Skip to main content
SpringerLink
Log in

Efficacy and Safety of Long-Term Antibiotics (Macrolides) for the Treatment of Chronic Rhinosinusitis

  • RHINOSINUSITIS (J MULLOL, SECTION EDITOR)
  • Published:
Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

Long-term treatment of airway inflammation/infection with macrolide antibiotics has now been in use for almost 30 years. Whereas the beneficial clinical effect in cystic fibrosis and COPD have been backed up by randomized controlled trials, the evidence from the upper airways is not as strong. We have identified 22 open studies in chronic rhinosinusitis, with and without polyps, but only 2 randomized controlled trials. Of the controlled trials, the one including CRS patients just without polyps, showed a significant effect in sino-nasal outcome test, saccharine transit time, nasal endoscopy, and IL-8 levels in lavage fluid after 12 weeks of roxithromycin, whereas, in the other RCT with a mixed study group of CRS patients with and without polyps, 12 weeks of azithromycin showed no effect compared to placebo. Concerns regarding the risk of macrolides to induce arrhythmia have been raised. Recent FDA guidelines changes has recommended caution in patients with risk factors such as long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia. Ototoxicity is another concern. Long-term macrolide antibiotics in the treatment of CRS patients is still a viable option in a select group of patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Kudoh S, Kimura H, Uetake T, et al. Clinical effect of low-dose, long-term macrolide antibiotic chemotherapy on diffuse panbronchiolitis. Jpn J Thorac Dis. 1984;22:254–4.

    Google Scholar 

  2. Wallwork B, Coman W, Feron F, Mackay-Sim A, Cervin A. Clarithromycin and prednisolone inhibit cytokine production in chronic rhinosinusitis. Laryngoscope. 2002;112(10):1827–30.

    Article  CAS  PubMed  Google Scholar 

  3. Wallwork B, Coman W, Mackay-Sim A, Cervin A. Effect of clarithromycin on nuclear factor-kappa B and transforming growth factor-beta in chronic rhinosinusitis. Laryngoscope. 2004;114(2):286–90.

    Article  CAS  PubMed  Google Scholar 

  4. Suzuki H, Shimomura A, Ikeda K, Furukawa M, Oshima T, Takasaka T. Inhibitory effect of macrolides on interleukin-8 secretion from cultured human nasal epithelial cells. Laryngoscope. 1997;107(12 Pt 1):1661–6.

    Article  CAS  PubMed  Google Scholar 

  5. Nakajima T, Yoshizawa I, Kawano Y, Noma T. [Suppressive effect of roxithromycin on the induction of IL-2 responsiveness by DF-stimulated lymphocytes from patients with bronchial asthma]. [Japanese]. Arerugi Jpn J Allergol. 1996;45(6):554–61.

    CAS  Google Scholar 

  6. Ishida Y, Abe Y, Harabuchi Y. Effects of macrolides on antigen presentation and cytokine production by dendritic cells and T lymphocytes. Int J Pediatr Otorhinolaryngol. 2007;71(2):297–305.

    Article  PubMed  Google Scholar 

  7. Tamaoki J. The effects of macrolides on inflammatory cells. Chest. 2004;125(2 Suppl):41S–50S. quiz 1S.

    Article  CAS  PubMed  Google Scholar 

  8. Ishizawa K, Suzuki T, Yamaya M, Jia YX, Kobayashi S, Ida S, et al. Erythromycin increases bactericidal activity of surface liquid in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2005;289(4):L565–73.

    Article  CAS  PubMed  Google Scholar 

  9. 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 Respirator Crit Care Med. 2008;178(2):139–48.

    Article  CAS  Google Scholar 

  10. Yamada T, Fujieda S, Mori S, Yamamoto H, Saito H. Macrolide treatment decreased the size of nasal polyps and IL-8 levels in nasal lavage. Am J Rhinol. 2000;14(3):143–8.

    Article  CAS  PubMed  Google Scholar 

  11. Wallwork B, Coman W, Mackay-Sim A, Greiff L, Cervin A. A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis. Laryngoscope. 2006;116(2):189–93.

    Article  CAS  PubMed  Google Scholar 

  12. Haruna S, Shimada C, Ozawa M, Fukami S, Moriyama H. A study of poor responders for long-term, low-dose macrolide administration for chronic sinusitis. Rhinology. 2009;47(1):66–71.

    PubMed  Google Scholar 

  13. Suzuki H, Ikeda K, Honma R, Gotoh S, Oshima T, Furukawa M, et al. Prognostic factors of chronic rhinosinusitis under long-term low-dose macrolide therapy. ORL J Otorhinolaryngol Relat Spec. 2000;62(3):121–7.

    Article  CAS  PubMed  Google Scholar 

  14. Ragab SM, Lund VJ, Scadding G. Evaluation of the medical and surgical treatment of chronic rhinosinusitis: a prospective, randomised, controlled trial. Laryngoscope. 2004;114(5):923–30.

    Article  PubMed  Google Scholar 

  15. Zeng M, Long XB, Cui YH, Liu Z. Comparison of efficacy of mometasone furoate versus clarithromycin in the treatment of chronic rhinosinusitis without nasal polyps in Chinese adults. Am J Rhinol Allerg. 2011;25(6):e203–7.

    Article  Google Scholar 

  16. Ba L, Zhang N, Meng J, Zhang J, Lin P, Zhou P, et al. The association between bacterial colonization and inflammatory pattern in Chinese chronic rhinosinusitis patients with nasal polyps. Allergy. 2011;66(10):1296–303.

    Article  CAS  PubMed  Google Scholar 

  17. Jiang RS, Wu SH, Tsai CC, Li YH, Liang KL. Efficacy of Chinese herbal medicine compared with a macrolide in the treatment of chronic rhinosinusitis without nasal polyps. Am J Rhinol Allerg. 2012;26(4):293–7.

    Article  Google Scholar 

  18. Luo Q, Chen F, Liu W, Li Z, Xu R, Fan Y, et al. Evaluation of long-term clarithromycin treatment in adult Chinese Patients with chronic rhinosinusitis without nasal polyps. ORL J Otorhinolaryngol Relat Spec. 2011;73(4):206–11.

    Article  CAS  PubMed  Google Scholar 

  19. Majima Y, Kurono Y, Hirakawa K, Ichimura K, Haruna S, Suzaki H, et al. Efficacy of combined treatment with S-carboxymethylcysteine (carbocisteine) and clarithromycin in chronic rhinosinusitis patients without nasal polyp or with small nasal polyp. Auris Nasus Larynx. 2012;39(1):38–47. This open study has a high number of patients, n = 425 and uses the validated SNOT-20 for evaluation.

    Article  PubMed  Google Scholar 

  20. Videler WJ, van Hee K, Reinartz SM, Georgalas C, van der Meulen FW, Fokkens WJ. Long-term low-dose antibiotics in recalcitrant chronic rhinosinusitis: a retrospective analysis. Rhinology. 2012;50(1):45–55. Analyses of other long-term antibiotics.

    CAS  PubMed  Google Scholar 

  21. Nakamura Y, Suzuki M, Yokota M, Ozaki S, Ohno N, Hamajima Y, et al. Optimal duration of macrolide treatment for chronic sinusitis after endoscopic sinus surgery. Auris Nasus Larynx. 2013;40(4):366–72.

    Article  PubMed  Google Scholar 

  22. Cervin A, Kalm O, Sandkull P, Lindberg S. One-year low-dose erythromycin treatment of persistent chronic sinusitis after sinus surgery: clinical outcome and effects on mucociliary parameters and nasal nitric oxide. Otolaryngol–Head Neck Surg: Off J Am Acad Otolaryngol-Head Neck Surg. 2002;126(5):481–9.

    Article  Google Scholar 

  23. Hashiba M, Baba S. Efficacy of long-term administration of clarithromycin in the treatment of intractable chronic sinusitis. Acta Otolaryngol Suppl (Stockh). 1996;525:73–8.

    CAS  Google Scholar 

  24. Peric A, Vojvodic D, Matkovic-Jozin S. Effect of long-term, low-dose clarithromycin on T helper 2 cytokines, eosinophilic cationic protein and the 'regulated on activation, normal T cell expressed and secreted' chemokine in the nasal secretions of patients with nasal polyposis. J Laryngol Otol. 2012;126(5):495–502.

    Article  CAS  PubMed  Google Scholar 

  25. Dabirmoghaddam P, Mehdizadeh Seraj J, Bastaninejad S, Meighani A, Mokhtari Z. The efficacy of clarithromycin in patients with severe nasal polyposis. Acta Med Iran. 2013;51(6):359–64.

    PubMed  Google Scholar 

  26. Videler WJ, Badia L, Harvey RJ, Gane S, Georgalas C, van der Meulen FW, et al. Lack of efficacy of long-term, low-dose azithromycin in chronic rhinosinusitis: a randomized controlled trial. Allergy. 2011;66(11):1457–68. One of only two placebo-controlled trials. This was a mixed group of CRS patients and no significant treatment effect was seen.

    Article  CAS  PubMed  Google Scholar 

  27. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2012. Rhinol Suppl. 2012;3(23):1–298. An important reference paper.

    Google Scholar 

  28. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper Jr JA, Criner GJ, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689–98.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Westphal JF. Macrolide - induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Brit J Clin Pharmacol. 2000;50(4):285–95.

    Article  CAS  Google Scholar 

  30. Pessayre D, Larrey D, Funck-Brentano C. Drug interactions and hepatitis produced by some macrolide antibiotics. J Antimicrob Chemother. 1985;16(Suppl H):181–94.

    Article  CAS  PubMed  Google Scholar 

  31. Bachmann K, Schwartz JI, Forney Jr R, Frogameni A, Jauregui LE. The effect of erythromycin on the disposition kinetics of warfarin. Pharmacology. 1984;28(3):171–6.

    Article  CAS  PubMed  Google Scholar 

  32. Wysowski DK, Bacsanyi J. Cisapride and fatal arrhythmia. N Engl J Med. 1996;335(4):290–1.

    Article  CAS  PubMed  Google Scholar 

  33. Yasui N, Otani K, Kaneko S, Ohkubo T, Osanai T, Sugawara K, et al. A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans: in vivo evidence for the involvement of CYP3A4 in alprazolam metabolism. Clin Pharmacol Ther. 1996;59(5):514–9.

    Article  CAS  PubMed  Google Scholar 

  34. Cohen LG, Chesley S, Eugenio L, Flood JG, Fisch J, Goff DC. Erythromycin-induced clozapine toxic reaction. Archiv Inter Med. 1996;156(6):675–7.

    Article  CAS  Google Scholar 

  35. Yee GC. Pharmacokinetic interactions between cyclosporine and other drugs. Transplant Proc. 1990;22(3):1203–7.

    CAS  PubMed  Google Scholar 

  36. von Rosensteil NA, Adam D. Macrolide antibacterials. Drug interactions of clinical significance. Drug Saf: Int J Med Toxicol Drug Exp. 1995;13(2):105–22.

    Article  Google Scholar 

  37. Yumibe N, Huie K, Chen K, Clement R, Caten M. Identification of human liver cytochrome P450s involved in the microsomal metabolism of the antihistaminic drug loratadine (Abstract). J Allergy Clin Immunol. 1994;93:234–4.

    Google Scholar 

  38. Patel AM, Shariff S, Bailey DG, Juurlink DN, Gandhi S, Mamdani M, et al. Statin toxicity from macrolide antibiotic coprescription: a population-based cohort study. Ann Inter Med. 2013;158(12):869–76.

    Article  Google Scholar 

  39. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Mosholder AD, Mathew J, Alexander JJ, Smith H, Nambiar S. Cardiovascular risks with azithromycin and other antibacterial drugs. N Engl J Med. 2013;368(18):1665–8.

    Article  CAS  PubMed  Google Scholar 

  41. Schembri S, Williamson PA, Short PM, Singanayagam A, Akram A, Taylor J, et al. Cardiovascular events after clarithromycin use in lower respiratory tract infections: analysis of two prospective cohort studies. BMJ. 2013;346:f1235. The most recent report in a large cohort, suggsting an increased risk of about 1.6.

    Article  PubMed  Google Scholar 

  42. Periti P, Mazzei T, Mini E, Novelli A. Adverse effects of macrolide antibacterials. Drug Saf: Int J Med Toxic Drug Exp. 1993;9(5):346–64.

    Article  CAS  Google Scholar 

Download references

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Anders Cervin and Ben Wallwork declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Royal Brisbane & Women’s Hospital, School of Medicine, University of Queensland, Level 9, Room 915, UQ Health Science Building, Herston, QLD, 4029, Australia

    Anders Cervin

  2. Department of Otorhinolaryngology, Princess Alexandra Hospital and School of Biomolecular and Biomedical Science, Griffith University Brisbane, Brisbane, Australia

    Ben Wallwork

Authors
  1. Anders Cervin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ben Wallwork
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anders Cervin.

Additional information

This article is part of the Topical Collection on Rhinosinusitis

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cervin, A., Wallwork, B. Efficacy and Safety of Long-Term Antibiotics (Macrolides) for the Treatment of Chronic Rhinosinusitis. Curr Allergy Asthma Rep 14, 416 (2014). https://doi.org/10.1007/s11882-013-0416-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11882-013-0416-2

Keywords

Search

Navigation