Could Taking That Antibiotic Have Serious, Long-Term Consequences?

 Michael O. Schroede
  31st-Aug-2018

IN A SUICIDE NOTE Oliver Newell left on his computer, he apologized to family and friends for leaving them and described, in brief, some of the struggles he'd endured over the preceding months: "all systems affected (muscles, joints, skin, nerves, heart, intestinal, memory, hearing, etc....). And really no end in sight to the ongoing and continually emerging symptoms."

To the very end, it seemed the 51-year-old software developer and member of the senior staff at MIT's Lincoln Laboratories, who lived in Billerica, Massachusetts, wanted to warn others about what had happened to him. He died by his own hand, but not in the stable state of mind that had characterized him for the 50 years prior, his siblings say. "He was a very resourceful and smart scientifically oriented tough guy. He's not someone who would go off and cry wolf about things," says his brother Nick Newell, who lives in Reading, Massachusetts.

Oliver hadn't suffered from mental health issues previously, Nick says, but everything changed after Oliver, who had been experiencing abdominal pain from what was suspected to be a prostate or urinary tract infection, took an antibiotic in February 2012. After just three doses Oliver felt weakness in his legs and tingling in his hands and feet. Due to side effects, the medication was quickly stopped, and in total, he took just seven pills of ciprofloxacin (Cipro) – one of a class of powerful, widely prescribed antibiotics called fluoroquinolones – according to records Oliver and his siblings kept.

But that was enough to begin a broad spectrum of rare but serious side effects that can occur with fluoroquinolones, which are now recognized by the Food and Drug Administration after years of patient advocacy, called the fluoroquinolone-associated disability, or FQAD. Side effects can not only last months and years but can be permanent. "This totally changed his trajectory and put him on … just a nightmare path," Nick says. "He was basically tortured by these drugs from inside for seven months until he took his own life."

Oliver experienced severe muscle weakness. This was the most disabling of the effects Oliver experienced, Nick says. He could only use his muscles a few times before they became depleted,. "So he could walk just for short distances," Nick says. He had tendon pain, joint pain and swelling; "peripheral nervous system problems like burning sensations and tingling; central nervous system problems like what he described as 'brain fog' – which I interpreted as a reduced ability to think clearly. … He also had skin problems, including frequent rashes and his skin seemed to be more easily damaged. He had gastrointestinal problems, vision issues. He had tinnitus, insomnia, heart palpitations."

In addition, Oliver had anxiety and panic attacks, "which were particularly alarming to us because before taking the drugs he was just very stable, and nothing would bother him," Nick says. "It is clear to me that Cipro had a profound effect on his mental state," adds Oliver's sister Liz Newell, who lives Concord, Massachusetts. Oliver, who was single but well-connected socially and professionally, had to stop working because of the side effects he experienced. Liz described how he became not only anxious, but paranoid and hypervigilant, and says he was not in a healthy state of mind when he died.

In July of this year, adding to other black box warnings – the strongest warning that can be put on medication – the FDA announced that it was again requiring labeling information to be updated for fluoroquinolones. It reinforced safety information noting serious low blood sugar levels and mental health side effects can result from taking the drugs. "The low blood sugar levels can result in serious problems, including coma, particularly in older people and patients with diabetes who are taking medicines to reduce blood sugar," the FDA noted in its announcement. "We are making these changes because our recent review found reports of life-threatening low blood sugar side effects and reports of additional mental health side effects. We are requiring these updates in the drug labels."

But where fluoroquinolones have been around for decades and the first black box warning was only added in 2008 (for increased risk of tendonitis and tendon rupture), the agency has been criticized by patient groups and some experts who have studied FQ side effects for taking too long to update safety information and raise the profile of those concerns in the medical community. Many people who have been "floxed," or who've suffered serious adverse side effects from taking FQs, have turned to online forums like Floxie Hope for support and information after encountering health providers who either didn't believe the effects could be related to the drugs or weren't able to help. Oliver, despite much support from family, similarly found himself alone when he tried to get relief from doctors. "I can only imagine the isolating and demoralizing effect it must have on someone like Ollie to be thought a hypochondriac," Liz says.

While some report anecdotally finding at least partial relief for FQ side effects by taking supplements like magnesium, which has been shown to be depleted by FQs, there's no proven antidote to fluoroquinolone-associated disability experienced by a small but significant fraction (the exact number isn't known) of the roughly 30 million people who are prescribed the medications each year. "There is no treatment at the current time for FQAD – more research is needed here," says Dr. Charles Bennett, a hematologist and oncologist at the University of South Carolina's College of Pharmacy in Columbia, and director of the South Carolina SmartState Center for Medication Safety and Efficacy.

"The FDA received 210,705 adverse event reports for marketed FQs between 1997 and 2011, including 2,991 reports of fatalities," Bennett says of the data he and other researchers published in the Journal of Community and Supportive Oncology in 2016; and updated unpublished levofloxacin (Levaquin) data from 1997 to July 21, 2015, indicate that FDA received information about 98,710 adverse events and 1,594 deaths related to that drug. These reports range from neurologic issues to tendon damage and psychiatric effects. While the FDA says its database can't be used to estimate the total number of adverse events, it's well-established that what's reported to the FDA represents only a small fraction of all adverse events that occur.

Bennett has studied the side effects of FQs, including associated suicides and suicide attempts, combine reports of adverse events associated with the drugs in the FDA's database. In a letter to the European Journal of Internal Medicine detailing one study done by Bennett and his colleagues, the researchers noted that they searched the database for approved FQs – ciprofloxacin, levofloxacin, moxifloxacin (Avelox), gatifloxacin and ofloxacin – and included cases that involved individuals with no psychiatric history or who had stable, controlled, psychiatric illness, who had attempted or completed suicide, where an FQ was listed as "the suspected causal drug." The researchers found 108 FQ-associated suicides or suicide attempts that met their criteria – and 43 of those events occurred within two weeks or less of initiating the medications.

What's more, "it is possible that persons with FQ-associated suicidal toxicity and underlying psychiatric illness may not have been reported to the FDA as experiencing an FQ-related adverse event, thus leading to underreporting of these events among FQ treated persons with known psychiatric histories," the researchers note.

Clinicians emphasize that fluoroquinolones are highly effective and can be life-saving and overcome hard-to-treat infections that other antibiotics cannot tackle. "Cipro is the only approved drug we have for anthrax. These drugs are tremendously important drugs for certain people, like with renal transplants or renal disease, where they need an antibiotic," Bennett points out.

But often, experts say, the risks of antibiotics aren't fully appreciated – as side effects might be with other types of drugs. But those should be weighed against the potential benefit. For most, FQs are safe, and clinicians say they're highly effective. "So they're used incredibly broadly," says Dr. Lindsey Baden, an infectious disease doctor at Brigham and Women's Hospital and an associate professor at Harvard Medical School. "As we do that we see potential side effects that have to be understood and appropriately managed and minimized."

For its part, the FDA has advised clinicians in more recent years to use fluoroquinolones more sparingly – particularly when other alternatives exist. Clinicians say it's very important to assess the need, and potential for harm, on an individual basis.

Based on his research, Bennett says some people may be genetically predisposed to experience neuropsychiatric toxicities – thing like memory loss – and, he's working to develop a diagnostic test that could determine in advance of taking an FQ if a person is at high risk for such toxicities.

In the meantime, experts agree that the key is to first determine if an FQ is appropriate and needed and that there aren't other alternative options with less serious side effects that could be used instead. A report by the Infectious Diseases Society of America and the HIV Medicine Association shows there's still a long way to go.

When the FDA updated its black box warnings for FQs in 2016, it advised health providers not to use FQs when the potential risks outweigh the benefits; it specifically highlighted conditions such as acute bronchitis, or chest cold, where antibiotics are not typically required, as well as acute sinusitis, or sinus infection, "and uncomplicated urinary tract infections for which other effective antibiotic treatment options exist," the Infectious Diseases Society of America and the HIV Medicine Association report points out. Yet, while it can be difficult to track precisely, researchers note, "This analysis suggests that a quarter of FQ prescriptions were given for conditions for which no antibiotics are indicated, or for which FQ are not recommended first-line therapy. With the threats to patient safety and rising rates of antibiotic resistance, FQ should not be prescribed for conditions where alternative effective therapies are recommended."

Although it's difficult to determine what would have been the best course of action, Nick doesn't think the issues Oliver faced were serious enough to warrant fluoroquinolones. While Oliver's loss is still difficult to deal with, Nick says raising awareness about the serious, disabling side effects Oliver experienced associated with FQs has helped him cope. That included speaking about those before the FDA in 2015, and seeing the agency take subsequent action.

"Assessment of information concerning adverse reactions and other safety concerns is an ongoing FDA responsibility," Theresa Eisenman, a spokesperson for the agency, said in an email responding to criticism that the FDA hasn't moved quickly enough. "As information about a new adverse reaction is initially reported, the association with the drug may not be clear. Often, adequate information supporting this association develops over time. The FDA has sought to inform healthcare providers and patients about serious side effects associated with fluoroquinolone antibacterial drugs as soon as adequate information was available."

As scrutiny of FQs continues, experts who've studied the drugs and individuals who have experienced the most serious side effects, as well as their loved ones, say its critical patients and their health providers fully discuss risks and consider alternatives, where available and appropriate. "Read the label. Understand the side effects. Take them seriously," Nick says. The Newells have continued to advocate for the safety of others following Oliver's death. "What's actually helped me move on, and make me feel a bit better about it," he adds, "is that we're able to make a change, which can potentially prevent thousands of other people from being disabled, and many, many from dying."

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