{"id":1937,"date":"2015-09-13T06:42:49","date_gmt":"2015-09-13T10:42:49","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1937"},"modified":"2018-10-31T13:41:02","modified_gmt":"2018-10-31T17:41:02","slug":"mme-erava-and-the-mysterious-case-of-auto-combustion","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/09\/13\/1937\/mme-erava-and-the-mysterious-case-of-auto-combustion\/","title":{"rendered":"Mme Erava and The Mysterious Case of Auto-Combustion"},"content":{"rendered":"

\"sherlock-holmes-slider\"<\/a><\/p>\n

SH:\u00a0<\/strong>My dear Watson, did you read the news of the astonishing debacle that befell Mme Erava and made the headlines, creating anxiety of hitherto unknown proportions in Tetraland?<\/p>\n

Dr.W.:<\/strong> A disaster of epic proportions, for sure, and a mystery, an explanation which will require some very expert investigation. There is talk of some supernatural reason for the calamity as all natural causes of failure have been eliminated, it seems.<\/p>\n

SH:<\/strong> Well, of course, that is the general view of the uneducated classes.\u00a0 But, as we have seen in just so many cases, efforts to avoid responsibility and exposure are reactions to be reckoned with. These are self-serving attempts to obfuscate and shift blame. One must not forget that most disasters can be traced to some faulty design, trivial at times. Just think of the booster rocket O-ring\u2026.<\/p>\n

Dr. W.:<\/strong> I am not sure I follow your reasoning as this IGNITE-2 problem has already stymied some of our best analytical minds. Certainly, the usual wise crackers and know-it-alls will now come forward with their pat answers, snickering and trying to look smart after the fact.\u00a0 Nobody can honestly claim to have foreseen that IGNITE-2 would auto-combust, wouldn\u2019t you agree?

It doesn’t matter how beautiful your theory is, it doesn’t matter how smart you are. If it doesn’t agree with experiment, it’s wrong.<\/span>
\nRichard Feynman<\/span><\/p>\n<\/div><\/p>\n

SH:<\/strong>\u00a0 Well, with the IGNITE studies we have not only fire and light but also a lot of smoke. When the cIAI data were published many weak points were glossed over.\u00a0 Watson, have you read Plato recently?<\/p>\n

Dr. W.<\/strong>: What makes you think we need to go back 2000 years to unravel a 21st<\/sup> century riddle?\u00a0 Have you become a sophist, a cynic, a dialectic follower of Socrates?\u00a0 Are you asking because you believe his methods would be used profitably in this case?<\/p>\n

SH:<\/strong> It has occurred to me that his way of challenging orthodoxy may be applicable to many of today\u2019s problems.\u00a0 Dear Watson, do you believe in the power of tetracyclines to destroy bacteria?<\/p>\n

Dr. W.:<\/strong> First, let me say that I intend to respond to any sophistic rhetoric with solid scientific arguments; I will also not stray away from the ethics laid down in the Hippocratic oath I swore.<\/p>\n

SH:<\/strong> You will then kindly tell me whether you believe in the \u2018ethical drug business\u2019?\u00a0 Or do you think it is just another euphemism?<\/p>\n

Dr. W.:<\/strong> There is a good deal of \u2018framing\u2019 going on in the drug business, no doubt.<\/p>\n

SH:<\/strong> Do you believe that the \u2018ethical business\u2019 approach demands thorough investigation\u00a0whether a drug works in a certain indication?<\/p>\n

Dr. W.:<\/strong> Certainly this is a reasonable expectation.<\/p>\n

SH:<\/strong> Would you be inclined to think that ethical drug development wants to clarify what dose is just barely adequate for efficacy, or do you believe they would rather test a dose which certainly works but may have toxicity?<\/p>\n

Dr. W.:<\/strong> Neither suggestion is correct \u2013 in anti-infectives the goal is to find the \u2018sweet spot\u2019 right from the get-go, without any testing of the efficacy or safety limits\u2026<\/p>\n

SH:<\/strong> What, then, is the \u2018sweet spot\u2019 and how do you find this most appropriate dose when you are dealing with a population never tested before, with a PO dose never tested before, a dose regimen derived indirectly from markers, and \u2026<\/p>\n

Dr. W.:<\/strong> You are most unkind, Sherlock. The good folks in Tetraland have modeled exposure and attainment, making allowances for numerous factors, indeed all variables that one can humanly think of. Then they fed it all into their most powerful Cray computers.<\/p>\n

SH:<\/strong> You argue convincingly that we should eliminate poor dose selection as a cause of clinical failure.\u00a0 Yet failure we saw. \u00a0I ask you again: Do you believe in the power of tetracyclines?<\/p>\n

Dr. W.:<\/strong>\u00a0 They are potent drugs, and we trust them for trivial and not-so trivial infections… of the respiratory kind, especially.<\/p>\n

SH:<\/strong> When did you last use a tetracycline for UTI?\u00a0 Have you seen articles on cUTI and the efficacy of doxycycline or tigecycline?<\/p>\n

Dr. W.:<\/strong> There are other drugs that have been used more often. Nonetheless, tetracyclines are still often tried for prostatitis which is a special case of UTI and a difficult one at that, wouldn\u2019t you agree?<\/p>\n

SH:<\/strong>\u00a0 You are making a good point, Watson, but we are not treating Chlamydia, or GC, or prostatitis here: I was strictly referring to\u00a0efficacy data in cUTI patients. \u00a0My\u00a0Baker Street Irregulars have been unable to find any well-done comparative trials against a beta-lactam or fluoroquinolone.\u00a0 When you look for anecdotal reports, you will not be disappointed.\u00a0 But that is just about all you\u2019ll find, and it is not much.<\/p>\n

So, it should make us wonder why there are no studies of tetracyclines in cUTI.\u00a0 Without such precedents and clinical validation points as\u00a0anchors, how do the PK modelers arrive at the \u2018right dose\u2019?<\/p>\n

Dr. W.:<\/strong> We should not be too narrow in our thinking.\u00a0 Modelling is a powerful tool, and inferences can be made based on urinary levels and MIC data; in addition, much can be deduced from other drugs studied in cUTI.<\/p>\n

SH:<\/strong>\u00a0 But of course! \u00a0How could I neglect all the good PK\/PD work done for fluoroquinolones\u00a0and beta-lactams? \u00a0In those cases, was a correlation with clinical outcomes available which validated the methodology?<\/p>\n

Dr. W.:<\/strong>\u00a0 Yes, of course. It was with these drug classes that the science was established.\u00a0 It is now mature enough to be expanded to other drugs with other MoA and PK profiles.<\/p>\n

SH:<\/strong> There is much truth in the concept you just expounded.\u00a0 Extrapolation to other antibiotic classes makes sense and is justified by logic.\u00a0 But where are the safeguards that the concept can be extended and applied to a new antibiotic class?<\/p>\n

When you lean over a ledge, it helps to know your body\u2019s point of gravity. Armed with such knowledge you might find it fun to explore the physics, but people have fallen from the balcony because the railing was not strong enough!<\/p>\n

Dr. W.:<\/strong> Sometimes, people lean over the ledge because they have no fears.\u00a0 Or they think they know the risks and choose to ignore them. And some are just lucky and walk right up to the ledge without a problem. But when Mme. Erava steps out, the railing collapses. Call it bad luck, blame the gods of statistics…<\/p>\n

SH:<\/strong>\u00a0 But it was not a railing that collapsed, my dear Watson, it was a case of auto-combustion\u2026not a minor slip!\u00a0\u00a0 We are dealing with a case of colossal structural failure: remember, that none of several carefully chosen efficacy endpoints were actually met.<\/p>\n

Dr. W.:<\/strong>\u00a0 Yes, yes, and I was also surprised by the fact of how clean the adverse event profile supposedly was. So many unusual findings, all in a very sizeable and credible study. Do you think we will ever learn why there were so many atypical and strange and unforeseen outcomes?<\/p>\n

SH:<\/strong>\u00a0 I think I just heard a knock at our front door.\u00a0 There is a gentleman pacing the sidewalk as you will have noticed, and he seems quite distraught.\u00a0 Please excuse me for a moment to check up on our new visitor. \u00a0No, it is not our friend Lestrade but someone with a cart-load of papers, all figures and tables it seems\u2026<\/p>\n

<The next issue of this serialized story will appear after ICAAC \u2013 The Editors.<\/em>><\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

SH:\u00a0My dear Watson, did you read the news of the astonishing debacle that befell Mme Erava and made the headlines, creating anxiety of hitherto unknown proportions in Tetraland? Dr.W.: A disaster of epic proportions, for sure, and a mystery, an explanation which will require some very expert investigation. There is Continue reading Mme Erava and The Mysterious Case of Auto-Combustion<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1938,"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":[19,3,18],"tags":[403,354,1372,59,355,1324,427,1329,425,384,1322,1321,1331,1325,39,1326,1371,1323,1328,263,1327,435,43,1330,426],"class_list":["post-1937","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-the_news","category-the_viewpoint","tag-antibiotic-blog","tag-ciai","tag-clinical-trial","tag-clinical-trial-results","tag-cuti","tag-dose-selection","tag-doxycycline","tag-dr-watson","tag-eravacycline","tag-failed-clinical-trials","tag-failed-trial","tag-ignite-studies","tag-ignite-2","tag-modeling-and-simulation","tag-pkpd","tag-prostatitis","tag-qidp","tag-reasons-for-failure","tag-sherlock-holmes","tag-tetracycline","tag-tetracyclines-for-uti","tag-tetraphase","tag-tigecycline","tag-tp-434","tag-tygacil"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/sherlock-holmes-slider.jpg?fit=1358%2C560&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-vf","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":1958,"url":"https:\/\/allphasepharma.com\/dir\/2015\/09\/24\/1958\/after-icaac-some-more-thoughts-on-eravacycline-in-cuti-and-ignite-2\/","url_meta":{"origin":1937,"position":0},"title":"After ICAAC: Some More Thoughts on Eravacycline in cUTI and IGNITE-2","author":"Harald","date":"September 24, 2015","format":false,"excerpt":"When a well-designed pivotal Phase 3 trial fails to show NI, it demands an explanation.\u00a0 While awaiting the company\u2019s analysis of the data, many possible explanations are bandied about.\u00a0 So it was not surprising that the eravacycline cUTI study (IGNITE-2) was mentioned quite often during ICAAC 2015, in sessions and\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"Erava2blog copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/Erava2blog-copy.jpg?resize=350%2C200 1x, 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analytical or strategic readjustment at\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/11\/Watertown-copy.jpg?fit=640%2C280&ssl=1&resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/11\/Watertown-copy.jpg?fit=640%2C280&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/11\/Watertown-copy.jpg?fit=640%2C280&ssl=1&resize=525%2C300 1.5x"},"classes":[]},{"id":1408,"url":"https:\/\/allphasepharma.com\/dir\/2015\/05\/07\/1408\/no-such-thing-as-a-free-ride\/","url_meta":{"origin":1937,"position":2},"title":"No Such Thing as a Free Ride\u2026","author":"Harald","date":"May 7, 2015","format":false,"excerpt":"..when it comes to FDA review of antibiotic NDAs.\u00a0 Some seem to have forgotten the dismal record of antibiotic approvals in the last 15 years, and the long list of failed submissions.\u00a0 Many failed not because of lack of efficacy or a bad safety profile but because of changes in\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"theBMJ","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/05\/theBMJ.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":1693,"url":"https:\/\/allphasepharma.com\/dir\/2015\/07\/10\/1693\/brilacidin-qidp-drug-at-a-critical-juncture\/","url_meta":{"origin":1937,"position":3},"title":"Brilacidin – QIDP Drug At a Critical Juncture","author":"Harald","date":"July 10, 2015","format":false,"excerpt":"At around this time (July 2015), Cellceutix is\u00a0expected to hammer out a Phase 3 program for brilacidin, its defensin-mimetic and host-defense protein (HDP) mimic structurally similar to magainin, with FDA. Brilacidin is certainly an interesting novel compound, coming from a new class, with a unique mode of action.\u00a0 It has\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"brilacidin - slider2 copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/brilacidin-slider2-copy1.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/brilacidin-slider2-copy1.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/brilacidin-slider2-copy1.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":2911,"url":"https:\/\/allphasepharma.com\/dir\/2016\/11\/25\/2911\/prospecting-antibiotics\/","url_meta":{"origin":1937,"position":4},"title":"Prospecting for New Antibiotics","author":"Harald","date":"November 25, 2016","format":false,"excerpt":"The QIDP designation was introduced in 2012 to incentivize drug development in antiinfectives. QIDP came with several attractive features, such as prolongation of patent life, FDA\u00a0expedited review and more.\u00a0 In addition, FDA made it quite easy to garner the label.\u00a0 As you can see, there is really no downside to\u2026","rel":"","context":"In "Did you know...?"","block_context":{"text":"Did you know...?","link":"https:\/\/allphasepharma.com\/dir\/category\/interesting_facts\/"},"img":{"alt_text":"engine-qidp-blog","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/11\/Engine-QIDP-blog.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/11\/Engine-QIDP-blog.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/11\/Engine-QIDP-blog.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":2205,"url":"https:\/\/allphasepharma.com\/dir\/2015\/12\/23\/2205\/qidp-antibiotics-2015-year-end-update\/","url_meta":{"origin":1937,"position":5},"title":"QIDP Antibiotics – 2015 Year-End Update","author":"Harald","date":"December 23, 2015","format":false,"excerpt":"Here an updated listing of all QIDP drugs we are aware of as of 12\/24\/2015. 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