New Study Links Fluoroquinolones to Life-Threatening Blood Vessel Complication

A recent study published in the BMJ (previously called the British Medical Journal) sheds further light on the adverse effects of fluoroquinolones, a class of commonly prescribed — often overprescribed — antibiotics used to treat bacterial infections in many parts of the body. This study reinforced previous findings linking these drugs to an increased risk of a potentially life-threatening adverse cardiovascular event called aortic aneurysm.[1]

The new study’s results further bolster the Food and Drug Administration’s (FDA’s) 2016 assessment that the serious adverse effects of fluoroquinolones generally outweigh their benefits for patients with acute sinusitis, acute bronchitis and uncomplicated urinary tract infections.[2] For such patients, fluoroquinolones should be used only if there is no other treatment option.

Fluoroquinolones and collagen damage

Six fluoroquinolones are currently available in either oral or injection form in the U.S. (see table, below). Five have been approved by the FDA for treating several types of bacterial infections. The sixth and newest, delafloxacin (BAXDELA), is approved only for acute bacterial skin infections. These antibiotics are easily recognized as members of the fluoroquinolone family because their generic names all end with “floxacin.”

Fluoroquinolones Available in the U.S. for Oral or Intravenous (IV) Use

Animal and laboratory cell culture studies have shown that fluoroquinolones can damage collagen, the most abundant protein in the body that provides the supporting connective tissue framework for many of the body’s tissues, such as tendons, muscles, bones and blood vessels.[9],[10],[11]

Collagen damage is the most likely cause of the tendinitis, tendinopathy (disease of the tendon) and tendon rupture (particularly of the Achilles tendon) commonly seen in patients using fluoroquinolones. In 2006, in response to hundreds of reports of tendon rupture and tendinitis occurring in patients taking fluoroquinolones, Public Citizen successfully petitioned and sued the FDA for a prominent black-box warning on all fluoroquinolone labels about the risk of such adverse events.[12]

Given that collagen is also a major component of the aorta — the largest artery in the body, which originates at the heart and continues down through the length of the chest and abdomen — there has been concern for several years that treatment with fluoroquinolones also may damage the aorta. Indeed, prior research has demonstrated an association between fluoroquinolone use and an increased risk of aortic aneurysms.[13],[14]

Aortic aneurysms occur when a segment of the aorta becomes weakened, allowing it to expand like a balloon. Aortic aneurysms can exist for many years without causing symptoms. However, as an aneurysm becomes larger, there is an increasing risk of rupture, which is a medical emergency and is almost always fatal unless treated promptly. Some of the risk factors associated with aortic aneurysms include sex (males are more susceptible), older age, high blood pressure, smoking and a family history of aortic aneurysms.[15]

The BMJ study[16]

For the BMJ study, published on March 8, 2018, researchers in Sweden investigated whether fluoroquinolone use was associated with an increased risk of either aortic aneurysm or aortic dissection (another serious, sometimes fatal condition in which the inner lining of the aorta tears). Using Swedish national electronic databases that contained detailed information on filled prescriptions, hospitalizations, emergency room visits and deaths, they identified all adults in Sweden age 50 or older who had been prescribed since July 2005 either an oral fluoroquinolone antibiotic or amoxicillin, an antibiotic from the penicillin family.

The researchers excluded from the study anyone who had had an aortic aneurysm or aortic dissection prior to receiving the antibiotic, as well as anyone taking additional antibiotics at the same time as the fluoroquinolone or amoxicillin. The final study population included approximately 282,000 patients who had received an oral fluoroquinolone and 279,000 patients who had received amoxicillin. Importantly, the two groups of patients were similar in age and health status.

The researchers then determined whether the included patients were diagnosed with an aortic aneurysm or aortic dissection within 60 days after the start of antibiotic treatment. They found that patients treated with a fluoroquinolone had a statistically significant 66-percent greater risk of aortic aneurysm or aortic dissection within 60 days of starting treatment than those treated with amoxicillin. The period of greatest risk was the first ten days after the start of treatment. In an additional analysis assessing the risk of aortic aneurysm only, they found that patients treated with a fluoroquinolone had a 90-percent higher risk of this adverse event than those treated with amoxicillin.

In an accompanying editorial published in the BMJ, Prof. David Juurlink of University of Toronto stated that the Swedish study was “arguably the strongest” study to date to assess the association between fluoroquinolone use and the risk of aortic aneurysm.[17] Juurlink concluded that “this study strengthens the link between fluoroquinolones and aortic disease,” but he cautioned that the available data still do not prove that fluoroquinolones cause aortic aneurysms. Also, he noted that the absolute risk is very low: an estimated 82 additional cases of aortic aneurysm or dissection within 60 days for every million courses of fluoroquinolone treatment.

What You Can Do

Whenever your doctor prescribes you a fluoroquinolone, you should ask whether your illness requires any antibiotic and, if so, whether an alternative antibiotic would be as or more effective. You should not take a fluoroquinolone for acute exacerbations of chronic bronchitis, acute uncomplicated bladder infection or acute sinusitis unless there is no other alternative.

If your doctor does decide that a fluoroquinolone is the best course of treatment, you should discuss the drug’s serious risks. In addition to the risks of tendon injury and aortic aneurysm, the adverse effects of fluoroquinolones include seizures, tremors, disabling nerve disorders, skin damage and abnormal heart rhythms. If you develop sudden severe chest, back or abdominal pain, which could be a sign of an aortic aneurysm, seek immediate emergency medical attention.

References

[1]Pasternak B, Inghammar M, Svanström H. Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study. BMJ. 2018 Mar 8;360:k678.

[2]Food and Drug Administration. FDA drug safety communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. May 12, 2016. http://www.fda.gov/Drugs/DrugSafety/ucm500143.htm. Accessed July 9, 2018.

[3]Bayer HealthCare Pharmaceuticals. Label: ciprofloxacin hydrochloride (CIPRO). July 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019537s087,020780s044lbl.pdf. Accessed July 9, 2018.

[4]Melinta Therapeutics. Label: delafloxacin (BAXDELA). June 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208610s000,208611s000lbl.pdf. Accessed July 12, 2018.

[5]Merus Labs. Drug label: gemifloxacin mesylate (FACTIVE). July 2016. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021158s023lbl.pdf. Accessed July 9, 2018.

[6]Cipla USA. Drug label: levofloxacin. April 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3c5219e9-b75b-4898-aaf5-8357ddb36373. Accessed July 9, 2018.

[7]Bayer HealthCare Pharmaceuticals. Drug label: moxifloxacin (AVELOX). September 2016. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021085s061s062,021277s057s058lbl.pdf. Accessed July 9, 2018.

[8]Larken Laboratories. Drug label: ofloxacin. October 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=6a3dcc79-bde4-4c32-8a0e-ea14a1e1a191&type=pdf&name=6a3dcc79-bde4-4c32-8a0e-ea14a1e1a191. Accessed July 9, 2018.

[9]Lee CC, Lee MT, Chen YS, et al. Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone. JAMA Intern Med. 2015;175(11):1839-1847.

[10]Badal S, Her YF, Maher LJ. Non-antibiotic effects of fluoroquinolones in mammalian cells. J Biol Chem. 2015;290(36):22287-22297.

[11]Fox AJ, Schär MO, Wanivenhaus F, et al. Fluoroquinolones impair tendon healing in a rat rotator cuff repair model: A preliminary study. Am J Sports Med. 2014;42(12):2851-2859.

[12]Public Citizen. Public Citizen v. Food and Drug Administration (FDA) (Fluoroquinolone). http://www.citizen.org/litigation/forms/cases/getlinkforcase.cfm?cID=444. Accessed July 9, 2018.

[13]Lee CC, Lee MT, Chen YS, et al. Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone. JAMA Intern Med. 2015;175(11):1839-1847.

[14]Daneman N, Lu H, Redelmeier DA. Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open. 2015;5(11):e010077.

[15]Mayo Clinic. Abdominal aortic aneurysm. https://www.mayoclinic.org/diseases-conditions/abdominal-aortic-aneurysm/symptoms-causes/syc-20350688. Accessed July 9, 2018.

[16]Pasternak B, Inghammar M, Svanström H. Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study. BMJ. 2018 Mar 8;360:k678.

[17]Juurlink DN. Fluoroquinolones and the aorta:Possible link with aortic pathology but the absolute risk appears very low. BMJ 2018 Mar;360:k988.