Common antibiotics linked to increased risk of aortic dissection

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Exposure to fluoroquinolones—one of the most popular classes of antibiotics in the world—is associated with more than double the risk of aortic aneurysm (AA) or aortic dissection (AD), according to a study published online in the Journal of the American College of Cardiology.

Using national databases from Taiwan, researchers analyzed fluoroquinolone prescriptions among 1,213 patients hospitalized for AA or AD from 2001 to 2011. They compared exposure to the drug in the 60 days leading up to the AA/AD event to a randomly selected 60-day interval between 60 and 180 days before the event.

Lead author Chien-Chang Lee, MD, ScD, and colleagues found 1.6 percent of patients had been exposed to fluoroquinolone in the two months leading up to their event, versus only 0.6 percent in a preceding 60-day period. That translated to a 2.71-fold risk of AA/AD related to more recent fluoroquinolone use.

In addition, Lee et al. found that prolonged exposure to the antibiotics further increased risk. Those who were prescribed the drugs for between three and 14 days showed a 2.41-fold increased risk versus no prescription at all, while those prescribed fluoroquinolones for more than 14 days demonstrated a 2.83-fold risk.

“Typically, AA/AD develop slowly in patients, but our data suggest that use of fluoroquinolone can contribute in the short term to aneurysm progression or rupture that may require emergency department visits and hospitalization,” wrote Lee, with the department of emergency medicine at National Taiwan University Hospital, and coauthors.

Population-based studies support that AA and AD are rare diseases, occurring in between three and 20 people per 100,000 population each year. However, annual incidence among elderly individuals rises to as much as 130 per 100,000 people, the researchers noted.

Despite the relative rarity of the conditions, Lee et al. suggested the rising prescriptions of fluoroquinolones may be cause for concern, particularly since AA and especially AD are life-threatening without timely treatment.

The authors estimated 25.2 million U.S. outpatients were prescribed fluoroquinolones in 2012, which they calculated would result in an additional 2,591 cases of AA/AD.

“In the United States alone, fluoroquinolone prescriptions have more than tripled, from 7 million in 1995 to 22 million in 2002. With an estimated 25 million people prescribed with fluoroquinolones in the United States annually, which is expected to increase even more, it is clear that fluoroquinolones may contribute substantially to the current and future burdens of AA/AD.”

In a related editorial, Sonal Singh, MD, MPH, and Amit Nautiyal, MD, noted fluoroquinolones “have been known to cause tendon rupture mediated by their adverse effects on collagenous structures”—and the aorta is rich in type I and type III collagen.

“Although the exact biological mechanism remains unknown, several plausible mechanisms have been proposed to explain how fluoroquinolones might affect the synthesis or structural integrity of collagen in the aortic wall,” Lee and colleagues wrote. “First, fluoroquinolones have chelating properties against several metal ions (e.g., calcium, magnesium, aluminum), which are essential for type 1 collagen synthesis. Second, fluoroquinolones can decrease collagen synthesis by increasing the expression of matrix metalloproteinases, which lead to extracellular matrix degradation and medial layer degeneration.”

Based on the biological plausibility of those experimental studies—as well as the consistently increased risk found in epidemiological research—Lee et al. believe there is strong evidence to support that fluoroquinolone contributes to the incidence of AA and AD.

“Although the rare incidence of AA/AD attenuates the public health impact, the rapid increase of fluoroquinolone consumption still poses a large burden of AA/AD in the general population,” they wrote. “Clinicians are advised to consider alternative antibiotic regimens in patients with pre-existing collagen-related disorder or aortic aneurysm.”

Singh and Nautiyal agreed, saying the “cumulative strength” of multiple studies, with different designs and different patient populations, makes it unlikely an unknown confounding factor is biasing all of the studies.

“It would be prudent to entertain the possibly of aortic aneurysms/aortic dissection associated with fluoroquinolones use in patients presenting with chest pain, shortness of breath, or syncope after recent exposure to the fluoroquinolones,” they wrote. “Although one should be careful in extrapolating from mechanistic studies, judicious use of fluoroquinolones may be particularly warranted among patients with risk factors for aortic aneurysms such as increasing age, the presence of smoking, hypertension, and Marfan’s syndrome.”

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