Fluoroquinolone antibiotics are commonly used to treat a variety of illnesses such as respiratory, skin, and urinary tract infections. According to CDC data, nearly 30 million fluoroquinolone prescriptions are dispensed in the United states each year. (1)
Musculoskeletal providers are painfully aware of how those drugs endanger connective tissues; including a nearly four-fold risk of tendonitis and tendinopathy. (2) Now, researchers have established a new and more threatening link to cervical arterial dissection (CAD). Check out the new findings, and review the essential question that you need to ask your patients before treatment.
A Novel Hypothesis
- ciprofloxacin (Cipro)
- gemifloxacin (Factive)
- levofloxacin (Levaquin)
- moxifloxacin (Avelox)
- norfloxacin (Noroxin)
- ofloxacin (Floxin)
In 2018, James Demetrious DC, FACO published a hypothesis that fluoroquinolone (FQ) antibiotics could be an unrecognized contributor to spontaneous cervical arterial dissection. (3) Dr. Demetrious based this suspicion on three primary factors.
1. Fluoroquinolones Degrade Connective Tissue, Including Arterial Walls
“Fluoroquinolone antibiotics have been recognized for their degradative effects on connective tissue. Aortic and cervical arteries are comprised of connective tissue. Recent studies have implicated fluoroquinolones in the genesis of aortic artery dissection and aneurysms.” (3)
Demetrious supported a potential causative link based upon the following data:
- The tunica adventitia of the aortic, carotid, and vertebral arteries is comprised of dense irregular connective tissue containing loosely organized collagen fibers. (4)
- Collagen degradation due to fluoroquinolones reportedly involves the upregulation of matrix metalloproteinases resulting in a reduction in the quantity and quality of collagen fibrils. (5)
- Multiple studies suggest that exposure to fluoroquinolones have an associated increased risk of an aortic aneurysm and dissection. (5-8)
In subsequent discussions, Dr. Demetrious referenced an additional paper by Campos (9) that may have incorrectly identified “infection” as a causative factor for cervical arterial dissection (CAD):
“The authors attributed cervical artery dissection to infection, despite a history of fluoroquinolone utilization reported in the patient’s history. I think they missed the true causative event. I suspect that many (other) cases of fluoroquinolone causation have been missed and improperly attributed to chiropractic interventions.” (10)
2. Arterial Dissections and Antibiotic Prescriptions Share Similar Seasonal Variations
“The frequency of infections, fluoroquinolone utilization, and cervical artery dissections increase during winter months.” (3) Demetrious based his observation, on the following data:
- A seasonal variation has been reported with cervical artery dissection more likely to occur in the winter. (11)
- A history of recent infection has been associated as a risk factor for cervical artery dissection. (12,13)
- A national database of outpatient antibiotic prescriptions in the United States reported an average of 24.5% more antibiotic prescriptions were dispensed in the winter months than in the summer. (14)
3. Fluoroquinolone Consequences Could Be Latent
“In a review of 98 case reports of fluoroquinolone associated tendinopathy (aka collagen degradation), symptoms were reported as occurring within two hours of taking the medication to as long as six months after the cessation of treatment, with the median time of onset of six days. (15) The FDA reports that side effects occurred within hours to weeks after starting the fluoroquinolone, for an average of fourteen months to as long as nine years after stopping the medicines. (16)”
In 2019, independent medical research added support to Dr. Demetrious’ hypothesis.
“Overall, 284 cases and 568 controls qualified for the analysis. 10.6% of patients in the CAD group and 2.8% in the non-CAD group were fluoroquinolone users. The use of these antibiotics was associated with a more than twofold increased risk of CAD after adjusting for confounders. The risk was more substantial in the subgroup of patients with dissection involving the carotid artery and in females. It (also) seems plausible that the detrimental effect of fluoroquinolones might be acute in onset. Conclusion: Fluoroquinolones may represent a novel contributing factor involved in the pathogenesis of CAD.” (17)
Now that independent medical research has initially confirmed his hypothesis in a case-control study, Dr. Demetrious recommends further consideration:
- Chiropractors should be aware of this very plausible risk factor;
- Chiropractic colleges should include this risk factor in their curricula;
- Cases of cervical artery dissection and stroke must be reviewed for the presence of prior FQ utilization as a contributory factor that predates chiropractic care;
- Further study is needed by qualified researchers to assess the confidence, importance, validity and statistical value of FQ’s as a risk factor;
- It is important to define predictive factors and consider FQ latency, CAD symptoms, signs and possible co-morbidities to identify developing CADs for medical referral;
- The pharmacologic role of FQs in the development of CADs needs to be shared with allied physicians and therapists.
“ The relationship of fluoroquinolones to cervical artery dissection must be carefully reported. As a practicing doctor of chiropractic, I am interested in understanding possible risk factors. CAD are rare events with infrequent severe adverse events making research quite difficult. In a recent article published in the Annals of Internal Medicine (18), authors Chaibi and Russell confirmed once again that, “Manual therapy does not result in an increased risk of CAD.” It appears that pharmacologic adverse events are responsible for CAD and stroke. (10)
* ChiroUp extends a special thank you to Dr. James Demetrious for his blog contribution, and moreover, his lifetime commitment to advancing our profession.
Chiro Up has already incorporated this cutting-edge information into your clinical tools in your account.
The Review of Systems form and Provider CAD infographic now include the risk factor “Recent history of fluoroquinolone antibiotics.”
Several of the subsequent references have been harvested directly from Demetrious (3)
- CDC Website https://www.cdc.gov/antibiotic-use/community/programs-measurement/state-local-activities/outpatient-antibiotic-prescriptions-US-2016.html Accessed 8/25/19
- Alves C et al. Fluoroquinolones and the risk of tendon injury: a systematic review and
meta-analysis. Eur J Clin Pharmacol. 2019 Jul 4.
- Demetrious, JS. “Spontaneous cervical artery dissection: a fluoroquinolone induced connective tissue disorder?” Chiropractic & Manual Therapies 2018;26:22.
- Histology guide. MH 063 Carotid Artery and Brachiocephalic Vein. T. Clark Brelje and Robert L. Sorenson. 2017. http://www.histologyguide.com/slideview/MH-063-carotid-artery-and-brachiocephalic-vein/09-slide-1.html?x=0&y=0&z=-1&page=1. Accessed 8 Feb 2018.
- Daneman N, Lu H, Redelmeier DA. Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open. 2015;5:e 010077.
- Lee CC, Lee MG, Chen YS, Lee SH, Chen YS, Chen SC, Chang SC. Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone. JAMA Int Med. 2015;175(11):1839–47.
- Singh S, Nautiyal A. Aortic dissection and aortic aneurysms associated with fluoroquinolones: a systematic review and meta-analysis. Am J Med. 2017; 130(12):1449–57.
- Pasternak B, Inghammar M, Svanström H. Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study. BMJ. 2018;360:k678.
- Campos, Cynthia Resende, et al. “Internal carotid artery dissection in a patient with recent respiratory infection: case report of a possible link.” Arquivos de neuro-psiquiatria 63.2B (2005): 523-526.
- email communication from James Demetrious to Tim Bertelsman, August 2019.
- Paciaroni M, Georgiadis D, Arnold M, Gandjour J, Keseru B, Fahrni G, et al. Seasonal variability in spontaneous cervical artery dissection. J Neurol Neurosurg Psychiatry. 2006;77:677–9.
- Guillon B, Berthet K, Benslamia L, Bertrand M, Bousser MG, Tzourio C. Infection and the risk of spontaneous cervical artery dissection: a case control study. Stroke. 2003;34:e79–81.
- Grau AJ, Brandt T, Buggle F, Oberk E, Mytilineos J, Werle E, et al. Association of cervical artery dissection with recent infection. Arch Neurol. 1999;56:851–6.
- Suda KJ, Hicks LA, Roberts RM, Hunkler RJ, Taylor TH. Trends and seasonal variation in the outpatient antibiotic prescription rates in the United States, 2006 to 2010. Antimicrob Agents Chemother. 2014;58(5):2763–6.
- Khaliq Y, Zhanel GG. Fluoroquinolone-associated tendinopathy: a critical review of the literature. Clin Infect Dis. 2003;36(11):1404–10
- FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. 2016. https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm. Accessed 2 Feb 2018.
- Del Zotto, E., and Alessandro Pezzini. “Use of fluoroquinolones and the risk of spontaneous cervical artery dissection.” European journal of neurology (Jan 29, 2019).
- Chaibi A, Russell MB. A risk–benefit assessment strategy to exclude cervical artery dissection in spinal manual therapy: a comprehensive review. 2019;51(2): 118-127.
About the Authors
Dr. Tim Bertelsman
DC, CCSP, DACO
Dr. Tim Bertelsman graduated with honors from Logan College of Chiropractic and has been practicing in Belleville, IL since 1992. He has lectured nationally on various clinical and business topics and has been published extensively. He has served in several leadership positions within the Illinois Chiropractic Society and currently serves as past president of the executive board.
Dr. James Demetrious
Dr. Demetrious is a nationally distinguished chiropractic orthopedist, educator, author, and editor. He has published many peer-reviewed journal papers related to advanced differential diagnosis. He currently serves as an editor on behalf of the Journal of the Academy of Chiropractic Orthopedists. He is an editorial reviewer on behalf of the journals Spine, Annals of Internal Medicine, and Clinical Anatomy. Dr. Demetrious is a member of the NCMIC Speakers’ Bureau and provides postgraduate coursework throughout the United States. He has continually cared for patients over the past 32 years.
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