fluoroquinolone mitochondrial damage

The Fluoroquinolone Time Bomb – Answers in the Mitochondria

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Two of the more perplexing features of Fluoroquinolone Toxicity (an adverse reaction to a fluoroquinolone antibiotic – Cipro/Ciprofloxacin, Levaquin/Levofloxacin, Avelox/Moxifloxacin or Floxin/Ofloxacin) are delayed reactions and tolerance thresholds. Both of these features of Fluoroquinolone Toxicity can be explained by noting that fluoroquinolones have been shown to damage mitochondria and cause oxidative stress, and that delayed onset of a disease state, as well as tolerance thresholds, are features of illnesses brought on by pharmaceutical induced mitochondrial damage and oxidative stress.

Delayed Reactions and Tolerance Thresholds with Fluoroquinolone Reactions

By “delayed reactions” I mean that adverse reactions to fluoroquinolones can occur weeks, months or even years after administration of the fluoroquinolone has stopped.  For the lawsuit filed by Public Citizen on behalf of patients who tore or ruptured tendons after taking a fluoroquinolone, (a suit that prompted the addition of the black box warning on all orally and IV administered fluoroquinolones) notes that “Fluoroquinolones, including CIPRO®, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants”. Tendon tears and ruptures that occurred within one year of the patient taking the fluoroquinolone were accepted as being related to the patient’s fluoroquinolone use. Patient reports have noted that new adverse symptoms of fluoroquinolone toxicity have occurred years after administration of the fluoroquinolone has ceased.

Many patients also experience a tolerance threshold for fluoroquinolone use.  A patient can tolerate fluoroquinolones well, experiencing few or no side-effects, until his or her threshold is reached.  After the patient’s tolerance threshold is reached, multisymptom systemic illness ensues. This patient’s story, found on the Fluoroquinolone Wall of Pain, illustrates the issue of tolerance thresholds:

On April 15, 2013 I was prescribed Avelox. I had been on this drug many times for chronic sinus infections. This time was different. Within 10 minutes of the first dose I went into anaphylaxis. I stopped breathing, had numerous convulsions and two grand Mal seizures. Since that day I have suffered with seizures, convulsions, tremors, debilitating fatigue, muscle weakness, vision loss, severe neuropathic pain, vomiting, nausea, lack of appetite, tendon, and vein problems.

This patient tolerated Avelox (moxifloxacin – a fluoroquinolone) well until her tolerance threshold was reached. Once her tolerance threshold was reached, she experienced multi-symptom systemic illness.

I personally experienced both a delayed reaction to Cipro/Ciprofloxacin (also a fluoroquinolone) and a tolerance threshold for it. I took 7 500-milligram pills of Cipro in 2009 without notable incident. I was even able to hike the entire 500-mile Colorado Trail in 2010 (no peripheral neuropathy or weakness were present at that time). When I took 7 more 500-milligram pills in 2011 I experienced a severe adverse reaction that began two full weeks after I was done taking the pills. I experienced multiple musculoskeletal (I couldn’t walk more than a block) and nervous system symptoms (I lost my memory and reading comprehension), and I would describe the reaction as feeling like a bomb had gone off in my body.

Fluoroquinolone Time Bomb: It’s All About the Mitochondria

My experience of a delayed onset of systemic health issues after having previously tolerated Cipro/Ciprofloxacin well, is typical of diseases that are brought on by a pharmaceutical causing mitochondrial dysfunction. (Multiple journal articles have noted that fluoroquinolones cause mitochondrial damage and oxidative stress.)

In “Mechanisms of Pathogenesis in Drug Hepatotoxicity Putting the Stress on Mitochondria” it is noted that:

…damage to mitochondria often reflects successive chemical insults, such that no immediate cause for functional changes or pathological alterations can be established. There is indeed experimental evidence that prolonged injury to mitochondria, such as that which typifies oxidative injury to mitochondrial DNA or to components of the electron transport chain (ETC), has to cross a certain threshold (or a number of thresholds) before cell damage or cell death becomes manifest.

Each time mitochondria is injured, the patient gets closer to his or her personal tolerance threshold for mitochondrial damage. Once the threshold is crossed, cell damage and apoptosis occur – which manifest themselves in various states of illness.

It is further explained in “Mechanisms of Pathogenesis” that:

…approximately 60% of mitochondrial DNA must be deleted from the mouse genome before complex IV activity is compromised and serum levels of lactate are elevated. This non-linear response can be explained upon consideration that the molecules that subserve mitochondrial function (e.g., mitochondrial DNA, mRNA, and ETC proteins) are present in excess of amounts required for normal cell function. This reserve (or buffering) capacity acts as a protective mechanism; however, at a certain stage of damage, the supply of biomolecules needed to support wild-type mitochondrial function becomes compromised.

The lay person’s summary of the above excerpts is that we have excess mitochondrial DNA and that excess mitochondrial DNA keeps each of us from developing a systemic multi-symptom illness whenever mitochondrial DNA is adversely affected (many pharmaceuticals and environmental toxins adversely affect mitochondrial DNA). However, when mitochondrial DNA is depleted sufficiently, cellular dysfunction, oxidative stress and cell death, ensue.

Multiple studies have noted that fluoroquinolones deplete mitochondrial DNA (here, here and here).  When enough mitochondrial DNA are depleted, adverse reactions that are systemic and include multiple symptoms simultaneously, occur.

Multi-Symptom Reaction: Look to Mitochondrial Damage

It is often difficult for the patient who is experiencing a systemic multi-symptom illness to connect his or her illness to the mitochondria damaging drug or toxin that hurt him or her because of the time delay between the cause (mitochondria damaging chemical) and the effect (bomb going off in body and mind). Though the delayed onset of fluoroquinolone toxicity and mitochondrial dysfunction symptoms are noted in many articles (here, here), the reason for the delayed onset of symptoms is not known.  In “Mechanisms of Pathogenesis” it is hypothesized that “an initial adaptive response was followed by a toxic response” when cells are exposed to a mitochondria damaging chemical. Perhaps the delay in adverse reaction onset is due to a toxic response taking time to develop.

Many pharmaceuticals damage mitochondria. Bactericidal antibiotics (including fluoroquinolones), Statins, acetaminophen, some chemotherapy drugs, vaccines, and many others, cause mitochondrial dysfunction, oxidative stress and cell death. Mitochondrial dysfunction and oxidative stress are connected to a variety of ailments, from chronic fatigue syndrome to Alzheimer’s disease and obesity. However, the FDA and other drug regulatory agencies have systematically ignored damage to mitochondria caused by pharmaceuticals and “mitochondrial toxicity testing is not required by the US FDA for drug approval.”

The recognition of delayed adverse reactions and tolerance thresholds for mitochondrial damaging drugs and vaccines will go far in helping both doctors and patients to recognize mitochondrial damage related adverse drug reactions (and adverse vaccine reactions). Once the reactions are recognized, perhaps some pressure can be put on the FDA and/or the pharmaceutical companies to test how drugs affect mitochondria before they are released onto the market. After all, mitochondrial damage and oxidative stress are causally related to almost every chronic illness.  It would be nice if doctors, those in the pharmaceutical industry, the FDA regulators, and others, recognized the harm that drugs do to mitochondria, and the symptoms of iatrogenic mitochondrial dysfunction.

Information about Fluoroquinolone Toxicity

Information about the author, and adverse reactions to fluoroquinolone antibiotics (Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin and Floxin/ofloxacin) can be found on Lisa Bloomquist’s site, www.floxiehope.com.

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If you have suffered from a fluoroquinolone or any other medication reaction, please consider sharing it on Hormones Matter.

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This story was published originally on Hormones Matter in March 2014.

 

 

What is Fluoroquinolone Toxicity?

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What happened to me? Why did it feel as if a bomb had exploded within my body and mind?  Why did I go from doing CrossFit to being unable to walk a block? Why did I lose my memory and reading comprehension?  Why was I so anxious and scared?  Why were my tendons so weak and sore?  Why did I suddenly lose my energy, endurance and flexibility?

I knew the short answer to those questions. I had suffered from an adverse reaction to ciprofloxacin, a fluoroquinolone antibiotic, and I had gone through fluoroquinolone toxicity syndrome—a multi-symptom, “mysterious” illness that involves damage to connective tissue (tendons, ligaments, cartilage, fascia, etc.) throughout the body, damage to the nervous systems (central, peripheral and autonomic), and more. Even though I knew why I was sick, I was still left wondering, what does fluoroquinolone toxicity mean?  How do fluoroquinolones damage tendons, muscles, cartilage and nerves?  What, exactly, is fluoroquinolone toxicity?  What happened in my body?

No doctors that I consulted were able to give me any answers to those questions, so I went digging around myself. Here are some hypotheses for the mechanisms by which fluoroquinolones cause nervous system and musculoskeletal damage that manifests as multi-symptom, often chronic, illness.

Mitochondrial Toxicity

Is fluoroquinolone toxicity syndrome a result of mitochondrial damage? This hypothesis has the most evidence to support it. The FDA noted, in their April 27, 2013 Pharmacovigilance Review, “Disabling Peripheral Neuropathy Associated with Systemic Fluoroquinolone Exposure,” that:

“Ciprofloxacin has been found to affect mammalian topoisomerase II, especially in mitochondria. In vitro studies in drug-treated mammalian cells found that nalidixic acid and ciprofloxacin cause a loss of motichondrial DNA (mtDNA), resulting in a decrease of mitochondrial respiration and an arrest in cell growth. Further analysis found protein-linked double-stranded DNA breaks in the mtDNA from ciprofloxacin-treated cells, suggesting that ciprofloxacin was targeting topoisomerase II activity in the mitochondria.”

It is also noted in an article in Science Translational Medicine entitled “Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells” that fluoroquinolones, and other bactericidal antibiotics, “damage mammalian tissues by triggering mitochondrial release of reactive oxygen species (ROS).” And that “increases in ROS led to DNA, protein, and lipid damage in vitro.”

Mitochondrial damage, and the vicious cycle of damaged mitochondria creating oxidative stress (another name for reactive oxygen species/ROS), which leads to more mitochondrial damage, which leads to more oxidative stress, and so on, and so on, can lead to multi-symptom, chronic illness. It is noted by Doctors Bruce H. Cohen, MD and Deborah R. Gold, MD, in Mitochondrial Cytopathy in Adults:  What we Know So Far, that:

“A problem that has vexed the study of mitochondrial diseases ever since the first reported case (in 1962) is that their manifestations are remarkably diverse. Although the underlying characteristic of all of them is lack of adequate energy to meet cellular needs, they vary considerably from disease to disease and from case to case in their effects on different organ systems, age at onset, and rate of progression, even within families whose members have identical genetic mutations. No symptom is pathognomonic, and no single organ system is universally affected. Although a few syndromes are well-described, any combination of organ dysfunctions may occur.”

Doctors Cohen and Gold go on to say that:

“symptoms (of mitochondrial damage) such as fatigue, muscle pain, shortness of breath, and abdominal pain can easily be mistaken for collagen vascular disease, chronic fatigue syndrome, fibromyalgia, or psychosomatic illness.”

Mitochondrial dysfunction, and ROS overproduction (aka, oxidative stress), are associated with many chronic diseases including Parkinson’s, Alzheimer’s, ALS, autoimmune diseases, cancer, fibromyalgia, chronic fatigue syndrome, autism and more.

Fluoroquinolone toxicity symptoms resemble those of autoimmune diseases, neurodegenerative diseases, and mysterious diseases. On many levels, it makes sense that fluoroquinolone toxicity syndrome is a disease of mitochondrial damage and ensuing oxidative stress. Mitochondrial damage and oxidative stress are almost certainly part of the fluoroquinolone toxicity puzzle.

Recommended reading:

  1. Science Translational Medicine, “Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells”
  2. Journal of Young Pharmacists, “Oxidative Stress Induced by Fluoroquinolones on Treatment for Complicated Urinary Tract Infections in Indian Patients
  3. Molecular Pharmacology, “Delayed Cytotocicity and Cleavage of Mitochondrial DNA in Ciprofloxacin Treated Mammalian Cells

Neurotransmitter Malfunctions in Fluoroquinolone Toxicity

The central nervous system (CNS) symptoms of fluoroquinolone toxicity include depression, anxiety, psychosis, paranoia, severe insomnia, paraesthesia, tinnitus, hypersensitivity to light and sound, tremors and suicidal ideation and tendencies. Many of the CNS symptoms of fluoroquinolone toxicity can be attributed to the effects of fluoroquinolones on GABA receptors. Fluoroquinolones “are known to non-competitively inhibit the activity of the neurotransmitter, GABA, thus decreasing the activation threshold needed for that neuron to generate an impulse.” (source)  Inhibition of GABA-A receptors, as well as activation of NMDA receptors, can lead to the many severe adverse effects of fluoroquinolones on the central nervous system.

Basically, fluoroquinolones do the same thing to GABA neurotransmitters as a protracted benzodiazepine withdrawal. It is noted in “Benzodiazepine tolerance, dependency, and withdrawal syndromes and interactions with fluoroquinolone antimicrobials” that:

“Chronic use of benzodiazepines causes compensatory adaptions which cause GABA receptors to become less sensitive to GABA. On discontinuation of benzodiazepines, withdrawal symptoms typically develop which may persist for weeks or months. Antagonism of the GABA-A receptor is believed to be responsible for the CNS toxicity of fluoroquinolones affecting 1–4% of patients treated. Fluoroquinolones have also been found to inhibit benzodiazepine receptor binding. The results of this small study seem to confirm that adverse reactions to fluoroquinolones occur more frequently in the benzodiazepine-dependent population than the 1–4% seen in the general public and may be severe.”

Those who have gone through benzodiazepine withdrawal can tell you that all aspects of one’s body are affected. It is possible that neurotransmitter dysfunction is at the root of all fluoroquinolone toxicity symptoms—though I strongly suspect that all of the potential theories that I mention in this post work in tandem.

Recommended reading:

  1. Toxicology Mechanisms and Methods, “Ciprofloxacin-induced neurotoxicity: evaluation of possible underlying mechanisms.
  2. British Journal of Clinical Pharmacology, “Neurotoxic effects associated with antibiotic use: management considerations
  3. Pharmacology Weekly, “What is the mechanism by which the fluoroquinolone antibiotics (e.g., ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin) can increase a patient’s risk for developing a seizure or worsen epilepsy?”

Magnesium Deficiency

Fluoroquinolones deplete intracellular magnesium. Magnesium is necessary for more than 300 enzymatic reactions, it is vital for the synthesis of vitamins, and magnesium depletion can lead to many symptoms of fluoroquinolone toxicity and other chronic diseases. Many people suffering from fluoroquinolone toxicity are helped by supplementing magnesium (in various forms). Studies have indicated that the binding of quinolones to DNA is mediated by magnesium.

The hypothesis that fluoroquinolones deplete intracellular magnesium is well described in the article, “Fluoroquinolone antibiotics and type 2 diabetes mellitus:”

“Fluoroquinolones are broad-spectrum antibiotics derived from nalidixic acid that inhibit bacterial topoisomerases. Although very effective therapeutically, fluoroquinolones have been linked with serious side effects such as tendinopathy, peripheral neuropathy, retinopathy, renal failure, hypertension, and seizures. These effects can be rationalized as resulting from a drug-induced magnesium deficiency, and according to the hypothesis it is not coincidental that they resemble the complications resulting from type 2 and gestational diabetes. There has, moreover, been a history of dysglycemia associated with certain fluoroquinolone antibiotics. Gatifloxacin was withdrawn from clinical use after reports of drug-induced hyperglycemia and other fluoroquinolones have been reported to interfere with glucose homeostasis.”

“The precise mechanism by which fluoroquinolones might induce intracellular magnesium deficiency is unclear. It may involve the metal-chelating properties of the 3-carboxyquinolone substructure that is common to all fluoroquinolone antibiotics and the fact that the 6-fluoro substituent on the pharmacophore gives rise to sufficient lipophilicity that the drugs can dissolve in and penetrate cell membranes. It has been suggested that intracellular fluoroquinolones may exist almost exclusively as the magnesium complex. Diffusion or active transport of such a complex into the extracellular environment would lead to depletion of intracellular magnesium – a process that may be stoichiometric or catalytic and would be only very slowly reversible, if at all. Thus, the effects of fluoroquinolones on intracellular magnesium levels might be considered to be almost cumulative (and it is noteworthy that the side-effects of fluoroquinolone therapy may manifest or persist many months after treatment). Alternatively, it is perhaps possible that fluoroquinolones could affect magnesium metabolism by disruption of renal reabsorption of this electrolyte.”

Recommended reading:

  1. Medical Hypotheses, “Fluoroquinolone antibiotics and type 2 diabetes mellitus
  2. Natural News, “Magnesium Helps Heal Cipro Damage
  3. Proceedings of the National Academy of Sciences of the United States, Biochemistry, “Quinolone Binding to DNA Mediated by Magnesium Ions

Microbiome Destruction

Fluoroquinolones are powerful antibiotics that wreak havoc on the bacteria in the gut. In addition to indiscriminately killing bacteria in the gut of the person who takes a fluoroquinolone, fluoroquinolones have also been shown to induce large amounts of oxidative stress within the gut.

The importance of the microbiome for all areas of health is just now being explored.  An unhealthy microbiome is associated with Parkinson’s, Alzheimer’s, depression, rheumatoid arthritis, diabetes, Crohn’s, and many other diseases. There are many who think that the root of all disease is in the gut.

Destruction of vital bacteria, and the induction of oxidative stress within the gut, could be responsible for the havoc wreaked on the health and well-being of those who take fluoroquinolones.

Recommended reading:

  1. Antimicrobial Agents and Chemotherapy, “The Fluoroquinolone Levofloxacin Triggers the Transcriptional Activation of Iron Transport Genes That Contribute to Cell Death in Streptococcus pneumonia
  2. National Institutes of Health, “Human Microbiome Project
  3. Scientific American, “Think Twice: How the Gut’s ‘Second Brain’ Influences Mood and Well-Being

Epigenetic Changes

Fluoroquinolones are topoisomerase interrupters. The mechanism for Cipro/ciprofloxacin, and all other fluoroquinolone antibiotics is:

“The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.”

Topoisomerases are enzymes that are necessary for DNA and RNA transcription.  Topoisomerase interrupting drugs have been found to profoundly affect gene expression.  It may be possible that fluoroquinolones trigger the expression of dormant genes. So, for example, those who have a predisposition toward an autoimmune disease may bring on the autoimmune disease with the fluoroquinolone. Anecdotally, it seems as if any existing weakness a person has is exacerbated by fluoroquinolones.

It is hypothesized in “Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology,” that all adverse reactions to fluoroquinolones are due to epigenetic mechanisms:

“The quinolones are a family of broad-spectrum antibiotics. They inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Eukaryotic cells do not contain DNA gyrase or topoisomerase IV, so it has been assumed that quinolones and fluoroquinolones have no effect on human cells, but they have been shown to inhibit eukaryotic DNA polymerase alpha and beta, and terminal deoxynucleotidyl transferase, affect cell cycle progression and function of lymphocytes in vitro, and cause other genotoxic effects. These agents have been associated with a diverse array of side-effects including hypoglycemia, hyperglycemia, dysglycemia, QTc prolongation, torsades des pointes, seizures, phototoxicity, tendon rupture, and pseudomembranous colitis. Cases of persistent neuropathy resulting in paresthesias, hypoaesthesias, dysesthesias, and weakness are quite common. Even more common are ruptures of the shoulder, hand, Achilles, or other tendons that require surgical repair or result in prolonged disability. Interestingly, extensive changes in gene expression were found in articular cartilage of rats receiving the quinolone antibacterial agent ofloxacin, suggesting a potential epigenetic mechanism for the arthropathy caused by these agents. It has also been documented that the incidence of hepatic and dysrhythmic cardiovascular events following use of fluoroquinolones is increased compared to controls, suggesting the possibility of persistent gene expression changes in the liver and heart.”

Fluoroquinolones have been found to deplete mitochondrial DNA, and mitochondria have been found to affect gene expression.

It is possible that fluoroquinolones are profoundly changing gene expression, and that the adverse effects of fluoroquinolones are a result of altered gene expression.  Fluoroquinolones are, after all, topoisomerase interrupters.

Recommended reading:

  1. Medical Hypotheses, “Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology
  2. Mutation Research, “Ciprofloxacin:  Mammalian DNA Topoisomerase Type II Poison In Vivo
  3. Nature, “Topoisomerases facilitate transcription of long genes linked to autism

Thyroid Harm

The harm that fluoroquinolones do to the thyroid is described well in “Fluoroquinolone Antibiotics and Thyroid Problems: Is there a Connection?” on Hormones Matter.  A more in-depth look at fluoroquinolone induced thyroid problems can be found on FluoroquinoloneThyroid.com.

Please don’t interpret the brevity of this section as a reason to discount it as a possible explanation for fluoroquinolone toxicity syndrome. Thyroid dysfunction can wreak havoc on a person’s health and the deleterious effects of fluoroquinolones on the thyroid are a potential explanation for the multi-symptom, chronic illness of fluoroquinolone toxicity. The articles by JMR on both Hormones Matter and fluoroquinolonethyroid.com explore the relationship thoroughly.

All of the source links in “Fluoroquinolone Antibiotics and Thyroid Problems: Is there a Connection?” on Hormones Matter are recommended.

Post-hepatic Syndrome / Liver Damage

Do fluoroquinolones form poisonous acyl glucuronides that lead to post-hepatic syndrome?

I think that it’s a definite possibility, but I also think that I’m not qualified or able to form a coherent and correct explanation of this hypothesis.  Please ask a biochemist to explain the following articles to you:

  1. Drug Metabolism and Disposition, “Acyl Glucuronidation of Fluoroquinolone Antibiotics by the UDP-Glucuronosyltransferase 1A Subfaminly in the Human Liver Microsomes”. 
  2. Current Drug Metabolism, “Editorial [Hot Topic:Acyl Glucuronides: Mechanistic Role in Drug Toxicity? (Guest Editor: Urs A. Boelsterli)]
  3. BMC Public Health, “Adverse effects of the antimalaria drug, mefloquine: due to primary liver damage with secondary thyroid involvement?”  (Note that mefloquine and fluoroquinolones are cousin drugs – they’re both quinine analogues.)

This is a long, and fairly complex, post. Yet I am leaving out many possible explanations for the causes of fluoroquinolone toxicity. Not even touched on are the possibilities that fluoroquinolone toxicity is a lysosomal disorder, autoimmune disease, fluoride overdose, “leaky gut,” histamine response, mast cell activation, serum sickness, and many other possibilities. I suspect that fluoroquinolone toxicity is a combination of all of the things mentioned above, and in this paragraph, and that there are multiple interactions between all of the biological systems. Fluoroquinolone toxicity is a systemic illness and all bodily systems work together.

Though fluoroquinolones can throw a wrench in our biochemistry, the multiple systems that work together to make us sick can also work together to make us well. We have amazing healing mechanisms that are less-understood than the mechanisms that make us sick (and those are pitifully poorly understood).  Our bodies are a complex and wondrous web.  All of our bodily systems work together perfectly most of the time, and they strive to return to health in every moment of life.

Though there are hundreds of articles about the deleterious effects of fluoroquinolones, the question – What is fluoroquinolone toxicity? – remains unanswered.  Any one of the possibilities mentioned above is complex. Put them all together and, well, comprehension becomes close to impossible.  Luckily, comprehension isn’t required for healing.  But it would be very, very, very nice if some efforts toward understanding adverse reactions to fluoroquinolones were being made.

Post script:  The first post I ever wrote on my site about fluoroquinolone toxicity (www.floxiehope.com) was a post like this one, also entitled, “What is Fluoroquinolone Toxicity?”  You can read it HERE.  The 2015 post above is much more thoughtful, well-researched and, in almost every way, it is better. But the 2013 post on Floxie Hope is interesting in its own right.  It went over what it feels like to go through fluoroquinolone toxicity, and it was written from the perspective of a recent victim of fluoroquinolones, not the perspective of someone who has spent hundreds of hours researching fluoroquinolones. The patient perspective, and noting what fluoroquinolone toxicity feels like is valuable, though I think that the connections made in this 2015 post are more accurate.

Information about Fluoroquinolone Toxicity

Information about the author, and adverse reactions to fluoroquinolone antibiotics (Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin and Floxin/ofloxacin) can be found on Lisa Bloomquist’s site, www.floxiehope.com.

Participate in Research

Hormones MatterTM is conducting research on the side effects and adverse events associated with the fluoroquinolone antibiotics, Cipro, Levaquin, Avelox and others: The Fluoroquinolone Antibiotics Side Effects Study. The study is anonymous, takes 20-30 minutes to complete and is open to anyone who has used a fluoroquinolone antibiotic. Please complete the study and help us understand the scope of fluoroquinolone reactions.

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Cipro, Levaquin and Avelox are Chemo Drugs

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When I first heard people referring to fluoroquinolone antibiotics (Cipro, Levaquin, Avelox, Floxin and a few others) as “chemotherapy drugs,” I thought that they were exaggerating or incorrect.  After all, fluoroquinolones are used to treat urinary tract infections, traveler’s diarrhea, anthrax, and other bacterial infections, not cancer. But then I started to do some research into how fluoroquinolones work and I discovered that they cause mitochondrial damage, which leads to oxidative stress and cell death (1, 2), they interfere with the DNA replication process of mitochondria (3), they disrupt tubulin assembly (4) and that they are being investigated for their tumor killing abilities (5, 6).  I also found that all other drugs that have the same mechanism for action as fluoroquinolones – topoisomerase interrupters (FDA warning label, 7) (topoisomerases are necessary for proper DNA replication) – are used as chemotherapy drugs – topotecan, amsacrine, etoposide, etc.  Fluoroquinolones are, truly, chemotherapy drugs – they just happen to be used as popular antibiotics. They can kill cancerous tumor cells because, in addition to killing bacterial cells, they also kill eukaryotic cells (8, 9).

Use of Fluoroquinolones for Cancer Treatment is Appropriate

There are almost certainly some legitimate and reasonable uses for fluoroquinolones as chemotherapy drugs (10).  As tumor killing agents, they may save lives of those with cancer.  Unfortunately, they’re not as targeted as the chemotherapy drugs that are currently in use.  Many chemotherapy drugs on the market specifically target quickly dividing cells – like tumor and hair cells; so they kill the cancer cells while leaving most other cells intact. Fluoroquinolones aren’t that precise. They indiscriminately kill cells throughout the body – including neurons and lymphocytes (11) (immune system cells).  The mitochondrial DNA (mtDNA) replication process is disrupted by fluoroquinolones (3), and the disruption of that process leads to mitochondrial damage, oxidative stress and cell death (12).  Fluoroquinolones are effective cell killers, but because they are indiscriminate cell killers, they are a step backward in chemotherapy drug technology.

Lousy Chemo Drugs?  Let’s Use Them as Antibiotics for Everyone!

Because they are not particularly good chemotherapy drugs, fluoroquinolones are rarely used for the purpose of killing cancer cells.  Instead, they are used as antibiotics. They are prescribed to treat sinus infections, bladder infections, strep throat, and they are even prescribed prophylactically (typically for future treatment of travelers’ diarrhea) when no infection is present. They kill bacteria, and are effective antibiotics, but they also damage mitochondria and destroy cells and therefore have many of the same side-effects as chemotherapy drugs, because, as noted above, they are chemotherapy drugs.

Side-Effects of Fluoroquinolones, and Other Chemotherapy Drugs

Some of the side-effects that fluoroquinolones share with chemotherapy drugs are (13, 14, 15, 16 and the FDA warning label for Ciprofloxacin – the warning labels for Levofloxacin and the other fluoroquinolones are similar):

  • Exhaustion / Loss of energy / Fatigue
  • Brain-fog / Loss of cognitive abilities
  • Anemia
  • Muscle Loss / Wasting
  • Neuropathy / Peripheral Neuropathy / Fibromyalgia

Additionally, Fluoroquinolones destroy connective tissue, especially tendons.  (17, 18, 19)

When one thinks of fluoroquinolones as chemotherapy drugs as opposed to antibiotics (yes, they do kill bacteria, but they should not be thought of in the same terms as benign drugs like penicillin and cephalosporins), many aspects of adverse reactions to fluoroquinolones make sense. Like several other chemotherapy drugs, there is a tolerance threshold (and/or lifetime limit) for fluoroquinolones (20, 21). Many people don’t react to their first dose of a fluoroquinolone. Rather, they tolerate the drugs up to a point – then they can no longer tolerate them and Fluoroquinolone Toxicity results. For fluoroquinolones, and possibly for other chemotherapy drugs, this tolerance threshold issue is because mitochondria are able to withstand a certain amount of damage before a disease state ensues. It is only after the tolerance threshold for damage is crossed that mitochondria stop adapting to harmful stimuli and a disease state ensues. (22)

Cellular Damage from Chemo Drugs can Lead to Cancer – Isn’t that Ironic?

Destruction of mitochondrial DNA can result in mitochondrial dysfunction and oxidative stress – which lead to apoptosis and necrosis of cells (23). When this occurs, a multi-symptom, chronic, autoimmune-disease-like reactions can occur (24, 25). However, if cell damage occurs but the cell does not die, but rather replicates the DNA errors, cancer can result (26, 27, 12).

Additionally, drugs that inhibit CYP450 liver enzymes [Cytochrome P450 enzymes metabolize xenobiotics and foreign chemicals from the body. (28)] leave people more susceptible to cancer-causing pathogens (29). Fluoroquinolones inhibit multiple CYP450 enzymes (30, FDA warning label). How ironic, isn’t it? Cancer can result from chemotherapy drugs. And when it is understood that fluoroquinolones are chemotherapy drugs that damage mtDNA and cause oxidative stress and apoptosis/necrosis, the irony of chemotherapeutic drugs causing cancer becomes horrifying, as opposed to thought-provoking.

Cellular Harm Results from Willful Ignorance About the Effects of Fluoroquinolones

There are articles that say that fluoroquinolones have an excellent safety record. (31)  None of those articles look at the effects of these drugs on the mitochondria – the depletion of mtDNA, the oxidative stress that results from damaged mitochondria, the DNA damage that is caused by the oxidative stress, etc.  In not looking at mitochondria, those articles are looking at the wrong things and they in no way negate the findings of the articles that note the deleterious effects of fluoroquinolones on human cells.

While it may be appropriate to give drugs that disrupt the process of mitochondrial DNA replication, have horrific side-effects and cause indiscriminate cell death, to people who are have cancer, it is absurd to give them to people who are healthy other than a minor infection. Even for major, difficult to treat infections, fluoroquinolones should be the drugs of last resort because of their effects on mitochondria. (1, 32)  Chemotherapy drugs should be used exclusively in life-or-death situations. They should not be used frivolously or without true informed consent of the patient, or without awareness of the consequences of the drug on the part of both the physician and the patient. Protocols should be in place for ensuring that they are used appropriately and that all parties are aware of the consequences of the drugs.

Sadly, appropriate informed consent around fluoroquinolones involves a complete shift in how physicians and patients alike think about them. In order for the risks of taking fluoroquinolones to be properly acknowledged, all parties involved need to see, and acknowledge, that fluoroquinolones are chemotherapeutic drugs that cause mitochondrial destruction and cell death, and that they should not be used lightly. But because fluoroquinolones have been given out frivolously – 26.9 million prescriptions for oral and IV fluoroquinolones were given out in 2011 alone (33) for simple infections, I don’t foresee the shift in how they are perceived as an easy one. It must involve many doctors admitting that they have been prescribing these drugs incorrectly for decades, that they have been wrong about the severity of adverse effects, and that they have been misled about the risks of fluoroquinolones.

The Effects of Drugs on Mitochondria are Systematically Disregarded

It should also be noted that the effects of drugs on mitochondria are systematically disregarded. Mitochondrial function, and drug-induced dysfunction, is important to all areas of human health.  An article published in Molecular Nutrition and Food Research entitled Medication Induced Mitochondrial Damage and Disease” noted that the effects of drugs on mitochondria are ignored by both the drug companies and the FDA when reviewing drug safety. Because of this omission in review and oversight, human mitochondrial DNA have been repeatedly damaged by fluoroquinolones and other pharmaceuticals. The consequences of this are, as of yet, unknown. (Though it should be noted that mitochondria and the signals that they produce influence gene expression (35) and that an article published in Nature in July, 2013 entitled “Topoisomerases Facilitate Transcription of Long Genes Linked to Autism” showed that topoisomerase interrupting chemotherapy drugs effect the expression of genes linked to Autism.) We can only hope that the FDA’s failure to force drug reviewers to look at the effects of drugs on mitochondrial DNA isn’t horribly consequential.

Sources:

  1. Science Translational Medicine, “Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells”
  2. British Journal of Cancer, “Ciprofloxacin Induces Apoptosis and Inhibits Proliferation of Human Colorectal Carcinoma Cells
  3. Molecular Pharmacology, “Delayed Cytotoxicity and Cleavage of Mitochondrial DNA in Ciprofloxacin Treated Mammalian Cells
  4. Current Medicinal Chemistry, “Recent Advances in the Discovery and Development of Quinolones and Analogs as Antitumor Agents
  5. Inorganic Chemistry, “New uses for old drugs: attempts to convert quinolone antibacterials into potential anticancer agents containing ruthenium
  6. Asian Pacific Journal of Cancer Prevention, “Comparative Evaluation of Antiproliferative Activity and Induction of Apoptosis by some Fluoroquinolones with a Human Non-small Cell Lung Cancer Cell Line in Culture
  7. Mutation Research, “Ciprofloxacin:  Mammalian DNA Topoisomerase Type II Poison In Vivo
  8. The Journal of Biological Chemistry, “Cytotoxicity of Quinolones toward Eukaryotic Cells:  Identification of Topoisomerase II as the Primary Cellular Target for the Quinolone CP-115,953 in Yeast
  9. Antimicrobial Agents and Chemotherapy, “Effects of Novel Fluoroquinolones on the Catalytic Activities of Eukaryotic Topoisomerase II:  Influence of the C-8 Fluorine Group
  10. Urology, “Quinolone antibiotics: a potential adjunct to intravesical chemotherapy for bladder cancer
  11. Nepal Medical College Journal, “Genotoxic and cytotoxic effects of antibacterial drug, ciprofloxacin, on human lymphocytes in vitro
  12. Toxicology and Applied Pharmacology, “Mitochondrial abnormalities–a link to idiosyncratic drug hepatotoxicity?
  13. National Cancer Institute, “Chemotherapy Side Effects Sheets
  14. The Annals of Pharmacotherapy, “Peripheral Neuropathy Associated with Fluoroquinolones
  15. Indian Journal of Psychiatry, “Levofloxacin Induced Acute Psychosis
  16. Journal of Antimicrobial Chemotherapy, “Peripheral Sensory Disturbances Related to Treatment with Fluoroquinolones
  17. The American Journal of Sports Medicine, “The Effect of Ciprofloxacin on Tendon, Paratenon, and Capsular Fibroblast Metabolism
  18. Physical Medicine and Rehabilitation (PM & R) “Musculoskeletal Complications of Fluoroquinolones: Guidelines and Precautions for Usage in the Athletic Population
  19. Laboratorie de Toxicologie, “In Vitro Discrimination of Fluoroquinolones Toxicity on Tendon Cells:  Involvement of Oxidative Stress
  20. Carcinogenesis, “Mechanisms of tolerance to DNA damaging therapeutic drugs
  21. Non-Hodgekin’s Lymphoma Cyberfamily
  22. Molecular Interventions, “Mechanisms of Pathogenesis in Drug Hepatoxicity Putting the Stress on Mitochondria
  23. Toxicology and Applied Pharmacology, “Mitochondrial abnormalities–a link to idiosyncratic drug hepatotoxicity?”
  24. Cleveland Clinic Journal of Medicine, “Mitochondrial cytopathy in adults: What we know so far”
  25. Antimicrobial Agents and Chemotherapy, “Ciprofloxacin Induces an Immunomodulatory Stress Response in Human T Lymphocytes
  26. Scitable by Nature Education, “DNA Replication and Causes of Mutation
  27. British Journal of Haematology, “Topoisomerase II Inhibitor Related Acute Myeloid Leukaemia”
  28. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, “Role of cytochromes P450 in chemical toxicity and oxidative stress: studies with CYP2E1
  29. Europe Pubmed Central, “Role of cytochromes P450 in drug metabolism and hepatotoxicity.”
  30. Pharmacy Times, “Get to Know an Enzyme: CYP1A2
  31. Expert Reviews, “Levofloxacin: update and perspectives on one of the original ‘respiratory quinolones’
  32. Journal of Young Pharmacists, “Oxidative Stress Induced by Fluoroquinolones on Treatment for Complicated Urinary Tract Infections in Indian Patients
  33. FDA Drug Safety Communications, “FDA Drug Safety Communication: FDA requires label changes to warn of risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by mouth or by injection
  34. Molecular Nutrition and Food Research, “Medication Induced Mitochondrial Damage and Disease
  35. BBA, “Mitochondrial DNA Damage and its Consequences for Mitochondrial Gene Expression
  36. Nature, “Topoisomerases Facilitate Transcription of Long Genes Linked to Autism

 

Information about Fluoroquinolone Toxicity

Information about the author, and adverse reactions to fluoroquinolone antibiotics (Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin and Floxin/ofloxacin) can be found on Lisa Bloomquist’s site, www.floxiehope.com.

Participate in Research

Hormones MatterTM is conducting research on the side effects and adverse events associated with the fluoroquinolone antibiotics, Cipro, Levaquin, Avelox and others: The Fluoroquinolone Antibiotics Side Effects Study. The study is anonymous, takes 20-30 minutes to complete and is open to anyone who has used a fluoroquinolone antibiotic. Please complete the study and help us understand the scope of fluoroquinolone reactions.

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