Macrolides for the Treatment and Prevention of BOS

  • Robin VosEmail author
  • Stijn E. Verleden
  • David Ruttens
  • Bart M. Vanaudenaerde
  • Geert M. Verleden
Part of the Respiratory Medicine book series (RM, volume 8)


Chronic lung allograft rejection or its clinical correlate, the bronchiolitis obliterans syndrome (BOS), characterized by a persistent decline in forced expiratory volume in 1 s (FEV1) from an established baseline, is the single most important cause of death in lung transplant recipients after the first postoperative year. BOS is thought to be the final common endpoint of various injuries to the pulmonary allograft, triggering different innate and adaptive immune responses. Most preventive and therapeutic strategies for BOS have thus far been largely unsuccessful. However, the introduction of macrolide antibiotics, such as clarithromycin or particularly azithromycin (AZI), in the field of lung transplantation (LTx) as of 2003 made it clear that some patients with established BOS might in fact benefit from such therapy due to its various anti-inflammatory and immunomodulatory properties, as summarized in this chapter. Particularly in patients with an increased bronchoalveolar lavage (BAL) neutrophilia, AZI treatment could result in an increase in FEV1 of at least 10 %. More recently, it has become clear that prophylactic therapy with AZI actually may prevent BOS and improve FEV1 after LTx. However, one should always be aware of possible adverse effects related to AZI when implementing this drug as prophylactic or long-term treatment. Even so, AZI therapy after LTx can generally be considered as safe.


Azithromycin Bronchiolitis obliterans syndrome Chronic lung allograft rejection Macrolide Lung transplantation Obliterative bronchiolitis 



G.M.V. is holder of the Glaxo Smith Kline (Belgium) chair in respiratory pharmacology at the KULeuven and is supported by the Research Foundation Flanders (FWO): G.0643.08 and G.0723.10 and Onderzoeksfonds KULeuven (OT/10/050). B.M.V., DEVR, and LJD are senior research fellows of the Research Foundation Flanders (FWO G.0518.06, G.0643.08, G.0723.10)

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript.


  1. 1.
    Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz M, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant. 2002;21: 297–310.PubMedCrossRefGoogle Scholar
  2. 2.
    Hagedorn PH, Burton CM, Carlsen J, Steinbrüchel D, Andersen CB, Sahar E, et al. Chronic rejection of a lung transplant is characterized by a profile of specific autoantibodies. Immunology. 2010;130(3):427–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Sharples LD, McNeil K, Stewart S, Wallwork J. Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant. 2002;21(2):271–81.PubMedCrossRefGoogle Scholar
  4. 4.
    Vos R, Vanaudenaerde BM, Geudens N, Dupont LJ, Van Raemdonck DE, Verleden GM. Pseudomonal airway colonisation: risk factor for bronchiolitis obliterans syndrome after lung transplantation? Eur Respir J. 2008;31:1037–45.PubMedCrossRefGoogle Scholar
  5. 5.
    Nawrot TS, Vos R, Jacobs L, Verleden SE, Wauters S, Mertens V, et al. The impact of traffic air pollution on chronic rejection and mortality after lung transplantation. Thorax. 2011;66(9):748–54.PubMedCrossRefGoogle Scholar
  6. 6.
    Blondeau K, Mertens V, Vanaudenaerde BA, Verleden GM, Van Raemdonck DE, Sifrim D, et al. Gastro-oesophageal reflux and gastric aspiration in lung transplant patients with or without chronic rejection. Eur Respir J. 2008;31(4):707–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Boehler A, Kesten S, Weder W, Speich R. Bronchiolitis obliterans after lung transplantation: a review. Chest. 1998;114(5):1411–26.PubMedCrossRefGoogle Scholar
  8. 8.
    Borthwick LA, McIlroy E, Gorowiec MR, Brodlie M, Johnson GE, Ward C, et al. Inflammation and epithelial to mesenchymal transition in lung transplant recipients: role in dysregulated epithelial wound repair. Am J Transplant. 2010;10(3):498–509.PubMedCrossRefGoogle Scholar
  9. 9.
    Vanaudenaerde BM, De Vleeschauwer SI, Vos R, Meyts I, Bullens DM, Reynders V, et al. The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant. 2008;8(9):1911–20.PubMedCrossRefGoogle Scholar
  10. 10.
    DiGiovine B, Lynch 3rd JP, Martinez FJ, Flint A, Whyte RI, Iannettoni MD, et al. Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8. J Immunol. 1996;157(9):4194–202.PubMedGoogle Scholar
  11. 11.
    Stewart S, Fishbein MC, Snell GI, Berry GJ, Boehler A, Burke MM, et al. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant. 2007;26(12):1229–42.PubMedCrossRefGoogle Scholar
  12. 12.
    Retsema J, Fu W. Macrolides: structures and microbial targets. Int J Antimicrob Agents. 2001;18(S1):S3–10.PubMedCrossRefGoogle Scholar
  13. 13.
    Kobayashi H, Ohgaki N, Takeda H. Therapeutic possibilities for diffuse panbronchiolitis. Int J Antimicrob Agents. 1993;3(S1):S81–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290(13):1749–56.PubMedCrossRefGoogle Scholar
  15. 15.
    Anwar GA, Bourke SC, Afolabi G, Middleton P, Ward C, Rutherford RM. Effects of long-term low-dose azithromycin in patients with non-CF bronchiectasis. Respir Med. 2008;102(10):1494–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Vos R, Vanaudenaerde BM, Dupont LJ, Van Raemdonck DE, Verleden GM. Transient airway colonization is associated with airway inflammation after lung transplantation. Am J Transplant. 2007;7:1278–87.PubMedCrossRefGoogle Scholar
  17. 17.
    Shinkai M, Henke MO, Rubin BK. Macrolide antibiotics as immunomodulatory medications: proposed mechanisms of action. Pharmacol Ther. 2008;117:393–405.PubMedCrossRefGoogle Scholar
  18. 18.
    Gielen V, Johnston SL, Edwards MR. Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur Respir J. 2010;36(3):646–54.PubMedCrossRefGoogle Scholar
  19. 19.
    Weinberg A, Lyu DM, Li S, Marquesen J, Zamora MR. Incidence and morbidity of human metapneumovirus and other community-acquired respiratory viruses in lung transplant recipients. Transpl Infect Dis. 2010;12(4):330–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Kai T, Tateda K, Kimura S, Ishii Y, Ito H, Yoshida H, et al. A low concentration of azithromycin inhibits the mRNA expression of N-acyl homoserine lactone synthesis enzymes, upstream of lasI or rhlI, in Pseudomonas aeruginosa. Pulm Pharmacol Ther. 2009;22(6):483–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Hoffmann N, Lee B, Hentzer M, Rasmussen TB, Song Z, Johansen HK, et al. Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(−/−) mice. Antimicrob Agents Chemother. 2007;51(10):3677–87.PubMedCrossRefGoogle Scholar
  22. 22.
    Sugimura M, Maseda H, Hanaki H, Nakae T. Macrolide antibiotic-mediated downregulation of MexAB-OprM efflux pump expression in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2008;52(11):4141–4.PubMedCrossRefGoogle Scholar
  23. 23.
    Kawamura-Sato K, Iinuma Y, Hasegawa T, Horii T, Yamashino T, Ohta M. Effect of subinhibitory concentrations of macrolides on expression of flagellin in Pseudomonas aeruginosa and Proteus mirabilis. Antimicrob Agents Chemother. 2000;44(10):2869–72.PubMedCrossRefGoogle Scholar
  24. 24.
    Halldorsson S, Gudjonsson T, Gottfredsson M, Singh PK, Gudmundsson GH, Baldursson O. Azithromycin maintains airway epithelial integrity during Pseudomonas aeruginosa infection. Am J Respir Cell Mol Biol. 2010;42(1):62–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Imamura Y, Yanagihara K, Mizuta Y, Seki M, Ohno H, Higashiyama Y, et al. Azithromycin inhibits MUC5AC production induced by the Pseudomonas aeruginosa autoinducer N-(3-Oxododecanoyl) homoserine lactone in NCI-H292 cells. Antimicrob Agents Chemother. 2004;48(9):3457–61.PubMedCrossRefGoogle Scholar
  26. 26.
    Murphy DM, Forrest IA, Corris PA, Johnson GE, Small T, Jones D, et al. Azithromycin attenuates effects of lipopolysaccharide on lung allograft bronchial epithelial cells. J Heart Lung Transplant. 2008;27(11):1210–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Ribeiro CM, Hurd H, Wu Y, Martino ME, Jones L, Brighton B, et al. Azithromycin treatment alters gene expression in inflammatory, lipid metabolism, and cell cycle pathways in well-differentiated human airway epithelia. PLoS One. 2009;4(6):e5806.PubMedCrossRefGoogle Scholar
  28. 28.
    Millrose M, Kruse M, Flick B, Stahlmann R. Effects of macrolides on proinflammatory epitopes on endothelial cells in vitro. Arch Toxicol. 2009;83(5):469–76.PubMedCrossRefGoogle Scholar
  29. 29.
    Khair OA, Devalia JL, Abdelaziz MM, Sapsford RJ, Davies RJ. Effect of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6, IL-8 and sICAM-1 by cultured human bronchial epithelial cells. Eur Respir J. 1995;8(9):1451–7.PubMedGoogle Scholar
  30. 30.
    Lin HC, Wang CH, Liu CY, Yu CT, Kuo HP. Erythromycin inhibits beta2-integrins (CD11b/CD18) expression, interleukin-8 release and intracellular oxidative metabolism in neutrophils. Respir Med. 2000;94(7):654–60.PubMedCrossRefGoogle Scholar
  31. 31.
    Vanaudenaerde BM, Wuyts WA, Geudens N, Dupont LJ, Schoofs K, Smeets S, et al. Macrolides inhibit IL17-induced IL8 and 8-isoprostane release from human airway smooth muscle cells. Am J Transplant. 2007;7(1):76–82.PubMedCrossRefGoogle Scholar
  32. 32.
    Willems-Widyastuti A, Vanaudenaerde BM, Vos R, Dilisen E, Verleden SE, De Vleeschauwer SI, et al. Azithromycin attenuates fibroblast growth factors induced vascular endothelial growth factor via p38(MAPK) signaling in human airway smooth muscle cells. Cell Biochem Biophys. 2011 Dec 29. [Epub ahead of print].Google Scholar
  33. 33.
    Daenas C, Hatziefthimiou AA, Gourgoulianis KI, Molyvdas PA. Azithromycin has a direct relaxant effect on precontracted airway smooth muscle. Eur J Pharmacol. 2006;553(1–3): 280–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Stamatiou R, Paraskeva E, Boukas K, Gourgoulianis KI, Molyvdas PA, Hatziefthimiou AA. Azithromycin has an antiproliferative and autophagic effect on airway smooth muscle cells. Eur Respir J. 2009;34(3):721–30.PubMedCrossRefGoogle Scholar
  35. 35.
    McDonald PJ, Pruul H. Phagocyte uptake and transport of azithromycin. Eur J Clin Microbiol Infect Dis. 1991;10(10):828–33.PubMedCrossRefGoogle Scholar
  36. 36.
    Idris S, Chilvers E, Haworth C, Mc Keon D, Condliffe A. Azithromycin therapy for neutrophilic airways disease: myth or magic? Thorax. 2009;64:186–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Meyer M, Huaux F, Gavilanes X, van den Brûle S, Lebecque P, Lo Re S, et al. Azithromycin reduces exagerated cytokine production by M1 alveolar macrophages in cystic fibrosis. Am J Respir Cell Mol Biol. 2009;41(5):590–602.PubMedCrossRefGoogle Scholar
  38. 38.
    Bosnar M, Cuzic S, Bosnjak B, Nujić K, Ergović G, Marjanović N, et al. Azithromycin inhibits macrophage interleukin-1β production through inhibition of AP-1 in lipopolysaccharide-induced murine pulmonary neutrophilia. Int Immunopharmacol. 2011;11(4):424–34.PubMedCrossRefGoogle Scholar
  39. 39.
    Hodge S, Hodge G, Jersmann H, Matthews G, Ahern J, Holmes M, et al. Azithromycin improves macrophage phagocytic function and expression of mannose receptor in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;178(2):139–48.PubMedCrossRefGoogle Scholar
  40. 40.
    Yamauchi K, Shibata Y, Kimura T, Abe S, Inoue S, Osaka D, et al. Azithromycin suppresses interleukin-12p40 expression in lipopolysaccharide and interferon-gamma stimulated macrophages. Int J Biol Sci. 2009;5(7):667–78.PubMedCrossRefGoogle Scholar
  41. 41.
    Murphy BS, Sundareshan V, Cory TJ, Hayes Jr D, Anstead MI, Feola DJ. Azithromycin alters macrophage phenotype. J Antimicrob Chemother. 2008;61(3):554–60.PubMedCrossRefGoogle Scholar
  42. 42.
    Wilms EB, Touw DJ, Heijerman HG. Pharmacokinetics of azithromycin in plasma, blood, polymorphonuclear neutrophils and sputum during long-term therapy in patients with cystic fibrosis. Ther Drug Monit. 2006;28(2):219–25.PubMedCrossRefGoogle Scholar
  43. 43.
    Miossec-Bartoli C, Pilatre L, Peyron P, N’Diaye EN, Collart-Dutilleul V, Maridonneau-Parini I, et al. The new ketolide HMR3647 accumulates in the azurophil granules of human polymorphonuclear cells. Antimicrob Agents Chemother. 1999;43(10):2457–62.PubMedGoogle Scholar
  44. 44.
    Tsai WC, Standiford TJ. Immunomodulatory effects of macrolides in the lung: lessons from in-vitro and in-vivo models. Curr Pharm Des. 2004;10(25):3081–93.PubMedCrossRefGoogle Scholar
  45. 45.
    Tamaoki J, Kadota J, Takizawa H. Clinical implications of the immunomodulatory effects of macrolides. Am J Med. 2004;117(9A):5S–11S.PubMedGoogle Scholar
  46. 46.
    Miyazaki M, Zaitsu M, Honjo K, Ishii E, Hamasaki Y. Macrolide antibiotics inhibit prostaglandin E2 synthesis and mRNA expression of prostaglandin synthetic enzymes in human leukocytes. Prostaglandins Leukot Essent Fatty Acids. 2003;69(4):229–35.PubMedCrossRefGoogle Scholar
  47. 47.
    Mizunoe S, Kadota J, Tokimatsu I, Kishi K, Nagai H, Nasu M. Clarithromycin and azithromycin induce apoptosis of activated lymphocytes via down-regulation of Bcl-xL. Int Immunopharmacol. 2004;4(9):1201–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Khan AA, Slifer TR, Araujo FG, Remington JS. Effect of clarithromycin and azithromycin on production of cytokines by human monocytes. Int J Antimicrob Agents. 1999;11(2):121–32.PubMedCrossRefGoogle Scholar
  49. 49.
    Stupin Polancec D, Munic VK, Banjanac M, Vrancic M, Cuzic S, Belamaric D, et al. Azithromycin drives in vitro GM-CSF/IL-4-induced differentiation of human blood monocytes toward dendritic-like cells with regulatory properties. J Leukoc Biol. 2012;91(2):229–43.CrossRefGoogle Scholar
  50. 50.
    Sugiyama K, Shirai R, Mukae H, Ishimoto H, Nagata T, Sakamoto N, et al. Differing effects of clarithromycin and azithromycin on cytokine production by murine dendritic cells. Clin Exp Immunol. 2007;147(3):540–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Iwamoto S, Kumamoto T, Azuma E, Hirayama M, Ito M, Amano K, et al. The effect of azithromycin on the maturation and function of murine bone marrow-derived dendritic cells. Clin Exp Immunol. 2011;166(3):385–92.PubMedCrossRefGoogle Scholar
  52. 52.
    Geudens N, Timmermans L, Vanhooren H, Vanaudenaerde BM, Vos R, Van De Wauwer C, et al. Azithromycin reduces airway inflammation in a murine model of lung ischaemia reperfusion injury. Transpl Int. 2008;21(7):688–95.PubMedCrossRefGoogle Scholar
  53. 53.
    Remund K, Rechsteiner T, Guo Z, Rentsch K, Boehler A. The macrolide clarithromycin inhibits experimental post-transplant bronchiolitis obliterans. Exp Lung Res. 2009;35(10): 830–40.PubMedCrossRefGoogle Scholar
  54. 54.
    Glojnaric I, Cuzic S, Erakovic-Haber V, Parnham MJ. The serum amyloid A response to sterile silver nitrate in mice and its inhibition by dexamethasone and macrolide antibiotics. Int Immunopharmacol. 2007;7(12):1544–51.PubMedCrossRefGoogle Scholar
  55. 55.
    Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax. 2002;57(3):212–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Verleden S, Vandooren J, Vos R, Willems S, Dupont LJ, Verleden GM, et al. Azithromycin decreases MMP-9 expression in the airways of lung transplant recipients. Transpl Immunol. 2011;25(2):159–62.PubMedCrossRefGoogle Scholar
  57. 57.
    Fietta AM, Meloni F. Lung transplantation: the role of azithromycin in the management of patients with bronchiolitis obliterans syndrome. Curr Med Chem. 2008;15(7):716–23.PubMedCrossRefGoogle Scholar
  58. 58.
    Frederica M, Nadia S, Monica M, Alessandro C, Tiberio O, Francesco B, et al. Clinical and immunological evaluation of 12-month azithromycin therapy in chronic lung allograft rejection. Clin Transplant. 2011;25(4):E381–9.CrossRefGoogle Scholar
  59. 59.
    Togami K, Chono S, Morimoto K. Distribution characteristics of clarithromycin and azithromycin, macrolide anti-microbial agents used for treatment of respiratory infections, in lung epithelial lining fluid and alveolar macrophages. Biopharm Drug Dispos. 2011;32(7):389–97.PubMedCrossRefGoogle Scholar
  60. 60.
    Zuckerman JM, Qamar F, Bono BR. Macrolides, ketolides, and glycylcyclines: azithromycin, clarithromycin, telithromycin, tigecycline. Infect Dis Clin North Am. 2009;23(4):997–1026, ix–x.Google Scholar
  61. 61.
    Beigelman A, Gunsten S, Mikols CL, Vidavsky I, Cannon CL, Brody SL, et al. Azithromycin attenuates airway inflammation in a noninfectious mouse model of allergic asthma. Chest. 2009;136(2):498–506.PubMedCrossRefGoogle Scholar
  62. 62.
    Martinez FJ, Curtis JL, Albert R. Role of macrolide therapy in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2008;3(3):331–50.PubMedGoogle Scholar
  63. 63.
    Sarahrudi K, Carretta A, Wisser W, Senbaklavaci O, Ploner M, Neuhauser P, et al. The value of switching from cyclosporine to tacrolimus in the treatment of refractory acute rejection and obliterative bronchiolitis after lung transplantation. Transpl Int. 2002;15(1):24–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med. 2003;168:121–5.PubMedCrossRefGoogle Scholar
  65. 65.
    Verleden GM, Dupont LJ. Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2004;77:1465–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Yates B, Murphy DM, Forrest IA, Ward C, Rutherford RM, Fisher AJ, et al. Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2005;172:772–5.PubMedCrossRefGoogle Scholar
  67. 67.
    Shitrit D, Bendayan D, Gidon S, Saute M, Bakal I, Kramer MR. Long-term azithromycin use for treatment of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant. 2005;24:1440–3.PubMedCrossRefGoogle Scholar
  68. 68.
    Verleden GM, Vanaudenaerde BM, Dupont LJ, Van Raemdonck DE. Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2006;174:566–70.PubMedCrossRefGoogle Scholar
  69. 69.
    Vos R, Vanaudenaerde BM, Ottevaere A, Verleden SE, De Vleeschauwer SI, Willems-Widyastuti A, et al. Long-term azithromycin for bronchiolitis obliterans syndrome: divide and conquer? J Heart Lung Transplant. 2010;29(12):1358–68.PubMedCrossRefGoogle Scholar
  70. 70.
    Porhownik NR, Batobara W, Kepron W, Unruh HW, Bshouty Z. Effect of maintenance azithromycin on established bronchiolitis obliterans syndrome in lung transplant patients. Can Respir J. 2008;15:199–202.PubMedGoogle Scholar
  71. 71.
    Gottlieb J, Szangolies J, Koehnlein T, Golpon H, Simon A, Welte T. Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2008;85: 36–41.PubMedCrossRefGoogle Scholar
  72. 72.
    Jain R, Hachem RR, Morrell MR, Trulock EP, Chakinala MM, Yusen RD, et al. Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2010;29(5):531–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Benden C, Boehler A. Long-term clarithromycin therapy in the management of lung transplant recipients. Transplantation. 2009;87(10):1538–40.PubMedCrossRefGoogle Scholar
  74. 74.
    Verleden GM, Dupont LJ, Vanhaecke J, Daenen W, Van Raemdonck DE. Effect of azithromycin on bronchiectasis and pulmonary function in a heart-lung transplant patient with severe chronic allograft dysfunction: a case report. J Heart Lung Transplant. 2005;24(8):1155–8.PubMedCrossRefGoogle Scholar
  75. 75.
    de Jongh PA, Vos R, Verleden GM, Vanaudenaerde BM, Verschakelen JA. Thin-section computed tomography findings before and after azithromycin treatment of neutrophilic reversible lung allograft dysfunction. Eur Radiol. 2011;21(12):2466–74.CrossRefGoogle Scholar
  76. 76.
    Verleden SE, Vos R, Mertens V, Willems-Widyastuti A, De Vleeschauwer SI, Dupont LJ, et al. Airway protein diversity in bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant. 2011;30(6):667–73.PubMedCrossRefGoogle Scholar
  77. 77.
    Mertens V, Blondeau K, Pauwels A, Farre R, Vanaudenaerde B, Vos R, et al. Azithromycin reduces gastroesophageal reflux and aspiration in lung transplant recipients. Dig Dis Sci. 2009;54(5):972–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Williams TJ, Verleden GM. Azithromycin: a plea for multicenter randomized studies in lung transplantation. Am J Respir Crit Care Med. 2005;172(6):657–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Corris PA, et al. Abstract presented at the 32nd Annual Meeting of the International Society for Heart and Lung Transplantation. Prague; 2012.Google Scholar
  80. 80.
    Vanaudenaerde BM, Vos R, Meyts I, Geudens N, De Wever W, Verbeken EK, et al. A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy. Eur Respir J. 2008;32(4):832–43.PubMedCrossRefGoogle Scholar
  81. 81.
    Vanaudenaerde BM, Vos R, Meyts I, De Vleeschauwer SI, Verleden SE, Widyastuti-Willems A, et al. Macrolide therapy targets a specific phenotype in respiratory medicine: from clinical experience to basic science and back. Inflamm Allergy Drug Targets. 2008;7(4):279–87.PubMedCrossRefGoogle Scholar
  82. 82.
    Vos R, Vanaudenaerde BM, Verleden SE, De Vleeschauwer SI, Willems-Widyastuti A, Van Raemdonck DE, et al. A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation. Eur Respir J. 2011;37(1):164–72.PubMedCrossRefGoogle Scholar
  83. 83.
    Dhillon GS, Valentine VG, Levitt J, Patel P, Gupta MR, Duncan SR, et al. Clarithromycin for prevention of bronchiolitis obliterans syndrome in lung allograft recipients. Clin Transplant. 2012;26:105–10.PubMedCrossRefGoogle Scholar
  84. 84.
    Brown BA, Griffith DE, Girard W, Levin J, Wallace Jr RJ. Relationship of adverse events to serum drug levels in patients receiving high-dose azithromycin for mycobacterial lung disease. Clin Infect Dis. 1997;24(5):958–64.PubMedCrossRefGoogle Scholar
  85. 85.
    Griffith DE, Brown BA, Girard WM, Griffith BE, Couch LA, Wallace Jr RJ. Azithromycin-containing regimens for treatment of Mycobacterium avium complex lung disease. Clin Infect Dis. 2001;32(11):1547–53.PubMedCrossRefGoogle Scholar
  86. 86.
    Rubinstein E. Comparative safety of the different macrolide. Int J Antimicrob Agents. 2001;18(1):71–6.CrossRefGoogle Scholar
  87. 87.
    Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20):1881–90.PubMedCrossRefGoogle Scholar
  88. 88.
    Westphal JF. Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol. 2000;50(4):285–95.PubMedCrossRefGoogle Scholar
  89. 89.
    Granowitz EV, Tabor KJ, Kirchhoffer JB. Potentially fatal interaction between azithromycin and disopyramide. Pacing Clin Electrophysiol. 2000;23(9):1433–5.PubMedCrossRefGoogle Scholar
  90. 90.
    Hickey AJ, Lu D, Ashley ED, Stout J. Inhaled azithromycin therapy. J Aerosol Med. 2006;19(1):54–60.PubMedCrossRefGoogle Scholar
  91. 91.
    Zhang Y, Wang X, Lin X, Liu X, Tian B, Tang X. High azithromycin loading powders for inhalation and their in vivo evaluation in rats. Int J Pharm. 2010;395(1–2):205–14.PubMedGoogle Scholar
  92. 92.
    Malhotra-Kumar S, Lammens C, Coenen S, Van Herck K, Goossens H. Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study. Lancet. 2007; 369(9560):482–90.PubMedCrossRefGoogle Scholar
  93. 93.
    Tait-Kamradt A, Clancy J, Cronan M, Dib-Hajj F, Wondrack L, Yuan W, et al. mefE is necessary for the erythromycin-resistant M phenotype in Streptococcus pneumoniae. Antimicrob Agents Chemother. 1997;41(10):2251–5.PubMedGoogle Scholar
  94. 94.
    Vanhoof R, Camps K, Carpentier M, De Craeye S, Frans J, Glupczynski Y, et al. 10th survey of antimicrobial resistance in noninvasive clinical isolates of Streptococcus pneumoniae collected in Belgium during winter 2007–2008. Pathol Biol. 2010;58(2):147–51.PubMedCrossRefGoogle Scholar
  95. 95.
    Tramper-Stranders GA, Wolfs TF, Fleer A, Kimpen JL, van der Ent CK. Maintenance azithromycin treatment in pediatric patients with cystic fibrosis: long-term outcomes related to macrolide resistance and pulmonary function. Pediatr Infect Dis J. 2007;26(1):8–12.PubMedCrossRefGoogle Scholar
  96. 96.
    Phaff SJ, Tiddens HA, Verbrugh HA, Ott A. Macrolide resistance of Staphylococcus aureus and Haemophilus species associated with long-term azithromycin use in cystic fibrosis. J Antimicrob Chemother. 2006;57(4):741–6.PubMedCrossRefGoogle Scholar
  97. 97.
    Gillis RJ, White KG, Choi KH, Wagner VE, Schweizer HP, Iglewski BH. Molecular basis of azithromycin-resistant Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother. 2005;49(9):3858–67.PubMedCrossRefGoogle Scholar
  98. 98.
    Stover DE, Mangino D. Macrolides: a treatment alternative for bronchiolitis obliterans organizing pneumonia? Chest. 2005;128(5):3611–7.PubMedCrossRefGoogle Scholar
  99. 99.
    Mann JM, Sha KK, Kline G, Breuer FU, Miller A. World Trade Center dyspnea: bronchiolitis obliterans with functional improvement: a case report. Am J Ind Med. 2005;48(3):225–9.PubMedCrossRefGoogle Scholar
  100. 100.
    Khalid M, Al Saghir A, Saleemi S, Al Dammas S, Zeitouni M, Al Mobeireek A, et al. Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study. Eur Respir J. 2005;25(3):490–3.PubMedCrossRefGoogle Scholar
  101. 101.
    Wuyts WA, Willems S, Vos R, Vanaudenaerde BM, De Vleeschauwer SI, Rinaldi M, et al. Azithromycin reduces pulmonary fibrosis in a bleomycin mouse model. Exp Lung Res. 2010;36(10):602–14.PubMedCrossRefGoogle Scholar
  102. 102.
    Verleden GM, Vos R, De Vleeschauwer S, Verleden S, Dupont L, Nevens F, et al. Neutrophilic reversible airways dysfunction after liver transplantation: a case report. Transplant Proc. 2011;43(5):2078–81.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Robin Vos
    • 1
    Email author
  • Stijn E. Verleden
    • 1
  • David Ruttens
    • 1
  • Bart M. Vanaudenaerde
    • 1
  • Geert M. Verleden
    • 1
  1. 1.Lung Transplantation UnitUniversity Hospital GasthuisbergLeuvenBelgium

Personalised recommendations