Commonly prescribed drugs called fluoroquinolones, the fourth-most used class of antibiotics in the US, have been shown to cause rare, disabling side effects. Patients have experienced pain in tendons, joints and muscles, neurological and psychological difficulties. Researchers now have a few theories why such symptoms may occur.
In 2014, Miriam van Staveren went on holiday to the Canary Islands. The resort doctor prescribed a six-day course of antibiotic levofloxacin for her infection. After she had returned home to Amsterdam, her Achilles’ tendons started to hurt. She developed shooting pains in her legs and feet, as well as fatigue and depression.
Previously an active tennis player could barely walk. “I got sicker and sicker,” she said for Nature. “I was in pain all day.”
Levofloxacin belongs to the antibiotic family of fluoroquinolones and is massively prescribed, with doctors doling out 32 million prescriptions for the drug only in the US in 2015. Even though only a small percentage experience side effects it still amounts to thousands of people affected around the world. Some of them gather to share their frequently horrendous experiences on sites like Floxie Hope and My Quin Story. They describe symptoms ranging from semi-permanent and permanent psychiatric and sensory disturbances to problems with muscles, tendons, and nerves.
After years of skepticism, FDA accepted the existence of a fluoroquinolone-associated disability (FQAD) in 2016 and recommended that the drugs be reserved for serious infections only. The European Medicines Agency (EMA) is expected to publish the results of an extended EU-wide safety review this year.
Scientists and healthcare professionals are starting to realize that some antibiotics don’t just interfere with microbes. James Collins, a medical engineer at the Massachusetts Institute of Technology in Cambridge said: “Antibiotics are also disrupting our cells and in pretty hefty ways.”
Quinolone antibiotics kill bacteria by blocking enzymes called class II topoisomerases, which untangle DNA during cell replication. These enzymes usually cut the DNA’s double helix, pass another part of the strand through the gap, and then mend the cut. But quinolones bind to the enzymes, preventing them from mending their cuts. Researchers boosted effectiveness by adding fluorine atoms to the antibiotic, enabling it to penetrate tissues throughout the body.
“These are heavily used drugs because they are very effective,” said Joe Deweese, a biochemist who studies topoisomerases at Lipscomb University College of Pharmacy in Nashville, Tennessee.
Some FDA-approved fluoroquinolones, like trovafloxacin which led to liver damage, were withdrawn from the market after severe adverse reactions and several deaths were recorded. From the 1980s to the end of 2015, the FDA received reports from more than 60,000 patients detailing adverse events associated with the 5 fluoroquinolones still on the market. The fluoroquinolones have more disability effects than other more widely used antibiotics and the most common symptom is tendon rupture.
In 2008, the FDA announced a “black box” warning (call attention to serious or life-threatening risks) for tendon rupture. In 2013, it added a risk of irreversible nerve damage to that list of risks. In 2016, the FDA recognized FQAD as a syndrome on the basis of 178 cases. Otherwise healthy people who took fluoroquinolones for minor ailments developed disabling and potentially irreversible conditions.
Beatrice Golomb at the University of California, San Diego, suggests that fluoroquinolones are damaging mitochondria, cellular power plants. Because mitochondria retain some similarities to their bacterial ancestors, antibiotics pose a threat to them and every cell in the body can be affected. This explains why a wide range of symptoms can appear and get worse over time.
Toxicologist Yvonne Will and her colleagues at Pfizer in Groton, Connecticut, tested and detected mitochondrial damage early in drug development. Every fluoroquinolone they tested damaged mitochondria in human liver cells. In a 2013 study, Collins and his colleagues reported that antibiotics in several classes triggered oxidative stress in mitochondria and inhibited their function.
“We were surprised at how strong the effect was and how common the effect was across the different classes,” said Collins. But “the largest effects were seen in the quinolones”. “I think people generally assume that antibiotics do not impact mammalian cells,” he said.
Another theory caught scientists’ attention after a study was performed on human kidney cells. Researchers reported that fluoroquinolones can bind to iron atoms on active sites of several enzymes that modify DNA. This results in epigenetic changes that might be related to some of the drugs’ side effects.
Why only some people develop serious side effects and others don’t? Charles Bennett, a hematologist at the University of South Carolina’s College of Pharmacy in Columbia, published preliminary data that suggests a mutation might cause high levels of the drug to accumulate in cells, including in the brain. He took saliva samples from 24 people who reported neuropsychiatric side effects and found that 13 of them (57%) shared a gene variant usually seen in only 9% of the population. The gene site could be related to poor metabolism of the quinolones.
Researchers have more than one problem in making progress: 1) there is still no reliable biomarker that they can use to test for mitochondrial damage in people, tying cell-line research to clinical experience, 2) investigating medication that has been on the market for years isn’t a priority for research agencies, and 3) scientists’ reluctance to publish results that drug companies might find unfavorable.
“There’s a long history of adverse action against people who expose drug and chemical harms,” says Golomb.
The FDA’s warnings on drug labels are slowly producing results. Prescriptions for fluoroquinolone antibiotics didn’t fall between 2011 and 2015, according to the CDC, but US prescriptions for the drug did drop by around 10% in 2016.
Learn more about FQAD in the video below:
By Andreja Gregoric, MSc