In the first post about the EMA hearings (EMA Hearing on Fluoroquinolone Toxicity Part 1) I summarized the testimonials provided by Elizabeth Carmouche, Manex Bettan Arguinzoniz, Richard Cooknell, Markus Hamedinger, and Miriam Knight (who also spoke on behalf of Raymond Miller and Geoffrey Robinson). In Part 2, and all subsequent posts about the EMA hearings, rather than summarizing my take on the testimony given, I will quote people directly from the written submissions that they provided to the EMA. Please note that not everything said in the hearing is included in the written submissions, and significant valuable information and insight can be gleaned from listening to the hearing. You can view the entire hearing through the following video:

Speaker 6. Julie Le Normand, France

1. What is your view on the role of quinolones and fluoroquinolones in the treatment of infections?

2. What is your view of the risks associated with quinolone and fluoroquinolone use?

3. In your opinion, what further measures could be taken to optimise the safe use of quinolones and fluoroquinolones?

My name is Julie Le Normand, I’m 37, I’m a French citizen and I am not representing any organization.

Back in November 2017, I had a terrible experience with levofloxacin (TAVANIC 500 mg, to be exact, twice a day for 10 days). That was the first time I ever took fluoroquinolones in my life, and it will certainly be the last.

Quinolones and fluoroquinolones (hereinafter referred to as Q & FQ) are far too broadly prescribed for cases where much less intense medicine would more than suffice for an efficient treatment. Having spoken with numerous people from across the world suffering from their adverse effects, I have learned that Q & FQ have been prescribed for everything from non-complicated urinary tract infections and sinusitis all the way to… anthrax exposure and the plague. I, for example, was prescribed a course of Levofloxacin by my general practitioner for a case of bronchitis/sinusitis at the end of November 2017. I would like the committee to know that I was never warned about the possible severe, longlasting side-effects of this medication by the doctor, nor by any other medical staff. It only took me two days on Levofloxacin after which I had no choice but to stop the medication because of the sudden onset of its adverse effects.

The manufacturers’ notice of the risks associated with Q & FQ is listed merely as “rare.” My experience—and those numerous others who have suffered from them—can attest to the fact that the risks of use of Q & FQ are anything but rare, contrary to what all of us have been led to believe. Please allow me to kindly state to the Committee that I took merely 4 pills in total of levofloxacin over two days, 7 months ago. For some, the adverse effects affecting the musculoskeletal and/or nervous system occur weeks or even months afterwards, which makes it even more difficult to connect the delayed symptoms with a course of antibiotics taken several weeks/months before. For me, the onset was as immediate as it was intense. I started to feel an extreme weakness in my legs. It was so bad that I could neither stand up on my feet nor walk anymore. I cannot do justice to you in describing just how uncomfortable the sensations inside my legs were. It felt as if bugs were crawling on them. Both my ankles and my Achilles heels started to hurt and swell. I could hardly breathe. My blood pressure rose dramatically, and I was overcome with a feeling of confusion and agitation. The experience was so bad that afterwards, I was completely bedridden for more than 3 weeks and on sick leave from work for 6 weeks. I felt depressed. And 7 months out, I still feel weak emotionally. My face has aged suddenly though I’m 37. I did not used to be this way. I used to be a very healthy person. I loved hiking, skiing. I am still a mother to 2 children both under the age of 5. But now I am limited in my physical and emotional capacities, and this is extremely upsetting and unfair. I will say that there have been some concrete improvements since the episode, but a part of me still wonders whether I will ever be able to fully heal from this “toxicity syndrome.” I have seen several doctors, each of whom have been helpless with the various symptoms I experienced. Long-lasting symptoms simply after a few pills of levofloxacin.

Please allow me to state for the record that I’m convinced Q & FQ should be limited only to life or death situations as their adverse side-effects far exceed what they can otherwise treat! In fact, I fear there is no such thing as a “safe use” of Q & FQ as the side-effects seem to be very common, almost the norm. Please allow me to reiterate that in my view Q & FQ should ONLY be prescribed at the hospital in certain circumstances with very cautious care and a thorough monitoring of any possible side-effects. General practitioners should not be able to prescribe them anymore without identifying the bacteria to treat, and in any event, not as a secondary intention but rather as a last resort treatment.

If I may add a final remark, I believe that the topical Q/FQ (such as eyedrops, ear drops) should also be included in this safety review as they are known to cause adverse reactions as well, that can be as severe as those triggered by the oral or IV antibiotics.

I do hope that the outcome of this Public Hearing will lead to:

1. An acknowledgement of a so called FQ associated toxicity syndrome/disability within Europe. To my view, there is an urging need that the EMA acknowledges the existence of a so called FQ associated toxicity syndrome/disability (FQAD, like the US Food and Drug Administration did a couple of years ago).

2. If not a complete BAN of FQs, at least a STRONG restriction of their use within Europe This would be for sure a historic choice (much stronger that the current “black box warnings” used in USA) and would give Europe the leadership in FQ toxicity awareness.

Thank you for your time and consideration and for the opportunity to present my experience to the Committee.

Speaker 7. Elsa Leitão, Germany

My name is Elsa Leitao. I’m from Portugal and I’m currently living in Germany where I work as a scientist in the field of human epigenetics.

I’m 39 years-old and until three years ago I was fairly healthy. Then I was prescribed Ciprofloxacin to treat a regular urinary infection. I had no further warning from my physician about the special risks associated with this drug. After a few days I developed side effects: joint pain, muscle pain, difficulty in walking, lack of strength and general tiredness. It took me several months until I started feeling better but I never got back to my previous health state. I haven’t been able to run longer distances again due to the fragility I still feel in certain tendons. Even after three years, I have sporadic episodes of severe joint pain that I believe are related to the ingestion of certain types of food that I became unable to tolerate.

I think quinolones and fluoroquinolones should only be used in life threatening conditions such has extremely severe infections. These drugs should be avoided when other treatments are possible. I believe that patients prescribed with these antibiotics are in great risk of becoming sicker than before the treatment. Moreover, the side effects take much longer to subside than the initial illness would take to disappear with other treatment and may even become permanently debilitating.

There are a few measures I think should be taken to optimise the safe use of these drugs: 1) Physicians should be better instructed about the severe long lasting side effects the administration of these drugs might have; these instructions should be clearly passed to medical school teachers, medical students and working physicians, so all links in the chain can simultaneously acquire this knowledge. 2) Physicians should inform the patients about the potential toxicity, so the patients can be alert to the appearance of potentially alarming signs. 3) Packages should contain clear warning labels. 4) The products information should be changed with regard to the use of these drugs to the treatment of non-severe infections.

Although this public hearing is more focused in trying to improve the future use of these drugs, I think the past shouldn’t be forgotten nor the patients whose life was most severely and permanently affected. In this regard, efforts should also be taken in understanding how to treat these patients.

Speaker 8. Jarosław Linka, Poland

1) What is your view on the role of quinolones and fluoroquinolones in the treatment of infections?

Fluoroquinolone (FQs) antibiotics are currently one of the most frequently prescribed drugs in Europe and play a very important role in treatment for bacterial infections, such as pneumonia, sinusitis, bronchitis, urinary tract infections, as well as for prostatitis. However, FQs are extremely toxic, have high potentials for adverse effects (AE) and associated with potentially long-lasting, frequently permanent, serious sides effects. Adverse reactions (ADRs) are often delayed for some weeks or months after cessation of FQs drug therapy, which makes it extremely difficult to make a correct medical diagnosis and apply symptomatic treatment. They belong to the group of broad-spectrum antibiotics, effective for both gram-positive and gram-negative bacteria. FQs employ their antibacterial effect by preventing bacterial DNA from unwinding and duplicating through inhibition of their topoisomerase and gyrase, which differentiate them from other common antibacterial agents. This mechanism places them closer to chemotherapy drugs then other antibiotics, which mostly interfere with specific steps in homeostatic cell wall biosynthesis. As a result of this broad-spectrum and misunderstanding of their safety profile, doctors in Europe consider them as a safe treatment option and prescribe them even as an empirical first line antibiotics therapy. This is leading to an overuse of FQs, and in consequence tens of thousands of people suffer by them each year, yet nearly all those damages remain misdiagnose or undiagnosed. Patients after FQs ADRs frequently are diagnosed as having Lyme disease, multiple sclerosis, neuropathies of every kind, lupus, rheumatoid diseases and most often fibromyalgia. Only a handful of doctors are aware of a devastating effects of FQs. The rest are uninformed and often deny the existence of fluoroquinolone associated disability (FQAD).

2) What is your view of the risks associated with quinolone and fluoroquinolone use?

According to the latest research and available literature, FQs toxicity results from many causes, including the formation of reactive oxygen species, and generation of oxidative stress damage of the mitochondrial DNA, as well as from the chelation of metals and a change in gene expression. These mechanisms explain the reason why FQs are often reported, to cause permanent and serious sides effects to: tendon, muscles, joints, nerves and other organs. Other long-lasting problems involve the cardiovascular system (QT interval prolongation), musculoskeletal system disorders (arthropathy, muscle weakness, joint pain and swelling), chronic fatigue and diabetes mellitus. Moreover, FQs have recently been discovered to induce delayed adverse neuropsychiatric effects including dizziness, sleep disturbance, anxiety, suicidal thoughts, hallucinations, psychosis, depression and recurrent mania. All the side effects should be mentioned on the patient info label, especially including psychiatric and potential delayed mitochondrial toxicity (like mitochondrial DNA depletion and mutations.)

3) In your opinion, what further measures could be taken to optimise the safe use of quinolones and fluoroquinolones?

The overuse of FQs and the growing number of reports on ADRs often leading to the fluoroquinolone associated disability (FQAD) is the main reason to avoid FQs when other safer alternatives are available. FQs should only be used as the last resort, exclusively in a hospital, by a well trained specialist. Unfortunately routine blood and urine tests are generally non-contributory to diagnoses of FQ’s ADR or FQAD, so specific molecular and genetic tests should be provided as quickly as possible. Special studies are necessary to find genetic factors underling susceptibility and the genotypes predisposing to ADRs. Multicenter clinical trials on long-lasting FQAD in large groups of patients are also required. Immediately, the basic guidelines and standard treatment methods for ADR and FQAD should be developed. This can’t be left to desperate patients and only several aware doctors who try to help them, like it was in my case. After one year of visiting numerous clinics in Poland, Germany, China, and USA I have finally found doctors, who were willing to help me and are aware of the FQ toxicity syndrome. Based on published data analysis and subsequent empirical searching, an individualised treatment plan was developed, which significantly reduced or even reversed some of my damage caused by Levofloxacine. Although, after three years my quality of life is better, a lot of environmental factors can induce intermittent episodes of symptoms. I am still suffering from chronic fatigue, Achilles and other tendons tendinopathy, multilevel degenerative disc disease, peripheral and small fibre neuropathy, uncommon food sensitivities, muscle weakness and headaches. A Review of currently available knowledge of possible ways to treat of FQAD, inspired by my case, was published last year in the Oxidative Medicine and Cellular Longevity under the title: “Treatment of the Fluoroquinolone-Associated Disability: The Pathobiochehemical Implications”

I hope that a PRAC meeting will set new restrictions for FQs and new procedures of their use only in hospitals, under long-term supervision and as a last resort treatment. Limited action from EMA such as just copying FDA’s warning from June 26, 2016 will probably keep the current status quo for their use and spreading of their devastating delayed side effects, what we can still observe with the growing number of cases of FQAD from the United States.

https://doi.org/10.1155/2017/8023935

Speaker 9. Andrea Noya, Italy

As someone who’s suffered and is still suffering serious side effects from a fluoroquinolone, prescribed to me more then a year ago, I’d like to share my experience, in the hope that more consciousness would be applied, when using these types of drugs and also in the hope of bringing these side effects to the attention of the many doctors, that still seem to ignore them.

Answering the questions:

1. I think quinolones and fluoroquinolones are powerful and effective drugs that should be only prescribed for serious or life threatening infections.

2. The risks, in my opinion, exceed the benefits. A patient shouldn’t suffer serious or disabling side effects from a drug prescribed to treat or even prevent a common infection.

3. In my opinion, more restricting laws should be applied to this class of drugs and it should be mandatory for doctors to be better informed and trained on the use of quinolones and fluoroquinolones.

(Please note that Andrea Noya goes into significantly more detail about his experience with fluoroquinolone toxicity in his testimony.)

Speaker 10. Joshua Sutton, UK

My name is Joshua Sutton and I am a business student at Sheffield Hallam University.

I would like to begin by saying that there is a place for Fluoroquinolones in modern medicine, and the use of them in a proper manner could be very effective. However, the current use of them is far too frivolous and exceptionally dangerous. These drugs have such strong capabilities of causing major damage, as two days after the treatment of Ciprofloxacin for an unconfirmed and nonurgent infection my neurological health greatly deteriorated. The impact that these drugs have had on my life is beyond belief.

My view on the risks of Fluoroquinolones is that they very often outweigh the benefits, especially for unconfirmed and non-urgent infections. I was prescribed Ciprofloxacin on the 5th June 2017 by my GP. It was the 17th June when I first realised something was wrong, where my vision became very slurry and I felt very disorientated. This was accompanied by a horrible brain fog sensation that has never gone away, extreme light sensitivity and then walls of black snakes down the walls which ended up being the development of eye floaters.

Starting on the next day, the 18th June, I developed a terrible tremor and loss of sensation in my hands and feet where I quickly lost the ability to do even the most basic of tasks; tying my shoe laces, holding a knife and fork or even dressing myself. I would have excruciating deep rooted pains and aches down my glutes and hamstrings down into my feet, and the same down my arms into my hands that would refine me to my bed. The tops of my hands and feet would also be extremely sore, where moving my toes or fingers or clenching a fist would be agony.

I have burning and tingling pains and sensations all over my peripherals and head and face, and my limbs would consistently go numb. I couldn’t hold my phone up to use it as my hands and arms would quickly go numb and I would awake every morning with both my arms hanging by my side completely dead. I would and still get burning sensations down my back and limbs that makes even the weight of a cotton t-shirt against my skin excruciating. In addition to this, I would also find it impossible to empty my bladder and would have to strain to do so even a little bit.

Onto the fatigue and weakness, I would be so weak to the point where I couldn’t turn over a chicken breast in a frying pan or pick my feet up as I was walking so I would simply trip up over my own feet regularly. I would find it impossible to complete daily tasks. I was very reliant on my Mum to look after me and care for me during this period and I have had to make some major lifestyle adjustments in result of all of this. I am still very fatigued to this day and have great difficulty concentrating on anything. My cognitive abilities have been greatly affected by all this.

Alongside this, I have also been seeing a Cognitive Behavioural Psychotherapist to help me handle the anxiety involved with these symptoms.

Moving on, my opinion on further measures to optimise the safety of Fluoroquinolones should be to discontinue the use of them for unconfirmed and non-urgent infections, only allow GP’s to use them as a last resort, perhaps if the patient has allergies or sensitivities to many other alternative antibiotics. Also, the use in hospitals should also be as a last resort, and any prescribing doctor should not only be fully aware of the adverse capabilities of Fluoroquinolones but also discuss any adverse reaction symptoms with the patient so they are well informed because if they begin to have adverse symptoms during their course and continue taking them they are going to be very unwell for a very long time.

Fundamentally, this is all an iatrogenic catastrophe and there needs to be immediate regulation to mitigate these risks involved.

Ciprofloxacin took away my health, my fitness and my sanity, and for that, its unforgivable.

*****