Fluoroquinolones are a common type of antibiotics, but they can produce rare side effects. Researchers are trying to explore the mechanism of side effects.
When Miriam infection to the Canary Islands vacation in 2014, ears and nose hurt, had to go to a local doctor. The doctor gave her the levofloxacin for six days.
But after she returned to Amsterdam, two weeks after taking the medicine, her Achilles tendon began to ache. Then her knees and shoulders began to ache. Her legs and feet began to tingle, and she felt tired and depressed all the time.
Her condition is more and more serious, everyday was hurt badly. Miriam, 61, is a doctor. Once upon a time, she was a very active tennis player, and she loved to travel on foot. But now she can barely walk. She can only crawl on the ground with her hands and feet.
She found a lot of medical experts, some doctors thought her condition was caused by mental problems, and some doctors thought she should be suffering from fibromyalgia or chronic fatigue syndrome. But she herself did not believe these diagnoses, because she firmly believed that the antibiotics she had taken had poisoned her.
In fact, Miriam is not the only victim, levofloxacin is a fluoroquinolone, which is currently one of the most widely used antibiotics in the world. In 2015, only 32 million prescriptions were published in the United States, making it the fourth most commonly used antibiotics in the world.
For a small number of people, however, fluoroquinolones have long been notorious. Facebook and groups of forums are active in groups named Floxie Hope or MyQuin Story, and thousands of patients who have been treated with fluoroquinolones but have serious side effects are sharing their experiences in these groups.
For many of these people, the consequences of these side effects are devastating. Patients sometimes appear to include mental, somatosensory, and even muscles, tendons, and peripheral / central nervous problems as time goes on. These symptoms will not disappear after the drug is stopped. They usually call these side effects “floxed”.
For decades, regulators and medical experts have been wondering whether short-term antibiotic therapy can cause such serious long-term adverse effects. But with the unremitting efforts of the group of patients, when FDA first issued a warning in 2008 to remind doctors and patients that fluoroquinolones might lead to a tendon rupture and an irreversible nerve injury, their attitudes began to change gradually.
In 2016, FDA recognized the presence of the side effects of the fluoroquinolone -associated disability (FQAD), known as the fluoroquinolone, and suggested the use of such drugs only in cases of severe infection.
The move has also prompted drug regulators in other countries to start reassessing the safety of the antibiotics. In January 2017, Health Canada warned doctors that the use of such antibiotics could cause rare, persistent and potentially depressing side effects. EMA will also release the safety assessment results of this class this year.
Fluoroquinolones are a class of valuable medicines, which are safe for most people. But because the drug is too widely used, it has been harmful to millions of people in the United States and even hundreds of thousands of patients who have taken it.
We have long believed that antibiotics will only play a role in bacteria and do not harm human cells, and the presence of fluoroquinolone side effects is a good example of antibiotics that can harm normal human cells. Until the last two years, the field of antibiotic side effects has remained in the study of the effects of antibiotics on the group of human microbes, but antibiotics can also affect human cells, and the effects are sometimes very serious.
In the 60s of last century, scientists discovered the existence of quinolones, which can kill bacteria by inhibiting the activity of II topoisomerase. By 80s, researchers tried to add fluorine atoms to the nucleus of the quinolone structure to improve the drug’s drug properties, so that it could better penetrate human tissues including the central nervous system and improve its effectiveness against a series of bacterial infections.
Some of the fluoroquinolones, such as flevofloxacin, which could lead to serious side effects and even cause severe liver damage, have been delisted in 1999, despite the fact that FDA has been approved to be listed on the market, but the withdrawal of the fluoroquinolone drugs, such as TF, can lead to severe side effects and even the death of the patient. However, other drugs of the same type have become the treatment options for severe infections and even regular infections, although these drugs have rare side effects.
The use of this kind of drug is very extensive. In the 90s last century, American soldiers who participated in the Gulf War used ciprofloxacin to prevent infection caused by the possible contact of anthrax spores. Ciprofloxacin sales in 2001 were also surged due to a series of terrorist attacks using anthrax bacteria. The Centers for Disease Control and Prevention recommended the use of ciprofloxacin for 60 days.
But at that time, there were already serious problems. In 1998, American journalist Stephen Fried published a book called Bitter Pills, which tells the experience of his wife’s long-term neurotoxic side effects because ofofloxacin.
The publication of this book has also led to other people with similar experiences posted on the Internet to describe their unfortunate experiences. For example, on the website of Quinolone Antibiotics Adverse Reaction Forum, there were more than 5000 posts by 2001.
The late Jay Cohen, a neurologist in UCSD, once contacted the poster on the site and soon published a case study involving 45 patients. Cohen has warned the public that the use of fluoroquinolones may cause serious side effects involving multiple organs. These side effects are very rapid and can last for months or even years.
As the case came from the Internet forum, Cohen’s work at that time did not cause much concern. However, the side effects of taking such drugs have not been reduced. From the 80s of the last century to 2015, FDA received a report on five fluoroquinolones, more than sixty thousand patients with severe side effects, including tendon rupture and mental abnormalities, and 6575 related death reports were received.
FDA said that based on these reports submitted by pharmaceutical companies, doctors and patients, the conclusion that drug safety is very serious can not be reached. However, the side effects of fluoroquinolones are indeed more than those of other widely used antibiotics. It is presumed that less than 10% of the drug side effects will be reported to FDA, that is, in the United States alone, the side effects of fluoroquinolone may have hurt more than a dozen or even millions of people.
In 2008, FDA asked pharmaceutical companies to add a black frame warning to the label of a fluoroquinolone antibiotic to remind doctors and patients that the drug could cause a tendon rupture in the patient. After that, many patients thought that the pharmaceutical companies did not correctly advise the drug risk and sue them. But pharmaceutical companies believe that their response to risks is reasonable, and they have been working with FDA to update drug labels.
In November 2015, FDA, based on 178 cases they had collected, believed that the case of causality was very obvious, thought that FQAD was a syndrome, and those very light patients had been disabled or other irreversible side effects after taking a fluoroquinolone. FDA also reported that the proportion of the severe side effects of fluoroquinolones is much higher than that of other types of antibiotics compared with other types of antibiotics.
UCSC Beatrice Golomb has been studying these patients affected by fluoroquinolones for more than ten years. His first subject was a police David Melvin. In 2007, when he was suspected of having epididymitis, the doctor asked him to take levofloxacin. After that, he had to spend the rest of his life in a wheelchair because of the side effects of the drug.
Golomb says there is now more and more evidence that fluoroquinolones can damage mitochondria, which actually explains why the side effects of such drugs are so wide, and that it will gradually increase over time.
There are many types of drugs that can cause mitochondrial toxicity, because there is a certain similarity between mitochondria and their ancestral bacteria. The mitochondria themselves are evolved from cells that are capable of interacting with other cells billions of years ago. So antibiotics that kill bacteria can also cause harm to them, for example, researchers found that aminoglycoside antibiotics can cause the patient to appear in the ear by damaging the mitochondria of the ear hair cells. Deafness.
Since the 80s of last century, some studies have found that fluoroquinolones can damage mitochondria. In 2013, one of the most convincing studies found that some types of antibiotics could trigger oxidative stress in the mitochondria and inhibit the mitochondrial function in a series of mammalian cells.
Scientific researchers from pharmaceutical companies also found this phenomenon, in 2010, Pfizer’s toxicologist Yvonne Will reported a way to detect mitochondrial damage early in the drug study. They found that some antibiotics could damage mitochondria, and they also discovered some antibiotics that did not have this effect. But every fluoroquinolone they tested can cause mitochondrial damage in liver cells.
In spite of this, the damage of antibiotics to mitochondria is still not being paid attention to by antibiotic drug developers and medical workers. The common view is that antibiotics do not affect mammalian cells, which seems to have become a stereotype.
On the other hand, there is still no reliable biomarker that can enable researchers to predict the extent of mitochondrial damage in the patient’s body, and the detailed mechanism of the fluoroquinolone’s damage to human cells is still not clear.
In 2013, a study on the safety assessment of antibiotics in FDA cited a study in 1996 that suggested that ciprofloxacin could lead to mitochondrial DNA breakage in a series of mammalian cells. But Neil Osheroff of Vanderbilt University is skeptical about the study, because his own study found that fluoroquinolones do not play a role in human DNA in the concentration of drugs that can produce therapeutic effects.
Moreover, mitochondrial damage is not the only theory to explain the side effects of these drugs. A 2015 study based on human kidney cells found that fluoroquinolone could combine the iron atoms with the active sites of enzymes that interact with DNA, leading to epigenetic changes in cells. This may also be associated with the side effects of such drugs.
At a meeting last September, Bennett reported some preliminary experimental data to explain why only a part of the patients had serious side effects after the use of fluoroquinolones. After analyzing the saliva of 24 patients who had the side effects of the nervous system, they found that the genotype of one gene in 13 patients belonged to the same class, but the proportion of the genotypes was only 9% in the total population. Bennett did not disclose the specific gene for patent reasons, but he speculated that the genotype was associated with poor metabolism of fluoroquinolones. This genotype may lead to high levels of drugs and accumulate in cells such as the brain.
Bennett is conducting clinical trials in the hope of repeating the previous results in a larger number of patient samples. If this conclusion can be verified, it is possible to avoid the side effects of high risk people through genetic testing.
Most of the scientists interviewed by Nature believe that the side effects of fluoroquinolones need to be studied more deeply, but these studies are often difficult to get support from all sides. This is also a common problem in the field of drug safety research, which has been difficult to be the focus of research for years on the market, and pharmaceutical companies will not sponsor academic institutions to allow them to conduct research in this field, especially those that have lost patent protection, such as ciprofloxacin and levofloxacin.
On the other hand, scientists are reluctant to publish results that pharmaceutical companies do not like. There are many other pressing problems in the field of antibiotics, such as how to curb the emergence of drug-resistant bacteria and to develop new antibiotics.
But there is no doubt that doctors should not use other antibiotics to treat patients who are not seriously ill. The FDA’s black box warning is not as large as it has been. According to the data provided by CDC from 2011 to 2015, the dosage of the drugs did not decline, which suggests that the warning is not enough to change the doctor’s medication habits.
In the past four or five years, the label of fluoroquinolones has been changed more than 20 times. It is difficult for doctors to follow up the information. But in the United States, the amount of fluoroquinolone prescriptions in the United States did drop by 10%, and data in the first half of 2017 showed that the volume of prescriptions last year could be further reduced. 2016.
Miriam in Amsterdam is a doctor who has a strong medical background, but she still can not find a doctor who can trust her. She is waiting for EMA to warn of the side effects of fluoroquinolones, like FDA.
She said she hoped the relevant agencies could inform doctors about the risks associated with drugs, and even if these side effects were rare, they should alert patients. She also wants everyone to be aware of these risks, and everyone can take these warnings cautiously.
References: Nature 555, 431-433 (2018).