Fluoroquinolone Antibiotics Can Increase the Risk of Aortic Rupture, FDA Warns

On Dec. 20, 2018, the Food and Drug Administration (FDA) warned that use of fluoroquinolones, a commonly prescribed family of antibiotics, can increase the occurrence of rare but serious ruptures or tears in the aorta — the largest artery in the body.[1] These tears, also called aortic dissections, and ruptures can lead to severe bleeding and death.

Six FDA-approved fluoroquinolones are currently available in the U.S. in either oral or injection form (see Table below). These antibiotics are approved to treat a variety of bacterial infections and are easily recognized as members of the fluoroquinolone family because their generic names all end with “floxacin.”

The new FDA warning further reinforces the agency’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 Available in the U.S. for Oral or Intravenous (IV) Use

*Designated as Limited Use
**Designated as Do Not Use for Seven Years (Until June 2024)
***Designated as Do Not Use

Fluoroquinolones damage collagen

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.[3],[4],[5]

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 to the FDA 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.[6]

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 — concern that treatment with fluoroquinolones also may damage the aorta arose several years ago. Indeed, prior research has demonstrated an association between fluoroquinolone use and an increased risk of aortic aneurysms.[7], [8]

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.[9]

The new FDA warning

The FDA’s December 2018 warning about the increased risk of aortic ruptures or tears with fluoroquinolone use was prompted by two reviews of adverse events submitted to the agency, as well as studies published in medical journals.[10] These studies investigated the association between fluoroquinolone use and aortic tears and aneurysms.

An initial search of the FDA’s adverse events reporting database in 2015 revealed 15 cases of aortic aneurysms or tears associated with fluoroquinolone use through December 15, 2015. The agency at that time also reviewed a single observational study that found fluoroquinolone use was associated with a more than twofold increase in the risk of developing aortic aneurysms or aortic tears.[11] However, the agency noted that this study had significant limitations. In May 2017, the agency announced that there was insufficient data to conclude that these antibiotics result in aortic aneurysms and tears.[12]

In 2018, a second search of the FDA’s adverse events reporting database revealed 56 additional cases of aortic aneurysm or tearing from December 15, 2015, through April 30, 2018, that occurred during or after treatment with fluoroquinolones. The agency also identified three additional observational studies that showed that fluoroquinolones increased the risk of developing aortic aneurysms or tears by approximately twofold.[13]

One of these studies compared the risk of developing aortic aneurysm during the first 60 days after starting an oral fluoroquinolone with that of another antibiotic, amoxicillin, in patients 50 years of age or older.[14] The study found that the risk of developing an aortic aneurysm was significantly higher in patients taking fluoroquinolones than in patients taking amoxicillin in the first 10 days of treatment.

Based on its second review, the FDA advised doctors and patients that fluoroquinolones should not be used in people who are at increased risk of these adverse events involving the aorta unless there are no other treatment options available.[15] Patients at increased risk include the elderly and those who have a history of blockages or aneurysms of the aorta or other arteries, high blood pressure or certain genetic disorders that lead to weakening of the walls of arteries.

The FDA required that new warnings about these risks be added to the product labeling of all fluoroquinolones and to the FDA-approved patient Medication Guides that are to be given to patients when they fill a prescription for any of these antibiotics. However, given the severity of ruptures or tears in the aorta, the FDA should have required that this new warning be added to the existing black-box warning in the product labeling for all fluoroquinolones.

What You Can Do

You should not take a fluoroquinolone for acute exacerbations of chronic bronchitis, uncomplicated bladder infection or acute sinusitis unless there is no alternative. You should not discontinue the use of any medication without first consulting your prescribing doctor.

When taking a fluoroquinolone, you should be alert for symptoms of aortic aneurysms or tears. Although aortic aneurysms can occur without signs or symptoms, you should seek emergency medical attention if you experience a throbbing sensation in the stomach area; jaw, neck, chest, back or abdominal pain; difficulty breathing or shortness of breath; or coughing or hoarseness.
 

References

[1] Food and Drug Administration. FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. December 20, 2018. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics. Accessed May 7, 2019.

[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. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-advises-restricting-fluoroquinolone-antibiotic-use-certain. Accessed May 7, 2019.

[3] 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.

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

[5] 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.

[6] Public Citizen. Public Citizen v. Food and Drug Administration (FDA) (Fluoroquinolone). http://www.citizen.org/litigation/forms/cases/getlinkforcase.cfm?cID=444. Accessed May 7, 2019.

[7] 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.

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

[9] Mayo Clinic. Abdominal aortic aneurysm. https://www.mayoclinic.org/diseases-conditions/abdominal-aortic-aneurysm/symptoms-causes/syc-20350688. Accessed May 7, 2019.

[10] Food and Drug Administration. FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. December 20, 2018. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics. Accessed May 7, 2019.

[11] 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.

[12] Food and Drug Administration. FDA drug safety communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. Updated May 10, 2017. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-updates-warnings-oral-and-injectable-fluoroquinolone-antibiotics. Accessed May 7, 2019.

[13] Food and Drug Administration. FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. December 20, 2018. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics. Accessed May 7, 2019.

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

[15] Food and Drug Administration. FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. December 20, 2018. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics. Accessed May 7, 2019.