August 2014 Phoenix Pulmonary Journal Club: The Use of Macrolide Antibiotics in Chronic Respiratory Disease

This month's journal club reviewed  the role of macrolide antibiotics in chronic respiratory disease. Macrolide usage was suggested from observational studies in Japan in diffuse panbroncholitis, a disorder associated with chronic respiratory infection, usually Pseudomonas aeruginosa (1). Clinical improvement was noted despite doses of antibiotics well below the minimal inhibitory concentration (MIC) of the antibiotic. This  suggested the antibiotic was likely working by an anti-inflammatory effect. These observations were extended to cystic fibrosis (CF) where prophylactic macrolide therapy in CF patients infected with Pseudomonas has become standard therapy (2). More recently, low dose macrolide therapy has been applied to non-CF lung diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis and asthma.

Time did not permit a review of all studies so a representative sample was discussed. In patients with COPD, the four randomized, placebo-controlled trials reviewed all suggested that chronic therapy with macrolide antibiotics reduced COPD exacerbations (3-5). This beneficial effect was confirmed by 2 recent meta-analysis (6,7). Similarly,  three recent randomized trials in bronchiectasis demonstrated a reduction in exacerbations (8-10). In asthma the data is not as clear. A recent trial did not demonstrate an overall reduction in asthma exacerbations or lower respiratory tract infections (11). However, in the patients with non-eosinophilic, predominantly neutrophilic, asthma there was a reduction.  An excellent review of the use of macrolides in acute and chronic asthma was recently published. (12). The article includes a review of the anti-inflammatory and immunomodulatory properties of the macrolides.

The respiratory disorders where macrolides have been shown to have clinic benefit such as diffuse panbroncholitis, cystic fibrosis, COPD, bronchiectasis and non-eosinophilic asthma are all diseases associated an influx of neutrophils into the airways. The beneficial clinic effects of macrolides are consistent with their effect in reducing neutrophil chemotactic factors such as interleukin (IL)-8 (13). However, macrolides have also been reported to have adverse clinical effects such as QT prolongation in patients with heart disease, impaired hearing and development of bacterial resistance (4,6,14). Whether all COPD patients should be treated with macrolides is controversial but most in the audience used these in patients with frequent exacerbations. It was also pointed out that other antibiotics such as the tetracyclines also have anti-inflammatory effects and have been shown to be efficacious in some respiratory diseases (15). Whether the tetracyclines are equally or more effective than the macrolides with fewer serious side effects is unknown.

Richard A. Robbins, MD¹

Allen R. Thomas, MD²

Manoj Mathew, MD³

¹Phoenix Pulmonary and Critical Care Research Foundation, ²Phoenix VA Medical Center, ³Banner Good Samaritan Medical Center.

References

1. Nagai H, Shishido H, Yoneda R, Yamaguchi E, Tamura A, Kurashima A. Long-term low-dose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration. 1991;58(3-4):145-9. [CrossRef] [PubMed] 
2. Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY, Accurso FJ, Campbell PW 3rd; Macrolide Study Group. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290(13):1749-56. [CrossRef] [PubMed]
3. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178(11):1139-47. [CrossRef] [PubMed]
4. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. [CrossRef] [PubMed]
5. Uzun S, Djamin RS, Kluytmans JA, Mulder PG, van't Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2(5):361-8. [CrossRef] [PubMed]
6. Li H, Liu DH, Chen LL, Zhao Q, Yu YZ, Ding JJ, Miao LY, Xiao YL, Cai HR, Zhang DP, Guo YB, Xie CM. Meta-analysis of the adverse effects of long-term azithromycin use in patients with chronic lung diseases. Antimicrob Agents Chemother. 2014;58(1):511-7. [CrossRef] [PubMed]
7. Herath SC, Poole P. Prophylactic antibiotic therapy in chronic obstructive pulmonary disease. JAMA. 2014;311(21):2225-6. [CrossRef] [PubMed]
8. Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, Milne D, Fergusson W, Tuffery C, Sexton P, Storey L, Ashton T. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):660-7. [CrossRef]  [PubMed]
9. Altenburg J, de Graaff CS, Stienstra Y, Sloos JH, van Haren EH, Koppers RJ, van der Werf TS, Boersma WG. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA. 2013;309(12):1251-9. [CrossRef] [PubMed] 
10. Serisier DJ, Martin ML, McGuckin MA, Lourie R, Chen AC, Brain B, Biga S, Schlebusch S, Dash P, 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(12):1260-7. [CrossRef] [PubMed]
11. Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, Verleden G, Demedts IK, Verhamme K, Delporte A, Demeyere B, Claeys G, Boelens J, Padalko E, Verschakelen J, Van Maele G, Deschepper E, Joos GF. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013 Apr;68(4):322-9. [CrossRef] [PubMed] 
12. Wong EH, Porter JD, Edwards MR, Johnston SL. The role of macrolides in asthma: current evidence and future directions.  Lancet Respir Med. 2014 2:657-70. [CrossRef] [PubMed]
13. Abe S, Nakamura H, Inoue S, Takeda H, Saito H, Kato S, Mukaida N, Matsushima K, Tomoike H. Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 2000;22(1):51-60. [CrossRef] [PubMed] 
14. Albert RK, Schuller JL; COPD Clinical Research Network. Macrolide antibiotics and the risk of cardiac arrhythmias. Am J Respir Crit Care Med. 2014;189(10):1173-80. [CrossRef] [PubMed] 
15. Rempe S, Hayden JM, Robbins RA, Hoyt JC. Tetracyclines and pulmonary inflammation. Endocr Metab Immune Disord Drug Targets. 2007;7(4):232-6. [CrossRef] [PubMed] 

Reference as: Robbins RA, Thomas AR, Mathew M. August 2014 Phoenix pulmonary journal club: the use of macrolide antibiotics in chronic respiratory disease. Southwest J Pulm Crit Care. 2014;9(2):130-2. doi: http://dx.doi.org/10.13175/swjpcc109-14 PDF

March 2012 Pulmonary Journal Club

Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-98. (Click here for full text of article)

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of morbidity and the major cost of COPD care. Chronic use of macrolide antibiotics have been shown to benefit patients with cystic fibrosis, bronchiectasis and COPD by preventing exacerbations presumably by their anti-inflammatory rather than their antibiotic effects. Albert et al. performed a randomized, placebo-controlled, double-blinded trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD. A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. Azithromycin improved the median time to the first exacerbation (266 days vs.174 days, p<0.001); the frequency of exacerbations was (1.48 vs. 1.83 per patient-year, p= 0.01); scores on the St. George’s Respiratory Questionnaire (2.8±12.8 vs.0.6±11.4, p = 0.004); and the percentage of participants with more than the minimal clinically important difference of −4 units (43% vs. 36% p= 0.03). Hearing decrements were slightly more common in the azithromycin group than in the placebo group (25% vs. 20%, p = 0.04). Colonization with respiratory pathogens was lower in the azithromycin group (12 vs. 31%, p<0.001) although when present colonization with macrolide resistant organisms was more frequent (81 vs. 41%, p<0.001). Mortality was low and did not differ between the groups.

This study confirms a previous study by Seemungal et al. (1) who also performed a randomized, double-blind, placebo-controlled study of another macrolide, erythromycin, administered at 250 mg twice daily to 109 patients with COPD over 12 months. Exacerbations for the erythromycin-treated patients were reduced compared with placebo-treated patients (p<0.003). These two well done, randomized studies lend strong support to chronic use of macrolide antibiotics in COPD. In both studies complications were low and antibiotic resistance remained mostly a laboratory observation rather than a clinical problem. Details such as the optimal doses and frequency of antibiotic administration will need further investigation. Other antibiotics such as the tetracyclines also have anti-inflammatory effects and may be alternatives to macrolides (2). It now seems that the concept of chronic use of some antibiotics as anti-inflammatories is well established in respiratory disease and I would urge consideration of their usage in patients who have had or are likely to have a COPD exacerbation.

Richard A. Robbins, M.D.

Editor, Southwest Journal of Pulmonary and Critical Care

 References

1. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008;178:1139-47.
2. Rempe S, Hayden JM, Robbins RA Hoyt JC. Tetracyclines and pulmonary Inflammation. Endocrine, Metabolic & Immune Disorders - Drug Targets 2007;4:232-6.

Reference as: Robbins RA. March 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;4:78-9. (Click here for a PDF version of the journal club)