{"id":839,"date":"2014-09-03T14:53:13","date_gmt":"2014-09-03T18:53:13","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=839"},"modified":"2014-09-03T14:53:13","modified_gmt":"2014-09-03T18:53:13","slug":"the-futile-quest-of-proofing-a-negative-in-the-presence-of-overwhelming-absence-of-harm","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2014\/09\/03\/839\/the-futile-quest-of-proofing-a-negative-in-the-presence-of-overwhelming-absence-of-harm\/","title":{"rendered":"The Futile Quest of Proofing a Negative in the Presence of Overwhelming Absence of Harm"},"content":{"rendered":"

The cartilage damage caused by fluoroquinolones in juvenile beagle dogs is not subtle:\u00a0 blister formation and erosions occur in a dose-dependent fashion resulting in reversible cartilage damage.\u00a0 \"beagle<\/a>These lesions can be seen not just histologically but even macroscopically.\u00a0 The animals are unable to walk as weight-bearing joints are predominantly affected.\u00a0 \u00a0For levofloxacin and ciprofloxacin, the threshold or NoEL was found to be 3 mg\/kg\/day and 10 mg\/kg\/day, respectively, when the drug was administered for 14 days; below this dose joint damage did not occur in the beagle dog model [1, 2],.\u00a0 We are not aware of any other animal species that has a similar toxic response.<\/p>\n

Now, Bradley and colleagues from J&J just published the results of a prospective trial in which children were followed for 5 years after the initial exposure to a fluoroquinolone (FQ), levofloxacin [2].\u00a0 This study was an extension of a larger 1-year safety trial; it concentrated on a subset of \u2018higher-risk\u2019 patients identified by a list of criteria which included growth retardation, abnormal bone or joint symptoms\/signs, or persistent musculoskeletal pain.<\/p>\n

Studies of this nature are difficult to execute, and this one was no exception.\u00a0 Compliance is an issue because of the\u00a0long-term follow-up period, and there always is concern about bias.\u00a0 In this case, neither parents nor investigators were blinded, but members of the DSMB of the 5-yr extension cohort supposedly were.\u00a0 Establishing whether there existed a relationship between an AE and the study drug several years after initial exposure also seems highly problematic. \u00a0One\u00a0could call it ‘expert guesswork’.<\/p>\n

The results came out as expected and were anticlimactic.\u00a0 Of the enrolled 124 children with previous exposure to levofloxacin and the 83 comparator subjects only half completed the 5-yr observation period in each arm.\u00a0 There were 3 cases of musculoskeletal AEs in each group.\u00a0 In the levofloxacin group, hypermotility (sic!), arthralgia, and arthritis were noted, mostly mild in nature.\u00a0 However, 1 patient developed severe synovitis.\u00a0 There was no difference in growth between the 2 groups.\u00a0 Taken together, there was no safety signal of concern.<\/p>\n

The results of this trial will sway nobody\u2019s mind regarding the role of FQ in pediatrics.\u00a0 Even if there were a very small risk of arthropathy, the incidence must be exceedingly small making it impossible to rule it out or estimate its frequency with any precision.\u00a0 A prospective controlled clinical trial is a very blunt tool and unsuitable to address the question at hand.<\/p>\n

After 30 years of FQ use, and hundreds of million doses prescribed, one would assume that even rare AEs would eventually have declared themselves and become manifest.\u00a0 Such was the case for azithromycin (cardiac side effects) and some\u00a0other drugs like tramadol (also cardiac events).<\/p>\n

As the use of antibiotics for AOM is now much more restricted, concerns about a possible \u2018abuse\u2019 of FQ for trivial viral infections should be much less of an issue nowadays [3].\u00a0 With minimal harm, if at all, and in light of more appropriate use of antibiotics in children which now includes \u2018watchful waiting\u2019, and no evidence of persistent arthropathy, the pediatric labeling in the Package Insert should be revised.<\/p>\n

Maybe, just maybe, a fresh look at the risk-to-benefit ratio would result in wording that states that prolonged or prophylactic use is not appropriate. \u00a0In its\u00a0current form, the FQ Warnings\/Precautions on pediatric use seem overly restrictive and unbalanced.<\/p>\n

References:<\/strong><\/p>\n

[1] Von Keutz.\u00a0 Arch Toxicol. 2004; 78(7):418
\n[2] J Bradley.\u00a0 Pediatrics 2014;134:e146
\n[3] A. Lieberthal.\u00a0 Pediatrics 131, 2013 pp. e964<\/p>\n","protected":false},"excerpt":{"rendered":"

The cartilage damage caused by fluoroquinolones in juvenile beagle dogs is not subtle:\u00a0 blister formation and erosions occur in a dose-dependent fashion resulting in reversible cartilage damage.\u00a0 These lesions can be seen not just histologically but even macroscopically.\u00a0 The animals are unable to walk as weight-bearing joints are predominantly affected.\u00a0 Continue reading The Futile Quest of Proofing a Negative in the Presence of Overwhelming Absence of Harm<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":841,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2},"jetpack_post_was_ever_published":false},"categories":[227,18],"tags":[520,393,403,519,511,211,510,513,517,42,525,524,5,509,523,512,516,213,521,518,514,522,526,515],"class_list":["post-839","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-recent_literature","category-the_viewpoint","tag-acute-otitis-media","tag-adverse-event","tag-antibiotic-blog","tag-aom","tag-arthropathy","tag-azithromycin","tag-beagle-dogs","tag-cartilage-damage","tag-cipro","tag-ciprofloxacin","tag-data-safety-monitoring-board","tag-dsmb","tag-fda","tag-fluoroquinolones","tag-jj","tag-juvenile-beagles","tag-levaquin","tag-levofloxacin","tag-musculoskeletal","tag-noel","tag-package-insert","tag-pediatric-use","tag-tramadol","tag-warningsprecautions"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/09\/beagle-dog.jpe","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-dx","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":1907,"url":"https:\/\/allphasepharma.com\/dir\/2015\/09\/03\/1907\/mrsa-fluoroquinolones-an-interesting-bunch-playing-a-high-stakes-game\/","url_meta":{"origin":839,"position":0},"title":"MRSA Fluoroquinolones \u2013 An Interesting Bunch Playing a High-Stakes Game","author":"Harald","date":"September 3, 2015","format":false,"excerpt":"Fluoroquinolones (FQ) of the ofloxacin\/ciprofloxacin generation were mainly active against Gram-negative bacteria, distinguishing themselves as cidal IV\/PO drugs with high\u00a0potency\u00a0against most lactose- and non-lactose fermenters.\u00a0 They were excellent against problem pathogens like P. aeruginosa, had excellent efficacy\u00a0against Salmonellae, the Gonococcus and other Neisseriae, and you could count on them for\u2026","rel":"","context":"In "The News"","block_context":{"text":"The News","link":"https:\/\/allphasepharma.com\/dir\/category\/the_news\/"},"img":{"alt_text":"antiMRSA 1 copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/antiMRSA-1-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/antiMRSA-1-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/antiMRSA-1-copy.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1608,"url":"https:\/\/allphasepharma.com\/dir\/2015\/06\/25\/1608\/why-moxifloxacins-approval-for-plague-is-so-disturbing\/","url_meta":{"origin":839,"position":1},"title":"Why Moxifloxacin\u2019s Approval for Plague Is So Disturbing","author":"Harald","date":"June 25, 2015","format":false,"excerpt":"PLEASE SHARE YOUR OPINION AND VOTE\u00a0BELOW On May 8th, 2015 moxifloxacin\/Avelox was approved for treatment of inhalational plague.[1]\u00a0\u00a0 We learn that the approval followed the \u2018animal rule\u2019 process, and that treatment with moxifloxacin was 100% effective in the African Green Monkey (AGM) model of lung infection.\u00a0 By contrast, 0% of\u2026","rel":"","context":"In "Did you know...?"","block_context":{"text":"Did you know...?","link":"https:\/\/allphasepharma.com\/dir\/category\/interesting_facts\/"},"img":{"alt_text":"AGM - 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