{"id":1216,"date":"2015-01-06T03:05:40","date_gmt":"2015-01-06T08:05:40","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1216"},"modified":"2015-01-06T03:05:40","modified_gmt":"2015-01-06T08:05:40","slug":"meropenem-dosing-for-vap-high-prolonged-beats-conventional-dosing","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/01\/06\/1216\/meropenem-dosing-for-vap-high-prolonged-beats-conventional-dosing\/","title":{"rendered":"Meropenem Dosing for VAP: High + Prolonged Beats Conventional Dosing"},"content":{"rendered":"<p>Sometimes an article pops up addressing a question we have been mulling over for quite some time.\u00a0 It so happened with a recent publication which shed new light on penem dosing for ICU patients<a href=\"#_ftn1\" name=\"_ftnref1\">[1]<\/a>.<\/p>\n<p>Conducted at a single Belgian centre (sic!), a standard dose of meropenem (1 g IV q8h infused over 30 min) was compared to prolonged 3 h administration of 1 and 2 g q8h, measuring not only plasma exposure but also ELF levels by micro-BAL.\u00a0 PK\/PD analyses in this fairly large study of 25 and 30 patients per cohort suggested that we may be underdosing the drug for pneumonia patients.\u00a0 Here the main findings:<\/p>\n<ul>\n<li>Standard 1 g qh8 dosing achieves adequate attainment rates in plasma but not in ELF<\/li>\n<li>Not even 2 g IV q8h day infused over 3 hours achieved ELF levels sufficiently high to attain 40% T&gt;MIC profile for pathogens with MIC of 2 mg\/L.<\/li>\n<\/ul>\n<p>In all scenarios, continuous infusion was superior to intermittent standard dosing, not a surprise given earlier work by Nicolau suggesting the same benefit <a href=\"#_ftn2\" name=\"_ftnref2\">[2]<\/a>.\u00a0 Again it was noticed that many ICU patients (approx. 30%) had hypernormal Clcr rates of &gt; 120 mL\/kg x min; obviously, this subpopulation would really stand to benefit from higher dosing regimens, not just when P.aeruginosa is involved.<a href=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/01\/3-arrows-slider.jpg?ssl=1\"><img data-recalc-dims=\"1\" loading=\"lazy\" decoding=\"async\" class=\"alignright size-full wp-image-1218\" src=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/01\/3-arrows-slider.jpg?resize=530%2C149&#038;ssl=1\" alt=\"3 arrows - slider\" width=\"530\" height=\"149\" srcset=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/01\/3-arrows-slider.jpg?w=640&amp;ssl=1 640w, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/01\/3-arrows-slider.jpg?resize=300%2C84&amp;ssl=1 300w\" sizes=\"auto, (max-width: 530px) 100vw, 530px\" \/><\/a><\/p>\n<p>Meropenem is approved in Europe for pneumonia (community-acquired and nosocomial) <a href=\"#_ftn3\" name=\"_ftnref3\">[3]<\/a>.\u00a0 Dosing recommendations specifically mention that for severely ill patients or infections with borderline susceptible pathogens a dose of 2g q8h should be considered.\u00a0 This is good advice and sound judgement now confirmed by the Frippiat trial.\u00a0 Meropenem is also approved for bacterial meningitis, cUTI, peri-partum infections and for cystic fibrosis patients because these infections are often caused by the same bacteria.\u00a0 In other words: EMA approval was not just indication-driven, but appropriately considered the overlapping pathogen spectrum seen with these infections.<\/p>\n<p>Not so in the US where the indication list is very short:\u00a0 meropenem is only approved for cIAI (1 g q8h) and cSSSI (500 mg q8h or 1 g q8h for P. aeruginosa).\u00a0 Why this difference in labeling when both regulatory authorities certainly had access to the same data?\u00a0 This obvious lack of harmonization is the product of different regulatory philosophies; in contrast, bacteria have no problem achieving global MIC collaboration.<\/p>\n<p>Given FDA\u2019s tough new VAP\/HAP standards<a href=\"#_ftn4\" name=\"_ftnref4\">[4]<\/a> few companies will attempt to go after this indication.\u00a0\u00a0 Tigecycline<a href=\"#_ftn5\" name=\"_ftnref5\">[5]<\/a> tried and failed, and so did doripenem<a href=\"#_ftn6\" name=\"_ftnref6\">[6]<\/a>.\u00a0 Ceftobiprole is in need of funding to run another pneumonia program<a href=\"#_ftn7\" name=\"_ftnref7\">[7]<\/a>.\u00a0 HAP\/VAP registration trials have become very expensive and no company will make this commitment lightly.\u00a0 But that\u2019s not a concern for regulators.<\/p>\n<p>Is imipenem at 1 g q8h still an acceptable comparator drug for a NI study?\u00a0 I am not sure but as the only penem with a \u201clower respiratory tract infection\u201d label <a href=\"#_ftn8\" name=\"_ftnref8\">[8]<\/a>, it should be an acceptable comparator for registration studies although the approved dose seems very suboptimal.<\/p>\n<p>From all we now know about the penems, meropenem at 2 g q8h infused over 3-4 hours could upstage imipenem and become the premier penem for this indication.\u00a0 There may be some concern that such a high-dose regimen may result in higher seizure rates.\u00a0 However, with prolonged dosing, high peak levels are avoided making previous safety concerns less relevant.\u00a0 Any bets?<\/p>\n<p><strong>References:<\/strong><\/p>\n<p><a href=\"#_ftnref1\" name=\"_ftn1\">[1]<\/a> F Frippiat.\u00a0 JAC 2015; 70:207<br \/>\n<a href=\"#_ftnref2\" name=\"_ftn2\">[2]<\/a> Nicolau.\u00a0 CID 2008; 47: S32<br \/>\n<a href=\"#_ftnref3\" name=\"_ftn3\">[3]<\/a> http:\/\/mri.medagencies.org\/download\/NL_H_1727_001_PAR.pdf<br \/>\n<a href=\"#_ftnref4\" name=\"_ftn4\">[4]<\/a> Draft Guidances from 2010 and most recently 2014 &#8211; http:\/\/www.fda.gov\/downloads\/Drugs\/GuidanceComplianceRegulatoryInformation\/Guidances\/UCM234907.pdf<br \/>\n<a href=\"#_ftnref5\" name=\"_ftn5\">[5]<\/a> http:\/\/www.medscape.org\/viewarticle\/812167<br \/>\n<a href=\"#_ftnref6\" name=\"_ftn6\">[6]<\/a> http:\/\/www.fda.gov\/Drugs\/DrugSafety\/ucm285883.htm<br \/>\n<a href=\"#_ftnref7\" name=\"_ftn7\">[7]<\/a> http:\/\/www.basilea.com\/chameleon\/public\/de7cde4b-8150-0816-4ebb-77bfe8cb1ef5\/620981.pdfline<br \/>\n<a href=\"#_ftnref8\" name=\"_ftn8\">[8]<\/a> http:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2014\/050587s076lbl.pdf<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Sometimes an article pops up addressing a question we have been mulling over for quite some time.\u00a0 It so happened with a recent publication which shed new light on penem dosing for ICU patients[1]. Conducted at a single Belgian centre (sic!), a standard dose of meropenem (1 g IV q8h <a class=\"more-link\" href=\"https:\/\/allphasepharma.com\/dir\/2015\/01\/06\/1216\/meropenem-dosing-for-vap-high-prolonged-beats-conventional-dosing\/\">Continue reading <span class=\"screen-reader-text\">  Meropenem Dosing for VAP: High + Prolonged Beats Conventional Dosing<\/span><span class=\"meta-nav\">&rarr;<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1218,"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":[227,18],"tags":[403,749,753,756,442,114,354,82,741,432,752,625,5,99,78,439,443,627,750,346,747,751,754,39,742,748,731,755,43],"class_list":["post-1216","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-recent_literature","category-the_viewpoint","tag-antibiotic-blog","tag-antibiotic-dosing","tag-attainment-rate","tag-bal","tag-cap","tag-ceftobiprole","tag-ciai","tag-csssi","tag-doribax","tag-doripenem","tag-elf-levels","tag-ema","tag-fda","tag-fda-guidance","tag-hap","tag-hapvap","tag-icu","tag-imipenem","tag-labeling","tag-meropenem","tag-merrem","tag-nosocomial-pneumonia","tag-penem","tag-pkpd","tag-primaxin","tag-seizure","tag-tmic","tag-tigecyc","tag-tigecycline"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/01\/3-arrows-slider.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-jC","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":1201,"url":"https:\/\/allphasepharma.com\/dir\/2014\/12\/24\/1201\/why-did-pkpd-modeling-fail-doripenem-in-vap\/","url_meta":{"origin":1216,"position":0},"title":"Why Did PK\/PD Modeling Fail Doripenem in VAP?","author":"Harald","date":"December 24, 2014","format":false,"excerpt":"When imipenem is dosed at 1 g q8h for serious infections, it is infused over 40-60 min. Its label states that it is indicated for \u201clower RTI\u201d, an old-fashioned term from the days when bronchitis and pneumonias were still lumped together, CAP was not differentiated from HAP, and HAP and\u2026","rel":"","context":"In &quot;The Viewpoint&quot;","block_context":{"text":"The Viewpoint","link":"https:\/\/allphasepharma.com\/dir\/category\/the_viewpoint\/"},"img":{"alt_text":"see reference Von Wart et al.","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/12\/PKPD-1-copy.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":972,"url":"https:\/\/allphasepharma.com\/dir\/2014\/09\/29\/972\/perusing-the-literature\/","url_meta":{"origin":1216,"position":1},"title":"Perusing the Literature","author":"Harald","date":"September 29, 2014","format":false,"excerpt":"Inhibitor\u00a0of the\u00a0NDM\u00a0Enzyme Aspergillomarasmine (AMA) was identified as an inhibitor of the New Delhi metallo-betalactamase (NDM) enzyme. This substance, when combined with meropenem, restored antibiotic activity against an NDM lab strain.\u00a0 \u00a0AMA is a substance which was already tested in the past in humans.\u00a0 Concerns about interference with human metalloenzymes proved\u2026","rel":"","context":"In &quot;Recent Literature&quot;","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\/09\/NewLit-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\/09\/NewLit-slider-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/09\/NewLit-slider-copy.jpg?fit=640%2C200&ssl=1&resize=525%2C300 1.5x"},"classes":[]},{"id":3100,"url":"https:\/\/allphasepharma.com\/dir\/2017\/01\/24\/3100\/kill-mocking-bug-cre-crab-variety\/","url_meta":{"origin":1216,"position":2},"title":"To Kill A Mocking Bug &#8211; of the CRKP or CRAB Variety","author":"Harald","date":"January 24, 2017","format":false,"excerpt":"Meropenem stands out as an antibiotic to be used first in ESBL and MDR infections, given its efficacy profile and safety record (see earlier blog). It also would seem to be appropriate to use relatively high doses or prolonged infusion times \u2013 or both - to improve T>MIC for the\u2026","rel":"","context":"In &quot;Recent Literature&quot;","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\/2017\/01\/Mero-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/01\/Mero-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/01\/Mero-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":689,"url":"https:\/\/allphasepharma.com\/dir\/2014\/08\/04\/689\/some-thoughts-about-eravacycline-based-on-the-phase-2-ciai-study\/","url_meta":{"origin":1216,"position":3},"title":"Some Thoughts about Eravacycline Based on the Phase 2 cIAI Study","author":"Harald","date":"August 4, 2014","format":false,"excerpt":"Solomkin et al. conclude that the efficacy and safety of eravacycline compares favorably to the control drug, ertapenem.[1]\u00a0 This top-level assessment is made with the usual caveats (insufficient statistical power, small sample size), but a few points deserve comment. Eravacycline is a fluorocycline; as a tetracycline derivative it follows into\u2026","rel":"","context":"In &quot;QIDP Antibiotics&quot;","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\/2014\/08\/eravacycline-copy.jpg?fit=481%2C212&ssl=1&resize=350%2C200","width":350,"height":200},"classes":[]},{"id":1981,"url":"https:\/\/allphasepharma.com\/dir\/2015\/10\/05\/1981\/polyphor-pol-7080-and-the-journey-to-the-land-of-pyocyanea-part-1\/","url_meta":{"origin":1216,"position":4},"title":"Polyphor POL7080 And The Journey to The Land of Pyocyanea\u00a0 (Part 1)","author":"Harald","date":"October 5, 2015","format":false,"excerpt":"When Roche inlicensed Polyphor\u2019s anti-pseudomonas drug POL7080 in November 2013, it marked a turning point. It seemed that Big Pharma that had all but abandoned the field in the last decade and was getting engaged in anti-infectives again. When a company with as\u00a0much experience in antibiotic drug development as Roche\u2026","rel":"","context":"In &quot;QIDP Antibiotics&quot;","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"bridge Pyocyanea copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/10\/bridge-Pyocyanea-copy.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1451,"url":"https:\/\/allphasepharma.com\/dir\/2015\/05\/14\/1451\/no-easy-day-dose-calculations-for-aminoglycosides-and-vancomycin\/","url_meta":{"origin":1216,"position":5},"title":"No Easy Day: Dose Calculations for Aminoglycosides and Vancomycin","author":"Harald","date":"May 14, 2015","format":false,"excerpt":"Searching data on antibiotic use in surgery prophylaxis, I came across an article from the Mayo Clinic\u00a0[1].\u00a0 The authors mention that approx. 75% of patients that developed surgical site\u00a0infections did not get proper antibiotic prophylaxis.\u00a0 Errors were made in (1) selection of the antibiotic, (2) timing of administration, (3) antibiotic\u2026","rel":"","context":"In &quot;Did you know...?&quot;","block_context":{"text":"Did you know...?","link":"https:\/\/allphasepharma.com\/dir\/category\/interesting_facts\/"},"img":{"alt_text":"Dosing Nomogram","src":"http:\/\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/05\/Dosing-Nomogram.jpe","width":350,"height":200},"classes":[]}],"jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/1216","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=1216"}],"version-history":[{"count":2,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/1216\/revisions"}],"predecessor-version":[{"id":1219,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/1216\/revisions\/1219"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media\/1218"}],"wp:attachment":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media?parent=1216"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/categories?post=1216"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/tags?post=1216"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}