Fibromyalgia, Fluoroquinolone, Antibiotics

Environmental Medicine Update

Fibromyalgia and Fluoroquinolone Toxicity- A Case of Antibiotic-Induced Fibromyalgia

By Marianne Marchese, ND

Introduction

In October 2018, a 48-year-old woman came to see me for severe muscle and joint pain that affected her sleep, moods, energy levels, and overall quality of life. Her symptoms began suddenly five months prior while she was taking ciprofloxacin (Cipro) for a urinary tract infection. She had been a previously healthy woman who worked in health care at a large hospital. She had never taken Cipro in the past nor did she get frequent UTIs. The dose was standard for an uncomplicated UTI, 500 mg ER once a day for three days, prescribed by her primary care physician for confirmed UTI. A day after completing the course of treatment, she developed abdominal pain, cramping, and loose yellow stool with muscle and joint pain. The muscle pain gradually worsened and moved around her body including arms, legs, and abdomen. It continued to worsen and on May 31, 2018, she went to the emergency room and had an abdominal/pelvic CT scan, urinalysis, and basic blood work. She was sent home because everything came back normal. By the time she came to my office five months later, she had already seen her primary care doctor, a gastroenterologist, a cardiologist, two neurologists, a rheumatologist, urologist and two other naturopathic doctors.

Her symptoms since taking ciprofloxacin were muscle pain, joint pain, green stool with undigested food, thirst, frequent urination, and anxiety causing a 10-pound weight loss. She had a colonoscopy, EGD, cystoscopy, brain MRI, cervical and thoracic MRI, pelvic MRI, and numerous blood and stool tests for bacteria and yeast. All labs and imaging where normal. Lyme disease, viruses, valley fever and autoimmune conditions were ruled out. She was also screened for hormone imbalance and heavy metals all which were normal. The only abnormal lab was a blood cortisol of 24, which was most likely due to the muscle pain and the stress and anxiety; but she went to an endocrinologist for further work-up anyway, and all other endocrine tests came back normal.

She had already tried two courses of prednisone, a non-fluroquinolone antibiotic for possible gastroenteritis despite normal stool tests, anti-fungal medication, PPI, gabapentin, and valium. The gabapentin and valium helped the most, and she was on these when she came to my office for a consult. She was diagnosed with fibromyalgia by the rheumatologist, which eased her mind somewhat to have a diagnosis.

Every doctor she had seen since May 31, 2018 told her the symptoms were induced by the course of ciprofloxacin and that it would take time to resolve. Symptom management was what was offered. She researched her condition online and discovered numerous reports of people having similar side effects from ciprofloxacin and other fluroquinolones, (FQs) and that a new term has emerged called ‘floxed.’ She came to me seeking treatment for fibromyalgia induced by a fluroquinolone antibiotic.

Fluroquinolones and the FDA

Oral fluoroquinolones (FQs) are one of the most prescribed classes of antibiotics in the world. The fluoroquinolone antibiotics include ciprofloxacin (Cipro), gemifloxacin (Factive), levofloxacin (Levaquin), moxifloxacin (Avelox), and ofloxacin (Floxin). They are used to treat or prevent numerous bacterial infections. For years there have been reports of severe side effects prompting the FDA to issue warnings about fluroquinolones, yet the class of drug remains on the market. Side effects range from ruptured tendons, and muscles, to pain in the joints and muscles, and effects on the nerves and central nervous system.

The FDA first added a boxed warning to fluoroquinolones in July 2008 for the increased risk of tendinitis and tendon rupture. In February 2011, the risk of worsening symptoms for those with myasthenia gravis was added to the warning. In August 2013, the FDA required updates to fluroquinolone labeling to disclose the potential for irreversible peripheral neuropathy from fluroquinolones. In 2016, an FDA safety review showed that systemic fluoroquinolone use is associated with permanent and disabling adverse effects involving the musculoskeletal and nervous systems. The FDA stated then that the negative side effects associated with fluoroquinolone drugs outweigh the benefits for patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections and that other treatments should be considered.¹ In July 2018, the FDA issued warnings about the risks of mental health side effects and serious blood sugar disturbances with fluoroquinolones.² Most recently in December 2018, the FDA issued a warning about fluroquinolones and increased risk of ruptures or tears in the aorta blood vessel.

In November 2015, an FDA review coined the phrase “Fluroquinolone-Associated Disability, FQAD” to track FQ adverse effects in patients being treated for UTIs, sinusitis, and bronchitis. It states a patient must have adverse events from two or more of the following body systems: musculoskeletal, neuropsychiatric, peripheral nervous system, skin, cardiovascular, and senses (vision, hearing, etc), that last 30 days or longer after stopping the fluoroquinolone. A summary can be viewed at; https://www.fda.gov/media/104060/download. Despite thousands of disability reports from hundreds of cases, fluroquinolones remain on the market.

Fluroquinolones and Fibromyalgia

The American College of Rheumatology (ACR) updated its fibromyalgia diagnostic criteria in 2016 and acknowledges that the widespread pain syndrome most likely stems from the central nervous system. It described fibromyalgia as a “central pain amplification disorder” that has some triggering event—something sets off the symptoms of fibromyalgia. FDA warnings and published case studies point to fluroquinolones as a possible trigger. Many doctors managing patients with fibromyalgia may not be making the connection to past use of antibiotics.

A 2018 meta-analysis aimed to compare the adverse effects of fluroquinolones to other commonly prescribed antibiotics in primary care. It concluded that the occurrence of gastrointestinal-related and central nervous symptom-related adverse events were

higher with fluroquinolones compared to any other antimicrobials such as macrolides or cephalosporins.³

However, in 2019, the British Journal of Clinical Pharmacology published a large case-controlled study with a different conclusion. It looked at patients diagnosed by a rheumatologist with fibromyalgia and controls. It found the risk of fibromyalgia with fluroquinolones is similar to that with amoxicillin and azithromycin. The risk of fibromyalgia was higher for use of any antibiotic verses none.⁴ This study had numerous limitations but did hypothesize that the fibromyalgia symptoms were not triggered by the antibiotic but triggered by the infectious process for which the drug was prescribed. There are indeed numerous studies aligning viral and bacterial infection to fibromyalgia risk. It also hypothesized that the antibiotics changed the gut microflora, which has been linked to fibromyalgia.⁴

As early as 2012, there have been published reports of fluroquinolone-induced musculoskeletal conditions such as fibromyalgia. Often these patients seek help via chiropractic manipulation and massage therapy, which may or may not help. Depending on when the patient presents with symptoms or diagnosis of fibromyalgia, the doctor may overlook the link to the use of FQs. Fluoroquinolone-induced muscle pain seems to be caused by several factors, including inhibition of cell proliferation in tendons, inhibition of tenocyte migration, and increased matrix metalloproteinase expression, which induces collagen degradation.⁵ A researcher at the University of California-San Diego believes FQs are damaging mitochondria. This kind of harm can affect every cell in the body, explaining why a wide range of symptoms can appear and get worse over time. Current studies are taking place to prove this theory.⁶

The FDA isn’t the only agency issuing warnings about fluroquinolone antibiotic. The European Medicines Agency (EMA) has also issued warnings on disabling and potentially permanent side effects of fluoroquinolones. However, neither agency has pulled the medications from the market; instead, they advise doctors that FQs should not be used in situations where other options are available or where the use of antibiotics is questionable.

Treatment for Fluroquinolone Side Effects

Despite FDA black box warnings and published reports of FQ toxicity, there is very little published research on how doctors should manage patients experiencing acute or chronic symptoms. Numerous integrative medicine clinics offer treatment information on their websites for patients who have been ‘floxed.’ Treatments range from minerals, vitamins, amino acids, antioxidants (both oral and intravenous), detoxification protocols, ozone therapy, hyperbaric oxygen, and many others. Blogs and forums have emerged on the internet offering treatment advice as well. Yet there is very little published research on these treatments being effective for fluroquinolone adverse effects.

In 2012, a case report of fibromyalgia induced by fluroquinolones outlined a four-month treatment program consisting of intravenous glutathione, glutamine, d-ribose and n-acetyl cysteine, an oral probiotic and gluten-free/soy-free diet. Over the course of treatment, the patient did improve.⁵

A 2017 published article looked at possible areas of treatment to focus on including reduction of oxidative stress, restoring reduced mitochondrion potential, supplementation of cations that are chelated by FQs, stimulating the mitochondrial proliferation, removing FQs permanently accumulated in the cells, and regulating the disturbed gene expression and enzyme activity.⁷ Options for achieving this include N-acetyl cysteine, vitamin C, vitamin E, resveratrol, selenium, minerals, and CoQ10.⁷ These treatments are based on the proposed mechanism of how fluroquinolone adversely affect the body.

Most practitioners will at some point have patients with symptoms induced by fluroquinolone antibiotics. The symptoms may be acute or chronic, and health providers need to take a thorough history asking about antibiotic use in the ten years prior to onset of symptoms. Treatments should be individualized, focused on symptom management, and directed at the mechanism of fluroquinolones’ toxic effects in the body.

Case Report

The patient who came to see me in 2018 was having muscle pain, joint pain, and green-colored stool for five months post a three-day course of a fluroquinolone antibiotic for urinary tract infection. She previously had been healthy, and these symptoms, tests, doctors’ appointments, and failed treatments were creating stress and anxiety and weight loss. As a reminder, all labs, tests, and imaging were normal except mildly elevated cortisol. The only diagnosis she had been given was fibromyalgia. She was currently on gabapentin and valium, no supplements, and still symptomatic.

I began by working on stress management with meditation and deep breathing instruction and encouraged counseling. I placed her on vitamin D3 (4,000 iu a day), magnesium (250 mg twice a day), N-acetyl cysteine (600 mg twice a day), herbs to lower the cortisol, CBD oil, and a very high dose probiotic. The probiotic is key because people with fibromyalgia have an altered gut microbiome, and one of the proposed mechanisms of fluroquinolone toxicity is an alteration of the gut microflora.^4,8 The patient wanted off gabapentin due to side effects; and the magnesium, vitamin D, and CBD oil were to assist in managing the muscle pain. Later low-dose naltrexone (3 mg) was added as well to help ween off gabapentin. LDN has great published research on its benefit for fibromyalgia.^{9, 10}

I recommended infrared sauna therapy designed to increase blood flow to the organs of elimination and perspiration. She was asked to spend 10 minutes in the hot sauna, then do a 60-second cold shower rinse and repeat these five times ending with the cold rinse. This equaled one hour of time, and it was recommended she do this one or two times a week. The research on using sauna therapy, hydrotherapy for fibromyalgia, and elimination of toxins is outstanding.^11-13

Initially the patient was non-compliant and continued to seek advice from other doctors, friends, family, co-workers, and the internet. Eventually she returned and stuck to the plan, and her symptoms have slowly improved.

Summary

Fluoroquinolones are one of the most prescribed classes of antibiotics in this country. The fluoroquinolone antibiotics include ciprofloxacin (Cipro), gemifloxacin (Factive), levofloxacin (Levaquin), moxifloxacin (Avelox), and ofloxacin (Floxin). For years the FDA has issued warnings about severe and debilitating side effects, including fibromyalgia-type symptoms. Instead of removing these drugs from the market, the FDA urges physicians to only prescribe them when absolutely necessary. Fibromyalgia affects about 4 million adults in the US, causing widespread muscle pain and often taking years to diagnose. There is typically some triggering event for the condition, and fluroquinolone use is emerging as common trigger. Doctors are encouraged to take a thorough history looking for past use of antibiotics in patients with fibromyalgia. Since there is very little published research on how to manage fluroquinolone-induced fibromyalgia, most physicians are left managing the symptoms and known mechanisms of FQ-adverse effects on the body.

References

1. US Food and Drug Administration. FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. http://www.fda.gov/Drugs/DrugSafety/ucm500143.htm (Accessed on July 26, 2019)

2. US Food and Drug Administration. FDA Drug Safety Communication: FDA updates warnings for fluoroquinolone antibiotics on risks of mental health and low blood sugar adverse reactions. https://www.fda.gov/news-events/press-announcements/fda-updates-warnings-fluoroquinolone-antibiotics-risks-mental-health-and-low-blood-sugar-adverse (Accessed on July 26, 2019)

3. Tandan M, Cormican M, Vellinga A. Adverse events of fluoroquinolones vs. other antimicrobials prescribed in primary care: A systematic review and meta-analysis of randomized controlled trials. Int J Antimicrob Agents. 2018 Nov;52(5):529-540.

4. Ganjizadeh-Zavareh S, et al. Oral fluoroquinolones and risk of fibromyalgia. Br J Clin Pharmacol. 2019 Jan;85(1):236-239.

5. Strauchman M, Morningstar MW. Fluoroquinolone toxicity symptoms in a patient presenting with low back pain. Clin Pract 2012 Oct 12; 2(4): e87.

6. University of California, San Diego. UCSD Fluoroquinolone Effects Study. http://www.fqstudy.info/Fluoroquinolone_Effects_Study/Welcome.html (Accessed on July 26, 2019)

7. Michalak K, et al. Treatment of the Fluoroquinolone-Associated Disability: The Pathobiochemical Implications. Oxidative Medicine and Cellular Longevity. 2017;Article ID 8023935.

8. Minerbi A, et al. Altered microbiome composition in individuals with fibromyalgia. Pain. 2019 Jul 2. [Epub ahead of print]

9. Metyas S, et al. Low Dose Naltrexone in the Treatment of Fibromyalgia. Curr Rheumatol Rev. 2018;14(2):177-180.

10. Younger J, et al. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013;65(2):529-38.

11. Mooventhan A, Nivethitha L. Scientific Evidence-Based Effects of Hydrotherapy on Various Systems of the Body. N Am J Med Sci. 2014;6(5):199–209.

12. Matsumoto S, et al. Effects of thermal therapy combining sauna therapy and underwater exercise in patients with fibromyalgia. Complement Ther Clin Pract. 2011;17(3):162-6.

13. Sears ME, et al. Arsenic, Cadmium, Lead, and Mercury in Sweat: A Systematic Review. J Environ Public Health. 2012; 2012: 184745.