In recent years, studies have shown that a once-popular class of antibiotics can present a variety of serious health risks. Ciprofloxacin (commonly just called Cipro) is a type of fluoroquinolone, which has been associated with an increase in health problems like retinal detachment, tendonitis and tendon rupture. Other types of connective tissue, which holds us together, may also be affected. These side effects have led to a black box warning for the drug, which is meant to focus attention on life-threatening risks a drug poses. Scientists wanted to learn more about how another part of the body was impacted.
"A natural tissue to worry about is the aorta, a blood vessel that relies heavily on having a sound connective tissue component - called the extracellular matrix - to maintain its integrity," said Dr. Scott A. LeMaire, the first author of a new report on this research in JAMA Surgery. He is the director of research in the division of cardiothoracic surgery and vice-chair for research and professor of surgery and molecular physiology and biophysics at Baylor College of Medicine.
A clinical investigation assessed the cardiovascular health outcomes of patients on fluoroquinolones. "They found that patients who received fluoroquinolones had a higher risk for aneurysms (formation of balloon-like areas in the aorta that weaken the integrity of the vessel), ruptures or dissections (tears in the wall) than patients who did not receive the antibiotics. This has raised important concerns," LeMaire said.
These kinds of association studies do not prove a cause and effect relationship, so LeMaire and colleagues used a mouse model of aortic aneurysms and dissections (ADD) to learn more. "In our study, mice with normal or moderately stressed aortas received either ciprofloxacin or placebo, and after four weeks we looked at their aortas," said senior author Dr. Ying H. Shen, director of the Aortic Diseases Research Laboratory and associate professor of surgery at Baylor College of Medicine.
Ciprofloxacin did not have a negative impact on an unstressed mouse aorta. In mice with aortas under moderate stress, 45 percent of the placebo group developed AAD, 24 percent developed aortic dissection and no ruptures. But when those mice with moderately stressed aortas also got the antibiotic, 79 percent developed AAD, 67 percent had aortic dissection, and in 15 percent there was a fatal rupture.
"Our study suggests that in this model of moderately stressed mouse aortas, ciprofloxacin exposure results in the disease progressing more rapidly and more severely, which is exactly the concern," Shen explained.
They wanted to know more about why this was happening and found that cell death pathways were also more active in mice with stressed aortas that got antibiotic. They also saw that a critical enzyme called LOX was low, there was more fragmentation in their elastic fibers and an increase in MMP, which is a degradative enzyme. The MMP and LOX results were then confirmed in a human cell model.
"Our findings support the concerns raised by previous retrospective clinical studies and suggest that ciprofloxacin and other antibiotics of the same class should be used with caution in patients with aortic dilatation," Shen said.
"If we consider the clinical data and our experimental results that prove causation in a reliable model of AAD, I believe we have enough evidence for changing guidelines on the use of fluoroquinolone antibiotics for people who have an aneurysm or are at risk for getting an aneurysm," LeMaire said. "I am hopeful that these guidelines can be changed in short order."
Sources: AAAS/Eurekalert! Via Baylor College of Medicine, FDA, Jama Surgery