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InFocus: Fluoroquinolone Side Effects Just Got Scarier

Roberts, James R., MD

doi: 10.1097/01.EEM.0000547204.98717.6a
InFocus

Dr. Roberts is 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, at http://bit.ly/EMN-ProceduralPause, and read his past columns at http://bit.ly/EMN-InFocus.

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Fluoroquinolones were rather remarkable antibiotics when first introduced to our clinical armamentarium. They had a broad spectrum and relatively few known side effects, and they quickly became the drug of choice for some common conditions. But fluoroquinolones, as with many antibiotics, have been overused. Serious side effects have been associated with them over the years, and numerous cautions from the FDA limit their use. A number of label changes have been mandated, and some fluoroquinolones even have black box warnings. Google “fluoroquinolones” if you want to be flabbergasted about patient issues and lawsuits.

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Fluoroquinolone Antibiotics: FDA Requires Labeling Changes Due to Low Blood Sugar Levels and Mental Health Side Effects

FDA Drug Safety Communications

July 10, 2018; http://bit.ly/2OQvFmh

Clinicians were recently warned of additional adverse side effects of fluoroquinolones, further limiting their use. Many emergency clinicians have not seen some of the particular problems with these drugs because they don't see patients on a continuing basis and don't follow them in the hospital. And the side effects are so peculiar you wouldn't have automatically made the connection between some of them and fluoroquinolones, such as tendon rupture and peripheral neuropathies. Now the FDA has identified two additional side effects associated with fluoroquinolones: low blood sugar and mental health conditions.

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Table

We have been warned about these complications in the past, but the FDA thought it was necessary to strengthen the current warnings. Broad-spectrum antibiotics have been used for more than 30 years, have been quite effective, and have been frequently prescribed, but their use has waned due to drug complications, changes in antibiotic resistance, and the development of new antibiotics.

Their drug labels warn that changes in blood sugar can be high or low depending on the fluoroquinolone class. High or low blood sugar is easily recognized and proven, but the mental health side effects may be more subtle. They include conditions from simple insomnia, a very common reaction to fluoroquinolones, to disturbance in attention, disorientation, agitation, nervousness, memory impairment, seizures, and full-blown delirium. Diabetic patients have been warned to check their blood sugar more frequently when on fluoroquinolones because of possible changes in glucose levels. Many of the complications with fluoroquinolones are self-limited, and may even go unnoticed by family and clinicians, but some can be permanent.

Achilles tendon rupture is a classic complication that requires surgery. The side effects of fluoroquinolones can occur quickly, with only one or two pills or injections creating a problem, though side effects are generally related to the duration of therapy.

Comment: Five fluoroquinolone antibiotics are currently available for use in the United States, and five others have been withdrawn from the market since the late 1990s. The drugs and some culpable side effects are listed in the table.

Fluoroquinolones are the only class of antibiotics in clinical use that are direct inhibitors of bacterial DNA synthesis. Ultimately, the effect on DNA damages the bacterial cell, making it incapable of surviving. Fluoroquinolones have a true bactericidal effect, but it's a mystery why halting bacterial DNA would cause such unusual systemic effects.

Reports have shown that Staphylococcus aureus exposed to fluoroquinolones for only five days is associated with significant drug resistance. Resistance has also developed in Klebsiella pneumoniae, Escherichia coli, and Enterobacter. These organisms apparently have a mechanism that will protect bacterial DNA enzyme from fluoroquinolone action. U.S. fluoroquinolone resistance has been more common with methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Fluoroquinolones are no longer recommended for treating gonorrhea in the United States because of the emergence of resistance by Neisseria gonorrhoeae. Fluoroquinolone resistance has emerged over time for a variety of organisms, but the percentage of susceptible strains varies among institutions and localities, requiring clinicians to know local sensitivity.

The most frequent adverse effects occur in the GI tract (3-15% of patients) as anorexia, nausea, vomiting, and abdominal discomfort. Mild diarrhea is usually not significant, but fluoroquinolones can cause Clostridium difficile-associated diarrhea.

The next most frequent adverse effects involve the central nervous system, unusual for an antibiotic but seen in 10 percent of patients. That's a rather high incidence. Many patients have mild symptoms, such as headache, dizziness, and insomnia. Nonspecific alterations in mood are quite common. Frank hallucinations, delirium, and seizures can occur. Patients treated with fluoroquinolones are at higher risk for developing clinical neuropathies that include pain, burning, tingling, weakness, and a change in the sensations of light touch or sense of body positioning. Peripheral neuropathy can occur at any time during treatment, can last for years, and is quite problematic for some patients. Clinical neuropathy can occur within a few days of use, and no specific treatment exists.

Fluoroquinolones have neuromuscular blocking activity and can exacerbate muscle weakness in patients with myasthenia gravis. They have also been associated with pseudotumor cerebri, though the incidence is low, and they decrease the protection afforded by sunscreens.

Arthropathy, with cartilage erosions and effusions, has been seen in animals given fluoroquinolones, and it was initially a concern in children, but it is probably uncommon and has little clinical presence. Arthropathy appears to be reversible.

The fluoroquinolone complications that have garnered these drugs a block box warning are tendinopathy and tendon rupture. Most cases involve the Achilles tendon, but they can occur in other tendons, such as the shoulder or hand. Patients should be warned to stop fluoroquinolones at the first sign of tendon pain or inflammation because Achilles tendon rupture can occur rather early in the course. Tendon rupture can develop without associated symptoms of tendonitis, and minimal trauma can cause complete tendon rupture.

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Some fluoroquinolones have been associated with QT prolongation and arrhythmias (torsades de pointes). The QT prolongation from torsades de pointes can be life-threatening. The two fluoroquinolones most likely to cause QT prolongation have been removed from the market, but experts recommend avoiding moxifloxacin and levofloxacin in patients with known QT interval prolongation, hypokalemia, and hypomagnesemia. The use of class 1 antiarrhythmics (quinidine, procainamide, amiodarone, and sotalol) may also put a patient at risk.

All these complications led the FDA to issue warnings that the serious adverse effects associated with fluoroquinolones generally outweigh the benefits in patients with acute sinusitis, acute bronchitis, or uncomplicated urinary tract infections, and they should not be prescribed when other treatments are available. Many of these cases are viral rather than bacterial infections, but it was once common for clinicians to prescribe a quinolone for acute bronchitis, UTI, or acute sinusitis. Note that ciprofloxacin is no longer considered a first-line drug for uncomplicated urinary tract infection. Antibiotic choices for patients hospitalized with acute community-acquired pneumonia still include levofloxacin and moxifloxacin or a combination of the beta lactam and a macrolide. Many clinicians are eschewing fluoroquinolones in favor of a beta lactam and a macrolide.

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FDA Advises Restricting Fluoroquinolone Antibiotic Use for Certain Uncomplicated Infections, Warns about Disabling Side Effects that Can Occur Together

“5-12-2016: The U.S. Food and Drug Administration is advising that the serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections.

An FDA safety review has shown that fluoroquinolones, when used systemically (i.e., tablets, capsules, and injectable) are associated with disabling and potentially permanent serious side effects that can occur together. These side effects can involve the tendons, muscles, joints, nerves, and central nervous system.”

Reader Feedback: Readers are invited to ask specific questions and offer personal experiences, comments, or observations on InFocus topics. Literature references are appreciated. Pertinent responses will be published in a future issue. Please send comments to emn@lww.com.

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