Fluoroquinolones are a popular class of antibiotics that kill bacteria or prevent their growth. They are used to treat a variety of infections, with newer drugs in the class developed with a broader range of indications and effectiveness. But these medications have also been associated with several serious side effects and toxicities, some of which can be deadly.
Several fluoroquinolones have been removed from the market, including grepafloxacin in 1999, removed worldwide after adverse reports of cardiac episodes, and sparfloxacin (brand name Zagam) removed from the U.S. market in 2001, mostly due to poor sales performance.
The FDA, over the years, has strengthened the drug labeling for remaining fluoroquinolones with the addition of three black box warnings, the agency’s most serious type of warning, from 2008 to 2016.
These black box warnings advise patients taking fluoroquinolones of their heightened risk of developing the following conditions:
- Tendinitis and tendon rupture
- Worsening of myasthenia gravis (a neuromuscular/autoimmune disease)
- Permanent nerve damage (peripheral neuropathy)
The FDA also advised that the following patients avoid the use of the antibiotics, including those with:
- Acute bacterial sinusitis (inflammation of the sinuses)
- Acute exacerbation (worsening) of chronic bronchitis
- Uncomplicated urinary tract infections that can be cured with the use of other medicines
Fluoroquinolones and Tendinitis & Tendon Rupture
Tendons are flexible bands of tissue (fibrous structures) that connect muscles to bones, according to the National Institutes of Health (NIH). They aid muscles in the movement of bones. When a tendon becomes severely swollen (inflamed), the condition is called tendinitis.
Tendinitis is often referred to in combination with the body part involved in the injury, such as Achilles tendinitis, when the condition affects the heel. Other commonly affected areas include the elbow, knee, shoulder, thumb and wrist.
Tendinitis is typically an acute condition, meaning it comes on suddenly, is generally severe and lasts for just a short time. When the symptoms of tendonitis last for more than six months, it becomes a condition called tendinosis (or chronic tendinitis), which means the tendon has experienced damage at a cellular level (tendon degeneration).
Tendinosis may lead to an increase in tendon repair cells causing reduced tensile strength and increasing the risk of tendon rupture. A tendon rupture occurs when part or all of the tendon is torn. If untreated, this can result in permanent disability.
Tendon Injury Link to Fluoroquinolones
The first published report of a tendon injury associated with the use of fluoroquinolones was published in New Zealand in 1983, according to the Journal of Clinical and Aesthetic Dermatology. Many anecdotal case reports and case-controlled studies reporting similar findings came out after the publication, most originating in France.
Tendon rupture can result in permanent disability for some patients taking fluoroquinolones.
A World Health Organization (WHO) survey in Australia found that ciprofloxacin was the cause of 90 percent of fluoroquinolone-induced tendon injuries. But other reports have also indicated norfloxacin, pefloxacin, ofloxacin and levofloxacin in such injuries. As a result, in July 2008, the FDA required all fluoroquinolone manufacturers to include a black box warning indicating the increased risk of tendon rupture in patients taking these medications.
The drug label addition also advised patients and health care providers that this risk is even greater for individuals over the age of 60, in those who have received kidney, heart or lung transplants, and with the simultaneous use of steroid therapy.
Symptoms of Tendinitis
Tendinitis primarily results in pain and soreness around a joint. Other symptoms of the condition may vary depending on the cause and location of the injury.
Patients taking fluoroquinolones that result in tendon injuries, such as tendinitis, may experience the following symptoms:
- Stiffness, especially in the morning
- Difficulty moving a muscle or pain that worsens with movement
Symptoms of tendon rupture that may require immediate emergency medical care include:
- Hearing or feeling a snap or pop in a tendon area
- Bruising after an injury to a tendon area
- Inability to move or carry weight on an affected area
Treatment of Tendinitis
Tendinitis can be diagnosed following a physical exam, which will look for signs of pain and tenderness when the muscle attached to the tendon is moved in various ways; or if the tendon is inflamed, the skin covering it may be warm and red. Other tests might include an ultrasound, X-ray or MRI.
Treatment is intended to relieve pain and reduce inflammation. Resting the affected tendon as it heals is often recommended as well. This can be accomplished by using a splint or a removable brace. Applying heat or cold to the affected area can also assist with recovery and offer some relief from any pain or discomfort.
Patients may be advised to take over-the-counter (OTC) pain relievers, such as NSAIDS like aspirin or ibuprofen, which are effective in relieving symptoms of both pain and inflammation. Steroid injections can also be administered into the tendon sheath when necessary to control pain.
Ciprofloxacin was determined to account for 90 percent of all tendon injuries resulting from patients’ use of fluoroquinolones.
Patients may undergo physical therapy (PT) to stretch and strengthen the tendon as well as the attached muscle. PT may also be effective in restoring the tendon’s ability to function properly, improve healing and prevent future (or repeat) injury. In some more severe cases, surgery may be needed to remove the inflamed tissue from around the tendon.
Approximately 50 percent of patients with tendinitis in their heel as a result using fluoroquinolones recover within 30 days, after discontinuation of the drug and the start of PT, according to the Journal of Clinical and Aesthetic Dermatology. Another 25 percent of those same patients will have symptoms that persist longer than two months.
Early diagnosis is key in preventing tendon rupture.
Fluoroquinolones and Myasthenia Gravis
Myasthenia gravis is a neuromuscular disorder and an autoimmune disease that causes weakness in voluntary or skeletal muscles, such as those responsible for facilitating breathing and moving parts of the body, including the arms and legs, as well as eye movement, facial expressions and swallowing.
A neuromuscular disorder involves the muscles and the nerves that control them, while an autoimmune disease occurs when a person’s immune system mistakenly attacks otherwise healthy tissue. In people with myasthenia gravis, the body produces antibodies (proteins made by the immune system when it suspects harmful substances in the body) that block the nerve cells and muscles cells from communicating via neurotransmitters (or chemicals that brain cells — neurons — use to send messages).
The name myasthenia gravis, which is Latin and Greek in origin, means “grave, or serious, muscle weakness,” according to the National Institutes of Health (NIH). The condition is likewise characterized with muscle weakness that worsens after various movements and periods of activity and improves with rest.
Muscles that can be affected include those that control:
- Eye and eyelid movement
- Facial expression
- Neck and limb movements
Myasthenia gravis can affect people of all ages, but it is most commonly diagnosed in young women and older men.
Myasthenia Gravis Link to Fluoroquinolones
Exposure to fluoroquinolones may result in the worsening of myasthenia gravis in patients, according to a 2011 study published by the National Institutes of Health (NIH). The authors of the study concluded that health care professionals should be aware of this serious link between the drug and the disease and carefully weigh the benefits to the risks associated with fluoroquinolones when treating infections in patients with myasthenia gravis.
The study, designed to evaluate post-marketing adverse event reports submitted to the FDA and case reports published in scientific literature, identified a total of 37 cases that reported myasthenia gravis exacerbation following the use of fluoroquinolones.
In February 2011, the FDA necessitated a black box warning, advising consumers that taking ciprofloxacin, a type of fluoroquinolone, may worsen muscle weakness in people with myasthenia gravis, causing severe difficulty breathing or even death.
Symptoms of Myasthenia Gravis
The onset of myasthenia gravis may be sudden and symptoms are not always immediately recognized as resulting from the disorder. The first noticeable symptom is often weakness of the eye muscles. In some, however, the first signs may be difficulty swallowing and slurred speech.
The degree of muscle weakness associated with the condition can vary greatly from one person to another, ranging also from a localized form affecting a limited area of muscles to a severe or generalized form affecting many muscles, including those involved in breathing.
Autonomic (involuntary or unconscious; relating to the autonomic nervous system) muscles of the heart and digestive tract are typically not affected.
Symptoms most commonly associated with myasthenia gravis include:
- Breathing difficulty because of weakness of the chest wall muscles
- Chewing or swallowing difficulty, causing frequent gagging, choking or drooling
- Difficulty climbing stairs, lifting objects or rising from a seated position
- Difficulty talking
- Drooping head and eyelids
- Facial paralysis or weakness of the facial muscles
- Hoarseness or changing voice
- Blurred or double vision, due to weakness of the muscles that control eye movements
- Difficulty maintaining steady gaze
- Weakness in the arms, hands, fingers, legs and neck
Treatment of Myasthenia Gravis
There is no known cure for myasthenia gravis. Treatment can allow for some patients to have periods without any symptoms (called remission), but this is usually only temporary. Available treatments can assist in the control of symptoms to allow for a relatively high-quality (normal or near-normal) life for individuals suffering from the condition.
Anticholinesterase and Immunosuppressive medications
Certain medications can help improve nerve-to-muscle messages as well as strengthen muscles. Other medications can prevent the body from producing so many abnormal antibodies. However, these medicines can have major side effects and therefore, should be used with caution.
Treatments available can filter abnormal antibodies from the blood or add healthy antibodies supplied from donated blood. This procedure is called plasmapheresis, and is often undertaken in more severe cases or where crisis has occurred, meaning the muscles that control breathing are weakened to the point of individuals requiring a ventilator to breathe. Plasmapheresis is often attempted prior to surgery.
A second procedure called intravenous immunoglobulin (IVIg) can also be effective for some patients. It works by injecting a large amount of highly concentrated antibodies, from healthy donors, directly into the bloodstream, temporarily changing the way the immune system operates. The helpful antibodies bind to the ones causing the condition, thereby removing them from circulation.
The final option is surgery to remove the thymus, called a thymectomy. This gland is often abnormal in individuals with myasthenia gravis and its removal can result in permanent remission or reduced symptoms in some patients, especially when there is a tumor present, thereby also reducing a patient’s need for medications. Remissions that are long-lasting are the goal of surgery, with the NIH estimating that this is possible in about 50 percent of individuals undergoing a thymectomy.
Eye surgery may also be recommended to treat the eye muscles, if affected.
Most patients with myasthenia gravis have a normal life expectancy. However, sometimes the severe weakness associated with myasthenia gravis can cause respiratory failure, which necessitates emergency medical intervention, as it can potentially result in death.
Warning for myasthenia gravis patients
The use of fluoroquinolones by myasthenic patients can result in difficulty breathing that can be deadly.
Fluoroquinolones and Peripheral Neuropathy
Peripheral neuropathy is “very common,” affecting about 20 million Americans, according to the National Institutes of Health (NIH). It occurs when the peripheral nervous system is damaged by injury (physical trauma), illness or exposure to certain drugs, like fluoroquinolones.
Peripheral nerves carry information to and from the brain as well as signals to and from the spinal cord and to the rest of the body. When a person has peripheral neuropathy, these nerves don’t work properly. NIH compares the disorder of the peripheral nerves to “static on a telephone line,” with the nerves distorting or interrupting the messages between the brain and the rest of the body.
The condition can occur because of damage to a single nerve (mononeuropathies), a group of nerves (polyneuropathy) or it can affect nerves throughout the entire body. Some peripheral neuropathies are due to damage to the axons (or the long, slender projection of the nerve cell), with others caused by damage to the myelin sheath (a fatty white substance that coats and insulates the axon), or a combination of the two.
Peripheral Neuropathy Link to Fluoroquinolones
In 2013, the FDA announced it was strengthening warnings in the labels for fluoroquinolones to better describe the disabling side effect of peripheral neuropathy. Previous warnings about this serious nerve damage were not strong enough or clear enough, the FDA said. Specifically, the federal agency said older labels failed to explain fully that neuropathy damage can happen immediately after taking the drugs and can be permanent. The FDA told doctors and consumers to discontinue the medication immediately if symptoms of nerve damage surface.
Patients who develop peripheral neuropathy after taking fluoroquinolones can experience life-long nerve damage.
FDA data shows a continued association between the drugs and the crippling nerve disorder, which occurs in the arms and legs. In fact, the onset of peripheral neuropathy after starting fluoroquinolone therapy was rapid, often within a few days. In some patients, the symptoms had lasted for more than a year, even after users had stopped taking the drugs. Several patients were continued on fluoroquinolones despite their showing signs of the disorder. The FDA ultimately concluded peripheral neuropathy can occur at any time during treatment with fluoroquinolones and can last for months to years after the drug is stopped or be permanent.
A study published in 2014 by the peer-reviewed journal Neurology further supported the FDA’s findings. The study showed long-time users of fluoroquinolones had twice the risk of developing peripheral neuropathy, while new users had a slightly greater risk. Researchers said, “Clinicians should weigh the benefits against the risk of adverse events when prescribing these drugs to their patients.” Researchers studied more than 30,000 men in the U.S. from 2001 to 2011.
Fluoroquinolones can cause nerve damage that lasts for months to years after the drug is stopped.
Symptoms of Peripheral Neuropathy
Symptoms of peripheral neuropathy vary depending on what nerves are damaged (i.e. motor, sensory or autonomic). Motor nerves control voluntary movement of muscles used for walking, grasping things or talking; sensory nerves transmit information that results in feeling from touch or pain from injury; and autonomic nerves control organ activity activities that are automatic, such as breathing, digesting food, and heart and gland functions.
In some cases, all three types of nerves can be affected.
Damage to the nerves interferes with the messages coming from the brain to the rest of the body. These confused messages can wreak havoc on the types of sensations someone feels. For example, a person may feel severe pain in response to sensations that should not cause pain, like feeling pain from bed sheets, or numbness in fingers and toes. The nerves in the hands and feet are the first to be affected.
Symptoms often start gradually, and then worsen over time. The most common symptoms of the condition include:
Pain or numbness
Burning or tingling
Sensitivity to touch, pain or temperature
Neuropathy is typically not fatal, but it can cause a lifetime of suffering. Some more severe symptoms of neuropathy include:
Burning pain at night
Organ or gland dysfunction
Poor sexual function
Poor bowel control
Diagnosis and Treatment of Peripheral Neuropathy
There are over 100 different kinds of neuropathy. Each type has its own symptoms, prognosis and treatment. Typically, a doctor starts by performing a physical exam and asks about the patient’s health history and symptoms. The doctor may also recommend blood tests to look for causes of nerve damage.
Other diagnostic tests include:
- Electromyography (EMG) – involves inserting a fine needle into a muscle to detect abnormal electrical activity in muscles and to help differentiate between muscle and nerve disorders.
- Nerve conduction velocity (NCV) – uses probes to electrically stimulate a nerve fiber and measures how quickly signals travel among nerves.
- Magnetic resonance imaging (MRI) – produces detailed pictures that can help rule out tumors and other abnormalities that can cause neuropathy.
- Nerve biopsy – involves removing a sample of nerve tissue (most often from the lower leg) and examining it under a microscope.
- Skin biopsy – involves removing a thin skin sample and examining nerve fiber endings.
After doctors diagnose a specific type of nerve damage, they discuss treatment options. First, they will address the cause such as hormones, vitamin deficiencies or exposure to toxic medications. Sometimes, eliminating the issues that caused the damage allows nerves to regenerate.
“Peripheral nerves have the ability to regenerate axons, as long as the nerve cell itself has not died, which may lead to functional recovery over time,” according to the National Institute of Neurological Disorders and Stroke. “Correcting an underlying condition often can result in the neuropathy resolving on its own as the nerves recover or regenerate.”
Surgery treatment option
Patients may choose to undergo surgery that releases the nerve from the tissues compressing it. Surgery that destroys problematic nerves to stop pain is only considered after all other courses of action are exhausted and only works when a single nerve is affected. Some peripheral neuropathies don’t respond to surgery of any type.
Adopting a healthy diet and exercise can help manage symptoms. Exercise, for example, can reduce cramps, improve muscle strength and prevent muscle from wasting away. A doctor may recommend supplements or injections to people who have low levels of B12 or other vitamins. Anyone with diabetes should become more knowledgeable on how to control blood sugar, and people who drink alcohol should stop.
Some people participate in therapy to learn exercises to improve their muscle strength and control. Doctors may recommend using a wheelchair, braces and splints to improve movement or even help a patient regain the ability to use an arm or leg that has nerve damage. Orthopedic shoes are another option and can help prevent foot injuries in people who can’t feel pain.
In many cases, doctors may have to prescribe strong drugs including pain killers, antidepressants and anticonvulsants. Antidepressants and anticonvulsants tend to be the medications that are most effective at reducing neuropathic pain. Antidepressant medications can include Elavil (amitriptyline), Cymbalta (duloxetine hydrochloride) or Effexor (venlafaxine). Frequently used anticonvulsant medications include gabapentin, pregabalin, topiramate and carbamazepine.
These drugs typically do not bring back loss of feeling and are generally prescribed to people with neuropathy to reduce pain in the feet, arms and legs. They have their own laundry list of side effects. Opioid pain killers can also leave some people addicted.
Some people may turn to alternative medicine to supplement their treatment. These therapies may include acupuncture, alpha-lipoic acid, fish oil supplements, amino acids and herbs, such as curcumin, geranium oil and evening primrose oil.
Topical medications — such as topical lidocaine, an anesthetic agent, and capsaicin, a substance found in hot peppers that modifies peripheral pain receptors — may also improve neuropathic pain. Another non-invasive method is transcutaneous electrical nerve stimulation (TENS). It involves attaching electrodes to the skin and releasing an electrical current. The efficacy of this therapy in treating peripheral neuropathy has not been tested in controlled clinical trials. However, some studies have shown it improves symptoms of diabetic neuropathy.
How well a patient does depend on the cause and extent of the nerve damage. Sometimes, even with treatment, nerve damage can be permanent. Long-term (chronic) pain is likely, with numbness in the feet often leading to skin sores that are hard to heal, which, in rare cases, require amputation.
Fluoroquinolones and Heart Problems
The lining of the aorta is made up of collagen. Scientists suspect that fluoroquinolones break down collagen in the body. Two 2015 studies published in JAMA and BMJ medical journals reveal a connection between fluoroquinolones and collagen damage that may lead to aortic aneurysms.
An aortic aneurysm is a bulge in the aorta, which is the artery responsible for carrying blood from the heart through the chest and torso.
Aortic aneurysms can act in two ways:
- Tears can form in the aorta, allowing blood to leak in between the layers of tissue in the vessel wall, separating them. This is called aortic dissection.
- The aneurysm can also rupture, which is when it bursts completely, causing bleeding inside the body.
According to the JAMA study, fluoroquinolones were associated with a two-fold increase in risk of dissection and aneurysm within 60 days of using the drug. Authors said, “Clinicians should continue to be vigilant for the appearance of aortic aneurysm and dissection in high-risk patients treated with fluoroquinolones.”
The BMJ study found nearly a three-fold increase in the risk of aneurysm. Authors of this study followed about 1.7 million patients and found one third of them received a prescription for a fluoroquinolone. “Reducing unnecessary fluoroquinolone treatments or prolonged treatment courses might have possibly prevented more than 200 aortic aneurysms in this population,” study authors said.
Aortic aneurysms were the primary cause of 9,863 deaths in 2014, and dissections and ruptures are the cause of most deaths from aortic aneurysms, according to the Centers for Disease Control and Prevention.
Aortic Aneurysm Rupture
Aortic aneurysms weaken the aortic wall and are more likely to burst. They can occur in the abdomen (abdominal aortic aneurysm) or in the chest (thoracic aortic aneurysm). These weak spots are extremely dangerous, and once they burst, a patient has a 50 percent chance of survival.
Aneurysms often have no symptoms. These bulges may be found while testing for other conditions on a CT scan or ultrasound of the heart. When the thoracic aneurysm ruptures, people have difficulty breathing, severe chest pain or severe back pain or may lose consciousness.
A ruptured aneurysm is an emergency situation and must be treated immediately. Doctors may prescribe surgery or an aortic stent.
Dissection interrupts the blood flow to other organs by blocking other blood vessels that feed them. This can lead to stroke, paralysis, kidney failure and other problems. All dissections can lead to death, and it is extremely important to catch them early. Doctors typically use CT scans to diagnose them. Treatment may or may not require surgery to replace the dissected portion of the aorta.
Symptoms of aortic dissection include:
- Chest pain
- Paralysis of an arm or leg
- Appearance of having a stroke or heart attack
- Loss of pulse in affected arm or leg
- Flu-like symptoms
- Back pain
- Loss of consciousness
- Difficulty speaking
- Loss of vision
- Dizziness or confusion
In May 2017, the FDA updated a 2016 safety alert to include new information regarding aortic aneurysm and aortic dissection. The agency said it found cases submitted to the FDA and published in medical literature do not support reports that fluoroquinolones may result in aortic aneurysm and aortic dissection.
“FDA will continue to assess safety issues with fluoroquinolones and will update the public if additional actions are needed,” the agency said.
Kristin Compton is a medical writer with a background in legal studies. She has experience working in law firms as a paralegal and legal writer. She also has worked in journalism and marketing. She’s published numerous articles in a northwest Florida-based newspaper and lifestyle/entertainment magazine, as well as worked as a ghost writer on blog posts published online by a Central Florida law firm in the health law niche. As a patient herself, and an advocate, Kristin is passionate about “being a voice” for others.