treatment for 6 months or longer showed that inhaled colistin 1 mU twice daily for 6 months continuously in patients chronically infected with P. aeruginosa prolonged the time to the next exacerbation in patients who adhered to their therapy 80% of the time or more. In a single-blind study, long-term nebulized gentamicin over 1 year (80 mg twice daily) in patients chronically infected with any potential pathogenic organism and having two or more exacerbations annually improved time to the next exacerbation and reduced overall exacerbations. There was also improved bacterial clearance, sputum color, health-related quality of life, and exercise tolerance., However, a benefit-to-risk assessment is required, and side effects include bronchospasm, which occurs in about 10% of patients treated with inhaled aminoglycosides despite a negative challenge test to the inhaled antibiotic. Another issue is the high cost of inhaled antibiotics vs macrolide therapy. Macrolide therapy also has the benefit of ease of administration.,,,, There is no evidence to date about the safety and efficacy of combined macrolide and inhaled antibiotics, although combination therapy is common in patients with cystic fibrosis and chronic P. aeruginosa infection. More research is needed to understand the benefit-risk ratio of each of these treatment approaches before recommendations for appropriate use can be given.

Long-term macrolide use should be considered in patients with bronchiectasis and three or more exacerbations per year in whom airway clearance has already been optimized. The benefits and risks need to be explained to patients. Further work is needed to understand the optimal drug, dose, and regimen; the mechanisms behind these benefits; appropriate patient selection; sustainability of efficacy; potential long-term risks to the lung microbiome; and their place with or without inhaled antibiotic treatment.

Financial/nonfinancial disclosures: None declared.

Other contributions: The author would like to acknowledge Highfield Communication, Oxford, England for providing medical writing and editorial support with funding from Bayer Pharma AG.

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Angrill J. .Agusti C. .De Celis R. .et al Bronchial inflammation and colonization in patients with clinically stable bronchiectasis. Am J Respir Crit Care Med. 2001;164:1628-1632 [PubMed]journal. [CrossRef] [PubMed]
 
Chalmers J.D. .Smith M.P. .McHugh B.J. .Doherty C. .Govan J.R. .Hill A.T. . Short- and long-term antibiotic treatment reduces airway and systemic inflammation in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2012;186:657-665 [PubMed]journal. [CrossRef] [PubMed]
 
Mandal P. .Chalmers J.D. .Graham C. .et al Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial. Lancet Respir Med. 2014;2:455-463 [PubMed]journal. [CrossRef] [PubMed]
 
Murray M.P. .Govan J.R. .Doherty C.J. .et al A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2011;183:491-499 [PubMed]journal. [CrossRef] [PubMed]
 
Fan L.C. .Lu H.W. .Wei P. .Ji X.B. .Liang S. .Xu J.F. . Effects of long-term use of macrolides in patients with non-cystic fibrosis bronchiectasis: a meta-analysis of randomized controlled trials. BMC Infect Dis. 2015;15:160- [PubMed]journal. [CrossRef] [PubMed]
 
Wu Q. .Shen W. .Cheng H. .Zhou X. . Long-term macrolides for non-cystic fibrosis bronchiectasis: a systematic review and meta-analysis. Respirology. 2014;19:321-329 [PubMed]journal. [CrossRef] [PubMed]
 
Hill A.T. .Welham S. .Reid K. .Bucknall C.E. . British Thoracic Society national bronchiectasis audit 2010 and 2011. Thorax. 2012;67:928-930 [PubMed]journal. [CrossRef] [PubMed]
 
Hill A.T. .Routh C. .Welham S. . National BTS bronchiectasis audit 2012: is the quality standard being adhered to in adult secondary care? Thorax. 2014;69:292-294 [PubMed]journal. [CrossRef] [PubMed]
 
Aliberti S. .Lonni S. .Dore S. .et al Clinical phenotypes in adult patients with bronchiectasis. Eur Respir J. 2016;47:1113-1122 [PubMed]journal. [CrossRef] [PubMed]
 
Serisier D.J. .Martin M.L. .McGuckin M.A. .et al Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial. JAMA. 2013;309:1260-1267 [PubMed]journal. [CrossRef] [PubMed]
 
Altenburg J. .de Graaff C.S. .Stienstra Y. .et al Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA. 2013;309:1251-1259 [PubMed]journal. [CrossRef] [PubMed]
 
Wong C. .Jayaram L. .Karalus N. .et al Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380:660-667 [PubMed]journal. [CrossRef] [PubMed]
 
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Figures

Tables

Table Graphic Jump Location
Table 1 Comparison of Design and Baseline Patient Demographics and Characteristics in the Three Largest Studies of Macrolide Therapy in Bronchiectasis

BAT = Bronchiectasis and Long-Term Azithromycin Treatment; BLESS = Bronchiectasis and Low-Dose Erythromycin Study; EMBRACE = Effectiveness of Macrolides in Patients with Bronchiectasis Using Azithromycin to Control Exacerbations.

Table Graphic Jump Location
Table 2 Comparison of Clinical Outcomes in the Three Largest Studies of Macrolide Therapy in Bronchiectasis
a Postbronchodilator FEV1 % predicted, mean (SD).
b Postbronchodilator FEV1 difference 0.07 L (95% CI, –0.03 to 0.15).
c Postbronchodilator FEV1 difference 0.07 L (95% CI, –0.01 to 0.15).

NR = not reported; NS = not significant; SGRQ = St. George’s Respiratory Questionnaire. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
Table 3 Long-Term Macrolide Therapy Risk Analysis and Pretreatment Considerations

ECG = electrocardiogram; NTM = mycobacterial infection; QTc = corrected Q-T interval.

References

Wilson C.B. .Jones P.W. .O'Leary C.J. .Cole P.J. .Wilson R. . Validation of the St. George's Respiratory Questionnaire in bronchiectasis. Am J Respir Crit Care Med. 1997;156:536-541 [PubMed]journal. [CrossRef] [PubMed]
 
Angrill J. .Agusti C. .De Celis R. .et al Bronchial inflammation and colonization in patients with clinically stable bronchiectasis. Am J Respir Crit Care Med. 2001;164:1628-1632 [PubMed]journal. [CrossRef] [PubMed]
 
Chalmers J.D. .Smith M.P. .McHugh B.J. .Doherty C. .Govan J.R. .Hill A.T. . Short- and long-term antibiotic treatment reduces airway and systemic inflammation in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2012;186:657-665 [PubMed]journal. [CrossRef] [PubMed]
 
Mandal P. .Chalmers J.D. .Graham C. .et al Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial. Lancet Respir Med. 2014;2:455-463 [PubMed]journal. [CrossRef] [PubMed]
 
Murray M.P. .Govan J.R. .Doherty C.J. .et al A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2011;183:491-499 [PubMed]journal. [CrossRef] [PubMed]
 
Fan L.C. .Lu H.W. .Wei P. .Ji X.B. .Liang S. .Xu J.F. . Effects of long-term use of macrolides in patients with non-cystic fibrosis bronchiectasis: a meta-analysis of randomized controlled trials. BMC Infect Dis. 2015;15:160- [PubMed]journal. [CrossRef] [PubMed]
 
Wu Q. .Shen W. .Cheng H. .Zhou X. . Long-term macrolides for non-cystic fibrosis bronchiectasis: a systematic review and meta-analysis. Respirology. 2014;19:321-329 [PubMed]journal. [CrossRef] [PubMed]
 
Hill A.T. .Welham S. .Reid K. .Bucknall C.E. . British Thoracic Society national bronchiectasis audit 2010 and 2011. Thorax. 2012;67:928-930 [PubMed]journal. [CrossRef] [PubMed]
 
Hill A.T. .Routh C. .Welham S. . National BTS bronchiectasis audit 2012: is the quality standard being adhered to in adult secondary care? Thorax. 2014;69:292-294 [PubMed]journal. [CrossRef] [PubMed]
 
Aliberti S. .Lonni S. .Dore S. .et al Clinical phenotypes in adult patients with bronchiectasis. Eur Respir J. 2016;47:1113-1122 [PubMed]journal. [CrossRef] [PubMed]
 
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