Skip to main content
SpringerLink
Log in

Fluoroquinolone Use and the Risk of Collagen-Associated Adverse Events: A Systematic Review and Meta-Analysis

  • Systematic Review
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Introduction

It has been suggested that fluoroquinolone antibiotics increase the risk of developing collagen-associated adverse events such as aortic dissection and aortic aneurysm. These are life-threatening emergencies that need to be prevented.

Objectives

We performed this systematic review to clarify the association between fluoroquinolones and three collagen-associated adverse events: aortic aneurysm or aortic dissection, retinal detachment, and tendon disorders.

Methods

We searched PubMed, Embase, and Scopus for observational studies up to January 2019. Cohort and case–control studies were included if they reported data on the risk of collagen-related adverse events associated with fluoroquinolone exposure versus no exposure. We assessed the quality of the included studies using the Newcastle–Ottawa Scale. Effect statistics were pooled using random-effects models. Sensitivity and subgroup analyses were performed to identify any source of heterogeneity.

Results

After screening 2729 citations, we included 22 observational studies (12 cohort studies and ten case–control studies) with 19,207,552 participants. Current use of fluoroquinolones was significantly associated with aortic aneurysm and aortic dissection (odds ratio [OR] 2.20; 95% confidence interval [CI] 1.92–2.52), tendon disorders (OR 1.89; 95% CI 1.53–2.33), and retinal detachment (sensitivity analysis, OR 1.25; 95% CI 1.01–1.53). Past fluoroquinolone use (> 30 and ≤ 365 days) was associated with retinal detachment (OR 1.27; 95% CI 1.09–1.47).

Conclusions

Fluoroquinolone use incurs a risk of developing three collagen-associated diseases (aortic aneurysm or aortic dissection, retinal detachment, and tendon disorders). Patients at an increased risk of collagen-associated diseases should not use fluoroquinolones unless no other options are available.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Hicks LA, Taylor TH, Hunkler RJUS. Outpatient antibiotic prescribing, 2010. New Engl J Med. 2013;368(15):1461–2. https://doi.org/10.1056/NEJMc1212055.

    Article  CAS  PubMed  Google Scholar 

  2. Pasternak B, Inghammar M, Svanstrom H. Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study. BMJ. 2018;360:k678. https://doi.org/10.1136/bmj.k678.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kaleagasioglu F, Olcay E. Fluoroquinolone-induced tendinopathy: etiology and preventive measures. Tohoku J Exp Med. 2012;226(4):251–8. https://doi.org/10.1620/tjem.226.251.

    Article  CAS  PubMed  Google Scholar 

  4. Redgrave LS, Sutton SB, Webber MA, Piddock LJV. Fluoroquinolone resistance: mechanisms, impact on bacteria, and role in evolutionary success. Trends Microbiol. 2014;22(8):438–45. https://doi.org/10.1016/j.tim.2014.04.007.

    Article  CAS  PubMed  Google Scholar 

  5. Akali AU, Niranjan NS. Management of bilateral Achilles tendon rupture associated with ciprofloxacin: a review and case presentation. J Plast Reconstr Aesthetic Surg. 2008;61(7):830–4. https://doi.org/10.1016/j.bjps.2006.08.005.

    Article  CAS  Google Scholar 

  6. Stinner DJ, Orr JD, Hsu JR. Fluoroquinolone-associated bilateral patellar tendon rupture: A case report and review of the literature. Mil Med. 2010;175(6):457–9. https://doi.org/10.7205/MILMED-D-09-00142.

    Article  PubMed  Google Scholar 

  7. Shybut TB, Puckett ER. Triceps ruptures after fluoroquinolone antibiotics: a report of 2 cases. Sports Health. 2017;9(5):474–6. https://doi.org/10.1177/1941738117713686.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tsai WC, Hsu CC, Chen CPC, Chang HN, Wong AMK, Lin MS, et al. Ciprofloxacin up-regulates tendon cells to express matrix metalloproteinase-2 with degradation of type i collagen. J Orthop Res. 2011;29(1):67–73. https://doi.org/10.1002/jor.21196.

    Article  CAS  PubMed  Google Scholar 

  9. Rampal S, Kaur R, Sethi R, Singh O, Sood N. Ofloxacin-associated retinopathy in rabbits: role of oxidative stress. Hum Exp Toxicol. 2008;27(5):409–15. https://doi.org/10.1177/0960327108092295.

    Article  CAS  PubMed  Google Scholar 

  10. Van der Linden PD, Sturkenboom MCJM, Herings RMC, Leufkens HGM, Stricker BHC. Fluoroquinolones and risk of Achilles tendon disorders: case-control study. Br Med J. 2002;324(7349):1306–7.

    Article  Google Scholar 

  11. Van der Linden PD, Sturkenboom MCJM, Herings RMC, Leufkens HMG, Rowlands S, Stricker BHC. 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. https://doi.org/10.1001/archinte.163.15.1801.

    Article  PubMed  Google Scholar 

  12. 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. https://doi.org/10.1002/pds.1214.

    Article  CAS  PubMed  Google Scholar 

  13. Van der Linden PD, Van de Lei J, Nab HW, Knol A, Stricker BHC. Achilles tendinitis associated with fluoroquinolones. Br J Clin Pharmacol. 1999;48(3):433–7. https://doi.org/10.1046/j.1365-2125.1999.00016.x.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Yee CL, Duffy C, Gerbino PG, Stryker S, Noel GJ. Tendon or joint disorders in children after treatment with fluoroquinolones or azithromycin. Pediatr Infect Dis J. 2002;21(6):525–9. https://doi.org/10.1097/00006454-200206000-00009.

    Article  PubMed  Google Scholar 

  15. 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. https://doi.org/10.1007/s00228-007-0265-9.

    Article  CAS  PubMed  Google Scholar 

  16. 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(8):886–9. https://doi.org/10.1002/pds.3285.

    Article  CAS  PubMed  Google Scholar 

  17. Morales DR, Slattery J, Pacurariu A, Pinheiro L, McGettigan P, Kurz X. Relative and absolute risk of tendon rupture with fluoroquinolone and concomitant fluoroquinolone/corticosteroid therapy: population-based nested case-control study. Clin Drug Investig. 2019;39(2):205–13. https://doi.org/10.1007/s40261-018-0729-y.

    Article  CAS  PubMed  Google Scholar 

  18. Tanne JH. FDA adds “black box” warning label to fluoroquinolone antibiotics. BMJ. 2008;337:a816. https://doi.org/10.1136/bmj.a816.

    Article  PubMed  Google Scholar 

  19. Etminan M, Forooghian F, Brophy JM, Bird ST, Maberley D. Oral fluoroquinolones and the risk of retinal detachment. J Am Med Assoc. 2012;307(13):1414–9. https://doi.org/10.1001/jama.2012.383.

    Article  CAS  Google Scholar 

  20. Pasternak B, Svanström H, Melbye M, Hviid A. Association between oral fluoroquinolone use and retinal detachment. J Am Med Assoc. 2013;310(20):2184–90. https://doi.org/10.1001/jama.2013.280500.

    Article  CAS  Google Scholar 

  21. Choi SY, Lim HA, Yim HW, Park YH. Administration of oral fluoroquinolone and the risk of rhegmatogenous retinal detachment: a nationwide population-based study in Korea. PLoS One. 2018;13(4):e0195563. https://doi.org/10.1371/journal.pone.0195563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Eftekhari K, Ghodasra DH, Haynes K, Chen J, Kempen JH, Vanderbeek BL. Risk of retinal tear or detachment with oral fluoroquinolone use: a cohort study. Pharmacoepidemiol Drug Saf. 2014;23(7):745–52. https://doi.org/10.1002/pds.3623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Daneman N, Lu H, Redelmeier DA. Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open. 2015;5(11):e010077. https://doi.org/10.1136/bmjopen-2015-010077.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lee CC, Gabriel Lee MT, Chen YS, Lee SH, Chen YS, Chen SC, et al. Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone. JAMA Intern Med. 2015;175(11):1839–47. https://doi.org/10.1001/jamainternmed.2015.5389.

    Article  PubMed  Google Scholar 

  25. 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. https://doi.org/10.1124/jpet.103.057984.

    Article  CAS  PubMed  Google Scholar 

  26. Baugé C, Leclercq S, Conrozier T, Boumediene K. TOL19-001 reduces inflammation and MMP expression in monolayer cultures of tendon cells. BMC Complement Altern Med. 2015;15(1):217. https://doi.org/10.1186/s12906-015-0748-7.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kumbhar GB, Khan AM, Rampal S. Evaluation of gatifloxacin for its potential to induce antioxidant imbalance and retinopathy in rabbits. Hum Exp Toxicol. 2015;34(4):372–9. https://doi.org/10.1177/0960327114530743.

    Article  CAS  PubMed  Google Scholar 

  28. Belavic JM. Fluoroquinolone-induced tendinopathy. Nurse Pract. 2009;34(1):17–8. https://doi.org/10.1097/01.NPR.0000343751.83969.1b.

    Article  PubMed  Google Scholar 

  29. Fife D, Zhu V, Voss E, Levy-Clarke G, Ryan P. Exposure to oral fluoroquinolones and the risk of retinal detachment: retrospective analyses of two large healthcare databases. Drug Saf. 2014;37(3):171–82. https://doi.org/10.1007/s40264-014-0138-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kuo SC, Chen YT, Lee YT, Fan NW, Chen SJ, Li SY, et al. Association between recent use of fluoroquinolones and rhegmatogenous retinal detachment: a population-based cohort study. Clin Infect Dis. 2014;58(2):197–203. https://doi.org/10.1093/cid/cit708.

    Article  CAS  PubMed  Google Scholar 

  31. Corrao G, Zambon A, Bertù 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. https://doi.org/10.2165/00002018-200629100-00006.

    Article  CAS  PubMed  Google Scholar 

  32. Moher D, Liberati AF, Tetzlaff J, Tetzlaff JF, Altman DG, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. (1539-3704 (Electronic)).

  33. Hartling L, Milne A, Hamm MP, Vandermeer B, Ansari M, Tsertsvadze A, et al. Testing the Newcastle Ottawa Scale showed low reliability between individual reviewers. J Clin Epidemiol. 2013;66(9):982–93. https://doi.org/10.1016/j.jclinepi.2013.03.003.

    Article  PubMed  Google Scholar 

  34. Singh S, Nautiyal A. Aortic dissection and aortic aneurysms associated with fluoroquinolones: a systematic review and meta-analysis. Am J Med. 2017;130(12):1449. https://doi.org/10.1016/j.amjmed.2017.06.029.

    Article  CAS  PubMed  Google Scholar 

  35. Chui CSL, Wong ICK, Wong LYL, Chan EW. Association between oral fluoroquinolone use and the development of retinal detachment: a systematic review and meta-analysis of observational studies. J Antimicrob Chemother. 2015;70(4):971–8. https://doi.org/10.1093/jac/dku507.

    Article  CAS  PubMed  Google Scholar 

  36. Alves C, Penedones A, Mendes D, Batel Marques F. A systematic review and meta-analysis of the association between systemic fluoroquinolones and retinal detachment. Acta Ophthalmol. 2016;94(5):e251–9. https://doi.org/10.1111/aos.12931.

    Article  CAS  PubMed  Google Scholar 

  37. Jupiter DC, Fang X, Ashmore Z, Shibuya N, Mehta HB. The relative risk of achilles tendon injury in patients taking quinolones. Pharmacotherapy. 2018;38(9):878–87. https://doi.org/10.1002/phar.2162.

    Article  CAS  PubMed  Google Scholar 

  38. Etminan M, Maberley DAL. Improving reporting quality in ophthalmologic observational studies that use big data: the case of retinal detachment associated with fluoroquinolone use. (2168-6173 (Electronic)).

  39. FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm.

  40. Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics. https://www.ema.europa.eu/en/documents/press-release/disabling-potentially-permanent-side-effects-lead-suspension-restrictions-quinolone-fluoroquinolone_en.pdf. Accessed 1 Mar 2019.

  41. Corps AN, Harrall RL, Curry VA, Fenwick SA, Hazleman BL, Riley GP. Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin-1beta in human tendon-derived cells. A potential mechanism of fluoroquinolone-induced tendinopathy. Arthritis Rheum. 2002;46(11):3034–40. https://doi.org/10.1002/art.10617.

    Article  CAS  PubMed  Google Scholar 

  42. LeMaire SA, Zhang L, Luo W, Ren P, Azares AR, Wang Y, et al. Effect of ciprofloxacin on susceptibility to aortic dissection and rupture in mice. JAMA Surg. 2018;153(9):e181804. https://doi.org/10.1001/jamasurg.2018.1804.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Amin M, Pushpakumar S, Muradashvili N, Kundu S, Tyagi SC, Sen U. Regulation and involvement of matrix metalloproteinases in vascular diseases. Front Biosci (Landmark edition). 2016;21:89–118.

    Article  CAS  PubMed Central  Google Scholar 

  44. Feltgen N, Walter P. Rhegmatogenous retinal detachment–an ophthalmologic emergency. Dtsch Arztebl Inter. 2014;111(1–2):12–22. https://doi.org/10.3238/arztebl.2014.0012.

    Article  Google Scholar 

  45. Baek YH, Park SJ, Jeong S, Oh IS, Jeong HE, Park KH, et al. Signal detection between fluoroquinolone use and the risk of rhegmatogenous retinal detachment: sequence symmetry analysis using nationwide South Korean healthcare database between 2004 and 2015. Clin Drug Investig. 2018. https://doi.org/10.1007/s40261-018-0708-3.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all the authors of the original articles. We also appreciate Dr. Mouniir SA Durgahee for editing work.

Author information

Authors and Affiliations

  1. Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xinyu Yu, Ding-sheng Jiang, Jing Wang, Rui Wang, Taiqiang Chen, Kan Wang & Xiang Wei

  2. School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Shiyi Cao

  3. Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China

    Ding-sheng Jiang & Xiang Wei

  4. NHC Key Laboratory of Organ Transplantation, Wuhan, China

    Ding-sheng Jiang & Xiang Wei

  5. Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China

    Ding-sheng Jiang & Xiang Wei

Authors
  1. Xinyu Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ding-sheng Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Taiqiang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shiyi Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiang Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shiyi Cao or Xiang Wei.

Ethics declarations

Conflicts of interest

Xin-yu Yu, Ding-sheng Jiang, Jing Wang, Rui Wang, Tai-qiang Chen, Kan Wang, Xiang Wei, and Shi-yi Cao have no conflicts of interest that are directly relevant to the content of this study.

Funding

This review was supported by the National Natural Science Foundation of China (NSFC, 71603091).

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1078 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, X., Jiang, Ds., Wang, J. et al. Fluoroquinolone Use and the Risk of Collagen-Associated Adverse Events: A Systematic Review and Meta-Analysis. Drug Saf 42, 1025–1033 (2019). https://doi.org/10.1007/s40264-019-00828-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-019-00828-z

Search

Navigation