Cipro, Floxin and Other Common Antibiotics Receive New Warnings From the FDA

The FDA has issued new warnings for a group of antibiotics called fluoroquinolones after a safety review confirmed what many patients have long-considered to be disabling side effects including irregular heartbeat, depression, nerve damage, ruptured tendons, and seizures.

The new FDA ruling calls for restricted use of fluoroquinolones including: ciprofloxacin (Cipro), levofloxacin (Levaquin), moxifloxacin (Avelox), ofloxacin (Floxin), and gemifloxacin (Factive).

An FDA expert advisory panel determined that the “potentially disabling and permanent” side effects caused by fluoroquinolones outweigh their benefit in treating ailments such as bronchitis, sinus infections, and urinary tract infections. According to Lindsey R. Baden, M.D., an infectious disease physician at Brigham and Women’s Hospital in Boston, Massachusetts, and a member of the FDA panel, “this class of antibiotics should be reserved for a second-line or even third-line treatment after other antibiotics have failed.”

Side Effects a Result of Mitochondrial Toxicity

Though the FDA is now requiring stricter warnings on these drug labels, these concerns are not new. Several studies, including an earlier FDA review in 2013, previously pointed to mitochondrial damage as an underlying mechanism for several of these side effects. In a 2013 Pharmacovigilance Review, the FDA reported results from a study evaluating oxidative stress in patients taking ciprofloxacin, levofloxacin, and gatifloxacin for complicated urinary tract infections. The study showed “increases in lipid peroxides can quickly overwhelm cellular antioxidants, leading to impairment of cell integrity and cell death.” In vitro studies of ciprofloxacin have demonstrated a loss of mitochondrial DNA (mtDNA), resulting in a decrease of mitochondrial respiration and retarded cell growth.

Following this review, the FDA issued a Drug Safety Communication on August 15, 2013 notifying the public that it was requiring the drug labels and Medication Guides for all fluoroquinolone antibiotics to be updated to better describe the serious side effect of peripheral neuropathy. The notice stated, “serious nerve damage potentially caused by fluoroquinolones may occur soon after these drugs are taken and may be permanent.”

This was not the first warning about the detrimental effects of fluoroquinolones. Earlier, the FDA conducted an analysis of the available literature and post-marketing adverse event reports of fluoroquinolone medications. The report, issued on July 8, 2008, reported that the use of fluoroquinolones was associated with an increased risk of tendon rupture. It also demonstrated that despite the current warning of tendon rupture in the labeling for the fluoroquinolone class, large numbers of tendon-related adverse events continued to be reported.

There have been over 2,500 documented deaths resulting from quinolone use and over 45,000 cases of side effects. Websites like Floxie Hope and Surviving Cipro have sprung up as forums for those who consider themselves victims of the drugs. Despite these alarming numbers, the FDA considers its system to reflect only about 10 percent of the actual incidence of drug side effects.

Are the Newest Warnings Too Little, Too Late?

Patients who have long-suffered from side effects thought to be a result of fluoroquinolones are pleased with the FDA’s new warnings. Lisa Bloomquist, a patient advocate stated, “they are acknowledging that fluoroquinolones can lead to multi-symptom chronic illness, and that’s huge! Fluoroquinolones don’t only cause one or two of the side effects listed on the warning label in isolation, they cause a syndrome of illness. For the FDA to acknowledge this is an enormous step in the right direction”.

Others are not so optimistic that this warning will be enough to halt unnecessary prescribing of these common drugs. While influential medical organizations such as the Infectious Diseases Society of America have updated their guidelines to caution against prescribing fluoroquinolones for milder infections, the concern still exists that many doctors have not been informed or will not heed this warning.

Despite Progress, Risk Remains

As patents expire, pharmaceutical companies are continuing to modify the chemical structure of fluoroquinolones in search of similar, effective antibiotics to patent. Some experts have expressed concern that based on their similar chemical structures, the newest generations of such drugs are potentially more likely to cause adverse effects than the now-popular ones like Cipro and Levaquin.

Patients should be sure to self-advocate if being prescribed an antibiotic for infection. Make sure to determine the class of drug that is being prescribed and inquire if it is the safest, most appropriate choice for your treatment.


Groundbreaking Technology Measures Drug-induced Mitochondria Toxicity

The liver plays a central role in metabolizing synthetic chemicals and is therefore the most common target for drug-induced toxicity. Drug toxicity is often due to an accumulation of damage to the cell’s mitochondria. Current methods to evaluate mitochondrial function rely on indirect tests, which provide limited prognostic information. Now researchers from the Hebrew University of Jerusalem have found a way to directly measure mitochondrial damage caused by drug toxicity.

Liver-on-Chip devices measure tiny changes in cellular metabolism in real time (seconds to minutes). This test relies on a computer-controlled switchboard that reports cellular changes when exposed to new drugs, permitting detection of chemical toxicity before any effects on cell or tissue viability can be observed.

Past research using this liver-on-chip technology allowed the Hebrew University team to identify a new cause of acetaminophen (Tylenol®) toxicity, suggesting the drug could directly block respiration in the kidneys and skin.

In a recently reported study, the team tested the new technology on troglitazone (Rezulin®), an antidiabetic and anti-inflammatory drug that has been removed from the U.S. market in 2000 due to severe drug-induced liver injury, costing Pfizer Inc. over $750 million in lawsuits. The researchers found that even at low concentrations previously regarded as safe, in which traditional tests do not reveal any damage to the cells, the new liver-on-chip technology was able to detect mitochondrial stress that forced the liver to increase its reliance on glucose metabolism.

This cutting edge technology may now allow laboratory researchers to pinpoint mitochondrial damage caused by pharmaceuticals and also has the potential to redefine the study of neurodegenerative diseases (Alzheimer’s, Parkinson’s), metabolic diseases (diabetes, obesity) virology and cancer, in addition to drug discovery.


Fluoroquinolone Antibiotics Linked to Mitochondrial Damage

Aside from the growing threat of antibiotic resistant superbugs, there is now mounting evidence pointing to mitochondrial damage caused by antibiotics belonging to the class known as fluoroquinolones, which includes Levaquin and Cipro. The fluoroquinolones are a family of broad spectrum, systemic antibacterial agents that have been used widely as treatment for respiratory and urinary tract infections.

The common side effects of fluoroquinolones are gastrointestinal disturbances, headaches, skin rash and allergic reactions. More severe side effects reported include seizures, hallucinations, tendon rupture, swelling of tissue under the skin, and photosensitivity. A series of studies have linked side effects of Levaquin and Cipro to nerve damage and kidney injury. In July 2008, the FDA required that a “black box” warning be added to fluoroquinolone drug warnings indicating increased risk of tendon rupture with intake of Levaquin and other fluorquinolone antibiotics.  

The Southern Network on Adverse Reactions (SONAR), a multidisciplinary pharmacovigilance group that conducts studies of adverse events reported to the FDA and other databases, estimates that mitochondrial toxicity could be the cause of as many as 31% of the nearly 80,000 Levaquin adverse events reported between November 1, 1997 and February 3, 2011. The group also notes that only between 1% and 10% of adverse events are estimated to actually be reported, suggesting the true extent of the problems may be substantially greater.

As of August 2013, the U.S. Food and Drug Administration (FDA) has required the drug labels and Medication Guides for all fluoroquinolone antibacterial drugs be updated to better describe the serious side effect of peripheral neuropathy. “This serious nerve damage potentially caused by fluoroquinolones may occur soon after these drugs are taken and may be permanent,” reports the FDA.

Bacterial antibiotics have been shown to increase toxic free radicals (ROS) in bacteria, leading to mitochondrial dysfunction. Researchers have found that cells given the bactericidal antibiotics have structural damage caused by oxidative stress—harm caused by the binding and oxidation of free radicals (ROS).

An interesting theory postulates as to why the mitochondria may be a target of this class of drugs. According to the endosymbiotic theory, mitochondria originated from free-living, aerobic bacteria. It is possible that antibiotics target mitochondria and mitochondrial components, similar to their action in bacteria that are being treated with the antibiotics.

In a paper titled, Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells, scientists suggest that patients with compromised antioxidant defense systems or those genetically disposed to developing a mitochondrial dysfunction disease might be at greater risk from bactericidal antibiotic treatments.

Clinical studies have shown that the detrimental effects of bactericidal antibiotics were alleviated when the antioxidant, N-acetyl-L-cysteine (NAC), was given in addition to the antibiotics. A research team at Boston University studying this effect found that the NAC reduced the antibiotic-induced increase of free radicals, but importantly it didn’t affect the antibiotics’ bactericidal activities. Mice given a urinary tract infection, then treated with an antibiotic, cleared the bacteria just as effectively whether or not they were given NAC along with an antibiotic treatment.

The growing concern over fluorquinolone-induced mitochondrial damage has some doctors reviewing their choice of antibiotic treatment. Overall, the message is that antibiotics should be used judiciously and only when absolutely necessary.


Is Your Medication Making You Sick?

Could the medication you are taking to heal or manage an illness be causing its own health problems?

In a 2009 interview with Dr. James Dykens, Director of Investigative Cellular Toxicity at Pfizer Drug Safety Research & Development and author of the 2008 book, “Drug Induced Mitochondrial Dysfunction”, Dr. Dykens reported pharmaceutical drug toxicity could be a cause of mitochondrial damage.

While studying why individuals have different effects from drug toxicity, Dykens’s team determined mitochondrial damage occurs across the board, in different degrees depending on a person’s ability to metabolize the drug. Damage is also dependent upon the build-up of a drug or drugs in the liver. People with mitochondrial disease may have an even lower threshold for certain drugs.

Several commonly prescribed classes of drugs such as antivirals, antibiotics, statins, as well as drugs to treat diabetes have shown various degrees of mitochondrial toxicity. Between 1960-2009, there were 44 drugs that were withdrawn from the market which demonstrated idiosyncratic mitochondrial dysfunction. There are another 384 drugs that are listed by the FDA as Black Box Warnings, where toxicity to mitochondria is higher than expected.

“It is known that the HIV antiviral drugs do in fact damage mitochondria and can induce mitochondrial disease symptoms. Use of these drugs means that physicians and patients must weigh the risks versus the benefits to determine which ones to use,” reported Dykens.

Dr. Dykens’s mission is to get the FDA to test all drugs for mitochondrial dysfunction. Fortunately, several new laboratory tests are now available to test medications for mitochondrial dysfunction during drug development. Until then, Dykens recommends patients advocate for themselves - “any time a new drug is prescribed for a mitochondrial patient, they should look the drug up on Pubmed on the Web - typing in the drug's generic name and ‘mitochondrial dysfunction’ to see if anything is known about liability/toxicity. Many drugs have not been tested yet, but this is a start.”

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