{"id":378,"date":"2014-06-23T00:50:47","date_gmt":"2014-06-23T00:50:47","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=378"},"modified":"2014-09-10T16:10:34","modified_gmt":"2014-09-10T20:10:34","slug":"fighting-p-aeruginosa-part-i","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2014\/06\/23\/378\/fighting-p-aeruginosa-part-i\/","title":{"rendered":"Fighting P. aeruginosa (Part I)"},"content":{"rendered":"<p><a href=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PA-01-on-Agar.jpg?ssl=1\"><img data-recalc-dims=\"1\" loading=\"lazy\" decoding=\"async\" class=\"alignright  wp-image-395\" src=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PA-01-on-Agar.jpg?resize=206%2C189&#038;ssl=1\" alt=\"PA-01 on Agar\" width=\"206\" height=\"189\" srcset=\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PA-01-on-Agar.jpg?resize=300%2C274&amp;ssl=1 300w, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PA-01-on-Agar.jpg?w=451&amp;ssl=1 451w\" sizes=\"auto, (max-width: 206px) 100vw, 206px\" \/><\/a>It has never been easy to cure Pseudomonas aeruginosa infections.\u00a0 Few antibiotics nowadays have reliable activity against this problem pathogen that seems to have more built-in resistance features than most other Gram-negatives.\u00a0 In the past, cephalosporins, aztreonam, penems, ciprofloxacin, and aminoglycosides were useful drugs with reliably cidal activity, especially when given in combination.\u00a0 However, this hardy organism has become less susceptible over time, with efflux systems and OMP changes being major defenses.[i]\u00a0 Despite toxicity concerns, colistin is being used more of late given the lack of better alternatives.\u00a0<!--more--><\/p>\n<p>Fortunately, there are a few antipseudomonal agents in the development pipeline:<\/p>\n<ul>\n<li>Ceftolozane (CXA-201), an\u00a0antipseudomonal\u00a0cephalosporin, has been developed by Cubist in combination with tazobactam.\u00a0 \u00a0Ceftolozane is a potent antipseudomonal agent in its own right and the combination covers some MDR \u00a0P. aeruginosa and strains resistant to carbapenems or piperacillin\/tazobactam as well \u00a0[ii],[iii].\u00a0 The NDA was submitted in April 2014.<\/li>\n<li>Plazomicin (ACH-490) \u00a0is a newer aminoglycoside in Phase 3 development at Achaogen with superior activity against many MDR K. pneumoniae and other CRE and ESBL producers. \u00a0It is less susceptible to aminoglycoside-modifying enzymes (AME) and may provide coverage where other aminoglycosides would fail.\u00a0 However, anti-pseudomonal activity seems to be only en par with amikacin [iv]. \u00a0 In a large study of recent clinical isolates, the MIC90 was 32 \u03bcg\/ml against for MDR \u00a0P. aeruginosa isolates [v].\u00a0 It is an IV drug and comes with the usual toxicity profile of the class.<\/li>\n<li>Polyphor\u2019s novel pseudomonas-specific drug, POL-7080 will be co-developed with Roche.\u00a0 It acts on a novel outer membrane target called LptD \/ OstA.\u00a0 It is a peptidomimetic for IV administration.\u00a0 Early clinical tests showed an acceptable safety profile and a Phase 2a PK study was recently started in Europe.\u00a0\u00a0 A unique feature is narrow Pseudomonas-specific activity: it has no activity against other Gram-negatives.\u00a0 This is a drug for which a companion diagnostic would seem very useful, both for the Phase 2\/3 studies as well as later in the clinic.<\/li>\n<li>LpxC inhibitors block the production of endotoxin (lipid A), a major virulence factor of Gram-negatives without killing the bacteria.\u00a0 This MoA is unique and drug activity cannot always be assessed by the traditional MIC or MBC tests.\u00a0 Several companies (Chiron \/ Novartis and Achaogen) are testing compounds with rather narrow-spectrum activity for P. aeruginosa and E. coli.\u00a0 There have been reports of cardiac toxicity in animals but the clinical significance of these effects are unclear [vi].\u00a0 ACHN-975 is in Phase 1 testing which should address this open issue.<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<hr \/>\n<p>References:<\/p>\n<address><span style=\"font-size: 8pt;\">[i] For a review of resistance trends:\u00a0\u00a0 http:\/\/www.medscape.com\/viewarticle\/515330<\/span><br \/>\n<span style=\"font-size: 8pt;\"> [ii] Zhanel.\u00a0 http:\/\/link.springer.com\/article\/10.1007%2Fs40265-013-0168-2<\/span><br \/>\n<span style=\"font-size: 8pt;\"> [iii] Craig. Antimicrob. Agents Chemother.April 2013\u00a0vol. 57\u00a0no. 4\u00a01577-1582<\/span><br \/>\n<span style=\"font-size: 8pt;\"> [iv] http:\/\/www.can-r.com\/posters\/ICAAC2012\/GGZ.%20Plazomicin.CANWARD%20ICAAC2012.pdf<\/span><br \/>\n<span style=\"font-size: 8pt;\"> [v] Walkty. \u00a0Antimicrob Agents Chemother<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24550325\">.<\/a>\u00a05:2554, 2014<\/span><br \/>\n<span style=\"font-size: 8pt;\"> [vi] Bornheim. \u00a0http:\/\/www.icaaconline.com\/php\/icaac2013abstracts\/data\/papers\/2013\/F\/2013_F-1231.htm<\/span><\/address>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>It has never been easy to cure Pseudomonas aeruginosa infections.\u00a0 Few antibiotics nowadays have reliable activity against this problem pathogen that seems to have more built-in resistance features than most other Gram-negatives.\u00a0 In the past, cephalosporins, aztreonam, penems, ciprofloxacin, and aminoglycosides were useful drugs with reliably cidal activity, especially when <a class=\"more-link\" href=\"https:\/\/allphasepharma.com\/dir\/2014\/06\/23\/378\/fighting-p-aeruginosa-part-i\/\">Continue reading <span class=\"screen-reader-text\">  Fighting P. aeruginosa (Part I)<\/span><span class=\"meta-nav\">&rarr;<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":868,"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":[3],"tags":[172,176,403,169,178,175,177,92,179,183,181,174,415,416,170,171,173,182,184,180],"class_list":["post-378","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-the_news","tag-achaogen","tag-aminoglycoside","tag-antibiotic-blog","tag-antipseudomonal-drugs-pipeline","tag-ceftolazone","tag-chiron","tag-colistin","tag-cubist","tag-cxa-201","tag-lpxc-inhibitor","tag-mdr","tag-novartis","tag-omp","tag-outer-membrane-protein","tag-plazomicin","tag-pol-7080","tag-polyphor","tag-resistance","tag-roche","tag-tazobactam"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PA123-e1410379729275.jpg?fit=260%2C73&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-66","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":1401,"url":"https:\/\/allphasepharma.com\/dir\/2015\/04\/30\/1401\/a-renaissance-for-old-drugs-fosfomycin-and-colistin\/","url_meta":{"origin":378,"position":0},"title":"A Renaissance for Old Drugs: Fosfomycin and Colistin","author":"Harald","date":"April 30, 2015","format":false,"excerpt":"Fosfomycin Who would have thought that a drug that has been around since 1969 [2] could become eligible for QIDP status in 2015? Well, Zavante Therapeutics recently garnered the coveted QIDP designation for fosfomycin IV. This formulation has been available in Europe for a quite some\u00a0time but not in the\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":"","width":0,"height":0},"classes":[]},{"id":653,"url":"https:\/\/allphasepharma.com\/dir\/2014\/07\/21\/653\/what-is-the-niche-for-ceftolozane-tazobactam\/","url_meta":{"origin":378,"position":1},"title":"What is the \u201cNiche\u201d for Ceftolozane \/ Tazobactam?","author":"Harald","date":"July 21, 2014","format":false,"excerpt":"There are currently a total of 6 beta-lactam + beta-lactamase inhibitor combinations in clinical trials. It will be a steep learning curve for the pharma reps (and physicians) to understand the resistance classifications, the confusing ESBL definitions, the CRE nomenclature, and how this all matters in clinical practice, on the\u2026","rel":"","context":"In &quot;QIDP Antibiotics&quot;","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"Tazobactam","src":"http:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/8\/84\/Tazobactam.svg\/220px-Tazobactam.svg.png","width":350,"height":200},"classes":[]},{"id":1362,"url":"https:\/\/allphasepharma.com\/dir\/2015\/04\/08\/1362\/arties-law-avoid-bad-advice-and-dont-follow-mission-impossible-advice\/","url_meta":{"origin":378,"position":2},"title":"Artie\u2019s Law: Avoid Bad Advice and Don\u2019t Follow \u2018Mission Impossible\u2019 Advice","author":"Harald","date":"April 8, 2015","format":false,"excerpt":"In this day and age, few truly broad spectrum antibiotics are in development, although this does not hold true for narrow-spectrums.\u00a0 Just think of all the MRSA drugs (quinolones, FabI inhibitors), the pseudomonas drugs (NCEs and monoclonals) or some narrow spectrum drugs that will need to be tested in MDR\u2026","rel":"","context":"In &quot;The Viewpoint&quot;","block_context":{"text":"The Viewpoint","link":"https:\/\/allphasepharma.com\/dir\/category\/the_viewpoint\/"},"img":{"alt_text":"","src":"","width":0,"height":0},"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":378,"position":3},"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":2186,"url":"https:\/\/allphasepharma.com\/dir\/2015\/12\/19\/2186\/aztreonam-plus-avibactam-a-new-bright-star-in-the-night-sky\/","url_meta":{"origin":378,"position":4},"title":"Aztreonam PLUS Avibactam \u2013 A New Bright Star in the Night Sky","author":"Harald","date":"December 19, 2015","format":false,"excerpt":"Looking at the molecular structure of ceftazidime (CTAZ) and aztreonam (ATM), the differences are clear, and so are the similarities: ATM does not have the cephem ring structure of CTAZ, only the 4-member beta-lactam ring.\u00a0 However, the side chains are identical in both CTAZ and ATM which explains the overlapping\u2026","rel":"","context":"In &quot;Recent Literature&quot;","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"Avibactam - slider","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/12\/Avibactam-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/12\/Avibactam-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/12\/Avibactam-slider.jpg?resize=525%2C300 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/12\/Avibactam-slider.jpg?resize=700%2C400 2x"},"classes":[]},{"id":2435,"url":"https:\/\/allphasepharma.com\/dir\/2016\/04\/17\/2435\/the-brave-new-world-of-infectious-diseases\/","url_meta":{"origin":378,"position":5},"title":"The Brave New World of Infectious Diseases","author":"Harald","date":"April 17, 2016","format":false,"excerpt":"Coming back from ECCMID, one\u00a0gets the impression that we are moving towards an era in which\u00a0we can diagnose everything but treat nothing. A late breaker session on colistin resistance provided much detail data on the situation in the EU. As we know, colistin resistance conferred by the mcr-1 gene has\u2026","rel":"","context":"In &quot;The News&quot;","block_context":{"text":"The News","link":"https:\/\/allphasepharma.com\/dir\/category\/the_news\/"},"img":{"alt_text":"ECCMID slider","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/04\/ECCMID-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/04\/ECCMID-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/04\/ECCMID-slider.jpg?resize=525%2C300 1.5x"},"classes":[]}],"jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/378","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=378"}],"version-history":[{"count":12,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/378\/revisions"}],"predecessor-version":[{"id":819,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/378\/revisions\/819"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media\/868"}],"wp:attachment":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media?parent=378"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/categories?post=378"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/tags?post=378"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}