{"id":1608,"date":"2015-06-25T06:26:22","date_gmt":"2015-06-25T10:26:22","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1608"},"modified":"2015-07-15T07:38:04","modified_gmt":"2015-07-15T11:38:04","slug":"why-moxifloxacins-approval-for-plague-is-so-disturbing","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/06\/25\/1608\/why-moxifloxacins-approval-for-plague-is-so-disturbing\/","title":{"rendered":"Why Moxifloxacin\u2019s Approval for Plague Is So Disturbing"},"content":{"rendered":"

PLEASE SHARE YOUR OPINION AND VOTE\u00a0BELOW<\/span><\/strong><\/h1>\n
\n

<\/h1>\n

\"AGM<\/a><\/p>\n

On May 8th<\/sup>, 2015 moxifloxacin\/Avelox was approved for treatment of inhalational plague.[1]<\/a>\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 animals receiving placebo survived the bacterial challenge.

\u201cToday\u2019s approval provides an additional therapy for the treatment of plague\u201d<\/strong><\/span> Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA\u2019s Center for Drug Evaluation and Research<\/p>\n<\/div><\/p>\n

The study was done with bioterrorism in mind and the parallels to inhalational anthrax (for which ciprofloxacin and doxycycline are approved) are clear.\u00a0 Yersinia pestis, the plague pathogen, is still around in the southwest of the US, and while most cases are of the bubonic (skin infection) variety, the inhalational route of infection has a high mortality in humans.\u00a0 The fact that Y. pestis can be weaponized is the rationale for the study and explains why the study was supported by NIAID.<\/p>\n

So far, so good.\u00a0 It sounds like sound science and good progress on the path to make America safer.<\/p>\n

Here is the rub: Why do we have to kill non-human primates again and again to show the obvious?\u00a0 It has been established beyond reasonable doubt that inhalational exposure to Y. pestis kills African Green Monkeys (AGM) very consistently.\u00a0 Like in: 100% if you expose them to multiples of the LD50<\/sub>.\u00a0 At this point, wouldn\u2019t it suffice to either have no placebo group or a much smaller number of controls? \u00a0The moxifloxacin trial used an equal number as controls as for the active treatment arm (10 animals each). \u00a0Wouldn’t it be great to design the study differently, esp. the placebo arm, significantly reducing the number of deaths of primates since it is already known that this illness results in 100% mortality in these primates?<\/p>\n

As it turns out, an almost identical active vs control experiment was done with levofloxacin \/ Levaquin in 2011. In that study AGM were given a lethal dose of the pest bacillus by aerosol and \u2013 once fever developed \u2013 received either placebo or study drug.[2]<\/a>\u00a0 The results were impressive: despite bacteremia and signs of pneumonia, all levofloxacin-treated animals survived. \u00a0Even then\u00a0there were no survivors in the control group (N=8).<\/p>\n

\u2026Animals were conditioned to a restraint collar, poles, restraint chairs, and limb restraints. Radiotelemeters (Model T30F, Konigsberg, Inc.) were implanted subcutaneously in the left abdominal wall for continuous monitoring of body temperature, intrathoracic pressure, respiratory rate, heart rate, and electrocardiographic traces. Venous access catheters (Broviac, Cohorts 1 and or Hickman dual-port, Cohort 3) were inserted in the right femoral vein, tunneled through the right flank and back, emerging through the skin of the upper mid-back and protected by a jacket\u2026<\/em><\/span>[from Ref. 2]<\/p>\n<\/div>\n

The same team at the Loveless Clinic established the value of the AGM model for the evaluation of promising drugs in pneumonic plague.[3]<\/a>\u00a0 They had the benefit of even earlier experiments, also done with AGM, which show just how superbly the model performs and how well fluoroquinolones control even an established infection.\u00a0 Already in 2006 ciprofloxacin was tested and proved efficacious.[4]<\/a>\u00a0 In earlier studies with\u00a0doxycycline, ketolides and beta-lactams there was\u00a0variable activity and survival rates (see [2] for details), while\u00a0the AGMs assigned to placebo again invariably died.<\/p>\n

Historical controls as a substitute for a placebo group should be encouraged by scientists. \u00a0They serve just as well knowing that all AGM die from inhalational plague if untreated.<\/p>\n

Drug companies and researchers really should not be surprised if\u00a0animal rights activists are objecting to such unnecessary killing of primates.\u00a0 It is upsetting to see the same experiment repeated over and over again, for no other reason than to demonstrate the already known and published outcomes.<\/p>\n

Should we thank the Loveless Clinic for this study in yet another quinolone, with the same results as in the prior quinolone studies of inhalational plague, the\u00a0results of which we could have anticipated and which brings only a small labeling change to the sponsor?<\/p>\n

[poll id=”2″]<\/p>\n

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

[1]<\/a> http:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncements\/ucm446283.htm
\n[2]<\/a> Layton R (2011) Levofloxacin Cures Experimental Pneumonic Plague in African Green Monkeys. PLoS\u00a0Negl Trop Dis 5(2): e959
\n[3]<\/a> Layton R:\u00a0 J Med Primatol. 2011; 40: 6
\n[4]<\/a> Pitt M.\u00a0 Ciprofloxacin treatment for established pneumonic plague in the African Green Monkey. Abstract B-576, 50th<\/sup> ICAAC meeting 2006<\/p>\n","protected":false},"excerpt":{"rendered":"

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 Continue reading Why Moxifloxacin\u2019s Approval for Plague Is So Disturbing<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1613,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_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}},"categories":[140,227,3,18],"tags":[1085,1086,1090,403,215,220,1094,1093,517,42,427,1091,5,1089,1092,924,516,213,1095,47,1096,1087,1088],"class_list":["post-1608","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-interesting_facts","category-recent_literature","category-the_news","category-the_viewpoint","tag-african-green-monkey","tag-agm","tag-animal-rule","tag-antibiotic-blog","tag-avelox","tag-bayer","tag-bioterrorism","tag-cder","tag-cipro","tag-ciprofloxacin","tag-doxycycline","tag-drug-approval","tag-fda","tag-inhalational-plague","tag-johnsonjohnson","tag-ketolide","tag-levaquin","tag-levofloxacin","tag-loveless-clinic","tag-moxifloxacin","tag-niaid","tag-plague","tag-yersinia-pestis"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/06\/AGM-slider-copy.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-pW","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":432,"url":"https:\/\/allphasepharma.com\/dir\/2014\/06\/28\/432\/qt-prolongation-with-azithromycin-and-levofloxacin\/","url_meta":{"origin":1608,"position":0},"title":"QT Prolongation with Azithromycin and Levofloxacin","author":"Harald","date":"June 28, 2014","format":false,"excerpt":"Several antibiotic classes are associated with QTc prolongation: macrolides, quinolones, the antimalarials that share the quinine structure, and many azole antifungals.\u00a0 FDA warned about the proarrhythmic effects of azithromycin in 2013 [i] but it is a recent publication by Rao which brings the message home again with some very disquieting\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"Levofloxacin_ball-and-stick copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/Levofloxacin_ball-and-stick-copy-300x212.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":2676,"url":"https:\/\/allphasepharma.com\/dir\/2016\/09\/13\/2676\/timely-new-information-on-next-generation-tetracyclines-part-1-omadacycline-and-cardiac-aes\/","url_meta":{"origin":1608,"position":1},"title":"Timely New Information on Next-Generation Tetracyclines \u2013 Part 1: Omadacycline and Cardiac AEs","author":"Harald","date":"September 13, 2016","format":false,"excerpt":"Several\u00a0interesting articles appeared recently which shed light on the efficacy of eravacycline and the safety of\u00a0omadacycline, both in Phase 3 and both in a head-to-head race to the market.\u00a0 Well, the term \u2018race\u2019 is bit of a stretch as both drugs have seen very significant delays in development. Omadacycline from\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"Horserace Tigecycline Omada","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/08\/Horserace-Tigecycline-Omada.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/08\/Horserace-Tigecycline-Omada.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/08\/Horserace-Tigecycline-Omada.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1265,"url":"https:\/\/allphasepharma.com\/dir\/2015\/02\/11\/1265\/commenting-on-comments-the-ceftaroline-trial-program-in-cabp\/","url_meta":{"origin":1608,"position":2},"title":"Commenting on Comments:\u00a0 The Ceftaroline Trial Program in CABP","author":"Harald","date":"February 11, 2015","format":false,"excerpt":"The ceftaroline (Teflaro\u00ae) program was executed at a time when FDA was debating a new CABP Guidance with new outcome measures: no longer was the time-honored TOC assessment acceptable, instead improvement on Day 3-5 was to become the new primary endpoint.\u00a0 FDA made other significant changes to the old 1998\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"Teflaro Ad CAP","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/02\/Teflaro-Ad-CAP.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/02\/Teflaro-Ad-CAP.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/02\/Teflaro-Ad-CAP.jpg?resize=525%2C300 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/02\/Teflaro-Ad-CAP.jpg?resize=700%2C400 2x"},"classes":[]},{"id":2830,"url":"https:\/\/allphasepharma.com\/dir\/2016\/10\/27\/2830\/solithromycin-solitaire-iv-so-so-results-for-a-so-so-drug\/","url_meta":{"origin":1608,"position":3},"title":"Solithromycin SOLITAIRE-IV: So-So Results for a So-So Drug","author":"Harald","date":"October 27, 2016","format":false,"excerpt":"Just before the November 4th AMDAC on solithromycin, we are being treated to a very fine piece of study write-up. Of course, we are speaking of the File paper on the SOLITAIRE-IV trial, and what a fine piece of crafty penmanship it is, if you haven\u2019t noticed. Just as a\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"soli-iv-newer","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/10\/SOLI-IV-newer.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/10\/SOLI-IV-newer.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/10\/SOLI-IV-newer.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":2466,"url":"https:\/\/allphasepharma.com\/dir\/2016\/05\/03\/2466\/solithromycin-cap-study-cap-the-details-in-the-publication\/","url_meta":{"origin":1608,"position":4},"title":"Solithromycin CAP Study: \u00a0Cap the Details (in the Publication)","author":"Harald","date":"May 3, 2016","format":false,"excerpt":"In a recent publication, the results of a large Phase 3 trial comparing solithromycin with moxifloxacin in the treatment of CAP are presented\u00a0[1]. As this was a global registration trial, we should refer to the indication as CABP, the current FDA acronym for a very defined entity which has some\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"Solitair ORAL - slider copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/04\/Solitair-ORAL-slider-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/04\/Solitair-ORAL-slider-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/04\/Solitair-ORAL-slider-copy.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":6432,"url":"https:\/\/allphasepharma.com\/dir\/2026\/02\/25\/6432\/the-new-default-1-one-single-pivotal-trial\/","url_meta":{"origin":1608,"position":5},"title":"The New Default: 1 (One) Single Pivotal Trial","author":"Harald","date":"February 25, 2026","format":false,"excerpt":"Statements that have the words \u2018FDA\u2019 and \u2018flexibility\u2019 in a single sentence need to be approached with some skepticism.\u00a0 Especially if made by the Agency. \u2018Flexibility\u2019 always sounds better than \u2018less rigidity\u2019. Regulators are tasked with providing a certain sense of consistency or stability in the drug development jungle where\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2026\/02\/slot-machines-winning-three-FDA-e1771883436805.jpg?resize=350%2C200&ssl=1","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2026\/02\/slot-machines-winning-three-FDA-e1771883436805.jpg?resize=350%2C200&ssl=1 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2026\/02\/slot-machines-winning-three-FDA-e1771883436805.jpg?resize=525%2C300&ssl=1 1.5x"},"classes":[]}],"jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/1608","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/comments?post=1608"}],"version-history":[{"count":15,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/1608\/revisions"}],"predecessor-version":[{"id":1740,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/1608\/revisions\/1740"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media\/1613"}],"wp:attachment":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media?parent=1608"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/categories?post=1608"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/tags?post=1608"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}