{"id":202,"date":"2014-05-27T10:47:19","date_gmt":"2014-05-27T10:47:19","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=202"},"modified":"2014-10-08T19:14:25","modified_gmt":"2014-10-08T23:14:25","slug":"the-breakpoint-dilemma","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2014\/05\/27\/202\/the-breakpoint-dilemma\/","title":{"rendered":"The Breakpoint Dilemma"},"content":{"rendered":"

As antibiotic resistance increases over the years, originally established susceptibility breakpoints (S-I-R) are becoming less relevant. \u00a0 This ‘creep’ towards higher MICs over time is a unique but well-known feature of antimicrobials ultimately making these drugs obsolete.<\/p>\n

In the past, FDA and CLSI did not bother to update breakpoints in a consistent fashion.\u00a0 Physicians just dealt with this situation by reviewing resistance trends from\u00a0antibiogram data\u00a0as compiled by their local microbiology labs on a yearly basis.<\/p>\n

Ever since FDA was given the mandate to update breakpoints for antibiotics, a massive and by definition a never-ending effort, we began to appreciate just how difficult this assignment was.<\/p>\n

Unfortunately, critical pieces in this data update puzzle only became available with significant lag time.\u00a0 It took years to down-adjust the vancomycin breakpoints. \u00a0How about other drug classes? \u00a0There are new breakpoints for carbapenems and cephalosporins.<\/p>\n

Carbapenem Revised Breakpoints\"Carbapenem<\/a><\/strong><\/p>\n

Cephalosporin Revised Breakpoints – Enterobacteriaceae\"Cephalosporin<\/a><\/strong><\/p>\n

Modified from J Hindler http:\/\/www.swacm.org\/annualmeeting\/2010\/Antimicrobial_Susceptibility.pdf<\/a><\/span><\/p>\n

Despite such fairly recent changes, PK\/PD experts tell us that the tigecycline breakpoints were too high all along, and cefepime breakpoints have come under renewed discussion.<\/span><\/p>\n

The transcript of the recent FDA Ad Board (Oct 17, 2013) on this topic makes for interesting reading. \u00a0It is clearly important to select breakpoints based on PK\/PD considerations (animal and clinical data, Monte Carlo simulation, protein binding, infection site, disease severity), and consider ADME and safety \/ tolerability issues.<\/p>\n

All this makes good sense and helps select an ‘appropriate’ dose, but can we actually increase drug doses as would be required by PK\/PD calculations and MICs which can vary by a factor of > 100 between the many susceptible and the few resistant?<\/p>\n

The proposal to push the antibiotic dose to the highest levels for which an antibiotic has been tested makes good sense but only allows for modest increases by a factor of 2-4 in the best of cases.\u00a0 Ciprofloxacin IV underwent a steady dose escalation in its history, starting with 200 mg BID which was eventually ramped up to 400 mg q8h, a 3x higher daily drug exposure.\u00a0 Even chromosomally mediated resistance can easily overcome such relatively small dose escalation.<\/p>\n

Obviously, there are major safety concerns when pushing up to higher doses.\u00a0 With around 30% of patients experiencing GI problems with standard doses of tigecycline, doses higher than 50 mg q12h seem problematic.\u00a0 Studies have shown dose-related QT prolongation with quinolones, like moxifloxacin, hence further dose increases are a non-starter.<\/p>\n

In the end, we will have much new regulatory action on breakpoints all of which will undoubtedly be set much lower than currently posted in the package inserts.<\/p>\n

This effort will predictably increase the awareness that we have few drugs for problem organisms, which is a good thing.<\/p>\n

It will also drive overuse of those fewer antibiotics on the \u201cS\u201d list and drive these towards earlier obsolescence.\u00a0 This cannot be a good thing.<\/p>\n","protected":false},"excerpt":{"rendered":"

As antibiotic resistance increases over the years, originally established susceptibility breakpoints (S-I-R) are becoming less relevant. \u00a0 This ‘creep’ towards higher MICs over time is a unique but well-known feature of antimicrobials ultimately making these drugs obsolete. In the past, FDA and CLSI did not bother to update breakpoints in Continue reading The Breakpoint Dilemma<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1055,"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":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[18],"tags":[6,40,44,42,41,5,45,47,39,46,43,48],"class_list":["post-202","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-the_viewpoint","tag-advisory-board","tag-breakpoint","tag-carbapenem","tag-ciprofloxacin","tag-clsi","tag-fda","tag-mic","tag-moxifloxacin","tag-pkpd","tag-susceptibility","tag-tigecycline","tag-vancomycin"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/05\/Breakpoint-slider-copy.jpg?fit=640%2C200&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-3g","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":1043,"url":"https:\/\/allphasepharma.com\/dir\/2014\/10\/08\/1043\/cre-surveillance-data-from-france\/","url_meta":{"origin":202,"position":0},"title":"CRE Surveillance Data from France","author":"Harald","date":"October 8, 2014","format":false,"excerpt":"Despite all the\u00a0concern about the emergence of CRE pathogens worldwide, it is quite difficult to obtain hard quantitative, prospectively collected incidence figures. A recent article by Robert\u00a0[1] and colleagues provides useful data from France.\u00a0 Using a practical definition of carbapenem-non-susceptibility (ertapenem > 0.5, imipenem, meropenem > 2, doripenem > 1),\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\/2014\/10\/CLSI-EUCAST-slider-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/10\/CLSI-EUCAST-slider-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/10\/CLSI-EUCAST-slider-copy.jpg?fit=640%2C200&ssl=1&resize=525%2C300 1.5x"},"classes":[]},{"id":1385,"url":"https:\/\/allphasepharma.com\/dir\/2015\/04\/21\/1385\/an-inconvenient-truth-ciprofloxacin-resistant-campylobacter\/","url_meta":{"origin":202,"position":1},"title":"An Inconvenient Truth: Ciprofloxacin-Resistant Campylobacter","author":"Harald","date":"April 21, 2015","format":false,"excerpt":"When Al Gore became a best-selling author with \u201cAn Inconvenient Truth\u201d he warned about climate change.\u00a0 When it comes to antibiotic resistance and the current situation of \u201cBad Bugs, No Drugs\u201d, there are many voices warning us about a return to the pre-antibiotic era. 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