Talk:Adverse effects of fluoroquinolones/Archive 1

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I copied the bulk of the material for this article from a users talk page User talk:96.254.65.104 who seems new to wikipedia. Administrators please remember that this article is in the very beginning stages of development and needs lots more work over the coming months so please remember that it is rated as start class and is brand new. Basically don't delete it please without giving it a chance to develop. I believe that once developed it will provide an excellent resource for doctors, pharmacists and patients alike on the subject of the toxicity of fluoroquinolones.--Literaturegeek | T@1k? 02:26, 22 January 2009 (UTC)

I had been reviewing that suggested addition since December (recently with help from MastCell). I have rewritten the article with our edited version, which is in accordance with WP:NPOV and WP:WEIGHT. This article should also probably be moved to Quinolone-associated tendinopathy, because a) it only covers tendon damage and b) this "syndrome", if you will, is associated with quinolones, not only fluoroquinolones. Fvasconcellos (t·c) 14:34, 22 January 2009 (UTC)

Hi FV, I am happy with rebalancing the article according to WP:NPOV and WP:WEIGHT standards. I am not sure about moving it to the suggested page because the toxicity profile of quinolones is extensive with regard to organ systems affected such as eyes, CNS, GI tract, muscuskeletal system, joints, peripheral nerve damage and so on. Infact CNS adverse effects are the most common adverse event from fluoroquinolones and can be very long lasting. I am planning on adding some info regarding CNS adverse effects.--Literaturegeek | T@1k? 16:30, 22 January 2009 (UTC)

P.S., I am sorry for jumping the gun and creating the page. I wasn't aware that you were still in the process of reviewing the material.--Literaturegeek | T@1k? 16:31, 22 January 2009 (UTC)

Suggestions regarding excessive lenght of article

I'm a professional of pharmacology, however, I think that this article is too much exhaustive and lengthy - a good wikipedia article should aim to the general public and should be understandable by those who are not experts of a specific field. Much of this article should appear only in professionals' pages. I would suggest to reformat it: a shorter summary presented in a style understandable by the general public followed by the detailed discussion. tgunda 09:15, 13 February 2009 (UTC)

We are diligently working on achieving that. But I respectfully disagree that most of this information should only appear in the professional pages. Mainly because the "professionals" have proven that they cannot be bothered to read such pages to begin with. If indeed they did, there would be no need for this article. Additionally the treating physcian, rarely if ever provides such information to the patient. In fact it has been my experience over the past decade that even the physician remains clueless, (as well as the dispensing pharmacist) and in fact often times denies that these associations even exist in the first place.

What you are viewing is a work in progress with the presentation of the raw data. It is our intention to refine this article considerably, reducing it's lenght by approximately 40%. It would be pointless to simply have it read like a package insert, presenting a laundry list of possible reactions with no explanations and no relevant histories. A detailed discussion would be rather difficult to do and still remain encyclopedic in nature. We are rather limited in the manner in which the information may be presented as we must stay true to what is being stated in the various citations being used. Restating this information in our own words, using everyday English, would only bastardize what these authors have stated within their papers and possibly change their entire meaning. And as such, proven facts may run the risk of becoming unsupported opinions.

But we are in agreement that the article is far too long, the question remains what to leave in and what to leave out. Considering what has been presented so far is less than half the research, with a number of significant and serious adrs not yet even touched upon, this indeed presents a real challenge. You must keep in mind that we are dealing with a class of drugs with a greater than 40% adverse drug reaction rate, (a number of which threaten the very life of the patient and have proven to be permanent injuries), a medical community who remains oblivious to this and in denial, together with the millions of affected patients. This makes this a rather unique situation when compared to any other class of drugs. As such the normal rules of presentation cannot be successfully applied here. We have already tried that and have failed miserably.Davidtfull (talk) 22:50, 13 February 2009 (UTC)

A Proposed opening statement for this article:

The adverse drug reactions (ADRS) to the fluoroquinolones have been associated with serious and detrimental effects upon the Multiskeletal System, Cardiovascular System, Central and Peripheral Nervous System, Circulatory System, Maxillofacial System, Endocrine System, Gastrointestinal System, Urological System, the Liver, the Brain, the Skin, all five senses; hearing, sight, taste, touch and smell, as well as the patient’s DNA, since the mid sixties (see Nalidixic Acid). (1)

The collective adverse drug reactions to the potent and toxic chemotherapeutic class of anitbacterials, commonly referred to as the Fluoroquinolones (or Quinolones), are commonly referred to as the “Fluoroquinolone Toxicity Syndrome” or “Quinolone Syndrome”. A term first employed by the Fluoroquinolone Toxicity Research Foundation (circa 2001)(2) and used extensively within the article “Quinolone antibiotics toxicity. A summary of closely followed cases” (Published Dec 2003 T. Boomer).(3) The distinction between a Quinolone drug and a Fluoroquinolone drug is the addition of the flourine atom to the drug’s pharmcore. The terms Quinolones and Fluoroquinolones are frequently used interchangeably.

Such adverse reactions manifest during, as well as long after fluoroquinolone therapy had been discontinued. These ADRS induced by the fluoroquinolones can be, for some patients, severe, prolonged and in some cases permanent and disabling. The dose, length of time and number of exposures to fluoroquinolones as well as combination with corticosteroids or NSAIDs may increase the risk of the patient suffering specific ADRS. The concurrent use of corticosteroids increases the risk of multiskeletal injury, manifesting as spontaneous tendon ruptures, and the concurrent use of NSAIDs may induce severe and prolonged seizures. (4) Increased and repeated exposure to the Fluoroquinolone class appears to increase the risk of the patient suffering multiple ADRS. Whilst people of all ages may experience a severe and prolonged ADR to the fluoroquinolones, the elderly and especially the young are particularly more susceptible to the toxic effects of fluoroquinolones and their use in these populations is often times discouraged.

Fluoroquinolones are not licensed by the FDA for use in children due to the risk of permanent injury to the multiskeletal system, with two exceptions. Ciprofloxacin being licensed for the treatment of Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli and Inhalational anthrax (post-exposure) and Levofloxacin recently being licensed for the treatment of Inhalational Anthrax (Post-Exposure). However the Fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK. Within one study it was stated that the pediatric patient has a 3.8% chance of experiencing a serious multiskeletal adverse event.(5)

The fluoroquinolones rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues.(6) For this reason the Fluroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The Flouroquinolones have also been reported as being present in the mother’s milk and are passed on to the nursing child,(7) which may increases the risk of the child suffering from this syndrome as well.

Toxic reactions to the fluoroquinolones have been reported to occur after a single dose and such reactions may last a lifetime. Additionally, as noted above, a child exposed to this class while nursing may experience such reactions. In principle, the Fluoroquinolone Syndrome may be classified as a TYPE III inmunological reaction, with added noninmunological toxicity. Manifesting in the patient as a series of cascading adverse events, in some cases lasting for years after therapy had been discontinued, involving the various body systems outlined above.

There are no known treatment protocols available for the majority of these reactions and the medical community often times fails to recognize such events as even being related to fluoroquinolone therapy.

References:

1. Package Inserts:

   Levofloxacin 2008
   Moxifloxacin 2008
   Ciprofloxacin 2008
   Gemifloxacin  2008
   Floxacin 2008
   Gatifloxacin 2008
   Lomefloxacin 2008
   Nalidixic Acid 2008
   Norfloxacin 2008
   Proquin XR 2008
  

2. www.fqresearch.org

3. http://www.fluoroquinolones.org/

4. Seizures Associated with Fluoroquinolones The Annals of Pharmacotherapy: Vol. 36, No. 7, pp. 1162–1167. Janine M Kushner, Howard J Peckman, and Clyde R Snyder

5. Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders. Noel GJ, Bradley JS, Kauffman RE, Duffy CM, Gerbino PG, Arguedas A, Bagchi P, Balis DA, Blumer JL.

Fluoroquinolone safety in pediatric patients: a prospective, multicenter, comparative cohort study in France.Chalumeau M, Tonnelier S, D'Athis P, Treluyer JM, Gendrel D, Breart G, Pons G; Pediatric Fluoroquinolone Safety Study Investigators. Perinatal and Pediatric Pharmacology Unit, Universite Rene-Descartes, Hopital Saint-Vincent-de-Paul (AP-HP), Paris, France.

6. Fetal and maternal tissue distribution of the new fluoroquinolone DW-116 in pregnant rats. Shin HC, Kim JC, Chung MK, Jung YH, Kim JS, Lee MK, Amidon GL.

Pharmacotherapy: Official Journal of the American College of Clinical Pharmacy Print ISSN: 0277-0008 Volume: 25 | Issue: 1 Cover date: January 2005 Page(s): 116-118

Larsen H, Nielsen GL, Schonheyder HC, Olesen C, Sorensen HT.Birth outcome following maternal use of fluoroquinolones. Int J Antimicrob Agents. 2001 Sep;18(3):259-62. PMID 11673039 [PubMed - indexed for MEDLINE]

Casey B, Bawdon RE.Ex vivo human placental transfer of trovafloxacin. Infect Dis Obstet Gynecol. 2000;8(5-6):228-9. PMID 11220482 [PubMed - indexed for MEDLINE]

7. Chung AM, Reed MD, Blumer JL.Antibiotics and breast-feeding: a critical review of the literature. Paediatr Drugs. 2002;4(12):817-37. Review. PMID 12431134 [PubMed - indexed for MEDLINE]

Dan M, Weidekamm E, Sagiv R, Portmann R, Zakut H.Penetration of fleroxacin into breast milk and pharmacokinetics in lactating women. Antimicrob Agents Chemother. 1993 Feb;37(2):293-6. PMID 8452360 [PubMed - indexed for MEDLINE]

Additional comments:

Rebalancing the article according to WP:NPOV and WP:WEIGHT standards would be extremely difficult if not impossible as it deals with a negative situation that has been well documented within the medical journals. There is no debate concerning whether or not this class has the potential to induce such reactions, so there is no oppossing position to present. The debate revolves around the appalling lack of knowledge concerning these reactions within the medical community. Not whether such reactions take place.

For the above reason(s)I have not edited to the article to include the above opening statement, as I am not too sure how to handle a situation such as this. Never the less I hope someone more experienced may feel free to edit the above suggestion as needed to meet the standards required by Wikipedia, or for reasons of brevity, with my blessings and change the article accordingly.Davidtfull (talk) 09:09, 24 January 2009 (UTC)

The above suggested text is too long for an introduction which is best get to a couple of relatively short paragraphs. I agree that the evidence is clear that such adverse reactions can and are induced by fluoroquinolones and don't think that they can be disputed. I guess it is the tone and weight given. Weight can often just mean giving the article too much information on one particular aspect of the topic rather than other aspects. I do think that you have given too much weight to the gastrointestinal, gut flora section. Such reactions, eg candidiasis and other super infections are not unique to fluoroquinolones but can occur with almost if not all antibiotics. Also fluoroquinolones are not the worst antibiotic for inducing such infections. Super-infections occur probably most frequently with clindamycin. I think that giving too much weight to this section also takes away from the toxicity of fluoroquinolones which is relatively unique to fluoroquinolones compared to other "safer" antibiotics. Also candidiasis is rarely "dangerous" unless someone has aids or has some other extreme immunocompromising condition. Thrush infections are relatively common with antibiotic therapy but are rarely serious, more often irritating. I suggest shortening and reducing the weight given to this aspect and adverse reaction of quinolones.--Literaturegeek | T@1k? 21:56, 24 January 2009 (UTC)

I added much of the text you suggest3ed but broke it up into pieces eg a section on children and beast feeding. I think the lead/introduction is as big as we should have it. Any bigger and it will be off putting to any potential readers. You can check the edit page on the article to see my additions.--Literaturegeek | T@1k? 22:44, 24 January 2009 (UTC)

I wonder what the pharmateutical companies will do when they see this article... JamesLockson (talk) 08:20, 1 February 2009 (UTC)

A good example of what the drug companies will do is what they are doing on the paroxetine page now. See the edit history of the article and also the talk page filled up with endless debates. Personally I don't think there is much that they can do as the article is well referenced. Admins can edit protect articles anyway if they get persistently vandalised and block users etc.--Literaturegeek | T@1k? 15:03, 5 February 2009 (UTC)

David, I have to backtrack a little on what I said. I was just talking to a doctor recently who works in a hospital and he stated that fluoroquinolones are one of the worst drugs for inducing clostridium difficile infections. So it is worth pointing out that fluoroquinolones are worse than most other antibiotic classes for causing clostridium difficile infections. There is a professor of microbiology who has been giving speeches around the UK recommending avoidance of fluoroquinolones and only using them as last resort type antibiotics due to their high risk of causing clostridium difficile infections.--Literaturegeek | T@1k? 15:03, 5 February 2009 (UTC)

In response to your suggestions and comments

LITERATUREGEEK: Thank you for your input, as well as the changes you had made. I have edited the gastro section following your suggestions.

My thoughts with the intro was to try to explain to the reader what the term "fluoroquinolone toxicity syndrome" actually encompassed. With most of the other antibiotics the side effects are unpleasant reactions that abate when you stop the drug and such reactions are intuative as we see them with all antibiotics. However, the adrs to the quinolones are far from being intuative (who would think you could be crippled for life as the result of taking ONE antibiotic?) and are life altering in nature. More to the point patients do not usually suffer one or two specific reactions, but dozens that cascade into dozens more. A never ending cycle that last for years on end.

Even more insidious is the fact that such reactions manifest long after therapy had been discontinued, which you rarely see with other antibiotics. For instances if I were to present to you complaining of ankle pain (possible tendon rupture), sudden manifestation of double vision (diplopia), ringing in the ears (tinittius), a skin rash, a raging yeast infection on my tongue, as well as psychiatric manifestations such as severe anxiety and chronic insomonia, you would no doubt label me a hypochrondriac. But this type of presentation is all too common with these drugs. And all too often dismissed out of hand by the treating physician as to having anything to do with these drugs.

As such I was trying to inform the readers that THIS is what we are referring to when we refer to the "Fluoroquinolone Toxicity Syndrome". The sudden manifestation of dozens of individual and bizarre adrs following fluoroquinolone therapy. And then use the rest of the article to get into each specific reaction as well as try to explain the known mechanims of action, to be found within this syndrome. Feel free to edit the intro as you see fit if you agree that this goal has merit. I would take no offense to you doing so. Hence my request that others take the raw data I am providing and mold it into a finished product that keeps the readers engaged.

Unfortunately within the peer review environment that I find myself in (on a daily basis running the Foundation), every statement made requires a dozen references and a detailed explanation as well. As such brevity is far from being one of our strong suits and I tend to error on giving far too much information, and too much detail rather than too little.

As per your suggestion I have removed the introduction. However may I suggest that you remove the following text from your intro as it is redundant, as you state this again under the children stub:

"Fluoroquinolones are not licensed for use in children due to increased toxicity except in cases of lower respiratory infections related to cystic fibrosis. Fluroquinolones are also contraindicated during pregnancy"

Additionally you may want to start a new paragraph where you stated "Whilst..." to improve readability. —Preceding unsigned comment added by Davidtfull (talk • contribs) 04:25, 25 January 2009 (UTC)

I would also like to add sub headings and provide stubs for the following adrs as well if appropriate. Do you think they should be grouped differently than this? Or should some of these be removed from this list or merged with others?

Fibromyalgia /Chronic Fatigue

Brain Damage

Dental Damage

Drug Interactions

Heart Damage

Kidney Damage

Liver Damage

Muscle Damage/ Tendon Ruptures/ Rhabdomyolysis

Phototoxicity and Skin Damage

Sleep Disturbances / Insomnia

Special Senses (Hearing Loss, vision damage, taste and smell perversions)

Another thought is whether the adr stubs should be listed aphabetically or by severity and frequency? Thanks for taking the time to guide me through this process.

On a side note regarding candidiasis or yeast infections rarely to be considered "dangerous", perhaps this case report cited to within:

FDA's ODS POSTMARKETING SAFETY REVIEW Consult: One-Year Post Pediatric Exclusivity Postmarketing Adverse Events Review Drug: Ciprofloxacin NDA: 19-537, 19-847, 19-857, 20-780, 21-473, 21-554 Pediatric Exclusivity Approval Date: December 22, 2003

helps explain my emphasis on this aspect:

"During the first 13 months of pediatric exclusivity there was one death, two reports of disability and four of hospitalization. The fatality was associated with a worsening disease progression in a patient diagnosed with chronic mucocutaneous candidiasis (CMC) despite therapy with several antibiotics and antifungal drugs." (end of qoute)

Now as you had stated candidiasis or yeast infections is not normally associated with a high degree of mortality, but in the above case the child took a turn for the worse, and expired, once Cipro was used to treat this overgrowth. I have to wonder how many other case such as this that there are where the treating physician assumed that the candidiasis or yeast infections induced by the quinolones would be of no consequence to a patient. Perhaps this is a fatal assumption that needed to be pointed out. Perhaps not. But research has indicated that this is yet another thing peculiar to the quinolone drugs. A fatal candidiasis infection. Hence my emphasis on this particular adr.Davidtfull (talk) 03:53, 25 January 2009 (UTC)

You are welcome. I have no doubt that there are many people who have had their fluoroquinolone induced toxicities misdiagnosed and that it is an under-recognised syndrome. I can see the article is now taking shape. I will tweak it and fix reference into their proper tag format when I have a chance. I removed from the intro the sentences that you suggested. I think that the suggested sections would be a helpful addition, if they can be referenced with peer reviewed citations. Interesting case of the child. I dunno if the child was immuno compromised or severely debilitated due to some other medical condition. As it is only a single case report, we can't conclude that this is anything more than an isolated case or something unique to quinolones. I would imagine that there are similar cases with other antibiotics. Super-infections are worth mentioning but just don't feel that they should be given paragraph after paragraph unless there is peer reviewed data showing an epidemic of deaths much more than other antibiotics from super infections like candida, c difficile etc.--Literaturegeek | T@1k? 18:45, 25 January 2009 (UTC)

I think that the gastrointestinal section as it is now is fine as it is currently. I was talking about the previous version. I don't think that it needs any editing apart from perhaps some minor tweaking and putting refs into proper tagged format.--Literaturegeek | T@1k? 19:25, 25 January 2009 (UTC)

My suggestions

Create subsections on CNS toxicity and explore the type of toxicities experienced regarding the CNS and their duration. Like how for some people they are short lasting and for others can persist for months or even years in cases of neurotoxicity. Create another section on occular toxicity and one on tendon and muscular toxicity and so on. Have a few short paragraphs on each of the toxicities. This information is greatly needed, especially for people suffering adverse toxicities of fluoroquinolones. The types of readers of this article, eg doctors, pharmacists and patients/victims of fluoroquinolones are going to be much more interested in the types of potential toxicities and how long they last for and so forth. A section on the mechanisms of toxicity would be of great value as well eg on GABA_A receptor antagonism and cellular toxicity. This may interest professionals, pharmacists, doctors etc. There is more than enough information on the legal and campaign side of the toxicity of fluoroquinolones so wiki editors please try and expand now on the actual fluoroquinolone toxicity syndrome as suggested above, describe it and use where ever possible credible peer reviewed sources.--Literaturegeek | T@1k? 02:34, 22 January 2009 (UTC)

I certainly hope creating this article was a good idea—this has the potential to quickly become a content fork. Fvasconcellos (t·c) 14:35, 22 January 2009 (UTC)

I have listed the numerous serious adverse reactions to this class on the fqresearch site, together with the supporting documentation. This may be an excellent jumping off point for those who are involved in writing this article. Due to numerous other projects I am already working on regarding these issues I simply do not have any hours left in the day to contribute a whole lot to this article. But as I have stated all the research has been done, including the citations and can be found on the research site which would make the fact checking a whole lot easier for those who wish to add to this article. Regards, David Fuller, Director, Fluoroquinolone Toxicity Research Foundation.96.254.65.104 (talk) 05:38, 23 January 2009 (UTC)

Adverse reaction is more accurate than side effects. You are increasing the toxic effect on cells because quinolones in combination with NSAIDs or corticosteroids are having a synergistic effect on adverse effects, maybe it just needs rewording. Quinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK and other countries. I don't have much time myself at the moment but will try to make small contributions every so often and hope more people will get involved.--Literaturegeek | T@1k? 12:41, 23 January 2009 (UTC)

There is a distinction between a side effect and an adverse reaction. A side effect is a response to the drug that abates once the drug has cleared the system. As such the side effect is short lived and abates once the drug is discontinued. An adverse reaction is the damage done WHILE the drug is in your system. Hence it can be prolonged long after the drug has cleared your system. As you are now dealing with the celluar damage done by the drug and not the bodies response to the drug. Perhaps I should have been more specific. The FDA has not approved the use of the fluoroquinolones to treat lower respiratory infections in children with cystic fibrosis here in the United States. Apperently each country must have it's own package inserts as the one available here in the States does not list that indication, and all of the published articles I have read indicate that this is a compassionate use, not a licensed one. Irregardless it is insanity to expose a child to these horrendous adverse reactions.

In the previous section I have submitted a proposed opening statement for this article for your consideration. Davidtfull (talk) 06:30, 24 January 2009 (UTC)

If you notice I said that adverse reaction is a better term than side effect and I also edited the article and changed it to adverse reaction yesterday. :=) I am going to try and incorporate the suggested text into the article.--Literaturegeek | T@1k? 21:58, 24 January 2009 (UTC)

Sorry for repeating myself. I'm still trying to get the hang of finding the responses to my comments. I have added a number of pages to my watch section, which should make it a lot easier to keep up with this. I just now found this response ( a week later). Hence my delay in acknowledging it.Davidtfull (talk) 04:28, 28 January 2009 (UTC)

Cochlear Vestibular Toxicity

Possibly a section on this?

I believe tinnitus is a manifestation of cochlear damage, not PNS damage.

119.95.204.176 (talk) 01:50, 28 January 2009 (UTC)

There will definately be a sections on hearing and vision loss. Cochlear damage induced tinnitus results mostly from exposure to noise, in my case the chronic tinnitus that I have (resultant from taking these drugs) had been diagnosis as irreversible nerve damage. Rather than the common ringing in the ears often found with cochlear tinnitus I suffer from a chronic form of "white noise" that varies in volume. This type of nerve damage has been reported on a number of quinolone forums as well. When I review the pertinent research in preperation of this stub I will explore this a bit further and present whatever findings result and make any changes accordingly.Davidtfull (talk) 04:20, 28 January 2009 (UTC)

Alpha Lipoic Acid quinolone induced tinnitus

A recent edit by (119.95.206.156) states:

However, aggressive treatment with Alpha Lipoic Acid and Acetyl-L-Carnitine, has shown some promise in reducing ototoxin induced tinnitus.

I am curious if we have any citations we could use to support this statement? All I could find were the unsupported statements made by the alternative medicine crowd which come no where near the standards of documentation required by Wikipedia. I would like to keep this edit in the article if it is justified but I need some supporting evidence to justify doing so. But if it cannot be verified using acceptable sources then it should be removed.Davidtfull (talk) 05:42, 30 January 2009 (UTC)

I agree, however, I did a recent check through google scholar, and both thesse compounds are definitely neuroprotective, and studies have shown that they may help prevent tinnitus from aminoglycoside antibiotics. Whether it will reverse quinolone induced tinnitus is unknown. JamesLockson (talk) 08:16, 1 February 2009 (UTC)

Section on delayed, worsening and permanent reactions

I believe we need this section, a majority of these reactions occur long after the first dose. Some appear months later, while some keep worsening. Moreover, these reactions may be non-abating even after the drug has been stopped. It is hard for most people to believe that this kind of reactions can actually occur. JamesLockson (talk) 08:16, 1 February 2009 (UTC)

We are rapidly running out of room on this article having already exceeded the 80-100 limit imposed by wikipedia. And this is with less than 25% of the relative information being added. We are working on restructuring this article due to the tremendous amount of research the clearly documents everybody's concerns. Heck, a book could be written about these issues. So if anyone has any ideas how to go about restructuring this feel free to speak up now, (or forever hold your peace :) We need all the help we can get from some of senior and experienced editors to reduce (4) four drawer file cabinets of legitamate and peer reviewed research that clearly documents the horrendous safety profile and scripting abuse associated with this class, the malfeasance of the regulatory agencies, and the appalling ignorance found within the medical community, not to mention the aggressive and unethical manner in which these drugs have been promoted to fit within this limit.Davidtfull (talk) 09:13, 1 February 2009 (UTC)

Try merging the pregnancy and children sections into a pediatrics section. GI damaged can be shortened to the damage specific to quinolones (that don't occur with other antibiotics). This article is getting a bit long. However, a section on delayed, worsening and permanent reactions would by far be the most useful section here. The regulatory history and dear doctor letters can be shortened or moved, as they are not very related to this syndrome, you can probably move them to the main fluoroquinolone article. Also, feel free to reply to my email :). JamesLockson (talk) 09:58, 1 February 2009 (UTC)

The above suggestions have merit, but I disagree concerning the regulatory history being irrelevant. In my opinion an article on this syndrome should not only explain what it is, what it is capable of doing and why, but also how it came in to being in the first place. The regulatory history shows how easily the manifestation of this syndrome could have been avoided years ago, as well as the continuing malfeseance of the regulator agencies concerning this. This information would be extremely valuable to a patient whose physician denies that this proven association is not even possible, as so many treating physicians have done over the past forty years. Physicians may not pay attention to peer reviewed studies, and other such references that we are using. But they do pay attention to the past actions taken by regulatory agencies. Hence the reasoning behind their inclusions. This is still a work in progress and all suggestions and discussions are more than welcomed, even negative ones. We want the article to have an A+ rating when it is completed, which would require the active participation of all concerned.Davidtfull (talk) 04:52, 2 February 2009 (UTC)

I have moved the stubs regarding pregnancy and drug interactions to the ciprofloxacin page, and will include them under each drug's heading as I revise those other articles in the future. This was done to make room for a stub concerning delayed reactions, which is pretty much the "meat and potatoes" of the toxicity syndrome. I'm having trouble finding a way to shorten the gastro section as this adr is particularly viscious with the quinolones in comparision to other antibiotics. It is not a matter of some digestive discomfort while on the drug, but the inducing of a life threatening gastro problems not usually found with the other antibiotics that turns into a chronic condition that in some cases last for years after the drug had been discontinued. A significant number of fatalities have been associated with these digestive concerns.Davidtfull (talk) 15:26, 8 February 2009 (UTC)

Brain damage/CNS, Vision and DNA Damage, suggestions

I believe brain damage and CNS events are closely related, maybe they can be joined together. Moreover, I feel that the DNA damage section can be further expanded, and explanations on how it causes delayed long term reactions could be added. Lastly, the citations could be more split up. Lastly, I believe it would be a good idea to add vision damage as a section to this article.

JamesLockson (talk) 12:26, 10 February 2009 (UTC)

The article is already at 100 kbs, so we have totally run out of room. We now have to severely edit what is there to make room for other stubs. I have yet to finish editing the DNA stub to move the citations into their proper place so that is why they have not been split up yet. As far as the brain damage stub this relates to hypoglycemia induced brain injury as well as vascular damage. This is not the same thing as the nerve damage as we find with the CNS injuries. This is why I decided to give it its own stub. They are related in the same manner as cousins would be, but they are not related as brother and sister. We have to work together to cut about 40KB before we even think about adding more stubs, no matter how important or valid they may be. How trashed DNA would cause delayed reactions is a no brainer. As the cells die thier natural death and are replaced with defective cells within a period of time critical mass is achieved and whatever organ contains these defective cells would start a cascade of events due to it not functioning properly. Which of course would affect other parts of the body manifesting as delayed reactions. But since nobody has bothered to seriously research this aspect of the quinolone damage I really don't have anything to site to that I could use to expand upon this theory. My own opinions are not to be considered research and unless someone else in the medical field has come to this same conclusion I can't mention it or expand upon it.Davidtfull (talk) 02:45, 11 February 2009 (UTC)

NPOV and neologism issues

This article provides many references on fluoroquinolone side effects. However, the term "Fluoroquinolone toxicity syndrome" has no supporting references on PubMed or Google, and no reliable ones on Google Scholar (basically, this one adequately summarises the lack of scientific consensus for this concept by acknowledging in a rant on fluoroquinolones that "fluoroquinolone toxicity syndrome is repeatedly discounted by medical professionals").

In believe this article should be redirected to a more neutral title (Side effects of fluoroquinolones) and that it is rewritten for neutrality. Also, I would ask editors who are proficiently working on this article that they don't include this neologism in other articles. --Steven Fruitsmaak (Reply) 15:12, 15 February 2009 (UTC)

I created the page so I will explain why I chose the name. There is if you search pubmed for terms such as "fluoroquinolone toxicity" or quinolone toxicity quite a range of results come back many of which address, report or review the individual or a range of toxicities of fluoroquinolones some of which can be permanently disabling, eg tendonitis, neurotoxicity, peripheral nerve damage and so forth. Whilst fluoroquinolone toxicity has been extensively documented in the medical literature, the word syndrome as you correctly point has not been added on to the phrase "fluoroquinolone toxicity" in the peer reviewed literature. I was aware of this when I created the page as I checked before I created the page. The word "syndrome", as I am sure that you know, basically means in medicine a "set of symptoms" or "multiple symptoms" usually relating to one specific cause or disease etc. That was why I used the term. As for the rant, my best guess is the physician who left that message and his knowledge of support groups etc is probably a victim of fluoroquinolones or has a family member who was harmed by them and was letting off some steam at his colleagues lack of awareness. I am not sure side effects of fluoroquinolones is a good title because when you are talking about severe and often permanent consequences of a drug, it is more than side effects but is cellular toxicity, neuorotoxicity so I do feel that toxicity is the most accurate term and that is a term used in the medical literature. If the article was based on transient acute side effects which all disappeared within days or weeks of discontinuing therapy and there were no long lasting symptoms or permanent damage then side effects would be a better term. I think that the best solution is to redirect to "fluoroquinolone toxicity". I may do that in the interim while we discuss this further and all editors share their views.--Literaturegeek | T@1k? 15:35, 15 February 2009 (UTC)

Hi Steve, I have removed most, hopefully all of what I saw to be original research or uncited data and unencyclopedic viewpoints and so forth. It is difficult to make an article neutral when talking about toxic effects. One can't for example say 50% of patients who developed neurotoxicity or tendonitis didn't mind being disabled or traumatised or sectioned in a mental health unit etc. I do think that we (editors) should be careful not to bring emotions or original viewpoints into the article and try to stick to factual data from reliable sources, statistics, symptomatology and time course and so forth, ie keep it encyclopedic. I have not contributed very much to this article other than mostly just tidying it up, making inline citations and so forth. I wonder have my edits today to the article content and renaming cleared up the bulk of the neutrality issues? Are there specific issues that in your opinion need addressing? Can we remove the neutrality tag now? I welcome your feed back.--Literaturegeek | T@1k? 17:05, 15 February 2009 (UTC)

The term "syndrome" severely misguiding since it implies that some people suffer multiple side effects simulateously; although all the side-effects mentioned are real, they don't have a specific tendency to occur simultaneously. Neutrality is indeed difficult if you use "toxicity" as a starting point; in a general discussion of side effects, sentences like "severe, prolonged and in some cases permanent, disabling and even fatal" could be avoided. There is no need to split "toxicity" off from a separate discussion on side effects. I really think that the tone of this article remains inappropriately stressing severe toxicity without putting it into a realistic context.

Any drug has side effects; sentences like "Increased and repeated exposure to the Fluoroquinolone class appears to increase the risk of the patient suffering multiple ADRS." only serves to increase drama. Many negative allegations remain uncited (for example, "the medical community oftentimes fails to recognize such events as even being related to fluoroquinolone therapy"). So no, I don't think the NPOV tag can be removed. --Steven Fruitsmaak (Reply) 18:12, 15 February 2009 (UTC)

I partly agree and partly disagree. If one took alcohol or benzodiazepine withdrawal syndrome as an example of a syndrome, one person may get mostly CNS effects and another may get mainly physical effects, one wouldn't get all systems severely affected unless they were experiencing a severe "syndrome". There are reports in the literature of people getting multiple toxicities to multiple organ systems from fluoroquinolones, I can find citations if you like. Whilst I think you are correct that a many people get one specific toxicity say tendon injury only, many others get multiple injuries to multiple systems. I think that it depends on the degree of exposure, number of exposures, dose, individual susceptibility and other factors. Multiple exposures to fluoroquinolones is a risk factor for more severe reactions (perhaps due to cellular kindling?), so whether that is dramatic it is still factual that with further courses adverse reactions tend to be worse than the previous exposure in affected people. I think you have a point in that not everyone who has adverse reactions has a severe, prolonged or permanent adverse reaction. This needs to be emphasised more in the article. I do accept what you say though that there are still neutrality issues to be ironed out here. I will do some more tweaking. David, another editor is the contributer and I am mainly the "tweaker" of this article so to speak. He is pretty new to wikipedia which is probably at least partly to do with the imperfect layout and use of original research and other neutrality issues. I will remove more uncited text and try to make article more neutral.--Literaturegeek | T@1k? 18:43, 15 February 2009 (UTC)

"sentences like "severe, prolonged and in some cases permanent, disabling and even fatal" could be avoided."

I am not sure that mention of severe and permanent symptoms can be avoided because it is the prolonged nature of symptoms and injury which occurs in a proportion of patients that sets fluoroquinolones apart from other antibiotic families such as penicillins, macrolides, cephalosporins. That is why this page exists otherwise we could have a seperate page for side effects of every drug on wiki. I don't think that we can water down the seriousness of some adverse reactions which can for some people in worse case scenarios permanently disable a person for life but equally it does need to be put in context as to frequency and acknowledge that most people don't meet a "grissly end" if they take a fluoroquinolone. I have added and started a new section called "epidemiology", which perhaps could serve putting into context to the reader the frequency of adverse effects and further the frequency of long lasting adverse effects. Perhaps an epidemiological section will help resolve the neutrality issues of putting things in context?--Literaturegeek | T@1k? 20:19, 15 February 2009 (UTC)

As far as name of the article I think that we should wait for some of the other editors to express their views. Possible choices could be leave the name as it is as fluoroquinolone toxicity or change it to long term effects of fluoroquinolones or fluoroquinolone adverse reactions.--Literaturegeek | T@1k? 20:34, 15 February 2009 (UTC)

I have added an epidemiology section. I think that such a section should resolve most of the neutrality issues remaining in the article. We need statistics on frequency of ADRs added to that section.--Literaturegeek | T@1k? 20:42, 15 February 2009 (UTC)

Yes, an epidemiology section surely would put things into context. I think one of the main causes of the conflict of interest on this page is explained here: User_talk:Davidtfull#Declaration_of_possible_COI_or_introduction_of_inadvertent_bias (Fluoroquinolone Toxicity Research Foundation director) and his mission "to assure that the articles being written concerning the fluoroquinolones and thier horrendous adverse reactions are factual in nature and well as the proper citations included in such entries".

Syndromes like benzodiazepine or alcohol withdrawal syndrome, like serotoninergic or cholinergic toxidrome, are indeed systemic manifestations of adverse drug events. I really doubt if quinolones have this kind of proven "syndrome" effect. Even if multiple adverse events occur in the same patient (which I have rarely seen in the hundreds of patients I've seen treated with them), that doesn't make it a "syndrome". Nevertheless, I would indeed like a citation for multisystem adverse events.

Any drug would get more adverse events when exposure is repeated; that doesn't make quinolones more dangerous than other drugs. I do acknowledge that in certain populations such as the elderly, there is an increased risk, which needs to be weighed against the disease for which it is used. Any drug has side effects, and certainly a potent class of antimicrobial drugs that adds to our daily arsenal.

The literature is detailed enough to write a separate "adverse events" article which couldn't be included in a general quinolone article. If there was enough material, I don't see why we couldn't have this kind of article for other drugs (if we had editors dedicated to writing them, apparently finding references is not a problem).

I don't really see the difference between "side effects of fluoroquinolones" and "fluoroquinolone adverse events", I would agree with both. --Steven Fruitsmaak (Reply) 21:11, 15 February 2009 (UTC)

This article summarises people's case histories in a table. As you can see many people had multiple organ system affected and there was often a pattern to their adverse reactions.Peripheral Neuropathy Associated with Fluoroquinolones pmid It was not a random controlled study so we can't say what percent of people experience adverse reactions like these with this citation but it does give a good picture of case histories and symptomatology. I think that provided David is willing to agree to address neutrality issues and resolve violations of wiki policy, that he can contribute productively. Well the toxic effects of fluoroquinolones are in part due to GABA antagonism and the symptomatology of benzo or alcohol withdrawal is much to do with reduced GABA function. If you scroll down a list of withdrawal symptoms from benzos or alcohol withdrawal they are not that far removed from many of the side effects from quinolones, at least CNS side effects. One could argue that quinolones cause an even greater syndrome than alcohol or benzo withdrawal (when the syndrome occurs) due to additional cytotoxic effects on tendons, muscle cells and so forth. However, as it is not called a syndrome in the medical literature, at least as of yet, I think that we are debating original research regarding syndrome so I think that we can conclude that the article should not be called a syndrome. I don't agree that re-exposure to drugs in general causes worse reaction the next time around. If a person was to take a 7 day course of propranolol for say anxiety and got moderate insomnia and then retryed the drug for 7 days 6 months later, you wouldn't expect the reaction to then develop into anything more significant than the previous side effects, like you wouldn't expect the next course to then develop into severe insomnia and then next 7 day course into hallucinations and psychosis and then next cource into prolonged neurotoxicity. The only things that I think fit the profile of worsening on re-exposure, is either drug or chemical allergy, a kindling phenomenom due to repeated serious neuromodulation or cellular modulation or due to repeated insult of a substance which is toxic to cells. There was a prior discussion on side effects versus adverse effects and it was felt adverse effects seemed more applicable term to describe long lasting as well as acute reactions whereas side effects was a term more suited to acute transient drug induced symptoms but anyway doesn't matter. I guess they technically mean the same thing.--Literaturegeek | T@1k? 21:49, 15 February 2009 (UTC)

The example of the study you provided is a really poor bid; it's a study based on cases gathered at specialised Internet fora! --Steven Fruitsmaak (Reply) 22:14, 15 February 2009 (UTC)

If using the study to get an idea of the pattern of symptoms which occur in severely affected people I think the study is ok for that which was what I was using it for but if using it for more than a discription of symptoms in severely affected people it is of limited value due to the bias of the nonrandomised selection process. Idealy from an academic point of view or encyclopedic point of view you would have randomised neurotoxic study where people were given various doses for various time frames or else placebos with the intention of trying to provoke a toxic rreaction and studying it but such studies would never pass an ethics approval board unless one was in nazi germany! ;=) You can't get randomised controlled studies on anaphylaxis to say peanut allergies so it has to be case studies unfortunately. It is the nature of the beast. I am sure better studies could be done, random sampling of patients in GP practices and what not. Here is a quote from an newspaper article on cipro, "57 percent reported adverse side effects while they were taking the drugs. Almost all were minor, with the most common being nausea, vomiting, headaches and dizziness, but some also suffered tendinitis, fainting spells and seizures. Sixteen percent of those people, including Jill Perel, were sick enough to require medical attention." It was quoting a Center for Disease Control (USA), a study on cipro when it was given for anthrax. However, the course was a 60 day long course which may at least partly explain the high number (16%) requiring medical attention for ciprofloxacin adverse events. I am trying to find the orriginal CDC report.--Literaturegeek | T@1k? 22:33, 15 February 2009 (UTC)

Ok, I found the Center for disease control study. It is quite interesting because of the large volume of people who couldn't complete the course. Bare in mind these people thought that they may have a life threatening anthrax infection but they still decided that they would rather take their chances with anthrax than continue with the ciprofloxacin. At least one person was crippled with tendonitis. I haven't read the full report, just skimmed it. If they were prescribed equally effective doxycycline instead which is relatively benign, would you have such a high discontinuation rate and from adverse reactions? Would people be getting anxiety and all sorts of bizarre side effects and would 16% require medical attention if they took doxycycline or any other antibiotic drug class? I doubt it. Maybe something like larium for malaria would have such high rates of adverse effects. Here is another interesting read.--Literaturegeek | T@1k? 22:53, 15 February 2009 (UTC)

Fluoroquinolone reactions are very real, and very serious. There are many people who have suffered tremendously for years due to these reactions. You cannot deny this fact. The fact that fluoroquinolones were given the Black Box by the FDA already indicates this danger. Moreover, don't you find it surprising how the package inserts for these drugs list "Irreversible Peripheral Neuropathy" as a side effect? Do you also not realize that many of these symptoms are delayed, and multi-systemic, resulting in a misdiagnosis such as Chronic fatigue syndrome, or fibromyalgia? The medical community has always been ignorant with these drugs. In a published study, only 1% of fluoroquinolones were prescribed appropriately. This article is not biased in any way, David has included many many published sources regarding fluoroquinolone toxicity. If you want firsthand experience of these adverse reactions, try taking 750mg/day of Levaquin for at least one week (in absence of an infection). Guaranteed you will be suffering from serious adverse reactions. JamesLockson (talk) 08:01, 16 February 2009 (UTC)

I'm not denying facts, I'm asking for references to prove it. Most reviews I've seen, even the ones specifically on toxicity, are not nearly as negativistic as you are all alleging. You're making it sound like a doomsday drug, which it obviously isn't. --Steven Fruitsmaak (Reply) 16:22, 16 February 2009 (UTC)

orginal editors response

I would have to step in here for a moment, with all due respect, and note that Steven is a classic example of the rampant ignorance found within the medical community regarding these drugs and what they are capable of doing. There is no question that the article needs a lot of work. It has clearly been noted from day one that this is a work in progress and I have asked for the assistance of the more senior editors to help keep it in compliance with wikis rules.

Let us take a moment and address his objections in the order raised:

"However, the term "Fluoroquinolone toxicity syndrome" has no supporting references on PubMed or Google."

I disagree. See Trovan syndrome for starters. The title should not be considered "neologism". It is a term that has come into common use to describe these adverse reactions. "This progression of the fluoroquinolone toxicity syndrome is well know by its sufferers and not recognized by health care givers." Dr. Todd Plumb 2008

"This very common fluoroquinolone toxicity syndrome is repeatedly discounted by medical professionals who continue to focus on only one facet of the adverse ..." bmj.com Rapid Responses for Cooper et al., 330 (7498) 1002

The adverse reactions to the fluoroquinolones have been well documented as being multiple in nature. A person experiences a number of reactions over a long period of time. A syndrome refers to the association of several clinically recognizable features, signs (observed by a physician). When you review the clinical studies and case reports this is EXACTLY what you find with this class. Irregardless of which drug found within the class you care to study. But as I did not entitle the article I will defer to the editor who did regarding this. But make no mistake about it these advere reactions are well documented within the liteature as having "several clinically recognizable features". To deny this is to deny reality, which is exactly the problem found regarding these drugs adverse events to begin with.

"The term "syndrome" severely misguiding since it implies that some people suffer multiple side effects simulateously; although all the side-effects mentioned are real, they don't have a specific tendency to occur simultaneously."

Again will all due respect Steve, your are agian mistakened here. This is EXACTLY what they do. No, a person would not be expected to suffer each and every adr listed. But a number of these reactions do take place at once or develop over a period of time. A person may very well suffer from gastro effects, tendonitis, the PNS and CNS effects all at the same time.

Why would it be neccassary to avoid stating "severe, prolonged and in some cases permanent, disabling and even fatal" when this is exactly what is taking place here? These reactions are severe, and they are prolonged. Any number of peer reviewed articles have proven this to be the case. Even the FDA's adviory panels have stated that they have been found to be both permanent and disabling in some cases. As such what would you suggest to be the appropriate context? That these drugs are wonderful drugs except to those who unfortunately have these reactions? If you will notice the adr rate for levaquin was found to be greater than 40% (one or more reactions) within the studies submitted to the FDA with the NDA. As such that would be about one out of every two patients.

"Increased and repeated exposure to the Fluoroquinolone class appears to increase the risk of the patient suffering multiple ADRS" only serves to increase drama. Why? How is this considered to increase "drama" when again this is a known association. Why do you think it is stated within the inserts that the use of this class in patients who have suffered a previous reaction is contraindicated? And why do we NOT rechallenge a patient who has these reactions? Because they have an increased risk of suffering one or more reactions.

Many negative allegations remain uncited "the medical community oftentimes fails to recognize such events as even being related to fluoroquinolone therapy".

Steve, let us be reasonable here. I could very well cite each and every statement found within that article. Common knowledge is not expected to be cited. Only those items that would be disputed or are rather obscure. The above statement is not an allegation. It is a fact. And I believe that statement indeed was cited later in the article under delayed and permanent injury:

Adverse Reactions to Fluoroquinolones http://www.em-news.com/pt/re/emmednews/pdfhandler.00132981-200811000-00012.pdf;jsessionid=JPCfCHnlc71XCxCpPfvnL1pTJR1fXbH3B1HQwcpGQz1M6q1vjxvj!1321082991!181195629!8091!-1

I believe it would be reduntant to cite to any statement similar in nature that expresses the same fact. But if you care to I would be more than obliged to do exactly that. But you will be finding a citation after every statement made, which is ridiculous.

You cited to my full disclosure as being the reason for the article containing any conflicts of interest: "factual in nature and well as the proper citations included in such entries". How would requiring that the quinolone articles be factual in nature with proper citations be considered a conflict of interest when you are demanding the very same thing yourself? It is not as if I had invented any facts here. My only failure would be the manner in which they are being presented. Being new to wikipedia this is to be expected, not critized.

The problem is that you are trying to push your overly negative point of view of these antibiotics by abusing references, often of poor quality. Your point has been determined in advance, you're just putting references behind it so it all seems credible. The problem is that even if the entire medical community is ignorant about fluoroquinolone toxicity, we still follow the consensus. Wikipedia is not a place to start changing the common perception, it is not a place for crusades. --Steven Fruitsmaak (Reply) 16:46, 16 February 2009 (UTC)

"I really doubt if quinolones have this kind of proven "syndrome" effect" and of course you are entitled to your opinion. But the fact of the matter is that they do. And this has been well stated within the liteature since 1962 and this is what the article is attempting to document.

"Even if multiple adverse events occur in the same patient (which I have rarely seen in the hundreds of patients I've seen treated with them), that doesn't make it a "syndrome"."

No? Then what would you consider to be the proper criteria to use, when a syndrome is defined as "several clinically recognizable features". Even you have admitted to seing multiple adverse events occur in the same patient who has taken these drugs. Rare is a relative term and meaningless in this context. With well over 600 million patients it is impossible to determine how extensive this actually is. Post marketing is a total and complete failure and clinical studies are bias to the point where known and published reactions are found to be "unrelated" to the study drugs by those running the trials. I would venture to say that if you were to interview the patients you had referred to, with the information provide within this article in mind, that you would discover a far greater frequency of this taking place in those patients.

The Cohen study, that you find to be inadequate, was performed by reviewing the patients actual medical histories and was published. The source of these patient is irrelevant, as it does not change what was found within their medical records. Never the less there are sufficient citations of this nature than can be used and will be added to satisfy your request for citations to support this argument.

I understand your concerns, as I (and others who have been gracious enough to help with this article) share them as well. This article at this point in time is in its infantcy. You are expecting it to be able to run a marathon when it just learning to walk. You are being unrealistic. It will take a tremendous amount of time and effort to bring it up to your standards. But the common view that you have expressed is false and misleading, which is exactly what this article is addressing. These are not side effects that dissapate when the drug is stopped. The frequency in which they occur is anything but "rare" and the patients are more likely than not to suffer multiple events at the same time. It is rather petty to argue about the title including the term "syndrome" when, by definition, this is as a correct description. Perhaps working together we can eliminate the bias you are trying to introduce (safe drugs, minimum side effects, blah, blah, blah) as well as my own bias which I freely admit to being present. (dangerous and toxic drugs) But bias does not change the facts. And the bottom line remains the same. These drugs introduce a syndrome that has not been recognized by the medical community. How then would you suggest we go about presenting this fact within the guidelines of wikipedia? Rather than attempting to dispute its existance? Introducing "rare" as a disclaimer of some sort defeats the whole purpose. It is only "rare" due to lack of proper post marketing survelliance, lack of knowledge among the treating physicians and the denial found within the medical community.

I know that this is not to be considered to be of any value, but of all the patients I have spoken with regarding these issues over the past decade (which is in the tens of thousands) 99% indicated that their physicians had NO knowledge concerning these events and their association with the fluoroquinolones. Rather than contribute to this continuing ignorance I would appreciate it if you were to contribute your medical knowledge to prevent it, rather than continue to encourage it. Attempting to deny the existance of a proven syndrome does nothing to help correct the errors to be found within this article. And I freely admit that there are some that need additional work. Rather than attempt to tear it down, let us see what you can contribute to build it up instead. This is what I am attempting to do and would hope that you would join me in doing this, rather than fight me to prevent it from taking place.

Your arguments would be valid if indeed I had hidden my association with these issues and was attempting to promote false and misleading information via a hidden agenda. But full disclosure was made from the get go, and there is no hidden agenda to be found. The ignorance within the medical community is a proven fact. Just ask any patient who suffered from these reactions. So let us work to together to create an article that tells the truth, rather than promote the false and misleading information being promoted by the drug companies and the FDA instead.

I am more than willing to temper my prose if you are willing to admit that you have been lied to about what these drugs are capable of doing to a patient. Let us start by admitting the existance of this syndrome and then go about citing to our proofs in a proper manner. Otherwise this whole situation would be hopeless and I would be wasting my time as well as yours to contribute anything further to this article. Perhaps I am the one that should give up in disgust and let Big Pharma continue to promote their false propaganda via wikipedia without further interference from me. As this appears to be your agenda judging by your comments regarding this article. Perhaps I am mistaken and have misjudged your motives. But your comments appear to be more of an attack on the article even being included on wikipedia, rather than an attempt to improve it. I offer no offense and I would hope none taken and surely I have taken no offense to your comments either. We are simply in disagreement concerning this article and I hope I have explained the reasoning behind some of the statements made therein.Davidtfull (talk) 03:26, 16 February 2009 (UTC)

Thank you for your statement. No offense taken and non meant on my part either (also note that I sometimes have been known to express myself strangely because I'm not a native Anglophone). I understand that you almost completely disagree. I'm not trying to be negative only. I'll try and edit the article where I think citation is needed or bias is present. I assure you, I'm open-minded and I do agree that up to a certain level, there is a problem with fluoroquinolones. I have been known in the past to change my mind about something when I see good references. I expect the same of others though. --Steven Fruitsmaak (Reply) 16:46, 16 February 2009 (UTC)

"the medical community oftentimes fails to recognize such events as even being related to fluoroquinolone therapy".

Idealy the above statement would need a citation, otherwise why can't someone add their uncited data saying the opposite? Facts should be referenced. It may be common sense statement to you but to the lay reader and perhaps even health professions it may not be common knowledge that the syndrome is often misdiagnosed. I think that while this article is developing there is going to be some dispute both by those who have been victims or harmed by the drug and by others who have been biased by being only exposed to the benefits of the drugs via their promotion in medical journals. The truth probably lies somewhere in the middle, which is some people are greatly harmed by the drug, sometimes for the rest of their lives and many take the drugs and thank God don't have any long lasting effects. This is why I think the epidemiology section is going to be the most important section to resolve disputes. Whilst I am sure that many people develop insomnia, anxiety, fibromyalgia, CFS, psychosis, ligament damage and so forth which is often misdiagnosed by the user of the drug, family and the medical community, blaming it on something else we can only speculate. One thing that I would say is that wikipedia does not seek the truth over neutral verifiability. See this link Wikipedia:Verifiability,_not_truth if it cannot be verified. Although this sounds strange there is good reason for this. Everybody's version of truth is different for a variety of reasons so it comes down to verifiability. So it may be true that there are hundreds of thousands of people perhaps millions who have certain symptoms or conditions which were caused by fluoroquinolones and perhaps it is true that they are not recognised due to promotion of benefits and downplaying the negatives by Big Pharma but if it is not verifiable then there is not a lot that can be done because wiki works by verifiability not the truth per se but the truth through verifiability and neutrality is a good aim however, if I am making sense. I also recommend reading this which I feel is important reading for an editor of a page under dispute. Wikipedia:No_original_research#Primary.2C_secondary_and_tertiary_sources I think that use of good review papers on the toxicities of fluoroquinolones and also FDA publications on the toxicities of fluoroquinolones would help resolve the dispute as well as improve the quality of the article. Primary sources can also be used and it is for the most part impossible to completely avoid using primary sources but good secondary sources are always benefitial in improving an article especially a disputed article.--Literaturegeek | T@1k? 14:58, 16 February 2009 (UTC)

inappropriate article?

While patrolling new pages and new edits, I came across this.

This is an extremely difficult article to write correctly. Even the warnings given by drug stores and the US FDA are not like this article. The printed government sanctioned information given to doctors is inappropriate for a WP article because the WP article does not include background information on different diseases and terminology. Merely having a blue wikilink is insufficient because having something available elsewhere but not in the article is not good enough.

Others could argue that this article is beyond what is appropriate for an encyclopedia.

This is a difficult question to resolve in WP. One idea is to merge the article. Another is to give up and let people with possibly hidden agendas go about their work.

Good luckChergles (talk) 21:17, 15 February 2009 (UTC)

I have no agenda and have not contributed much at all to the addition of data to the article. Mostly I have been passing views on the talk page, tidying up the article layout like inline citations and also been advising one of the new editors of this page on policies of wikipedia and how to best go about editing articles. Although I do think that this page is notable. I feel perhaps you are not familar with the safety profile of fluoroquinolones versus other antibiotics? Perhaps that is why you made the posts that you made regarding this article? With that said there are certainly issues with the article. Bare in mind it is only a C class article and it is only a few weeks old.--Literaturegeek | T@1k? 22:06, 15 February 2009 (UTC)

it's like lumping all Arabs as terrorists?

Not all drugs of this category does all of this. It may be inappropriate to lump all drugs of this class. They have different reactions. Consider having different articles like drug X toxicity, drug Z toxicity, etc. if you think a toxicity article is appropriate. Chergles (talk) 21:20, 15 February 2009 (UTC)

Not really because it is a class effect of fluoroquinolones.--Literaturegeek | T@1k? 21:52, 15 February 2009 (UTC)

"Not all drugs of this category does all of this" Yes they do Chergles. Just look at the package inserts for each drug in this class and you will find everything listed within the article being listed as a possible adverse reaction for each drug found in this class.Davidtfull (talk) 03:29, 16 February 2009 (UTC)

Package inserts are not useful sources. They simply list every single reaction encountered during phase II and phase III testing. If someone caught a cold while in a trial, this will be listed. Rather, this information needs to be sourced to peer-reviewed secondary sources. JFW | T@lk 07:28, 16 February 2009 (UTC)

Every adverse event listed can easily be sourced for every drug found within this class. As such, if required, I would be more than happy to add about a couple of dozen or more citations (one for every drug found within this class) following each adr listed. But would you not agree that would make the article unreadable? Your assumptions regarding package inserts I believe to be in error. It would only be listed in the package insert if the investigator felt it was somehow related to the study drug. (I am not referring to the post marketing section, I am referring to the adverse reaction sections in regards to that comment) Davidtfull (talk) 07:57, 16 February 2009 (UTC)

What is needed is a few good review papers on the individual toxicities, eg tendinonitis, CNS toxicity and use these to cite. I don't think it is necessary to add citations for individual ddrugs as it is largely accepted that most of the toxic effects of fluoroquinolones is a class effect. Chergles just isn't familar with the toxicity profile of fluoroquinolones. Review articles or other secondary sources are superior.--Literaturegeek | T@1k? 14:26, 16 February 2009 (UTC)

Fluoroquinolones in general

The fluoroquinolone articles in general have been a mess since the beginning of wikipedia, so I think the fact that there is actually some serious efforts to develop them is good. As long as editors are mindful and keep an eye out for too much undue weight given to specific topics and issues of neutrality and original research and keeping to what citations actually say rather than synthesising data I think that the editors here can end up with some good progress on the quinolone articles,,,, at long last.--Literaturegeek | T@1k? 22:12, 15 February 2009 (UTC)

What is urgently needed

To resolve neutrality issues raised on this talk page, we need citations on epidemiology from reliable sources.

• What percent or number of patients aquire Tendon injuries?
• What percent or number of patients experience CNS toxicity?
• What percent or number of patients develop PNS adverse effects?
• What percent or number of patients develop ototoxicity?

Can anyone provide citations to peer reviewed sources or other reliable sources?--Literaturegeek | T@1k? 01:30, 16 February 2009 (UTC)

Every article cites to a different percentage based upon the financial interest of those writing the article. Percentages are irrelevant if an insufficient population has been studied. The rates for tendon rupture for instance varies from 1 in a 100,000 to 5 out of a hundred depending upon what article is cited to. You will find thousands of such references on the fqresearch site. Just pick anyone at random I guess. As whatever is being cited to within whatever article you choose would be just as random as the percentages being presented.Davidtfull (talk) 03:35, 16 February 2009 (UTC)

I agree with David, there are numerous sources that have conflicting conclusions. However, CNS Toxicity such as Insomnia, Headache, and Dizziness, are amongst the most common adverse reaction of these drugs reported in clinical trials. Other postmarketing studies have revealed a litany of serious reactions, including tendon rupture and IRREVERSIBLE nerve damage. Because they are postmarketing studies, the manufacturers are not required to give a specific percentage.

JamesLockson (talk) 08:05, 16 February 2009 (UTC)

• What percent or number of patients aquire Tendon injuries?

This remains an unknown (and unciteable) as the treating physician fails to associate such reactions to the drugs to begin with and does not report them (statistically speaking in 99% of such cases). But tendon injury is the number one event reported to the Adverse Event Reporting System maintained by the FDA. And as previously demonstrated they are not included in some of the studies to begin with due to this same ignorance. But those references already stated within the article already would be an acceptable starting point in regards to ruptures, to wit:

The odds ratios (ORs) of suffering a spontaneous rupture of the achilles tendon are 4.3%, for current exposure 2.4%, recent exposure and 1.4% for past exposure to a fluoroquinolone drug, respectively, compared with non-exposure.

[28] (Avoiding Achilles tendon ruptures in the elderly - Literature Monitor Clinician Reviews, Oct, 2003 )

Within the Netherlands, a large simultaneous increase in non-traumatic tendon ruptures and fluoroquinolone use was observed in the period between 1991 to 1996 following the introduction of the fluoroquinolones. The authors of that study stated that the relative risk of suffering a spontaneous tendon rupture subsequent to fluoroquinolone therapy would be between 1.5% to 10.0%. The incidence of spontaneous tendon rupture within the kidney recipient population is even more common.

[29](Pharm World Sci. 2001 Jun;23(3):89-92. Related Articles, Links Fluoroquinolone use and the change in incidence of tendon ruptures in the Netherlands. van der Linden PD, Nab HW, Simonian S, Stricker BH, Leufkens HG, Herings RM. Department of Pharmacoepidemiology & Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands. vanderLinden@mi.fgg.eur.nl)

In the renal transplant population, an incidence of 12.2% - 15.6% is reported, compared with 0.6% - 3.6% for transplant recipients not receiving fluoroquinolones.

[30](Fluoroquinolones-induced tendinitis and tendon rupture in kidney transplant recipients: 2 cases and a review of the literature. Muzi F, Gravante G, Tati E, Tati G. Department of Oncologic Urology, S. Eugenio Hospital, Rome, Italy.)

In one study of 149 heart transplant patients fourteen (9.5%) patients developed Achilles tendinopathy, which in three patients (2.25%) progressed to tendon rupture.

[31](Donck JB, Segaert MF, Vanrenterghem YF. Fluoroquinolones and Achilles tendinopathy in renal transplant recipients. Transplantation 1994; 58:7367. First citation in article | PubMed)

[32](Leray H, Mourad G, Chong G, et al. Ruptures spontanées du tendon d'Achille après transplantation rénale: rôle des fluoroquinolones. Presse Med 1993; 22:1834. First citation in article | PubMed)

[33],( Heart Lung Transplant. 2008 Jan;27(1):46-51. Links Quinolone-related Achilles tendinopathy in heart transplant patients: incidence and risk factors. Barge-Caballero E, Crespo-Leiro MG, Paniagua-Martín MJ, Muñiz J, Naya C, Bouzas-Mosquera A, Piñón-Esteban P, Marzoa-Rivas R, Pazos-López P, Cursack GC, Cuenca-Castillo JJ, Castro-Beiras A. Heart Transplant Unit, Complejo Hospitalario Universitario Juan Canalejo, La Coruña, Spain. blargesbueno@hotmail.com)

Once again we see the FDA's assertion that such ruptures only occur in 4 out of a 100,000 cases already proven to be both false and misleading. But this is the number (4 out of a 100,000) that the medical community is running with after the addition of the Black Box warnings. See the futility of what you are requesting?Davidtfull (talk) 09:10, 16 February 2009 (UTC)

It isn't futile, such varying statistics are common for many drugs and conditions for a variety of reasons.

My recommendations or suggestion is adding something like this to the epidemiology section.

The frequency of fluoroquinolone induced tendonitis is controversial in the medical literature and varies from study to study. Estimates range 4 in every 100,000 patients to being as high as xxx percent.citation citation ,,,,,, In high risk groups including those with xxx condition or in those taking corticosteroids (heart transplant patients would have bbeen on corticosteroids as well as being debilhitated) the risk may be as high as xx%. citation citation,,,,,

Then CNS side effects

CNS side effects have been reported by the manufacturer to occur with a frequency of xxx percent, however, some studies have reported much higher rates of CNS adverse reactions with some studies finding as much as xx percent of people experienced CNS adverse effects.

Something like that, you get the picture. Tiny studies of say 10 or 15 study subjects should generally be avoided unless there was some very important finding in the study which cannot be found from a better and larger study. :-)--Literaturegeek | T@1k? 15:15, 16 February 2009 (UTC)

To play devils advocate again, most if not all of those references were studies of patients who were in a category who would be at a higher rate of tendon toxicity. For example most people were transplant patients (on corticosteroids to prevent organ rejection) and or were elderly and or had renal failure problems. These are all risk factors for a higher rate of tendon damage according to Comittee on Safety of Medicine UK government guidelines here. Whilst those studies do very strongly suggest biased statistics released by the FDA, one needs to be careful not to use (or misuse) the references to apply those statistics generally to the general public. However, the elderly and debilitated and those on corticosteroids make up a very high percentage of the populations. Obviously the doctors treating those patients were likely negligent in prescribing fluoroquinolones to groups of patients where it is contraindicated or not recommended when probably safer alternatives were available. The CSM guidelines here in the UK would have recommended that none of the patients in those studies were prescribed fluoroquinolones. I am not as knowledgeable about fluoroquinolones as you so feel free to disagree with me. I think that those references SHOULD be used in the article, but what I am saying is that they should be used accurately and in their correct context.--Literaturegeek | T@1k? 01:09, 17 February 2009 (UTC)

Another point, currently in the UK there is an increasing viewpoint that fluoroquinolones should generally be avoided and used as 2nd or third line drug with a London Professor of microbiology recommending "avoiding them if at all possible" and giving conferences/lectures to hospitals, due to their high association with C Difficile. Do you have any such view points from reliable sources? I am not sure on the policies on fluoroquinolones in other countries? Are fluoroquinolones used first line in countries outside the UK like penicillin is used in the UK? Mostly it is a 2nd or third line drug here.--Literaturegeek | T@1k? 01:09, 17 February 2009 (UTC)

Something to consider

Herein lies the problem regarding your request for statistics. Within a 2001 study the authors state that:

“However, the ADR rate for levofloxacin is still one of the lowest of any fluoroquinolone at 2% (compared to 2-10% for other fluoroquinolones). “ Citing to: Chemotherapy. 2001;47 Suppl 3:9-14; discussion 44-8. Links Comparison of side effects of levofloxacin versus other fluoroquinolones.Carbon C. Internal Medicine Unit, Bichat-Claude Bernard Hospital, Paris, France.

Of what value would it be to cite statistics that are so far removed from reality to be considered fantasy? Here we see the combined studies submitted to the FDA regarding levaquin,(found within the actual NDA) the same drug addressed in the above study, having an adr rate in excess of 40% and a number of related fatalities, yet the above authors are claiming this adr rate to be 2% and Levaquin is to be considered to have the lowest adr rate of any of the quinolones? The combined studies submitted to the FDA (as found within the NDA) clearly dispute these assertions as they have an adr rate in excess of 40% and a number of fatalities, to wit:

M92-040 One hundred fourteen (38.4%) of 297 subjects evaluated for safety in the levofloxacin treatment group reported at least one treatment-emergent adverse event during the study...Twenty-seven subjects discontinued the study drug due to adverse events (Table 8), including 11 (3.7 %) of the 297 subjects evaluabie for safety in the levofloxacin treatment group. Two levaquin-treated subjects experienced a serious adverse event within one week after completing study therapy (anemia in one subject and two instances of chest pain in another). These adverse events are summarized in Table 9. Both of these adverse events resulted in hospitalization...

Of course neither event was considered by the investigator to be unrelated to study drug, (even though anemia and heart problems are both known adrs to the drug).

Bottom line: “Levofloxacin was safe, well-tolerated, and effective in the treatment of subjects with acute bacterial sinusitis.”

N93-006 All 329 subjects enrolled in the study were evaluable for safety. One hundred twenty-nine (39.2%) subjects reported at least one treatment-emergent adverse event during the study...Eight (2.4%) subjects reported one or more adverse events of marked severity...Six (1 .8%) of the subjects enrolled in the study discontinued due to adverse events...One subject, a 65-year-old Caucasian woman with no reported history of cardiovascular disease, experienced a serious adverse event (myocardial infarction) 14 days after completing therapy.

And once again we find that this was considered by the investigator to be unrelated to study drug, (even though heart problems are both known adrs to the drug).

Bottom line: Efficacy for levofloxacin is somewhat less in this trial than in the other sinusitis trial, M92-040.

K90-070 Sixty-four (34.2%) of 187 evaluable subjects in the levofloxacin treatment group reported at least one treatment-emergent adverse event during the study...Twelve subjects (6.4%) discontinued the study drug due to adverse events (Table 10)...Two subjects in the levofloxacin treatment group reported a serious or potentially serious adverse event during or up to approximately one week after completing study therapy In all cases, the serious or potentially serious adverse event was considered by the investigator. to be unrelated or remotely related to the study drug...{hypoglycemia and another heart attack}

Bottom line: Levofloxacin was safe, well-tolerated, and effective in the treatment of subjects with acute bacterial exacerbation of chronic bronchitis.

m92-024 One-hundred twenty-seven (52.3%) of 243 evaluable subjects in the levofloxacin treatment group reported at least one treatment-emergent adverse event during the study...Seven subjects in the IevofIoxacin treatment group discontinued study drug due to adverse events The treatment-limiting adverse event was considered serious or potentially serious in one levofloxacin treated subject (dyspnea)...Nine subjects in the levofloxacin treatment group reported a serious or potentially serious adverse event during or up to approximately three weeks after completing study therapy. In all cases, the serious or potentially serious adverse event was considered by the investigator to be unrelated or remotely related to the study drug,

Bottom line: Levofloxacin was safe, well-tolerated, and effective in the treatment of subjects with acute bacterial exacerbation of chronic bronchitis.

K90-071 One hundred forty-six (50.2%) of 291 subjects evaluable for safety in the Ievofioxacin treatment group reported at least one treatment-emergent adverse event during the study...Twenty subjects in the levofloxacin group reported one or more events of marked severity. In the levofloxacin group, the most common of these events consisted of respiratory disorders (five subjects) and cardiac events (four subjects)...Thirteen subjects13 in the levofloxacin treatment discontinued the study drug due to adverse events (Table 9)...Twenty-three subjects in the levofloxacin treatment reported a serious or potentially serious adverse event during or up to approximately four weeks after completing study therapy (Table 10), including two deaths in the levofloxacin group. In the majority of the cases, the serious or potentially serious adverse event was considered by the investigator to be unrelated or remotely related to the study drug.

Bottom line: Levofloxacin was safe, well-tolerated, and effective in the treatment of subjects with community-acquired pneumonia.

M92-075 One hundred twenty-five {47.5Yo) of 263 evaluable subjects reported at least one treatment-emergent adverse event during the study...Nine subjects discontinued Ievofloxacin therapy due to adverse events (Table 10), including three subjects with rash, two with respiratory depression, and one each with abnormal hepatic function tests, nausea, cardiac arrest, and tinnitus. The treatment-limiting adverse events were considered serious or potentially serious in three subjects (respiratory depression, respiratory insufficiency, cardiac arrest), who died as a result of these adverse events after therapy was discontinued...Twenty-two subjects reported a serious or potentially serious adverse event, mostly respiratory or cardiovascular events and seven of these subjects died, during the study or up to approximately one month after completing study therapy (Table 11). Three of the subjects with serious or potentially serious adverse events withdrew from the study because of the adverse event(s). None of the serious or potentially serious adverse events were considered by the investigator to be definitely or probably related to levofloxacin.

Bottom line: Levofloxacin administered in iv. or oral doses of 500 mg once-daily, was safer well tolerated, and effective in the treatment of subjects with mild-to-moderate or severe community-acquired pneumonia.

So as you can see, even though I can easily find the required statistics, of what value are they when they are constantly being distorted in the above manner? 2% verse 40% is a huge difference, yet we find this to be the case, not only for levaquin, but for all of the drugs found within this class. The adr rates are consitently being reported in this manner, even though the studies submitted to the FDA with the NDAs clearly disputes these assertions.

What value do we derive from citing to studies that present distorted adr rates and then go on to state (insert drug name here) "...was safe, well-tolerated, and effective ..." and any of the serious events we have listed within this article are "considered by the investigator to be unrelated to study drug..." and hence removed from the statistics? For example, as I had previously stated, within one study concerning levaquin FOUR patients suffered a tendon rupture. The investigator stated that this was UNRELATED to the study drug, and since tendon rupture was not an end point these reports were EXCLUDED from the study. It is this unacceptable distortion of the data that we are trying to address within the article.

Citing the opinions of the "professional spin doctors" is all well and good and to be expected within a Madison Avenue propaganda piece promoting the use of the drugs, and unfortunately the adding such statistics here to provide a balance may be required as well. But I believe we will find the bias shifting in the other direction with those who disagree with the article citing to those studies that show a highly favorable view of the drug rather than the proven reality. How do we reconcile a report that states tendon ruptures occur one in a hundred thousand with one that states the risk is five out of a hundred? Or in the example above where the authors state 2% verses a half a dozen studies that state 40% with fatalities? If we use worse case we are to be accused of being unfairly bias, for within a report concerning levaquin the authors stated that the adr rate was found to be 100%. Would it not then be considerd unfair of me to cite to such a report? We also have to keep in mind that there are literaly millions of patients who have suffered these reactions who do not appear in any study, report or statistic. How then do we cite to them without conducting original research? So where is fair balance to be found? Using the propaganda that the article is disputing does not appear to be the answer here. But perhaps that is all we have to work with. Not trying to be difficult here, just being a realist is all.Davidtfull (talk) 08:41, 16 February 2009 (UTC)

Where there is a will there is a way. As you have pointed out there are some major biases, particularly in the studies conducted by the manufacturers. The study excluding 4 cases of tendon rupture and saying it was unrelated to the study drug was quite shocking. How many people were in that study out of interest? I think that instead of lumping all "side effects" together as a statistic a better way is doing it via how many people get a particular set of toxicities. The reason for this being is if you took a drug like erythromycin you could find studies showing as many as 40% got side effects, like nausea is especially common with erythromycin and then diarrhea as well and other side effects. So stating very high rates of side effects is missing the boat somewhat. So citing a percent of people who experience a side effect(s) is not what we should be trying to do. There are studies which show antidepressants, SSRIs cause in at least a 3rd of users sexual problems. So many drugs on the market have a side effect rate of 20%, 30%, 40% or higher and quite a lot of drugs have a discontinuation rate of 10%, 20%, 30% or higher due to side effects. The side effect and discontinuation rate due to side effects/adverse effects is not what sets fluoroquinolones apart from antibiotics or most other drugs but it is the serious, long lasting and sometimes permanent adverse effects which do, so we need to seperate them and focus on those related to fluoroquinolone toxicity. What we need to focus on is toxicities individually by group. So CNS adverse effects, rates of C. Difficile which occurs more frequently with quinolones than any other antibiotic save clindamycin (according to a london professor of microbiology who has been giving lectures here in the UK who recommends avoiding quinolones), rates of photophobia, rates of tendon disorders is what we need to try and cite. That will put things in context for the reader otherwise we run the risk of doing what the drug companies are doing and that is misrepresenting, because if we word the article to make it appear that the rates of side effects translates into long lasting fluoroquinolone toxicity we will be as bad as them. I know I am somewhat being devils aadvocate but just trying to get this article as neutral and within wiki guidelines as best possible and as accurate as possible within wikis verifiability guidelines.--Literaturegeek | T@1k? 15:45, 16 February 2009 (UTC)

See my post in the above section for my suggestions of how to move this forward.--Literaturegeek | T@1k? 15:56, 16 February 2009 (UTC)