Drug Safety

, Volume 36, Issue 9, pp 709–721

Tendon Injury and Fluoroquinolone Use: A Systematic Review

  • Anne L. Stephenson
  • Wei Wu
  • Daniel Cortes
  • Paula A. Rochon
Systematic Review

Abstract

Background

Fluoroquinolone antibiotics are commonly used to treat infections and are prescribed by general practitioners, medical specialists and surgeons. Tendon injury has been associated with the use of these medications but the risk associated with newer fluoroquinolones has not been established.

Objectives

The aim of this systematic review was to evaluate the evidence from observational studies to determine the strength of the association between fluoroquinolone use and tendinopathy, and to identify risk factors for this complication.

Methods

We searched MEDLINE, EMBASE and the Cochrane Collaboration from inception through May 2013 to identify observational studies focused on tendon injury and fluoroquinolones. Studies with original data were selected for inclusion following the PRISMA guidelines. Of the 560 abstracts screened, 16 relevant studies were independently rated by three authors (WW, AS, DC) using the Newcastle-Ottawa Quality Assessment Scale, and assigned a quality score out of 9. High-quality studies (i.e. scored 4.5 or higher) are summarized in detail in this article. Data were independently extracted by two authors (WW, AS).

Results

Overall, 16 studies were included in our study. Eight were deemed to be of high quality and five specifically evaluated Achilles tendon rupture. In addition, three studies examined Achilles tendinitis, and three included tendon disorders (including any tendon rupture) as an outcome. Results from these studies suggest that individuals exposed to fluoroquinolones are at increased risk for Achilles tendon rupture, particularly within the first month following exposure to the drug (odds ratios ranged from 1.1 to 7.1). One study showed an increased risk of tendon rupture in those over 60 years of age. Five studies stated that individuals taking fluoroquinolones and oral corticosteroids are at increased risk for tendon injury compared with those taking fluoroquinolones alone. Four studies examined the differential effect of a limited number of fluoroquinolones. Ofloxacin had the highest risk of tendon injury in three of the studies.

Limitations

Included studies are observational in nature and rely on self-report, which may lead to misclassification or underestimation of tendon injury.

Conclusions

Observational studies showed an increased risk of tendon injury, including tendon rupture and tendinitis, with exposure to fluoroquinolone antibiotic therapy. Although this complication appears to be rare, concomitant corticosteroids increase the risk for tendon injury, which varies depending on the fluoroquinolone used.

Supplementary material

40264_2013_89_MOESM1_ESM.doc (28 kb)
Supplementary material 1 (DOC 28 kb)

References

  1. 1.
    Mehlhorn AJ, Brown DA. Safety concerns with fluoroquinolones. Ann Pharmacother. 2007;41(11):1859–66.PubMedCrossRefGoogle Scholar
  2. 2.
    Beyer J, Schellong S. Bilateral plantar tendinitis during levofloxacin therapy (Review, 8 refs). Br J. Clin Pharm. 2006;61(5):609.CrossRefGoogle Scholar
  3. 3.
    Karistinos A, Paulos LE. “Ciprofloxacin-induced” bilateral rectus femoris tendon rupture. 17(5):406–7.Google Scholar
  4. 4.
    Braun D, Petitpain N, Cosserat F, Loeuille D, Bitar S, Gillet P, et al. Rupture of multiple tendons after levofloxacin therapy. Revue du Rhumatisme. 2004;71(6):586–7.Google Scholar
  5. 5.
    Burkhardt O, Kohnlein T, Pap T, Welte T. Recurrent tendinitis after treatment with two different fluoroquinolones. Scand J Infect Dis. 2004;36(4):315–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Mouzopoulos G, Stamatakos M, Vasiliadis G, Skandalakis P. Rupture of adductor longus tendon due to ciprofloxacin. Acta Ortho Belgica. 2005;71(6):743–5.Google Scholar
  7. 7.
    Khaliq Y, Zhanel GG. Musculoskeletal injury associated with fluoroquinolone antibiotics (Review, 43 refs). Clinics Plastic Surgery. 2005;32(4):495–502.CrossRefGoogle Scholar
  8. 8.
    Ever-Silva WA, Netto Hde B, Pinto JF, Ferry FR, Neves-Motta R. Severe shoulder tendinopathy associated with levofloxacin. Braz J Infect Dis. 2012;16(4):393–5.CrossRefGoogle Scholar
  9. 9.
    Tanne JH. FDA adds “black box” warning label to fluoroquinolone antibiotics. BMJ. 2008;337:a816.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhanel GG, Ennis K, Vercaigne L, Walkty A, Gin AS, Embil J, et al. A critical review of the fluoroquinolones: focus on respiratory infections. Drugs. 2002;62(1):13–59.PubMedCrossRefGoogle Scholar
  11. 11.
    Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27–72.PubMedCrossRefGoogle Scholar
  12. 12.
    O’Donnell DE, Hernandez P, Kaplan A, Aaron S, Bourbeau J, Marciniuk D et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease—2008 update—highlights for primary care. Can Respir J 2008;15(Suppl A):1A–8A.Google Scholar
  13. 13.
    Khaliq Y, Zhanel GG. Fluoroquinolone-associated tendinopathy: a critical review of the literature. Clin Infect Dis. 2003;36(11):1404–10.PubMedCrossRefGoogle Scholar
  14. 14.
    Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS. Fluoroquinolone prescribing in the United States: 1995 to 2002. Am J Med. 2005;118:259–68.PubMedCrossRefGoogle Scholar
  15. 15.
    Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M et al. The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.Google Scholar
  16. 16.
    Costa SM, Martins CC, Bonfim MC, Zina LG, Paiva SM, Pordeus IA, et al. A systematic review of socioeconomic indicators and dental caries in adults. Int J Environ Res Public Health. 2012;9:3540–74.PubMedCrossRefGoogle Scholar
  17. 17.
    Wise BL, Peloquin C, Choi H, Lane NE, Zhang Y. Impact of age, sex, obesity, and steroid use on quinolone-associated tendon disorders. Amer J Med. 2012;125(12):1228.e23–8.Google Scholar
  18. 18.
    Lapi F, Tuccori M, Motola D, Pugi A, Vietri M, Montanaro N, et al. Safety profile of the fluoroquinolones: analysis of adverse drug reactions in relation to prescription data using four regional pharmacovigilance databases in Italy. Drug Saf. 2010;33(9):789–99.PubMedCrossRefGoogle Scholar
  19. 19.
    Seeger JD, West WA, Fife D, Noel GJ, Johnson LN, Walker AM. Achilles tendon rupture and its association with fluoroquinolone antibiotics and other potential risk factors in a managed care population. Pharmacoepidemiol Drug Saf. 2006;15(11):784–92.PubMedCrossRefGoogle Scholar
  20. 20.
    Corrao G, Zambon A, Bertu L, Mauri A, Paleari V, Rossi C, et al. Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study. Drug Saf. 2006;29(10):889–96.PubMedCrossRefGoogle Scholar
  21. 21.
    van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH. Increased risk of Achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids. Arch Intern Med. 2003;163(15):1801–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Leone R, Venegoni M, Motola D, Moretti U, Piazzetta V, Cocci A, et al. Adverse drug reactions related to the use of fluoroquinolone antimicrobials: an analysis of spontaneous reports and fluoroquinolone consumption data from three Italian regions. Drug Saf. 2003;26(2):109–20.PubMedCrossRefGoogle Scholar
  23. 23.
    Chhajed PN, Plit ML, Hopkins PM, Malouf MA, Glanville AR. Achilles tendon disease in lung transplant recipients: association with ciprofloxacin. Eur Respir J. 2002;19(3):469–71.PubMedCrossRefGoogle Scholar
  24. 24.
    van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HG, Stricker BH. Fluoroquinolones and risk of Achilles tendon disorders: case-control study. BMJ. 2002;324(7349):1306–7.PubMedCrossRefGoogle Scholar
  25. 25.
    van der Linden PD, van Puijenbroek EP, Feenstra J, Veld BA, Sturkenboom MC, Herings RM, et al. Tendon disorders attributed to fluoroquinolones: a study on 42 spontaneous reports in the period 1988 to 1998. Arthritis Rheum. 2001;45(3):235–9.PubMedCrossRefGoogle Scholar
  26. 26.
    van der Linden PD, Nab HW, Simonian S, Stricker BH, Leufkens HG, Herings RM. Fluoroquinolone use and the change in incidence of tendon ruptures in the Netherlands (Review, 23 refs). Pharm World Sci. 2001;23(3):89–92.PubMedCrossRefGoogle Scholar
  27. 27.
    Pierfitte C, Royer RJ. Tendon disorders with fluoroquinolones. Therapie. 1996;51(4):419–20.PubMedGoogle Scholar
  28. 28.
    Hori K, Yamakawa K, Yoshida N, Ohnishi K, Kawakami J. Detection of fluoroquinolone-induced tendon disorders using a hospital database in Japan. Pharmacoepidemiol Drug Saf. 2012;21:886–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Barge-Caballero E, Crespo-Leiro MG, Paniagua-Martin MJ, Muniz J, Naya C, Bouzas-Mosquera A, et al. Quinolone-related Achilles tendinopathy in heart transplant patients: incidence and risk factors. J Heart Lung Transpl. 2008;27(1):46–51.CrossRefGoogle Scholar
  30. 30.
    Sode J, Obel N, Hallas J, Lassen A. Use of fluroquinolone and risk of Achilles tendon rupture: a population-based cohort study. Eur J Clin Pharmacol. 2007;63(5):499–503.PubMedCrossRefGoogle Scholar
  31. 31.
    van der Linden PD, van de Lei J, Nab HW, Knol A, Stricker BH. Achilles tendinitis associated with fluoroquinolones. Br J Clin Pharmacol. 1999;48(3):433–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Wilton LV, Pearce GL, Mann RD. A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies. Br J Clin Pharmacol. 1996;41(4):277–84.PubMedCrossRefGoogle Scholar
  33. 33.
    Le Huec JC, Schaeverbeke T, Chauveaux, Rivel J, Dehais J, Le Rebeller A. Epicondylitis after treatment with fluoroquinolone antibiotics. J Bone Joint Surg Br. 1995;77(293):295.Google Scholar
  34. 34.
    Schwald N, Debray-Meignan S. Suspected role of ofloxacin in a case of arthralgia, myalgia, and multiple tendinopathy. Revue du Rhumatisme. 1999;66:419–21.PubMedGoogle Scholar
  35. 35.
    Williams RJ III, Attia E, Wickiewicz TL, Hannafin JA. The effect of ciprofloxacin on tendon, paratenon, and capsular fibroblast metabolism. Am J Sports Med. 2000;28(3):364–9.PubMedGoogle Scholar
  36. 36.
    Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110:673–87.PubMedCrossRefGoogle Scholar
  37. 37.
    Pouzaud F, Bernard-Beaubois K, Thevenin M, Warnet JM, Hayem G, Rat P. In vitro discrimination of fluoroquinolones toxicity on tendon cells: involvement of oxidative stress. J Pharmacol Exp Ther. 2004;308(1):394–402.PubMedCrossRefGoogle Scholar
  38. 38.
    Maffulli N, Sharma P, Luscombe KL. Achilles tendinopathy: aetiology and management. J R Soc Med. 2004;97(10):472–6.PubMedCrossRefGoogle Scholar
  39. 39.
    McLauchlan GJ, Handoll HH. Interventions for treating acute and chronic Achilles tendinitis. Cochrane Database Syst Rev 2001;(2):CD000232.Google Scholar
  40. 40.
    Marie I, Delafenetre H, Massy N, Thuillez C, Noblet C, et al. Tendinous disorders attributed to statins: a study on ninety-six spontaneous reports in the period 1990–2005 and review of the literature. Arthritis Rheum. 2008;59(3):367–72.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Anne L. Stephenson
    • 1
  • Wei Wu
    • 2
  • Daniel Cortes
    • 3
  • Paula A. Rochon
    • 2
    • 4
    • 5
  1. 1.Department of Medicine and Keenan Research Centre in the Li Ka Shing Knowledge Institute, University of TorontoSt. Michael’s HospitalTorontoCanada
  2. 2.Women’s College Research InstituteWomen’s College HospitalTorontoCanada
  3. 3.Department of Pharmacy and Keenan Research Centre in the Li Ka Shing Knowledge InstituteSt. Michael’s HospitalTorontoCanada
  4. 4.Institute for Clinical Evaluative SciencesTorontoCanada
  5. 5.Department of Medicine and Institute of Health Policy Management and Evaluation, University of TorontoTorontoCanada

Personalised recommendations