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)

Psychosis

I just read this article again. It says fluoroquinolones cause psychosis. So if a person has a family member that is "crazy", they may easily conclude that the medicine caused it.

This article needs to put things in perspective. Hundreds of thousands of people take it without becoming psychotic. Try to write that and you could be accused of original research. Leave it out and we don't have an accurate article.

This is one of the reasons why this type of article may be unencyclopedic. It's a difficult question because some editors clearly want to write about it. I think if this article is kept, it needs a major rewrite, also explaining what is adverse effects are in the big picture. It also needs renaming as toxicity is when you overdose or get poisoned.Chergles (talk) 16:07, 16 February 2009 (UTC)

major error discovered

I just looked up online the package insert (USA) of a fluoroquinolone and psychosis is NOT listed. So the Wikipedia article is wrong. Chergles (talk) 16:12, 16 February 2009 (UTC)

Copied from above - 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)

So psychosis was never found even if the listing err on the side on listing more things. Chergles (talk) 16:14, 16 February 2009 (UTC)

Both the prescribing info for Levaquin and Cipro list psychosis, as well as the articles below... Page 10 of the prescribing information for Cipro from the Bayer website says under Central Nervous System Disorders: ...toxic psychosis have been reported in patients receiving fluoroquinolones, including ciprofloxacin... and rarely, suicidal thoughts or acts.

Section 6.3 Table 8 Postmarketing Reports of Adverse Reactions from the Levaquin prescribing information also lists psychosis and isolated reports of suicide attempts and suicide ideation.

Mulhall JP, Bergmann LS (July 1995). "Ciprofloxacin-induced acute psychosis". Urology 46 (1): 102–3. doi:10.1016/S0090-4295(99)80171-X. PMID 7604468. http://linkinghub.elsevier.com/retrieve/pii/S0090-4295(99)80171-X.

Reeves RR (1992). "Ciprofloxacin-induced psychosis". Ann Pharmacother 26 (7-8): 930–1. PMID 1504404. Respectfully submitted Dbcipro (talk) 18:29, 16 February 2009 (UTC)

I looked up the package insert for Vigamox online. The insert says it is a fluroquinolone. The insert (see http://ecatalog.alcon.com/pi/Vigamox_us_en.pdf ) does not say psychosis. Therefore, we have an error in Wikipedia. Anyone dispute this? Chergles (talk) 20:06, 16 February 2009 (UTC)

Vigamox looks like Moxifloxacin eye drops to me. Doesn't seem to me like eye drops would pass through as many bodily systems or pass the blood brain barrier as an ingested or IV drug could. Bayer's formulation of Moxifloxacin (Avelox) lists hallucinations, confusion, and rarely, suicidal thoughts, that could occur after only one dose. Dbcipro (talk) 20:40, 16 February 2009 (UTC)

So by not distinguishing Vigamox, the reader may have false negative opinion of Vigamox. So if Vigamox were a person, that would be a potential BLP violation. So let's be careful and write the article well. Chergles (talk) 21:37, 16 February 2009 (UTC)

Errr what? Why are we comparing an eye drop solution to Living persons policy? We have enough issues on this page raised. I think that we should forget about what happens if a simple minded person can't figure out an eye drop solution is not the same as an oral systemic therapy, at least for now. After the other issues have been resolved maybe then we can return to an "eye drop" versus "systemic therapy" adverse effects debate.--Literaturegeek | T@1k? 22:04, 16 February 2009 (UTC)

Regarding psychosis you said that "what happens if" a person reads psychosis as a side effect and then thinks, maybe my psychosis was caused by an antibiotic years ago when in their individual case it was not. This is an encyclopedia, which reports the facts. We can't just delete facts "just incase" someone wrongly attributes something as causing their psychosis. We could go and delete psychosis from all sorts of prescription drugs as a side effect, from illicit drugs. We could actually completely delete korsacoffs syndrome. Heck lets just delete the entire wikipedia database or even the entire internet and television, media, newspaper, ban them all just incase someone misattributes factual information to themselves wrongly. I had someone make a similar argument on another article about content that it might "frighten the elderly" and therefore needs deleting. I know I sound rude and that is not my intention but I am trying to make you realise what wikipedia is about and not about.--Literaturegeek | T@1k? 22:16, 16 February 2009 (UTC)

Renaming article

See the section immediately above. Toxicity is when you eat a crate full of the medicine. This article is not about the LD50. It is about not so common side effects. So the article name may imply bias. This is clearly a hot topic. I hope it's possible to reach a conclusion through polite discussion. Chergles (talk) 16:17, 16 February 2009 (UTC)

I totally agree. Toxicity is when you overdose. The current article discusses side effects with a negative bias. I propose to move to Side effects of fluoroquinolones. --Steven Fruitsmaak (Reply) 19:30, 16 February 2009 (UTC)

I respectfully disagree for the following reason: Toxicity is not limited to overdosing as you have implied. Peanuts are toxic to those who have an allergy to them. One peanut is not considered to be an overdose, but it is toxic to such a person. Toxic is defined as "containing or being poisonous material especially when capable of causing death or serious debilitation". And the article is about the fact that the fluoroquinolone class has been documented, since 1962, to contain a poisonous substance(s) or metabolites that are capable of causing death and serious debilitation with as little as ONE dose. It has little to do with how much of the drug you consume, though this is a factor, it is not the sole reason for the toxicity of this class. It has everything to do with the damage done as a result of such consumption. Toxicity is the degree to which a substance is able to damage an exposed organism. How then are you continuing to argue that describing such a toxicity is discussing side effects (which is not even a part of the article to begin with, as the article discusses adverse reactions) with a negative bias? Is there a positive way to discuss adverse reactions? Are they somehow beneficial to the patient? If so please explain how you believe this to be so.

I too do not wish to be argumentative but you are continuing to argue a frivolous position. How does one present an article that deals with the negative side of an issue in a postive light? Somehow doing so negates the whole purpose of the article to begin with. For example how does one do an article on the holocaust in a positive light and make Hitler out to be the good guy? Which comparatively speaking you feel should be done with this article if I understand you correctly here. How specificaly do you feel we have presented the facts in such a manner that a negative bias is present? Let us work on correcting that rather than dealing with your own bias opinions regarding the safety profile of this class. I have freely admitted to my own bias when I first started working on the article and have asked folks to point them out to me with suggestions for correcting them. So to correct this problem cite to the specific sentence(s) that needs to be worked on, rather than speaking in generalizations, or condemning the whole article and perhaps we can resolve this impass like gentlemen. But it appears that someone had already changed the name and relocated the page before a concensus had been reached, so perhaps I am arguing in vain here to keep the name as is.Davidtfull (talk) 01:31, 17 February 2009 (UTC)

I hate to be argumentative, but toxicity actually refers to death,,, or damage usually long lasting. See definition in online medical dictionary. Quinolones meet all 3 definitions listed in the medical encyclopedia. Toxicity is an accurate terminology for what the article is talking about. However, renaming the article to side effects of fluoroquinolones or fluoroquinolone adverse reactions, may actually serve the purpose of giving the web page more exposure in search engines since most people will be more likely to type in side effects than toxicity. For search engine optomisation a name change might have benefits in greatly increasing the volume of readers but the term toxicity I still feel is the most accurate. I can be swayed on a name change (for search engine purposes) but am on the fence at the moment.--Literaturegeek | T@1k? 19:49, 16 February 2009 (UTC)

We shouldn't be caring less about search engines, certainly while this article is under dispute. If you are supporting for that reason, please oppose. --Steven Fruitsmaak (Reply) 19:57, 16 February 2009 (UTC)

I believe in discussion and compromise. Here's an idea, not necessarily the one I favor, just one that I thought of. We keep the name of the article. We discuss toxicity. We also have a section on side effects (which would cover the bulk of the article). Chergles (talk) 20:02, 16 February 2009 (UTC)

I believe toxicity is an appropriate term for this article. Quinolones have been shown to be neurotoxic, chrondotoxic, cardiotoxic, and hepatoxic, even at minimal doses. All these adverse reactions are the result of direct chemical harm to living organisms. JamesLockson (talk) 12:58, 17 February 2009 (UTC)

Goldfrank's toxicology refers to what we are talking about as adverse events. Goldfrank's is basically the final word in the field. Therefore changed the name to reflect this.--Doc James (talk · contribs · email) 09:57, 19 February 2009 (UTC)

rewrite

I am better at reaching consensus through discussion rather than re-writing a controversial article so even though I've made 1-2 edits, I'll not do too many.

How about the following general framework.

1. Intro to the class of drugs, name the drugs.

2. Discussion of risk and benefits. (Going to the cinema runs a risk of car theft and robbery, it is not 100% safe).

3. Discussion of toxicity, what kills rats.

4. Discussion of common side effects, how they vary with each drug.

5. Discussion of less common side effects. Otherwise we run a risk of listing gobs of horrible and rare conditions.

6. Discussion of history of regulatory changes (that Dear Doctor section).

How's that for a start. By doing so, it would be a major revamp of the article. Let's work peacefully and slowly since there is controversy. Chergles (talk) 20:19, 16 February 2009 (UTC)

I'm having enough on my plate so I won't be able to help here any time soon, but for good examples of toxicity articles on the wiki see paracetamol toxicity or serotonin syndrome. Granted this one appears more complex. Xasodfuih (talk) 00:59, 17 February 2009 (UTC)

I'm confused as to why you would think that the article should be a carbon copy of the package insert, (which follows the exact pattern that you are suggesting). The article is about a specific syndrome that is induced by a specific class of drugs. Toxic is defined as "containing or being poisonous material especially when capable of causing death or serious debilitation". And the article is about the fact that the fluoroquinolone class has been documented, since 1962, to contain a poisonous substance(s) or metabolites that are capable of causing death and serious debilitation with as little as ONE dose. The article first explains what drugs we are talking about. It then describes the various events that are associated with this syndrome in a linear fashion. And we took it even one step further, and attempted to describe the mechanisms of action by which this takes place, if they were known. In this regard the article is factual. There is no reason for controversy concerning that aspect.

The only argument and controversy should be the manner in which the evidence is to be presented so that it remains neutral and unbias, not whether or not that the proven facts are somehow in error. With well over a couple of hundred citations sheparded from a database of well over 4000 we have pretty much provided a citation that supports every statement made. No doubt that a few statements can and should be reworded to comply with neutral/bias concerns. I have asked for such assistance before I even wrote the article. And stronger citations when found can be subsituted as well. Digging through a mountain of data is both time consuming and tedious so this alone should take a better part of half a year. But you cannot pick and choose what facts you will use and what facts you will not, to accomplish this. A fact is fact. Either it is proven to be or it is not. If it cannot be proven then of course we should remove it. But if it can be proven it should remain. If a statement is ambiquous or misleading in any particular it can always be rewritten as needed. That is what wikipedia excels at.

Risk/benefit should not be a part of such an article or a neutral/bias discussion in my opinion. We are not offering medical advice or attempting to treat a patient. We are writing an article on a medical syndrome induced by a specific class of drugs. Benefit is immaterial and irrelevant to such an article, risk however is indeed relevant. If you are interested in the risk/benefit then please take a look at the various articles written for each drug in this class as well as the worthless package insert, or better yet have such a discussion with your treating physician. Not here.

As such we should endeavor to state the facts that describe the known risk of suffering such a syndrome. The problem is that there is no consensus amongst the medical community that allows us to do so. Since we cannot create original research, where pray tell are we to find the known risk factor to cite too? Particulary when we are dealing with an issue that the medical community is in denial concerning. Bottom line is if it cannot be cited, it cannot be used. Hence my reason for not even attempting to do so within the article in the first place. Anything that we would present would be an educated guess at best, an opinion, not a fact. And someone else's at that, who in my opinion, would be far more bias in the other direction. As such if you wish to include a risk section then please provide us with citable sources that describe what it may be and I would be more than happy to add such a section and make reference to them. But to do so I need proven facts, not opinions.

As I was not involved in the naming the article I shall remain neutral as far as that issue is concerned and will defer to others who will debate and form a concensus as to what it shall be. I will accept whatever they decide without further comment or complaint. Other than to state that the original title is an accurate description of what was being written about. It stated the class of drugs, the fact that they are considered to be toxic (by definition) and again by definition are associated with a specific syndrome.

Please try and understand something else here as well. There is a DISTINCT difference between what is to be considered a side effect and what is to be considered an adverse reaction. The two terms CANNOT and should not be used interchangeably. To help you understand this basic concept allow me to present an example: The excessive consumption of alcohol has both a side effect and an adverse reaction. The hangover you get the following morning is to be considered a side effect. It dissapates once the alchohol leaves your system. The resultant damage to your liver, however, is an adverse reaction. It does NOT abate after the alcohol has left your system. In some cases this ends up being permanent damage that is fatal. No amount of absentance will correct the problem, it will only prevent it from getting worse. In time perhaps the body will heal, perhaps not.

But the hangover will always dissapate if you quit drinking. A side effect is what takes place while the drug is in your system and this too dissapates once the drug has been cleared. An adverse reaction however is the DAMAGE done while the drug WAS in your system and such damage may continue long after the drug has LEFT your system. And continue to manifest long afterwards as well, some times forever. As such, common side effects should play no part in the article, common adverse reactions however should, as the article deals with the adverse reactions of this class, NOT its common side effects.

Sorry if I come off a bit harsh, (the written word is always devoid of the body language by which we pick up clues concerning a persons benevolence) but copying the package insert is NOT an acceptable solution to Dr. Steve's concerns in my opinion. Best to eliminate the article completely instead, for doing so (copying the package insert) would not educate those who remain ignorant of this syndrome. And what is the sole purpose of an encyclopedia? To educate and eliminate ignorance. What is the SOLE purpose of this article? To do the same. Let us try to keep that in mind as we discuss these issues further.

On a side note would it not be considered proper etiquette to NOT be deleting or re-arranging the article, moving it to another location, changing it's title, etc, or otherwise attempt to change the whole focus of the article until a concensus has been reached? Or is it common on wikipedia to make the changes first, and then discuss the changes made after the fact? Since I am new here I am a little bit confused regarding this. Making such drastic changes without the benefit of a discussion and the reaching of a concensus seems a little heavy handed to me. Perhaps I am mistaken.Davidtfull (talk) 01:33, 17 February 2009 (UTC)

I think if talking about damage toxicity is a more accurate term. While adverse reaction is perhaps better term, adverse reaction is used sometimes instead of side effects. But anyway the article should not be laid out like a package insert. First of all it is not general article on a specific drug. These are guidelines for such an article.Wikipedia:WikiProject_Pharmacology/Style_guide They do not apply to this article though as it is addressing a specific topic of a drug and is not a general article.--Literaturegeek | T@1k? 02:04, 17 February 2009 (UTC)

Neutrality please tell me we are close to agreement

Ok, if anyone has checked the recent edit history they will notice that there has been some recent changes to the lead/introduction section. Steve introduced some content to resolve neutrality and then I followed up with some edits to resolve neutrality as well. Whilst there may be 1 or 2 sentences which may or may not be in dispute, are Steve and David and other editors feeling we are approaching a more neutral article? Is the dispute getting closer to being resolved? I am kind of getting tired of all the texting on wiki and hope so. What do you reckon Steve and David?--Literaturegeek | T@1k? 02:04, 17 February 2009 (UTC)

I reckon it best that I resign from this project. The other editors may do with the article as they see fit. It has become yet another attempt to white wash and trivalize the safety profile of this class and my continuing participation would only continue this controversy needlessly. I appreciate the help and guidance I have received from the others here and have enjoyed the experience. Unfortunately this article has proven to be in an exercise in futility. Feel free to use the citations found on the research site as you see fit, and I will continue to update the articles concerning the various drugs in this class as time allows.Davidtfull (talk) 02:57, 17 February 2009 (UTC)

This is a prime example of why I now feel I can no longer participate in this article: "Conjunctivitis and eye pain are possible adverse effect in moxifloxicin." Period. That is all that was said about the severe vision problems associated with this class.

Even though vision loss (both temporary and permanent) have been cited to being associated with a number of other drugs in this class, and myself being blinded by these drugs (permanent double vision and partial loss of vision), adverse reactions to the use of eye drops including retinal detachment (which has also been reported), etc., etc., my adding this information to the above stub would create yet another area of controversy and we would be off and running yet again. Best to simply admit defeat and part as friends and let Dr. Steve and his peers rewrite this article, rather than continue to try and provide cited input from the perspective of those who actually experienced such avoidable tragedies.Davidtfull (talk) 03:21, 17 February 2009 (UTC)

I think that you are over-reacting with due respect. When I scroll down the page I see brain damage credibly cited, dna damage credibly cited, hearing damage and so forth. I can't see that it is a white wash at all and to use an example I am sure the drug companies would agree with me and disagree with you! Not that the article is meant to be aimed as an attack on the drug companies, the article aim is to documenting factual encyclopedic data. The toxicities are documented in the article. Can I point out (or remind you) that one of the administrators recommended that package inserts are not good sources to use. The example that you used of conjunctivitis and eye pain is referenced to a package insert. Therefore there is nothing to stop you from deleting that part of the article. The person (username Chergles) who added that data is just a regular member of the public and not a staff member, I am not a staff member either. Anyone can edit wikipedia. What is to stop you from citing a reliable source and adding data about permanent visual damage? My comment regarding eye drops was specifically to counter the claim that psychosis does not occur with quinolones when it does. I NEVER said that eye drops do not have their own specific toxicities particularly local toxicities which may be severe and permanent. You are reading things into this which aren't there and were never said by me or anyone. No one denied local toxicities from eye drops, no one said eye drops had no adverse reactions. I think in all honesty you have set the bar too high and unfortunately on wikipedia it is rare that an editor gets an article completely the way they want it to be, due to neutrality. Unfortunately I doubt there are editors on wikipedia who have the knowledge of the literature to improve this article to the extent that you have. It is a shame that you are giving up so easily on this article. I would encourage you to not get down trodden over small changes to the article. I think someone with an interest in fluoroquinolone adverse effects would learn a lot more from this article than they would from a package insert so don't take things so seriously would be my advice and don't set the bar so high. Anyway I am off to bed, I just got up to get a drink of water and checked wikipedia.--Literaturegeek | T@1k? 03:48, 17 February 2009 (UTC)

If all that I see were small changes I would not have a bone to pick here with anyone. I am not downtrodden or discouraged in the least. It is not a matter of my setting the bar to high or others setting it too low. It is a matter of stating the truth whatever it may be found to be. If that is setting the bar too high, then I plead quilty as charged. But the following I do take rather seriously. I simply can't help it, so please bear with me for a moment. I know you are tired of reading long winded postings on the talk page, but you have treated me fair and square so far so I think you are entitled to a more detailed explanation regarding my decision. I do not consider the changes that have been made so far to be "small" or "minor" in the least, to wit:

Fluoroquinolone (or simply quinolone) antibiotics have a generally mild to moderate adverse drug reaction profile. Blatantly false statement. More than half of these drugs have been removed from clinical use due to severe toxicity. This is not to be considered “generally mild to moderate”

Fluoroquinolones (of which cipro-, levo- and moxifloxacin are the most widely used) are a popular class of antibiotics, and newer generations have a broad spectrum including Gram positive, negative, atypical and anaerobic bacteria, although resistance is also increasing.

Frivolous information. It is well known that these drugs treat bacterial infections. The physician rarely if ever chooses these drugs based upon 24-48 hour cultures. They are broad spectrum and that is all he needs to know or cares about. Collateral damage is not even given a moments consideration, let alone what bacteria they erradicate.

With increasing popularity of this class of antibiotics in sometimes benign indications, adverse events could become more frequent, and prudent use seems warranted.[4] Like any drug, the benefits of treatment should outweigh the risk of harm.

False and misleading. The scripting abuse involving these drug is, and has been, rampant for decades. This is NOT a new occurrence. Rarely if ever are they used properly. In one study 99% of the physicians got it wrong and more than seventy percent of the prescriptions written were for benign conditions. This is NOT “sometimes” this is ‘MOST OF THE TIME”.

The most common adverse drug reactions of quinolones are gastrointestinal upsets (diarrhea and nausea), central nervous system complaints (headache and dizziness) and skin problems (especially phototoxicity or skin rash following sunlight exposure).

Yet again false and misleading and if I may be so bold: “bullshit”. Any number of studies clearly refutes this line of crap from the manufacturers.

These are usually mild, reversible and do not require discontinuation of treatment.

Yet another misrepresentation.

In clinical trials, discontinuation rates of currently available quinolones amount to less than 4%, and quinolones with higher discontinuation rates (such as trovafloxacin or grepafloxacin) are no longer available.

Again not true and not supported within the studies submitted to the FDA.

Whilst for most patients the side effects reported were mild to moderate

They are NOT being reported as being mild to moderate by the patients. They are being reported as such by the investigators. Just take a look at the list of reactions these investigators are judging to be mild. They are anything but.

At the first sign of psychiatric, neurological or hypersensitivity reactions it is strongly recommended that therapy with fluoroquinolones be discontinued to prevent serious toxicity from occurring.

False and misleading. These reactions are NOT hypersensitivity reactions but direct toxicity. The serious toxicity had already occurred at the first sign of such events. Discontinuing the drug does NOT reverse such events or prevent serious toxicity from occurring. It had already taken place.

The controversy of fluoroquinolones is not the incidence rate of side effects but of the sometimes prolonged nature of certain adverse effects which for some people leads to prolonged suffering and sometimes permanent disability

Again misleading. The controversy is indeed the incidence rate of side effects together with the prolonged nature. These two issues are NOT separate.

Uncommon and potentially severe adverse events...

False and misleading. The whole controversy involves the false claims of the manufacturers that such events are “rare”. The failure to recognize such events contribute to them being considered “uncommon” and this statement supports such a contested view.

Their use has traditionally been avoided in children based on experimental observations of cartilage damage in young dogs and rats, although they are sometimes prescribed to children in clinical practice

False and misleading. It has already been established as far back as 1996 that this damage occurs in the pediatric population. Cited to within the 67 meeting.

Concers regarding growth plate damage are not adequately supported by human safety data (sic) Bullshit. Read the studies submitted to the FDA for pediatric exclusivity for starters then read the 67th meeting.

and the use of quinolones is not precluded in children if no other safe and effective antibiotic is available

Debatable. It is not a licensed use. Which would preclude its legal use in children. Any number of studies have stated that the use in the pediatric population is unacceptable, under any circumstances.

“If no other safe and effective antibiotic is available, then and only then, would this not be precluded in children” would be a factual way of stating this.

If a patient is predisposed to adverse events (for example because of diabetes, previous psychiatric or seizure disorder), a serious risk-benefit consideration is advisable.

If predisposed then the use is contraindicated. Period. A serious risk/benefit should be performed no matter what the circumstances may be. Whether the patient is predisposed or otherwise. Failure to do otherwise is sufficient grounds for a malpractice suit.

Certain quinolones are more strongly associated with a particular side effect, although a class effect is present in most cases. For example, moxifloxacin carries a higher risk of QTc prolongation,[18] and gatifloxacin has been most frequently linked to disturbed blood sugar levels, although all quinolones probably carry these risks

ALL QUINOLONES CARRY THESE RISKS. No “probably” about it. Have I not provided enough citations to prove this beyond a reasonable doubt all ready? Why is there NO mention of the fact that gatifloxacin had been removed from clinical use due to “disturbed blood sugar levels” that were found to be killing the patients?

Some quinolones were withdrawn from the market because of these adverse events (for example, sparfloxacin was associated with phototoxicity and QTc prolongation, thrombocytopenia and nephritis were seen with tosufloxacin and hepatotoxicity with trovafloxacin

SOME QUINOLONES? Try 50%. That is NOT “some” and notice that gatifloxacin, which was removed just last year, is NOT included within the above list. Perhaps the good doctor is unaware of this? OR simply choosed to ignore it?

For example, simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture

“one-third of quinolone-associated tendon rupture” Unsupported in the literature. This is an opinion, not a fact.

These are the kinds of things I find to be a white wash and a trivialization regarding these issues. It is not a matter of me giving up too quickly or over reacting. I have been down this road so many times it is pathetic. All that this recent editing has done is substitute the manufacturer’s line of b.s. and Dr. Steve’s own bias point of view in the place of my original text, which he had claimed to be too bias. The bias continues, only it has swung to other end of the spectrum.

The above text is not balanced, it is not neutral, it is not factual in some instances, it sways the reader by the use of exclusions and it sure as hell is just as bias my original text was accused of being. In fact it contains far more factual errors, opinions and presumptions in my opinion.

So what is the point of me arguing about all of this? There is no point. It is an argument that cannot be won by using citations. It is a matter of arriving at a middle ground we all can live with.

But the views being expressed now are so diametrically opposed to my own I am ashamed to even be associated with this article. Hence it best for all that I simply take my toys back to my own sandbox rather than do battle with such closed minded individuals. They will not be swayed no matter how much evidence I present. The outcome has already been predetermined. Why prolong the agony and make life miserable for everybody?

I’m not bitter, or angry, frustrated or anything else of that nature. I do not feel that I am over reacting in the least. Just being realistic is all. I knew this would be the end result before I even started. Guess I’m too much of an optimist for my own good some times.

I had high hopes, but even I knew them to be unattainable. I’ve had to deal with this so often over the past decade that I am far beyond taking any of this personal. As they say if you are not part of the solution you are part of the problem. It is utterly impossible for me to be part of the solution to making this article fair and balanced without a knock down dragged out fight. And after a decade of such battles this one simply is not worth the effort.

It is only a matter of time before the articles I had written for the various drugs are dismantled in the same fashion. I’ll save what little fight I have left in me for those instead. This was your baby to begin with. The individual drug articles I would consider to be mine. So you fight for you and yours, and I will do battle for what I consider to be mine when the time comes.

There is a time and place for everything, and fighting about this article here on wikipedia, is neither the time nor the place. I will just clean up the missing citations within the article and leave it at that. No hard feelings in the least and if any editor cares to consult me regarding the article I am more than willing to work with them any way I can. I just will not be writing anything further for this article is all. At the moment I am ashamed to have my name even associated with it. But that is my problem, my problem alone, and I have no intention of making it yours or anybody elses. As such do the best you can and I will assist you in any manner you may require. I've simply lost the desire to try to change the minds of folks who do not wish to be further confused by the facts. I will leave that task to you now. They have already exhausted me and we have yet to begin to even fight about these issues in earnest. So, God speed my friend. Now if you would be so kind as to lend a hand to this decrepit old man I will get off my soap box and say no more concerning this as I see the line has already formed to left of me to dispute all that I have just stated.Davidtfull (talk) 06:46, 17 February 2009 (UTC)

First of all you seem to take issue with people's lack of knowledge and expect people to have a photographic indepth knowledge of fluoroquinolone toxicity literature when you know that there is probably only a couple of dozen if that people who have close to the indepth knowledge of fluoroquinolone toxicity so I do believe that you are being unreasonable and are expecting a marathon type approach in the article and people's knowledge from how you are reacting. We cannot help it if the papers are misrepresenting the severity of reactions. If you know of peer reviewed papers that document adverse effects in your eyes accurately and the author comes to the same conclusion as you then please do cite them. Otherwise your disagreement is misdirected by blaming editors on wiki when it is really a matter of bias in drug company clinical trials. Many of the problems you have raised didn't need to be raised on the talk page but you could have tweaked, reworded etc the article text and left a short summary in the edit summary box to explain why a sentence was inaccurate. I was visiting your web site last night looking for citations and to be quite honest the vast majority of the medical literature whilst acknowledging serious toxicities generally conclude that such adverse effects are rare. One example is Dr Flockhart who I have seen mentioned several times on your website as an expert. He states in this citation that CNS side effects generally go away when the drug is stopped and that rarely they trigger an underlying condition. So he is clearly downplaying the established fact that quinolones are neurotoxic and claim persisting effects (which are rare in his opinion) are due to triggering of underlying mental health conditions. Toxic effects of drugs are often attributed by drug companies and drug enthusiasts as underlying conditions. A very pseudoscience speculative theory when the data would suggest a more rational theory is direct toxicity and neurotoxicity for persisting or long lasting CNS effects. I am not attacking flockhart, he has written some very good info on quinolones and has done a lot of good by my brief review of his writings and he is a respected senior pharmacology and expert in his field. My point IS that it is easy to disect and totaly demonise anyone and any article and any expert if one is to focus only on negative things a person or article says. So the question is why do you associated yourself with these opinions and experts on your website? I could easily disect statements by experts in more depth and medical papers on your site and ask the valid question why do you host such content or why do you promote or associate with experts who make such statements? You see my point is you are coming down very heavily on editors here when you yourself have medical abstracts, medical experts who say things which are more down playing the toxicity on your very own website. I am not down playing your efforts of advocacy or the quality of your website which is probably the most indepth website on fluoroquinolone toxicity. I am trying to show that it is impossible to reach perfection based on the medical literature and experts because humans are only human and are not God so imperfections exist in the literature. You have clearly contributed an amazing amount of data and helped and saved I am sure many thousands of peoples lives via your website perhaps 10's of thousands if we include your successful efforts of getting the black box onto quinolones in the USA. What I am trying to say is that neither wikipedia, nor the medical articles on your website are completely free of error and readers of either your web site or wikipedia will find some inaccuracies which are misleading. This is NOT your fault nor is it wikipedia's fault but is the fault of the peer reviewed data focusing on benefits and ignoring risks or the paper authors not having such an indepth knowledge of the data as what you have. Neither you nor wiki can help bias and promotional medical papers and articles focusing on the positive or repeating industry based clinical trial data rather than the negatives as well. You are blaming the wrong people. I would love to see more articles from reliable sources where the author comes to the same conclusion as you, then maybe we can cite them, otherwise wikipedia will be an imperfect article based on your standards if it can't be verified. Don't doubt me I believe these are toxic drugs, I believe that they should be treated similarly to aminoglycosides in that they should be restricted to hospital use only with strict safety guidelines or else if used outside of hospital only as 2nd or 3rd line drugs with strict safety guidelines. What is the exact number or even a reasonable guess as to what percent have long lasting symptoms from quinolones? I dunno. Is it 0.5% 5%, 10% in the general public, anyones guess unless we have a good quality study. But even if 1% of people get severe prolonged or permanent effects from these drugs we are talking about a huge number of people perhaps hundreds of thousands or more world wide who are chronically damaged with their lives adversely affected or even ruined when safer alternatives existed. If you are right about the severity of the high rate of misdiagnosis then who knows perhaps it is even millions who have had their health adversely affected chronically in one way or another. Sorry to be critical, I feel like piggy in the middle here. I have found myself getting in heated debates with you, with Steve, with other people on wikipedia and on wikipedia pharmacology and honestly you all are causing me too much drama and stress LOL. I honestly feel that I have tried to be diplomatic and have tried to make both you and Steve see some sense. Maybe I am the crazy one! Maybe I am being unreasonable?!? I dunno. If I am I plead guilty and my defense is I am human. I just wish you people could be more calm and reasonable. I have tried to be fair and now feel like David is angry at me, Steve is pissed at me and several other members aren't happy with me. It is not nice to be in the position I am in. I hope you understand my frustration as I understand yours. I would like you to stay around wikipedia and take a more relaxed approach to editing, with less debate and more productive editing. The moxifloxacin article needs developing as do other articles so there is much work needed on wiki on the quinolone articles. Even if the apocolypse happened and half your edits got deleted, the readers of wikipedia would still be very much more enlightened by the remaining edits whilst prior to your arrival on wiki readers wouldn't even know there was toxicity issues with quinolones. I think you are aiming for perfection which is rarely possible, we live in a imperfect world sadly. I think you are focusing on the negatives than the positives. I can pluck out lots of edits most of which have been done by you which are very favourable to your point of view of quinolone toxicity but you insist on focusing on the negatives and imperfections and mistakes. Prior to your edits on wiki there was virtually no good info on toxicity, now there is good info. That is progress from your point of view like it or not!--Literaturegeek | T@1k? 08:11, 17 February 2009 (UTC)

I am close to walking away from this article to as there is too much drama and it is simply unnecessary and I do think an overreaction. I couldn't be bothered argueing who is over reacting anymore either LOL. We seem to debate everything on this page and it is getting ridiculous.--Literaturegeek | T@1k? 08:11, 17 February 2009 (UTC)

I do not agree with Steve's edits to this article. It must be noted that quinolone reactions are not at all similar to other drug reactions. David has provided good research towards this, and they are not biased at all. Steve, please announce all your COI, including pharmaceutical company shares, etc. JamesLockson (talk) 07:05, 17 February 2009 (UTC)

JamesLockson, you are welcome to edit as long as you use reliable sources to back-up your claims, and you have even more reliable ones to contradict the statements from other reliable sources.

I will try and post a COI statement today at User:Stevenfruitsmaak/COI; but basically, I'm six months away from starting to earn as a doctor, I don't have any shares, I never even got anything from a drug representative. --Steven Fruitsmaak (Reply) 08:07, 17 February 2009 (UTC)

In Steve's defense. I do not believe Steve works for the drug companies. He is an established editor and administrator on wikipedia and respected.--Literaturegeek | T@1k? 08:24, 17 February 2009 (UTC)

In that case, I apologize for any insinuations. Steve probably isn't malicious, probably just misinformed. It is hard to comprehend the real life existence of such serious reactions, if you have not personally seen what these drugs can do to someone. JamesLockson (talk) 09:44, 17 February 2009 (UTC)

Off Topic: Talking about drug companies, here is a video of an actual Pharmaceutical Representative who has been suffering a horrendous reaction, even after many years. http://www.youtube.com/watch?v=qpDkN_KJmdA&fmt=18 Pretty ironic isn't it? JamesLockson (talk) 13:04, 17 February 2009 (UTC)

A sad video to watch, hopefully he will recover. He looked in a lot of pain from his peripheral neuropathy and other damage.--Literaturegeek | T@1k? 19:41, 17 February 2009 (UTC)

Honestly, I am not angry with anyone here. I do not believe that Dr. Steve or anyone else here has any ulterioir motives or bad intent. And I am certainly not trying to put anyone in an ackward position. Or cause any kind of drama. The reasons you see such a variety of research on the research site is the fact that that it what it is. A research site. It contains the good, the bad, and the ugly. People read what they care to and draw their own conclusions. Just as you would viewing pubmed. But the purpose of the article started out to be a report about a specific syndrome. It has changed to a report about the possible adverse effects of this class and the concensus is now that it should no longer be a report about this syndrome. In fact even the name "syndrome" has been removed. As such I would rather not be a part of it. No drama. I know if I continue to edit it I will be trying to redirect it to its original intent and others will edit it to bring in back to being a report about the possible adverse reactions. And THAT would cause drama and friction. And those editing it, unfortunately as you have stated, lack the specific knowledge required. So let it be a report about the possible adverse events and let it be cited to the popular view within the medical community, rather than trying to change this view, which I thought to be the original intent to begin with. I have no problem with that. Nor am I angry with anyone deciding this would be the best way to develop the article. I've been outvoted and accept that without complaint. I am not on a quest for perfection. But if the boat is heading south and you wish to travel north, does it not make sense to simply leave the boat rather than try to persuade the captian to turn it round solely for your benefit? Particulary if the other passengers wish to continue south? Seems to me that this is what logic would dictate that you do and hence this is what I have done. Makes perfect sense to me.

On a side note regarding Dr. Flockhart, after big pharma built him a new clinic he pretty much stopped all advocacy regarding the quinolones and started toting the company line. Since his work with Stephen Fried he has done little to nothing concerning these reactions. In a recent podcast interview following the black boxed warnings he in fact tended to downplay them considerably. He is indeed considered by some to be an expert to a degree and like all experts his funding comes directly from the manufacturers. He has received numerous research grants from big pharma which is not at all unusual for a college professor. In fact it is the norm. He has done some decent things in the past concerning these issues so his older work has value. His recent work however has been tainted. The research site contains both and I let people judge for themselves. I'm not Stalin and I don't purge just because people are later influenced by the drug companies. History is history and I don't try to rewrite it on the site. Just display it.Davidtfull (talk) 15:20, 17 February 2009 (UTC)

I am happy to hear that you are not angry with anyone. Syndromes and disorders are determined usually by panels of experts such as the American Medical Association or American Psychiatric Association etc. The very least that wikipedia needs is for a reliable peer reviewed source calling it a syndrome. Wikipedia can't say what is or isn't a syndrome. It is beyond wikipedia's scope. It doesn't matter if all the common sense and evidence says syndrome. As explained previously wikipedia can only go by what the citations say and the authors conclude. If that means saying that severe reactions only occur occasionally there is nothing that can be done unless you can provide a citation which concludes that severe reactions occur in the majority of users. We can cite sources of which I believe there is at least one already in the article that adverse and toxic effects of fluoroquinolones are often overlooked or misdiagnosed by doctors. Above that nothing can be done unless reliable sources can be provided. You would be asked to do the same if submitting a paper to a peer reviewed journal. I don't think that long term damage (peripheral nerve damage, CNS toxicity, tendon damage etc) is in dispute nor the effect on individual victims lives but what is in dispute is the incidence rate of such severe toxicity. Most if not all medical sources I have looked at on your website seem to suggest that such severe and/or prolonged reactions either occur occasionally or rarely but I admit I have not reviewed all of the peer reviewed literature you have cited on your website. Anyway I can see from what you have said that you feel staying here is going to cause a headache for yourself as well as everyone else as the direction of the article is not going the way you want it to go and thus you want to disassociate yourself from it. I understand your position. I don't know if you are disassociating yourself just from this article or are leaving editing wikipedia completely. Pitty about Dr Flockhart. That explains some of his conflicting statements. Anyway we have a number of editors Steve, myself and Jameslockson and a couple of others who may or may not continue to develop the article. Wikipedia relies on reliable sources and that is basically the crux of wikipedia.--Literaturegeek | T@1k? 19:37, 17 February 2009 (UTC)

I am curious about something you had stated previously. Why would Dr. Steve be pissed at you about anything? His dispute was resolved in his favor through private negations rather than public debate and consensus. And as a result I decided to withdraw from this article. That presented a win win for him, not something for him to be angry about in the least I would think. The resolution of this dispute presented a moral and ethical dilemma for me as it presented a conflict of interest that I felt I could not overcome. As I strongly disagree with the direction it was decided that the article should take it is only reasonable that I not participate in its continuation. But I was afforded an opportunity to present my arguments and proofs and they were rejected. Not something for me to be angry with either. I don’t expect to win every argument I engage in. I was treated with reasonable respect, everybody behaved rather well, and a decision arrived at.

As such I fail to see why any of the other pharmacy editors would be upset with you regarding anything concerning the resolution of this dispute or why Dr. Steve would be angry about the resolution of this dispute as it was decided in his favor. It allows the article to go forward without any further interference from me. Seems to me that everybody here should be pleased that the dispute had been resolved in a reasonable amount of time, the debaters showed reasonable restraint, and there now is no need for further debate. Seems this too is a win win for all concerned.

Should the editors change thier minds and decide that the article should head north, rather than south as it is now, there would no longer be a conflict of interest on my part and I would then be allowed (by my conscience) to continue to contribute to the article. But for the moment the article is heading south and I am not willing to sacrifice my ethics, morals and integrity by contributing to an article that rather than draw attention to a syndrome, provides the treating physician with yet another source to deny its proven reality. I may be a "bitch" to deal with at times as I am rather outspoken as well as opinionated regarding these issues, but I am not a "whore" that can be bought and sold like some of those found within the medical community that have written the citations we have reviewed.

I will continue to be a part of wikipedia, I will continue to work on the other fluoroquinolone articles, and if I am asked again to sacrifice the outrageously high standards I have set for myself I will simply decline and withdraw from that particular article. If I find that I cannot in good conscience edit an article due to the conflict of interest such a sacrifice would entail, the only option is not to participate further on that article. Just as I have done here. Wikipedia requires this from all its editors, and even with my ten years of study and expertise regarding these issues I am not to be an exception to this rule. Nor should anyone else for that matter. I may be new here but I fully understand the above rule and agree with it and will follow it to the best of my abilties.Davidtfull (talk) 23:40, 17 February 2009 (UTC)

I disagreed with both of you during this dispute, so I tread on both of your toes. You have added a lot of verifiable data to the article which will not be deleted so I don't think that there will be any winners. A person's side of the debate on wikipedia is only as good as the reliable citations. The same policies apply to all wikipedia articles. If you have a good secondary source saying that fluoroquinolones have an unfavourable risk/benefit ratio or a generally severe adverse/side effect profile then please do cite it. You could convert every editor on this page to your view on fluoroquinolones and you still wouldn't win because data must be reliably cited. Maybe your next battle should be with the National Institute for Health to try and get them to study say 1,000 randomised members who receive fluoroquinolones and follow symptoms up over a course of a year and document them. Then we will have an idea what percent get acute serious ADRs and what percent have persisting ADRs of users and then once published return to wikipedia and cite it. Not very likely to succeed in getting such a study done but who knows, you did achieve the black box warnings after all. Nice to hear that you are going to stay on wikipedia. By the way I have been in a similar position to you when I first joined wikipedia. I got off to a bumpy start on wikipedia when large blocks of my edits were challenged. I wasn't aware of the rules and very enthusiastic on the articles I was editing.--Literaturegeek | T@1k? 02:11, 18 February 2009 (UTC)

I've never considered someone disagreeing with me to be stepping on my toes. Everyone is entitled to an opinion and are free to express it, in my opinion. We don't have to agree on anything, all we have to do is discuss things in a rational manner and if a concensus cannot be reached agree to disagree and leave it at that. I never take such debates personal in the least, so you have yet to offend me in any way. But if for some reason you ever do, I will discuss it off line with you and see if we can resolve the issue privately.Davidtfull (talk) 02:49, 18 February 2009 (UTC)

Good. :--) Sounds like a good plan and good way to handle things. By the way you probably wouldn't want to be associated with a study that involved administrating a fluoroquinolone so maybe one which involves randomly selecting patients who have already taken a fluoroquinolone, but you get my idea.--Literaturegeek | T@1k? 02:55, 18 February 2009 (UTC)

"This was your baby to begin with. The individual drug articles I would consider to be mine."

I just noticed this part of your post that you made a couple of days ago, I must have missed it. I only started the article with cited data off of your talk page. You added the bulk of the material, (in record speed, I have never seen an article develop so fast). As you are new to wikipedia I would refer you to this page.Wikipedia:Ownership_of_articles. I don't own this article, just because I edited it first. Nobody can claim ownership of an article, although defending articles against vandals and being enthusiastic in developing them and taking a special interest in an article's development process is perfectly fine.--Literaturegeek | T@1k? 19:35, 18 February 2009 (UTC)

That was just an expression, it was not intended to be taken literally. The point being you had started something and I had volunteered to help with it. As such I would think it be a bit courteous of me to defer to you in regards to certain matters is all. I realize this is a group effort and nobody has absolute rights to anything. It is community property. But with all community property there is always someone who takes an greater interest in its well being and such folks should be granted a degree of respect concerning thier wishes. They certainly do not have to be followed, but they should at least be given serious consideration. That was the point I was trying to make is all. I have an annoying habit of using metaphors to explain a situation or a point of view, they are not to be taken literally. But any group effort tends to generate a leader of sorts, a straw boss if you will, I was just pointing out that at the moment that someone, in my view, appeared to be you, and not I.Davidtfull (talk) 00:17, 19 February 2009 (UTC)

Use of PMID 11793615

This is not a reliable source because it is an Internet-based study; this is more a hypothesis-generating study than a reliable source (see WP:MEDRS). For starters, it is a primary source and not a review. --Steven Fruitsmaak (Reply) 07:49, 17 February 2009 (UTC)

As long as the data in that article are not misused, given undue weight or misinterpreted or used to synthesise it is reliable. I think its use is fine if used cautiously. I read MEDRS. Primary sources are allowed. Also it is not a featured article so there is not such a focus on aiming for perfection. You all are making me stressed out! Sorry.--Literaturegeek | T@1k? 08:21, 17 February 2009 (UTC)

I agree with Literaturegeek. One should not conclude that just because data was collected over the internet, it is "not a reliable source". It is a very useful source that validates the existence and characteristics of various side effects. It was this source that prompted the FDA to include "Irreversible" Neuropathy as a side effect.

Steve, I do believe that this article has great potential. Why don't you come back in a few weeks, as right now they are doing a lot of editing and restructuring. All this arguing is not going to help at the present moment. JamesLockson (talk) 08:24, 17 February 2009 (UTC)

Yea and much of the adverse effects and many facts in that study can be verified using secondary sources anyway if it is demanded. Thanks james for understanding, a break is maybe a good idea.--Literaturegeek | T@1k? 08:27, 17 February 2009 (UTC)

odds ratio and relative risk

It appears David has mistakenly thought that these mathmatical calculations mean percent and as a result has inflated the data thousands of times what it is. Can someone track down this article Fluoroquinolones and Achilles tendinopathy in renal transplant recipients and see if it is talking about percent, relative risk or odds ratio? It is an easy mistake to make if not knowledgable in mathmatics. I have no doubt not all quinolone injuries are picked up by the FDA and the incidence for tendonopathy is higher than 4 per 100,000. I have heard anywhere from only 1% - 10% of serious adverse reactions are reported to regulatory bodies but still multiplying the data by many many thousands of times what it is by a mathmatical mistake is grossly distorting the data.--Literaturegeek | T@1k? 11:58, 17 February 2009 (UTC)

That paper is actually where you live Belgium Steven, so if you can track it down at least you will bee able to understand it! :=)--Literaturegeek | T@1k? 12:15, 17 February 2009 (UTC)

Actually I think that it is in an english journal.--Literaturegeek | T@1k? 12:16, 17 February 2009 (UTC)

Don't know what exactly is your question, but according to that paper, the incidence of tendon rupture in renal transplant patients who received a quinolone was 12%. Though I am certain I have read a published article showing that less than 10% of all ADRs are reported to the FDA, I'll see if I can find the article for you. Quinolones are definitely more underreported as the adverse reactions are almost always misdiagnosed, or delayed. Who would think your chronic insomnia came from an antibioitic you took months ago? How can an athlete attribute their tendon rupture to a few pills of antibiotics? JamesLockson (talk) 12:47, 17 February 2009 (UTC)

I was able to verify it from another peer review publication that quoted it. The stats in that article are correct. The other citations had multiplied the stats by many thousand fold by changing relative risk or odds ratio into percent. Looks like everything is ok now and cited properly. I fixed errors in article. Yea I hear what you are saying about people and doctors not attributing symptoms to a drug reaction. Drug reactions get misdiagnosed all the time though, not just quinolones. I know of other horror stories from friends and relatives with other drugs. One example was severe muscle wasting that put a friend in hospital for 3 months. Doctors were baffled why he was wasting away in in crippling agony and also why he was getting neuropsychiatric problems. It was an adverse reaction to a statin. Who would think a cholestoral drug would make you lose your memory and mind and destroy your muscles? Trust me he suffered, it wasn't benign and it could have led to permanent damage or even death if it wasn;t eventually correctly diagnosed,,,, 3 months later. The problem is doctors fit symptoms into a category and make a diagnosis without trying to do detective work and find the cause and think ok what is the recent drug history around the time these symptoms developed? Did patient recently start or abruptly stop a medication? I have a personal friend who spent several months in a psychiatric unit after an adverse drug reaction to a psychotropic drug. They kept them on it and even increased the dose and made her even more psychotic before a new doctor checked her history and diagnosed an adverse reaction and stopped the medication. She could have ended up a permanent mental health patient had the reaction not been spotted, permanently on antipsychotics to treat "psychosis" or schizophrenia or whatever. This happens all the time and lives are sometimes ruined and health destroyed. That is not to say medicine is evil, there are good drugs on the market and good doctors that use drugs sensibly.--Literaturegeek | T@1k? 13:16, 17 February 2009 (UTC)

I said 1 - 10% because I have seen studies showing as low as 1% report adverse reactions but I am thinking of the uk yellow card scheme scheme but should be similar in usa.--Literaturegeek | T@1k? 13:32, 17 February 2009 (UTC)

This is the text of the article in question, took me less than sixty seconds to find it:

Br J Clin Pharmacol > v.48(3); Sep 1999 

Stricker, B. Br J Clin Pharmacol. 1999 September; 48(3): 433–437. doi:10.1046/j.1365-2125.1999.00016.x. PMC 2014320

Copyright © 1999 Blackwell Science Ltd Achilles tendinitis associated with fluoroquinolones P D van der Linden,1 J van de Lei,2 H W Nab,1,4 A Knol,3 and B H Ch Stricker1 1Pharmaco-epidemiology Unit, Departments of Epidemiology and Biostatistics and Internal Medicine, Erasmus University Medical School, Rotterdam, The Netherlands 2Department of Medical Informatics, Erasmus University Medical School, Rotterdam, The Netherlands 3General Practitioner, Groningen, The Netherlands 4Dutch Medicines Evaluation Board, Rijswijk, The Netherlands Correspondence: Dr B. H. Ch. Stricker, Department of Epidemiology & Biostatistics, PO Box 1738, 3000 DR Rotterdam, The Netherlands. Received September 18, 1998; Accepted May 17, 1999.

This article has been cited by other articles in PMC. 

Aims To determine whether there is an association between use of fluoroquinolones and tendinitis in a large population under everyday circumstances.

Methods A retrospective cohort study was carried out in a dynamic population. Data came from the IPCI-database which consists of all data on consultations, morbidity, prescriptions and other interventions, as registered by GPs in a source population of approximately 250 000 persons. For this study data were collected from 41 general practices in the period from January 1st, 1995 through December 31st, 1996. All persons treated with either fluoroquinolones, amoxicillin, trimethoprim, cotrimoxazole or nitrofurantoin were followed from the first day of treatment until the outcome of interest, death, transfer to another practice, or end of the study period, whichever came first. The risk window was defined as the legend duration +1 month. Potential cases were defined as a registration of a tendinitis or tendon rupture. Patients with a history of tendinitis or tendon rupture, preceding trauma or inadequate diagnoses were excluded on the basis of a review of the patient profiles and additional clinical data, blinded as to the exposure status. Results were adjusted for age, gender, concurrent corticosteroid exposure and number of GP visits.

Results There were 1841 users of fluoroquinolones and 9406 users of the other antibacterial drugs with an average duration of 9 and 7 days, respectively. Tendinitis or tendon rupture was registered in 97 profiles, but after review only 22 complied with the case definition. The adjusted relative risk of tendinitis to fluoroquinolones was 3.7 (95%CI: 0.9–15.1) for Achilles tendinitis and 1.3 (95%CI: 0.4–4.7) for other types of tendinitis. Achilles tendinitis to ofloxacin had a relative risk of 10.1 (95%CI: 2.2–46.0) and an excess risk of 15 cases per 100 000 exposure days.

Conclusions Although the numbers in our study are small, our results suggest that some fluoroquinolones may increase the risk of Achilles tendinitis, and that this risk increase is highest for ofloxacin.

Discussion References IntroductionIn the past few years, there has been a marked increase in the number of spontaneous reports of tendinitis associated with fluoroquinolones [1–7]. In the vast majority of cases, the Achilles tendon was affected with symptoms compatible with painful tendinitis or with rupture, usually during the first 2 weeks of treatment. Fluoroquinolones form a relatively new class of antibacterial agents which act by inhibiting bacterial DNA gyrase [8]. The most frequently observed adverse effects are of gastro-intestinal origin, followed by CNS disorders and skin reactions [8]. Although in several case reports tendinitis has been attributed to fluoroquinolones, the epidemiological confirmation of the association is scanty. In order to assess whether there is an association between fluoroquinolones and tendinitis, and to determine the incidence and relative risk of tendinitis to the different products, we conducted a retrospective cohort study in a large population under everyday circumstances.

Data source Data were obtained from the Integrated Primary Care Information (IPCI) system, a research-orientated database with data from computerized patient records of general practitioners (GPs) throughout the Netherlands which was developed by the Department of Medical Informatics of the Erasmus University Medical School. The database includes all demographic information, patient complaints, symptoms, laboratory tests, diagnoses, discharge and consultant letters, and prescription details (including drug name, dosage form, dose, quantity prescribed, and indication). GPs write the prescriptions directly from the computer, thus ensuring automatic recording. Medication codes are based on the national database of drugs, maintained by the Royal Dutch Association for the Advancement of Pharmacy. A modification of The International Classification for Primary Care [9] is the coding system employed for patient complaints, diagnoses, and indications but these can also be entered as free text. At present, the IPCI-project monitors a population of about 250 000 patients on a continuous basis. The data used for this study were collected from 41 general practices in the period between January 1st, 1995 and December 31st, 1996.

Cohort definition The cohort consisted of all patients of 15 years and older with a permanent status who were treated in the study period with one of the following antibacterial drugs: fluoroquinolones (index group), amoxicillin, trimethoprim, cotrimoxazole and nitrofurantoin (reference group). The latter four drugs were chosen as a reference because these are commonly used drugs with a well-known safety profile, and have not been associated with tendinitis. Subjects had to have a computer-recorded history of at least 3 months duration prior to the date of first prescription in order to be eligible to participate in this study. All coded prescriptions were considered with the exclusion of dermatological and ocular preparations. The patients entered the study cohort on first prescription of one of the study drugs at which time contribution to person-time experience started. Subjects were followed until the outcome of interest, transfer to another practice, death, or end of the study period, whichever came first. Patients were excluded if gender, age, or dosage of the study drugs were unknown, if they were chronic users of the drugs under study (more than 60 days in 1 year), and if there was a history of inflammatory joint disease (e.g. rheumatoid arthritis, SLE), Reiter’s syndrome, polymyalgia rheumatica, gout or AIDS.

Exposure and outcome definition For each prescription, the legend duration was calculated as the amount of prescribed drug divided by the daily dose. The total exposed period of each subject was calculated as the sum of the legend durations, corrected for refill prescriptions. The risk period was defined as the exposed period plus 1 month. The month was added because any increased risk during exposure will have a carry-over effect and because a notification in GP-records may be delayed when patients present themselves with tendinitis several days after onset. Concomitant users of fluoroquinolones and one of the reference drugs during this risk period were excluded. To ensure maximal sensitivity and specificity, we followed a two-step selection procedure of case-finding (step 1) and case-validation (step 2). In step 1, potential cases of the outcome of interest were defined as the registration of one or more of the diagnoses or symptoms mentioned in Table 1 within the risk period. Moreover, all records were studied for a notification of ‘tendinitis’, ‘tendon disorder’, ‘tendon rupture’, ‘coup de fouet’ or ‘pain upper leg’ in the free text of each patient file. In step 2, for all selected patients a patient profile was generated and printed, where all prescriptions, GP medical diagnoses, laboratory results, hospital referrals and GP remarks were listed. The exposure to the study drugs in these patient profiles was blinded. Following an independent review of the patient profile by two GPs, patients were excluded if the patient had a history of tendinitis or tendon rupture before use of the study drugs, if another cause of the tendinitis was likely (e.g. trauma), or if the diagnosis was wrong (e.g. bursitis). In case of disagreement, the data were independently reviewed by a third medical practitioner. To confirm the adequacy of the validation procedure, the GPs of potential cases were sent a questionnaire requesting details of some of the clinical features and any correspondence available related to the diagnosis of interest. All patients’ personal identifiers were suppressed before sending.

Table 1

List of ICPC-codes included in the case definition.

Analysis The first outcome-related event that occurred was used in the analyses. The incidence density (ID) was calculated by dividing the number of events occurring in the risk windows by the total risk period, and was expressed as the number of events per 100 000 days at risk. Incidence densities for exposure to fluoroquinolones were compared with those for the reference drugs. The relative risk (RR) of tendinitis was calculated as an incidence density ratio, dividing the two incidence densities. The excess risk was calculated by subtracting the incidence densities in index and reference group. Confidence (95%) intervals for the crude and adjusted relative risks were estimated with Poisson regression analysis. Adjusted estimates of the RR were controlled for the potentially confounding effects of gender, age, number of GP visits and concurrent corticosteroid use.

Results

In the study period, 11 812 patients of 15 years and older received 18 428 prescriptions for the study drugs. Of these, 786 patients were excluded because dosage was unknown (n = 34), because of concomitant use of fluoroquinolones and the reference drugs in the risk period (n = 653) or because they were chronic user (n = 99). Furthermore, 226 patients were excluded because they had a history of rheumatoid arthritis (n = 76), SLE (n = 3), polymyalgia rheumatica (n = 28), gout (n = 118) or AIDS (n = 1). Hence, the study population consisted of 10 800 patients. During the study period, there were 1841 users of fluoroquinolones and 9406 users of the other antibacterial drugs (fluoroquinolones as well as one of the reference drugs may have been prescribed to the same patient outside the risk period), with an average duration of 9 and 7 days, respectively (Table 2). In total, 418 patients received 500 prescriptions for ofloxacin, 456 patients received 556 prescriptions for ciprofloxacin and 1030 patients received 1362 prescriptions for norfloxacin, with an average duration of 10, 9 and 8 days, respectively. Most index and reference drugs were used for urinary or respiratory tract infections at the recommended daily dosage. There was no significant difference in indication between index and reference group. The reference group consisted of relatively more female patients. The mean age in the index group was higher; patients in the index group visited the GP more often, and had a higher prevalence of renal failure (Table 2). During the total risk period of 548 919 days, possible cases of tendinitis or tendon rupture were registered in 97 patient profiles. After more extensive review of the computerized profiles of these potential cases by the medical reviewers, 68 (70%) cases were excluded from further analysis: 26 (38%) because the diagnosis was not tendinitis but mostly bursitis, 12 (18%) because tendinitis was probably caused by a trauma and 30 (44%) because there was a history of tendinitis or tendon rupture before intake of the study drugs. Concerning the remaining 29 cases, questionnaires were sent to the GPs which were all returned after some reminders. After blinded review, 7 additional patients were excluded: 2 cases because the diagnosis was not tendinitis, and 5 because tendinitis was caused by trauma. Consequently, 22 cases (all tendinitis; no rupture) complied with the case definition. In 8 of these patients, the Achilles tendon was affected. Of the 22 cases, 7 occurred during fluoroquinolones and 15 during use of a reference drug. The incidence density of tendinitis during fluoroquinolones was 7.74 per 100 000 days at risk and 3.27 for the reference drugs, which is compatible with a RR of 2.4 (95% CI: 0.96–5.80). Ofloxacin had a significantly increased crude RR of tendinitis of 6.5 (95%CI: 2.14–19.45), which declined after adjustment to 4.9 (95%CI: 1.57–15.06). No significant association was found for ciprofloxacin and norfloxacin (Table 3). After stratification for Achilles tendinitis and other types of tendinitis, fluoroquinolones as a group had an elevated RR of Achilles tendinitis of 4.4 (95% CI: 1.27–20.27), which declined after adjustment to 3.7 (95% CI: 0.93–15.14), while no association was found for the other types of tendinitis. Ofloxacin was associated with an increased RR of 10.1 for Achilles tendinitis (95% CI: 2.20–46.04), whereas no association was found with the other types of tendinitis for the different fluoroquinolone agents (Table 3). The risk difference between fluoroquinolones and the reference drugs was 4 cases per 100 000 days for tendinitis, and 4 cases per 100 000 days for Achilles tendinitis. Ofloxacin was associated with a risk increase of 15 cases per 100 000 days. A duration-or dose effect relationship could not be assessed as almost all courses were given for similar short periods and because the large majority of fluoroquinolone users took the recommended daily dose.

Table 2

Characteristics of the patient in the index group and in the reference group.

Table 3

The incidence densities stratified for achilles tendinitis and other tendinopaties among the drugs under study and relative risks stratified for achilles tendinitis and other tendinopaties.

In this study, we found that the risk of tendinitis with fluoroquinolones was higher than the risk with a reference group of four commonly used antibacterial agents with a known safety profile. As these are not known to cause tendinitis, they represent the background risk and even if some actually cause tendinitis, this would tend to underestimate the RR of fluoroquinolones. Ofloxacin had the strongest association with Achilles tendinitis. Although age, gender, and number of visits to the GP differed significantly between the fluoroquinolone users and the users of other antibacterial drugs, adjustment for these factors did not eliminate the association with tendinitis. None of the cases had renal failure, which has been suggested as a possible risk factor for tendinitis [7]. Use of corticosteroids, a suggested risk factor for tendon rupture, was not related to tendinitis in this study.

The validity of epidemiological studies may be endangered by selection bias, information bias, or confounding. As the association between fluoroquinolones and tendinitis was only recently widely recognized and as proven risk factors for tendinitis, such as physical training, are not a contra-indication for fluoroquinolones selection bias is unlikely. One of the advantages of a study using automated GP data is that information on disease and exposure are gathered by GPs who are not aware of the research hypothesis at the time of registration. Hence recall bias or other types of information bias are not very likely in this study. To avoid observer bias we conducted a review of the patient profiles which was blinded to exposure status. Another important aspect concerning the validity of follow-up studies with automated data resources is the proportion of unidentified eligible cases (false negatives) through the initial computerized search. We have tried to minimize this problem by performing not only a search on a wide range of ICPC-codes but also a text string search in the database. This explains in part why only 22 out of 97 possible cases passed the validation procedure. In the IPCI-project information is gathered only from GPs who are fully automated and do not use paper resources. Even if cases of tendinitis have been misclassified, misclassification was probably random. Hence, this will not affect the RR in a cohort study but might have some effect on the risk difference. Confounding by indication in this study is not very likely, as there was no association with indication, and because urinary-and respiratory tract infections are not a risk factor for tendinitis.

Apart from several case reports [1–7], a large case series in France reported on 100 cases which had been notified between 1985 and 1992 [10]. The Achilles tendon was affected in 96 patients and tendon rupture occurred in 31 persons. The average time between the start of the treatment and the onset of the symptoms was 13 days (range, 1–90 days). Long-term corticosteroid therapy was an associated risk factor. Pierfitte estimated the incidence rate of tendinitis among fluoroquinolone users at 15–20 per 100 000 prescriptions [11]. Others concluded that there was no increased risk of Achilles tendon rupture to ciprofloxacin [12]. In a study with prescription-event monitoring, the frequency rate of tendinitis, tenosynovitis or tendon rupture was 1/11 000 patients for ciprofloxacin, 3/11 000 patients for norfloxacin and 11/11 000 patients for ofloxacin, respectively [13]. Although the relatively high rate with ofloxacin is in line with our results, the incidence in our study is higher.

The pathophysiological mechanism linking tendinitis to fluoroquinolones remains unknown. Experimental data are restricted to cartilage injuries in immature animals [14, 15]. Some authors described the histological findings in damaged Achilles tendons and considered these changes to be due to an ischaemic process [16]. Other have considered the tendon disorders to be caused by a toxic effect on collagen fibres [17]. Furthermore, a role of mechanical factors has been suggested [18], and an autonomic nervous system disturbance or immuno-allergic phenomenon cannot be excluded [16].

Although the findings of our study support the hypothesis that fluoroquinolones are associated with tendinitis, definite conclusions should be drawn cautiously. Numbers of patients with tendinitis in our study are relatively small and follow-up is limited to only 2 years. In addition, the 95% confidence intervals of the risk estimates of the different fluoroquinolones do not differ significantly. Nevertheless, our results indicate that ofloxacin is strongly associated with Achilles tendinitis.

In conclusion, our results suggest that the risk of Achilles tendinitis to fluoroquinolones, especially ofloxacin, is higher than the risk to the other antibacterial drugs. To our knowledge, this is the first epidemiological study which demonstrates an increased risk. It should be emphasized, however, that the absolute numbers in our study are small and that an extra number of cases of Achilles tendinitis of 15 per 100 000 days may be acceptable when prescribed for severe infections.

References 1.Huston, KA. Achilles tendinitis and tendon rupture due to fluoroquinolone antibiotics. N Engl J Med. 1994;331:748. [PubMed] 2.McEwan, SR; Davey, PG. Ciprofloxacin and tenosynovitis. Lancet. 1988;2:900. [PubMed] 3.Pierfitte, C; Gillet, P; Royer, RJ. More on fluoroquinolone antibiotics and tendon rupture. N Engl J Med. 1995;332:193. [PubMed] 4.Ribard, P; Audisio, F; Kahn, MF, et al. Seven Achilles tendinitis including 3 complicated by rupture during fluoroquinolone therapy. J Rheumatol. 1992;19:1479–1481. [PubMed] 5.Szarfman, A; Chen, M; Blum, MD. More on fluoroquinolone antibiotics and tendon rupture. N Engl J Med. 1995;332:193. [PubMed] 6.Zabraniecki, L; Negrier, I; Vergne, P, et al. Fluoroquinolone induced tendinopathy: report of 6 cases. J Rheumatol. 1996;23:516–520. [PubMed] 7.Donck, JB; Segaert, MF; Vanrenterghem, YF. Fluoroquinolones and Achilles tendinopathy in renal transplant recipients. Transplantation. 1994;58:736–737. [PubMed] 8.Hooper, DC; Wolfson, JS. Fluoroquinolone antimicrobial agents. N Engl J Med. 1991;324:384–394. [PubMed] 9.Lamberts, H; Woods, M. International Classification of Primary Care. Oxford: Oxford University Press; 1987. 10.Royer, RJ; Pierfitte, C; Netter, P. Features of tendon disorders with fluoroquinolones. Therapie. 1994;49:75–76. [PubMed] 11.Pierfitte, C; Royer, RJ. Tendon disorders with fluoroquinolones. Therapie. 1996;51:419–420. [PubMed] 12.Shinohara, YT; Tasker, SA; Wallace, MR; Couch, KE; Olson, PE. What is the risk of Achilles tendon rupture with ciprofloxacin? J Rheumatol. 1997;24:238–239. [PubMed] 13.Wilton, LV; Pearce, GL; Mann, RD. A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies. Br J Clin Pharmacol. 1996;41:277–284. [PubMed] 14.Corrado, ML; Struble, WE; Peter, C; Hoagland, V; Sabbaj, J. Norfloxacin: review of safety studies. Am J Med. 1987;82:22–26. [PubMed] 15.Kato, M; Takada, S; Kashida, Y; Nomura, M. Histological examination on Achilles tendon lesions induced by quinolone antibacterial agents in juvenile rats. Toxicol Pathol. 1995;23:385–392. [PubMed] 16.Jorgensen, C; Anaya, JM; Didry, C, et al. Arthropathy with achilles tendon involvement induced by pefloxacin. Apropos of a case. Rev Rhum Mal Osteoartic. 1991;58:623–625. [PubMed] 17.Franck, JL; Bouteiller, G; Chagnaud, P; Sapene, M; Gautier, D. Rupture des tendons d’achille chez deux adultes traites par pefloxacine dont un cas bilateral. Rev Rhum Mal Osteoartic. 1991;58:904. [PubMed] 18.Blanche, P; Sereni, D; Sicard, D; Christoforov, B. Tendinopathies achileennes induites par la pefloxacine. A propos de 2 cas. Ann Med Interne (Paris). 1992;143:348. [PubMed] Davidtfull (talk) 01:50, 18 February 2009 (UTC)

Thanks David, a good ref, some good quality data.--Literaturegeek | T@1k? 02:14, 18 February 2009 (UTC)

Vigamox

There are some that seem to say "it's only eye drops". Eye drops is medicine. What we are seeing here is that different medicines are different. So a re-write is necessary to clearly cover the different side effects for different medicines (they are not all the same), toxicity, etc. Wikipedia is also balanced so the end product should not be that the reader thinks they will become psychotic and have orthopedic problems after taking a pill. This advice is to give the article some credibility. The way it is now is, intentionally or unintentionally, it looks like a angry and disgruntled patient's diary. Good luck on the rewrite. Some has already been done by someone else. Chergles (talk) 15:56, 17 February 2009 (UTC)