Floxing — primer to fluoroquinolone toxicity and iatrogenic harm for non-conspiracy theorists

Modern medicine is one of the cornerstones upon which contemporary societies are built. Many collective efforts allowed to greatly reduce global suffering — examples range from eradication of smallpox and rinderpest thanks to worldwide vaccination programs in the XX century to, more recently, developing (highly active) antiretroviral therapies allowing people with HIV lead healthier lives, where risk of transmission for majority of patients is close to zero1, including highly-stigmatized and criminalized sexual transmission (Undetectable = Untransmittable).

Partly due to this, but partly due to major capitalist players in the biomedical market diverting attention to those facts on purpose and incorporating various moral disengagement practices, there is very little space for discourse about drug safety. Anyone bringing up harm inflicted by doctors or medicines is going to attract dirty looks and will need to start with a sufficient disclaimer (as in the case of this post) to nip the tinfoil-hat accusations in the bud.

Fluoroquinolones-Associated Disability: It Is Not All in Your Head2

Fluoroquinolone-associated disability (FQAD), fluoroquinolone toxicity — or simply floxing — is a poorly-defined medical entity where previously healthy people suffered disabling, often multi-systemic3 long-lasting and sometimes irreversible adverse events due to taking an antibiotic belonging to the fluoroquinolone group, such as ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin. This phenomenon, even though generally considered rare, has happened regularly enough to warrant several (mostly useless4) warnings from government agencies — U.S. Food and Drug Administration (FDA)5 and European Medicines Agency (EMA).6

“But all drugs have some side-effects” — you may hear this this thought-terminating cliché from someone generous enough to admit that one may have experienced some serious harm from a medication, but at the same time insufferable enough to try to dismiss terrible suffering7 with this bumper sticker logic.
Fluoroquinolones had a disproportionately high percentage of disability reports in FDA Adverse Event Reporting System (FAERS) search when compared to other antibiotics:

Figure from: https://www.fda.gov/media/104060/download

As stated in my post about small fiber neuropathy — fluoroquinolones have been linked to small fiber neuropathy in multiple case reports.8,9,10,11 One nested case-control study of 5357 incident peripheral neuropathy cases and 17 285 matched controls showed that current use of systemic fluoroquinolone antibiotics increased the risk of peripheral neuropathy by 47%.12 In one third of patients, neuropathic symptoms occurred within 24h of treatment initiation,13 and in more than two-third within 1 week.14

Instead of these dry statistics, let’s look at some descriptions of actual harmed people in the case series from Golomb et al (2015):15

A 28-year-old woman, a professional educator, otherwise in good health, was given a 7-day course of 750 mg/day levofloxacin for a sinus infection, without noted problem, followed in several weeks by a 10-day course of 750 mg/day, as a precaution, after sinus surgery. During the second FQ [fluoroquionolone] course, symptoms emerged, including severe widespread tendon, muscle and joint pain, muscle weakness, peripheral nervous, somatic sensory, autonomic and special sense disturbances, cold extremities, gastrointestinal disturbances and CNS [central nervous system] problems extending to cognition (including confusion), sleep and mood. Her physician advised that these were FQ AEs [adverse events], and that she should discontinue the FQ immediately and inform all her physicians she should not receive FQs. Symptoms persisted and progressed after discontinuation, with emergence of new manifestations including fatigue, muscle atrophy, muscle spasms, fasciculations, shortness of breath and documented glucose dysregulation. The patient was bedridden throughout the year following levofloxacin use and unable to sit upright or bear weight on her feet unaided, with assistance required for feeding, bathing and toileting. Attempts at managing her pain were unsuccessful during the first year. She was referred to specialists including a rheumatologist, neurologist, orthopaedic surgeon, physical medicine and rehabilitation personnel, an internist, endocrinologist, podiatrist and physical therapist.16 Some but not all were familiar with FQ tendon AEs. None were aware of CNS or peripheral nervous system AEs associated with FQs.

Ciprofloxacin
Ciprofloxacin
by stockcatalog is licensed under CC BY 2.0.

A 46-year-old man in vigorous good health, employed in a physically demanding, high responsibility job, was treated with 750 mg/day levofloxacin for 21 days for an unconfirmed diagnosis of epididymitis; during treatment, low-grade muscle aches and pains newly emerged. Muscle aches continued following FQ discontinuation, with progression and emergence of symptoms including fatigue, muscle weakness and atrophy, peripheral neuropathic and autonomic disturbances (tachycardia, bradycardia), CNS manifestations (cognition and mood), vision abnormalities, with gastrointestinal manifestations and intestinal motility issues. Initially, after FQ use, he experienced what he termed an ‘autonomic storm’ comprising tachycardia, accompanied by very low energy, depression and anxiety. His symptoms evolved with tendinopathy emerging at 9 months affecting the Achilles tendons, feet and knees, and producing tendon pain with exercise in an athlete who previously ran or biked 10 miles a day. Limitations due to pain, and later fatigue, progressed, necessitating progressive curtailing of his cycling from 10 to 6, 4, 3 then 0 miles/day. He switched to walking, which then also became difficult. He purchased an exercise cycle in an effort to remain active, but discontinued use, as aerobic exercise produced delayed fatigue and pain. He stated, “I would expend energy and then pay for it later.” Bilateral patellar and foot tendon as well as knee pain with walking emerged, requiring him to stop and sit after walking 100 feet. Muscle strength seemed initially relatively preserved (compared to sustained activities—eg, he could open jars that his wife found problematic), but 15–30 min after application of effort he would experience significant fatigue, and muscle strength deteriorated with time. He was referred to specialists including neurologists, orthopaedists, endocrinologists and gastroenterologists, and referred to a teaching hospital where he underwent testing for a number of autoimmune conditions; questions were asked to screen for possible heritable conditions, and toxic exposures were assessed (all tests were reportedly negative). He underwent CT of the chest and abdomen, to screen for possible endocrine tumours or a paraneoplastic syndrome; results were unremarkable beyond non-specific hepatosplenomegaly. Over a period of approximately 3 years, multiple electromyography/nerve conduction velocity (EMG/NCV) studies were performed, which were unremarkable (2 were available for view, but as many as 8 were reportedly conducted). Biopsies of the thigh and calf to examine epidermal nerve fibre density revealed marked reductions in small nerve fibres (thigh value 4.8, normal ≥6.8; calf 4.0, normal ≥5.4—values are fibres per mm length of epidermis), with no indication of microinflammation, consistent with small fibre neuropathy. Other testing (table 2) was non-contributory. When the patient relayed the history of events starting with the FQ, an academic centre specialist reportedly told him that it could not be the FQ because the specialist had not come across this connection in the literature he had read. However, a local doctor did record this as possibly due to the FQ. The patient received a diagnosis of polyneuropathy of unknown origin and/or fibromyalgia. He initially received a prescription for pregabalin (which he discontinued), and two abortive trials of (different) benzodiazepines, which led to paradoxical adverse reactions (including anxiety). He remains on 10 mg of citalopram (without material relief), and several supplements, including zinc, for the peripheral neuropathy. More than 5 years after FQ use, this previously physically robust man remains affected with atrophy, profound muscle weakness, fatigue (recently evolving into a chronic fatigue-like condition), chronic gastrointestinal problems, mood disturbance, recurring muscle pain and tendinopathy, and painful peripheral neuropathy. Formerly vigorous, his problems necessitated limiting work in his physically demanding profession, and ultimately led to his early retirement. Notably, a brother had previously received an FQ for a prostate problem, which was followed by chronic fatigue syndrome that persisted for 5 years and then gradually abated.

If you want to delve deeper in the topic, you can see how people who have been affected describe the symptoms in their own reports in the EMA public hearing document — it makes for quite a depressing read; there is a video available as well. Social media are also full of similar reports,

Why does this keep happening if there are so many described cases?

The answer is complex. For one, there is a huge bias among doctors in that there is a tendency to discard rare diagnoses off-hand. A somewhat natural human tendency is to look for relatively simple answers, and it is easier to assume that the patient (whom you don’t personally know) is blowing symptoms out of proportion, manipulating or has psychogenic symptoms.17 More about this in the article about medical gaslighting.


To put things in perspective, let’s do some quick maths. We’re going to use data from Morales et al (2019), even though I suspect it is skewed, because SFN is underdiagnosed and awareness is poor among both the patients, as well as the medical professionals.18
The number needed to harm for a 10-day FQ course is 152 083. This means that this many 10-day courses have to be prescribed to patients for one person to develop peripheral neuropathy (in addition to “background” cases of spontaneous PN not related to fluoroquinolones). Let’s be extremely generous and assume that we have a very, very busy otolaryngologist who is throwing FQ left and right, and prescribes ten 10-day courses per day every day, including weekends (in case it’s not clear by now — this is a completely unrealistic scenario):

365*10=3650

152,083/3650=41.67

So, assuming that the data from Morales et al (2019) is correct,19 the above means that it would take nearly 42 years of continuously prescribing ten 10-day long FQ courses per day to see one case of peripheral neuropathy caused by fluoroquinolones.

The point is that most primary practitioners are normally “lucky” to see one case of some particular disease affecting 1 in 10 000 people, in their whole career. They are most likely not even expecting to see it. Now, if you look at the numbers that we arrived at above, even if we assume that they were massively understated (see footnote 18) and take into account that that study applies to just one of the serious side-effects, your regular doctor is still not very likely to see a patient with FQAD. This leads to them naturally veer towards more common explanations of someone’s symptoms, even if that patient knows everything else has been pretty much excluded, and knows the natural history of their own disease, or simply speaking what happened to their body when they took the medicine and how they feel. Nonetheless, it should be obvious for a responsible practitioner, that their own experience (or lack of thereof) is not going to be sufficient in cases of diseases happening as seldom as this, and they should rely more on literature.

But why is there so many people complaining of side-effects if these numbers are so low? – one may ask. Great question, my hypothetical reader. These figures may seem low when you consider them at a microscale of one prescriber. But when you look at a bigger picture of a country, like the USA, the situation will look as follows. The number of outpatient annual fills for fluoroquinolones was 21,100,050 for 2019 in the USA (if some of them were for the same people doesn’t matter for our calculations, as if you look at the previously quoted case reports, some people won’t develop FQAD until after they’ve had several courses).
So let’s look at a more realistic scenario — to simplify calculations, I am going to be cautious and assume each of those scripts was 10-days long again (some of them were probably 5-days and a lot 14-28-days, considering bacterial prostatitis is a common indication).
If a number needed to harm for a 10-day course is 152,083, it will look like this:

21,100,050/152,083=138.7

Which means that in 2019 alone, in the USA alone, you would have had roughly 139 patients who developed small fiber neuropathy alone as a result of a fluoroquinolone course given in an outpatient setting (the margin of error is quite big — probably to the antibiotics’ favour — as the calculations are very simplified to illustrate the point). When you take into account that people are more likely to talk about their extremely negative experience, that will explain why “there is suspiciously many tiktokers with rare diseases”. This may only surprise a doctor who doesn’t understand the basics of biostatistics/epidemiology and who hasn’t contemplated the fact that a tiktok about how someone cured their prostatitis with ciprofloxacin is not necessarily the thrilling story that is going to go viral.

Secondly, the etiology of fluoroquinolone disability, despite several theories,20 is not very well-understood and no biomarkers are available (notably, apart from small fiber neuropathy that can be proven by tests like skin biopsy; and some changes on imaging as applied to tendinopathies). This makes for a difficult diagnosis, more disbelief and more fibromyalgia or psychosomatic disorder labels.

Thirdly, there is a massive conflict of interest at the heart of drug regulators such as EMA:

Two out of every three drugs approved through conditional market authorisations (CMA) belong to the 21 pharmaceutical companies that pay most fees to EMA

When it formed in 1995 only 20 percent of funding came from industry, with the rest from the European Union. This year [2024], more than 90 per cent is forecast to come from industry fees and charges relating to medicine approvals.

In 2022, industry fees accounted for almost 86 percent of the regulator’s €417m in revenues its latest accounts show.

Investigate Europe can reveal how just 21 companies provided half of these fees received for drug authorisations. Novartis gave almost €20m, followed by Pfizer, AstraZeneca, Jannsen, Roche and GlaxoSmithKline, all of them paying more than €10m, data from freedom of information requests reveals.

Vivaldi building, the headquarters of the European Medicines Agency, shortly before completion.
Ceescamel, CC BY-SA 4.0 via Wikimedia Commons

You will find overview of some controversial drug authorisations in the linked article above.

One can imagine a situation where EMA needs to react to increasing discontent about irresponsible prescribing leading to suffering, but at the same time it needs to keep its clients satisfied. Some vague warning, being just guidelines bearing no legal power, would be good for that purpose, as they are going to be mostly ignored by prescribers.

Pharmaceutical companies are also guilty of withholding data. Via Wikipedia:

In September 2004, Merck voluntarily withdrew rofecoxib [nonsteroidal anti-inflammatory drug] from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib’s risks from doctors and patients for over five years, allegedly resulting in between 88,000 and 140,000 cases of serious heart disease.[3] Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.[4]

For more a more damning account of Vioxx controversy, including FDA inaction, see Freudenberg, N., & Galea, S. (2008)

Discourse around medical harm

A few mechanisms included in moral disengagement are also employed both on the side of the medical-industrial complex, as well as general population:

  • moral justification — one often invoked argument against mutual patient-to-patient warning about drug side-effects is that it may influence someone into not taking a life-saving medicine; while this is unlikely to be true anyway, as it is difficult to imagine a person in such a critical condition is going to go by what an internet stranger says rather than their doctor, it completely ignores that the consent for using some particular medication should be fully informed; meaning that the patient should be aware of possible serious adverse events before starting the treatment and withholding it is a method of manipulation;
    secondly — in 2014 in the US, 5% of fluoroquinolone prescriptions were given for conditions that no antibiotics should be prescribed for, and 20% for conditions where fluoroquinolones are not the recommended first-line therapy.21
  • displacement of responsibility — a government agency bureaucrat or a pharma company worker is so physically detached from the lived experience of a person severely harmed by a drug that this suffering is hardly going to evoke a reaction;
  • diffusion of responsibility — rather self-explanatory given the number of employees at the above institutions;
  • dehumanization — performed using indirect measures like presenting people as data points, avoiding presentation of qualitative data (i.e. patients describing their suffering in their own words), focusing on quantitative data (what disease they developed, when etc.) in scientific or government research.

There is a lot more to say on this topic that is beyond the scope of this post — this was supposed to be merely a primer and it’s already 2AM!
I hope that this post will become a small step on the path to moving to a slightly more open discourse about fluoroquinolones.

References:

  1. https://i-base.info/qa/factsheets/the-swiss-statement ↩︎
  2. Header taken from: Freeman, M. Z., Cannizzaro, D. N., Naughton, L. F., & Bove, C. (2021). Fluoroquinolones-Associated Disability: It Is Not All in Your Head. NeuroSci, 2(3), 235-253. https://doi.org/10.3390/neurosci2030017 ↩︎
  3. (=affecting more than one system, e.g. nervous system, skin, gastrointestinal tract) ↩︎
  4. “Conclusions: Our analysis clearly showed no significant differences [in the reported numbers of adverse events] before and after EMA warning, opening new insights in the role of the EMA warning in clinical practice.” in:
    DE Nunzio C, Nacchia A, Lombardo R, Franco A, Cicione A, Trucchi A, Labella M, Bartoletti R, Simonato A, Ficarra V, Tubaro A. Is EMA warning on quinolones and fluoroquinolones really assessed? An EudraVigilance database analysis. Minerva Urol Nephrol. 2023 Jun;75(3):374-380. doi: 10.23736/S2724-6051.23.05169-8. Epub 2023 Mar 20. PMID: 36940165.
    I suspect the actions taken have been particularly lenient on purpose, but more about this later. ↩︎
  5. https://www.fda.gov/news-events/press-announcements/fda-updates-warnings-fluoroquinolone-antibiotics ↩︎
  6. https://www.ema.europa.eu/en/news/fluoroquinolone-antibiotics-reminder-measures-reduce-risk-long-lasting-disabling-potentially-irreversible-side-effects ↩︎
  7. Quick search for the key word “suicide” on r/floxies subreddit yielded numerous results, I stopped counting around the thread number 100, as the list just kept growing longer. ↩︎
  8. Popescu C. Severe Acute Axonal Neuropathy Induced by Ciprofloxacin: A Case Report. Case Rep Neurol. 2018 May 30;10(2):124-129. doi: 10.1159/000489303. PMID: 29928218; PMCID: PMC6006604. ↩︎
  9. Francis JK, Higgins E. Permanent Peripheral Neuropathy: A Case Report on a Rare but Serious Debilitating Side-Effect of Fluoroquinolone Administration. Journal of Investigative Medicine High Impact Case Reports. 2014;2(3). doi:10.1177/2324709614545225 ↩︎
  10. Estofan LJF, Naydin S, Gliebus G. Quinolone-Induced Painful Peripheral Neuropathy: A Case Report and Literature Review. Journal of Investigative Medicine High Impact Case Reports. 2018;6. doi:10.1177/2324709617752736 ↩︎
  11. Oddly, Terkelsen et al (2017) mention antibiotic-related cases of SFN, but call them anecdotal, even though there was a large body of data of SFN linked to antibiotics, often confirmed by quantitative tests, by the time they wrote the article. ↩︎
  12. Morales D, Pacurariu A, Slattery J, Pinheiro L, McGettigan P, Kurz X. Association Between Peripheral Neuropathy and Exposure to Oral Fluoroquinolone or Amoxicillin-Clavulanate Therapy. JAMA Neurol. 2019;76(7):827–833. doi:10.1001/jamaneurol.2019.0887 ↩︎
  13. Cohen JS. Peripheral Neuropathy Associated with Fluoroquinolones. Annals of Pharmacotherapy. 2001;35(12):1540-1547. doi:10.1345/aph.1Z429 ↩︎
  14. Karin Hedenmalm, Olav Spigset, Peripheral sensory disturbances related to treatment with fluoroquinolones, Journal of Antimicrobial Chemotherapy, Volume 37, Issue 4, April 1996, Pages 831–837, https://doi.org/10.1093/jac/37.4.831 ↩︎ ↩︎
  15. Golomb BA, Koslik HJ, Redd AJ. Fluoroquinolone-induced serious, persistent, multisymptom adverse effects. BMJ Case Rep. 2015 Oct 5;2015:bcr2015209821. doi: 10.1136/bcr-2015-209821. PMID: 26438672; PMCID: PMC4600819.) ↩︎
  16. This siloization of medical care is another contributor to the difficulty of obtaining a diagnosis and help. ↩︎
  17. R/medicine, despite having some nice (presumably) doctors, unfortunately also tends to attract dismissive knobs that diagnose people with Munchausen syndrome based on a single TikTok video, with others deciding that using [unscientific] terms like MCAS, chronic Lyme, mold exposure by said tiktoker concludes the psychiatric diagnosis. This completely ignores the very likely possibility that these attempts at self-diagnosing are the outcome of impotent medical system that failed to recognize the patient’s real suffering. ↩︎
  18. Farhad, K. Current Diagnosis and Treatment of Painful Small Fiber Neuropathy. Curr Neurol Neurosci Rep 19, 103 (2019). https://doi.org/10.1007/s11910-019-1020-1
    Consider that in my case 2 out of 11 different doctors confirmed that my clinical picture was consistent with small fiber neuropathy. One of them was a neurologist who is an SFN researcher, the other one was a pain management specialist. ↩︎
  19. I think it’s massively understated for several reasons, even on the account that the bulk of those patients will be diagnosed with fibromyalgia due to poor awareness of SFN, clinician not wanting to pursue tests like skin biopsy that probably won’t change the treatment etc. ↩︎
  20. Stefan Pieper in his book Fluoroquinolone-Associated Disability (FQAD) – Pathogenesis, Diagnostics, Therapy and Diagnostic Criteria (2020) lists the following: Oxidative Stress/Mitochondrial Toxicity, Musculoskeletal Damage/Collagen Disorder, no described mechanism for neurotoxicity (immune-mediated, in my opinion, for several reasons), GABA inhibition for psychiatric effects.
    ↩︎
  21. Laura M King, Monina Bartoces, Katherine E Fleming-Dutra, Rebecca M Roberts, Lauri A Hicks, Changes in US Outpatient Antibiotic Prescriptions From 2011–2016, Clinical Infectious Diseases, Volume 70, Issue 3, 1 February 2020, Pages 370–377, https://doi.org/10.1093/cid/ciz225 ↩︎