FQAD - Term and Diagnostics
- Substantial limitation/disability of everyday life
- Two or more of the following systems are affected:
- Musculoskeletal System
- Peripheral Nervous System
- Cardiovascular System
- Sensory organs
- The Side-effects continue at least for 30 days or more after discontinuing the medication.
Unfortunately, there is no diagnosis code for FQAD in Europe yet. This is one of the most important missions of the Association for Awareness and Study of Fluoroquinolones Adverse Effects (AASFAE) (2).
In 2019, the European Medicines Agency (EMA) held a public consultation regarding fluoroquinolones, with the decision to issue another warning letter to physicians (known as a red hand letter) and further restrictions on therapeutic indications.
Pathophysiology and Symptoms
Meanwhile, there is an increasing body of literature regarding pathomechanism as well as potential therapeutic options for this disease. The Essential “Fluoroquinolone-Associated Disability FQAD: Pathogenesis, Diagnosis, Therapy and Diagnostic Criteria”(4) by Stefan Pieper, MD – the only “specialist” on FQAD in the German-speaking world, with experience of more than 300 patients treated – published in 2020 provides a good overview of the current state of research.
According to Stefan Pieper, MD, FQAD affects the following four body systems, which may vary depending on the patient:
- Mitochondrial dysfunction due to increase of oxidative Stress and inhibition of Topoisomerase II.
- Collagen damage through upregulation of various enzymes like Matrix metalloproteinases (especially MMP-2).
- Damage of the peripheral nervous system due to oxidative Stress, mitochondrial dysfunction or direct neurotoxic Action of the fluoroquinolone.
- Neuropsychiatric side effects due to fluoroquinolone-induced inhibition of the GABAergic system and activation of NMDA receptors.
- Chronic Fatigue Syndrom
- Tendinopathy, Tendon Rupture
- Aortic Aneurysm
- Paraesthesia, Dysaesthesia
- Muscle weakness, Myalgia, Fasciculations
- Sleeping Disorders, Depersonalisation and Suicidality
Potential therapy options
- Reduction of oxidative stress.
- Restoration of the reduced mitochondrial potential
- Supplementation of mono- and divalent cations, which are chelated by fluoroquinolones and probably ineffectively transported to the cell.
- Stimulation of mitochondrial proliferation.
- Removal of permanently accumulated fluoroquinolones from the cell (if this phenomenon occurs).
- Regulation of disrupted gene expression and enzyme activity.
Nevertheless, Krzysztof Michalak PhD emphasizes that the molecular activity of fluoroquinolone antibiotics in cells is largely unclear in many details.
Another starting point for the treatment of FQAD is the antagonistic effect of fluoroquinolones on the GABA A receptor described by Dr. med. Stefan Pieper (4) and reported in various studies, which has been described to be particularly enhanced in the case of simultaneous administration with an NSAID (6).
From previous experience with FQAD patients, we learnt that those affected with mostly neurological or neuropsychiatric side effects could benefit tremendously of the administration of potent benzodiazepine such as lorazepam or clonazepam, which facilitate the binding of GABA to the receptor through allosteric modulation of the GABA A receptor. Unfortunately, this has not yet been investigated in a study and is based solely on experience with over 100 people in our consultation. Benzodiazepines appear to be able to reduce excitotoxicity (7), which is hypothetically triggered by the antagonism of the fluoroquinolone at the GABA A receptor and the disinhibition of NMDA and can therefore alleviate symptoms such as sleep disorders, depersonalization and nerve pain. Another possibility appears to be an additional attempt to inhibit NMDA activity for example with the NMDA antagonist Memantine (8), while also but less pronounced with the non-competitive NMDA antagonist magnesium (9), to reduce excitotoxicity and thus alleviate side effects in this area. This is based on observation only. Please always discuss the information presented here with your treating physician!
Progression of the Disease
For a good overview of the different courses of the disease, see the website of the Association for Awareness and Study of Fluoroquinolones Adverse Effects (AASFAE) (10):
The severity and duration of side effects vary from case to case. For example, there are affected individuals with severe physical limitations who fully recover after a period of time, while other affected individuals with initially only moderate side effects experience a progressive course of the disease. Based on reported cases, the U.S. Food and Drug Administration (FDA) estimates an average duration of 14 months for severe side effects. However, quite a few cases of permanent damage have also been reported. A good indication of possible developments is provided by the Flox report. In it, possible moderate to severe courses are mapped using three different curves (see below). The data are based on observation of the disease courses of 49 patients. Excluded from this study are mild and conventional side effects, which usually disappear after discontinuation of the drug.
It should be mentioned that the Flox Report report was written by affected persons themselves and is not to be considered on a high scientific level. (11) In addition, it is already 14 years old. Many of the patients did not know about the above mentioned potential therapy options. Research findings on FQAD did not exist yet, nor was there a diagnosis code in the USA. Thus, well-designed studies are needed to investigate moderate as well as severe disease courses.
In conclusion, despite progress in research on the “young” clinical picture of FQAD, much remains to be learned in order to establish the exact cause as well as targeted therapeutic options. Also, the question of which subpopulation with which individual conditions (genetics, lifestyle, deficiency of minerals, vitamins and trace elements, etc.) suffers from the severe, sometimes irreversible side effects remains unresolved.
Marco Karrer B.Med.
Stefan Pieper, Fluoroquinolone-Associated Disability (FQAD) – Pathogenesis, Diagnostics, Therapy and Diagnostic Criteria (pages 43-60); 2021
Schwarzeck publishing house; Important drug information Systemic and inhaled quinolone and fluoroquinolone antibiotics: risk of quality-of-life-impairing, long-lasting and possibly irreversible side effects – restrictions on use; 2019
Stefan Pieper, Fluroquinolone-Associated Disability FQAD: Pathogenesis, diagnostics, therapy and diagnostic criteria; 2020
Krzysztof Michalak et al; Treatment of the Fluoroquinolone-Associated Disability: The Pathobiochemical Implications; 2017
MA Green, RF Halliwell Selective antagonism of the GABA A receptor by ciprofloxacin and biphenylacetic acid; 2009
GABA A Receptor Activation Attenuates Excitotoxicity but Exacerbates Oxygen-Glucose Deprivation-Induced Neuronal Injury In Vitro; 1996
Melinda K Kutzing, Vincent Luo, Bonnie L Firestein; Protection from glutamate-induced excitotoxicity by memantine
The International Journal of Neuropsychopharmacology; Bartłomiej Pochwat, Bernadeta Szewczyk, Magdalena Sowa-Kucma, Agata Siwek, Urszula Doboszewska, Wojciech Piekoszewski, Piotr Gruca, Mariusz Papp, Gabriel Nowak; Antidepressant-like activity of magnesium in the chronic mild stress model in rats: alterations in the NMDA receptor subunits; 2014