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Aortic Aneurysm and Dissection Added to List of Fluoroquinolone Side Effects

Roberts, James R. MD

doi: 10.1097/01.EEM.0000554289.40781.ad
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Figure

Hardly a day goes by that emergency physicians do not write a prescription for a fluoroquinolone, rarely giving it a second thought. No wonder: Five different ones are popular for a variety of infections, and they have a rather broad spectrum of activity for mainly gram-negativebacteria but also for some gram-positive organisms.

We rarely tell patients about all of the potential adverse effects that might occur—we don't even know many of the adverse side effects, or we rarely see them because we do not see patients for follow-up. But multiple serious toxicities have been associated with fluoroquinolone antibiotics. A number (grepafloxacin, sparfloxacin, trovafloxacin, gatifloxacin, and norfloxacin) have been withdrawn from the market in the United States because of adverse side effects.

Fluoroquinolones are bactericidal agents that have a rather unique mechanism of action. They inhibit the bacterial enzymes that have a distinct role in DNA replication and in blocking the enzyme system in bacteria, leading to cell death. Bacterial resistance to fluoroquinolones occurs rather frequently, but their use remains widespread. Fluoroquinolones were once the mainstay of therapy for gonorrhea, but are no longer recommended for this sexually transmitted disease in the United States. Resistance has also been creeping up for Campylobacter and Streptococcus pneumoniae. Levofloxacin is still recommended as single empiric therapy for community-acquired pneumonia.

A number of label changes have been mandated over the past few years, and black boxes warn against some fluoroquinolone side effects. Google “fluoroquinolones” to be surprised by the patient issues and lawsuits associated with these drugs.

The FDA has advised against using fluoroquinolones for patients with sinusitis, bronchitis, and uncomplicated urinary tract infections when other options exist. These drugs, particularly ciprofloxacin, used to be a mainstay for treating run-of-the-mill cystitis, but that drug was taken off the preferred antibiotic list by infectious disease society recommendations a number of years ago. This new information on potential lethal aortic problems is indeed concerning.

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Fluoroquinolone Use and Risk of Aortic Aneurysm and Dissection: Nationwide Cohort Study

Pasternak B, Inghammar M, Svanström H

BritMedJ

2018;360:K678

http://bit.ly/2VSCoPW

This Swedish study of 360,000 treatment episodes compared patients taking a fluoroquinolone, primarily ciprofloxacin, with a similar cohort of patients taking amoxicillin. It investigated whether oral fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection. The authors noted that fluoroquinolones can induce degradation of collagen and other structural components of the extra cellular matrix. They may also reduce the de novo production of collagen and induce oxidative stress. The pathophysiology of aortic aneurysm and dissection could be influenced by fluoroquinolones because the aorta's integrity depends heavily on an intact extracellular matrix. Previous studies have raised concerns about fluoroquinolones and aortic aneurysm and dissection, but the data were not convincing.

Table FDA

Table FDA

These authors reviewed all prescriptions filled in Swedish pharmacies, all hospital admissions, and all causes of death in a death registry from July 2006 to December 2013, and evaluated aortic issues up to 60 days after the prescription was filled. The primary outcome was the first diagnosis of aortic aneurysm or dissection of the thoracic or abdominal aorta. The data were believed to capture the first clinical encounter of aortic aneurysm or dissection.

Sixty-four cases of aortic aneurysm or dissection were found in those treated with a fluoroquinolone compared with 40 cases of those treated with amoxicillin within the 60-day risk period. The difference was noted within a 60-day risk period, though no difference was seen in the aortic pathology 61 to 120 days after treatment began. Fluoroquinolone use overall was associated with a 66 percent increased rate of aortic aneurysm or dissection within 60 days of treatment. The rate of aneurysm or dissection was 1.2 cases per 1,000 among the fluoroquinolone users and 0.7 cases per 1,000 among those taking amoxicillin.

Comment: The FDA warned in August 2013 of the risk of peripheral neuropathy with fluoroquinolone use that could develop soon after the drugs were taken; its effects could be prolonged or even permanent.

The FDA Safety and Information Adverse Event Reporting Program in 2016 issued a drug safety communication describing disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient. (May 12, 2016; http://bit.ly/2TS15Kr.) The FDA issued its strongest caution, a boxed warning, about these serious issues, and later added a black box warning that fluoroquinolones could cause tendonitis and tendon rupture, especially to the Achilles' tendon, particularly in patients over 60 and for those with kidney, heart, and lung transplants using concomitant steroid therapy. It was further advised that physicians should stop fluoroquinolone use at the first sign of tendon pain, swelling, or inflammation. Unfortunately, tendon rupture can occur without prior signs of tendonitis.

The FDA also recently required labeling changes to warn of fluoroquinolones causing low blood sugar levels and mental health issues. Other side effects include simple insomnia (a common reaction), attention disturbances, disorientation, agitation, nervousness, memory impairment, seizures, and full-blown delirium. I once saw a seizure in a patient who received two doses of oral ciprofloxacin.

It would be prudent for clinicians to warn patients of fluoroquinolone-related adverse effects, but it's not clear exactly what to tell them. Often stopping the drugs does not alter some of the adverse effects, and there appears to be no way to predict who will develop them. Many patients would not take the drugs if they were told all of the fluoroquinolone side effects, so one must temper warnings with clinical use. I have never seen the FDA become so involved in commenting on and warning about potential side effects of antibiotics as it has with fluoroquinolones.

Previous studies have raised concern that fluoroquinolones could be associated with the risk of aortic aneurysm or dissection. A systemic review and meta-analysis by Sing, et al., concluded that evidence from a small number of studies suggested that exposure to fluoroquinolones was consistently associated with a small but significantly increased risk of aortic dissection and aortic aneurysm. (Am J Med 2017;130[12]:1449.) The risk was considered modest, and the number needed to treat was 618 for aortic aneurysm in patients 65 and older who were current users of fluoroquinolones.

Table

Table

The proposed mechanism is that the antibiotics might jeopardize the integrity of the extracellular matrix of the vascular wall. The antibiotic most commonly studied was ciprofloxacin. Interestingly, these cases occurred within a mere 60 days of initiation of treatment, and the risk was most pronounced in the first 10 days. This is a rapid onset of a life-threatening vascular event in patients not known to have underlying pathology. That is difficult to comprehend!

These aortic complications were noted to be more common in certain patients, including those who had a known aneurysm, high blood pressure, and certain genetic diseases that involve the blood vessels, such as Marfan syndrome and Ehlers-Danlos syndrome. The FDA also suggested not using these drugs in the elderly or those with hypertension, a rather large cohort of patients. The agency also said patients should be told about potential problems and to seek immediate medical attention if they have symptoms suggestive of the aortic problems. The FDA, by the way, issued a statement in May 2017 that its findings did not show that these medicines would result in aortic aneurysm or dissection.

Considering the disabling and potentially permanent serious side effects associated with fluoroquinolones, one wonders whether these antibiotics should be prescribed at all. They have been excluded from FDA approval for sinusitis, bronchitis, and uncomplicated urinary tract infection if other antibiotics are possible for treatment. I would not be surprised if a black box warning were issued soon for the aortic issues. The fact that the aortic aneurysm or dissection occurred within 60 days of use, some within a short 10 days, is very unsettling. Fortunately, the number of patients exhibiting these aortic issues was quite small, and it is unlikely that a clinician would experience such a case in many years of practice.

In short, physicians should have great respect for fluoroquinolone side effects and not routinely prescribe them for sinusitis, bronchitis, or uncomplicated urinary tract infections. Psychosis, seizures, bizarre dreams, and hallucinations would not likely be attributed to an antibiotic by most patients or clinicians, but they are clearly associated with fluoroquinolones. It's best to provide a written list of potential complications at discharge using a computer-based program. Pharmacies now provide such written information with all prescriptions. Whether patients remember multiple warnings or react appropriately to such cautions is uncertain. A Google search yields some really bad press for these antibiotics, and the medicolegal issues have tweaked plaintiff lawyers. Reading some of the horror stories in chat rooms will inflame and convince many that fluoroquinolones have produced their multiple unexplained conditions, but the exact correlation of fluoroquinolone use with many bizarre and prolonged complaints is suspect.

The best approach is simply to limit the use of these antibiotics and carefully document that you cautioned patients about the side effects when you do prescribe them, though I don't know how a warning could stop aortic disease from occurring in a few days. Fortunately, given the small number of cases, producing aortic aneurysm or dissection from your fluoroquinolone prescription would be unlikely, but it is impossible to predict who will develop a specific adverse effect, especially when it can occur rapidly and with minimal use, and the only way to avoid them totally is to eschew the fluoroquinolone prescription.

Dr. Robertsis a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read the Procedural Pause, a blog by Dr. Roberts and his daughter, Martha Roberts, ACNP, PNP, athttp://bit.ly/EMN-ProceduralPause, and read his past columns athttp://bit.ly/EMN-InFocus.

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