{"id":653,"date":"2014-07-21T18:39:24","date_gmt":"2014-07-21T22:39:24","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=653"},"modified":"2015-10-07T03:41:49","modified_gmt":"2015-10-07T07:41:49","slug":"what-is-the-niche-for-ceftolozane-tazobactam","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2014\/07\/21\/653\/what-is-the-niche-for-ceftolozane-tazobactam\/","title":{"rendered":"What is the \u201cNiche\u201d for Ceftolozane \/ Tazobactam?"},"content":{"rendered":"
\"Tazobactam\"
Tazobactam<\/figcaption><\/figure>\n

There are currently a total of 6 beta-lactam + beta-lactamase inhibitor combinations in clinical trials.<\/p>\n

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 backdrop of the local hospital resistance situation. There will be a lot of misunderstandings and misrepresentations because we have not done a good job preparing ourselves for the claims and counter-claims that will certainly come once the competition heats up.<\/p>\n

Let\u2019s look at the most advanced project, Ceftolozane \/ Tazobactam, and review first what each component has to offer before putting the 2 ingredients back into the bottle together again, so to speak.<\/p>\n

\"Ceftolozane\"<\/a>
Ceftolozane<\/figcaption><\/figure>\n

Ceftolozane, aka CXA-101, is a cephalosporin with excellent P. aeruginosa (PA) coverage.\u00a0 It is more powerful than ceftazidime, cefepime, meropenem, ciprofloxacin, and as potent as amikacin or colistin by virtue of a set of unique features:\u00a0 it is not a substrate of several PA efflux systems and its uptake is independent of the OmpD porin channel.\u00a0 In addition, it has a low affinity for the AmpC B-lactamase.[1]<\/p>\n

Like other 3rd<\/sup> generation cephalosporins, it covers many other gram-negative rods but without any stand-out features that make it so compelling for PA.\u00a0 Activity against B. fragilis is not reliable enough to forgo metronidazole in cIAI.<\/p>\n

With this set of features alone, we would certainly want ceftolozane in our antibiotic quaver.<\/p>\n

Tazobactam is a good old friend, in use for some 20+ years by now, in combination with piperacillin.\u00a0 It is a B-lactamase inhibitor (BLI) inhibiting Ambler Class A BLs, which have been around since the 90ies, but it is not as potent an inhibitor for AmpC BL and other ESBLs which have been driving up carbapenem use lately.<\/p>\n

In summary, ceftolozane\/tazobactam looks like a great pseudomonas drug.\u00a0 It is also a cephalosporin with nice 3rd<\/sup> generation gram-negative activity.\u00a0 The addition of tazobactam has the benefit of widening the spectrum to include some but not all ESBL producers[2].\u00a0 Maybe the large daily doses of 4.5 g (for cUTI and cIAI) and 9 g (for VABP) will help ensure coverage.\u00a0 It is a significant improvement over piperacillin \/ tazobactam [3].<\/p>\n

Will it be relegated to a 2nd<\/sup> line drug or \u201crescue\u201d drug for intractable PA infections?\u00a0 It would certainly be a safer drug than colistin or any aminoglycoside, including plazomicin.\u00a0 Certainly, Cubist does not want a \u201cniche\u201d indication for this drug but rather present us a \u201cPA plus ESBL\u201d profile.<\/p>\n

It is difficult to collect sufficient numbers of ESBL patients in a clinical trial program and prove beyond a doubt that ceftolozane\/tazobactam\u00a0is en par with carbapenems.\u00a0 But to be fair:\u00a0 not everything can be demonstrated in a registration program.\u00a0 Once marketed, there will be more studies and we will hear \u00a0\u2018the rest of the story\u2019.<\/p>\n

Other BL\/BLI combination will benefit from avibactam\u2019s broader profile with solid ESBL and KPC coverage.\u00a0 This will not displace ceftolozane\/tazobactam as the premier anti-pseudomonas drug but it suggests that the ESBL claim may get hammered by the competition.<\/p>\n

Adverse events so far are not a major concern or differentiating factor.\u00a0 There seem to be more CNS events with ceftolozane than with ceftazidime (headaches, sleep disorders, and possibly infusion site reactions).\u00a0 Also, there are the odd \u201cpyrexia\u201d cases which pop up occasionally.\u00a0\u00a0 At this stage, it remains unclear if these are spurious clusters or, if real, of clinical relevance.<\/p>\n

Cubist has submitted the NDA in May 2014 and will get FDA Priority Review.\u00a0 The drug already has Fast Track and QIDP status.<\/p>\n

On Dec. 22, 2014, FDA approved\u00a0Zerbaxa\u00ae, the combination of ceftolozane and tazobactam for the indications cUTI and\u00a0cIAI.<\/strong><\/span><\/p>\n

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

[1] Shlaes.\u00a0 Ann. N.Y. Acad. Sci. (2013); 105: 1277
\n[2] Paterson.\u00a0 https:\/\/www.asid.net.au\/documents\/item\/65
\n[3] Hong.\u00a0 Infection and Drug Resistance 2013:6 215<\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

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 Continue reading What is the \u201cNiche\u201d for Ceftolozane \/ Tazobactam?<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"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":[360,176,357,403,353,352,44,347,345,344,349,354,42,177,363,355,359,350,362,727,351,346,197,348,170,361,196,9,180,356,728],"class_list":["post-653","post","type-post","status-publish","format-standard","hentry","category-qidp_antibiotic","category-the_news","category-the_viewpoint","tag-adverse-events","tag-aminoglycoside","tag-ampc","tag-antibiotic-blog","tag-avibactam","tag-beta-lactamase","tag-carbapenem","tag-ceftazidime","tag-ceftolozane","tag-ceftolozanetazobactam","tag-cephalosporin","tag-ciai","tag-ciprofloxacin","tag-colistin","tag-cre","tag-cuti","tag-cxa-101","tag-esbl","tag-fast-track","tag-fda-approval","tag-kpc","tag-meropenem","tag-p-aeruginosa","tag-piperacillintazobactam","tag-plazomicin","tag-priority-review","tag-pseudomonas","tag-safety","tag-tazobactam","tag-vabp","tag-zerbaxa"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-ax","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":378,"url":"https:\/\/allphasepharma.com\/dir\/2014\/06\/23\/378\/fighting-p-aeruginosa-part-i\/","url_meta":{"origin":653,"position":0},"title":"Fighting P. aeruginosa (Part I)","author":"Harald","date":"June 23, 2014","format":false,"excerpt":"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\u2026","rel":"","context":"In "The News"","block_context":{"text":"The News","link":"https:\/\/allphasepharma.com\/dir\/category\/the_news\/"},"img":{"alt_text":"PA-01 on Agar","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/PA-01-on-Agar-300x274.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":1408,"url":"https:\/\/allphasepharma.com\/dir\/2015\/05\/07\/1408\/no-such-thing-as-a-free-ride\/","url_meta":{"origin":653,"position":1},"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":1887,"url":"https:\/\/allphasepharma.com\/dir\/2015\/08\/26\/1887\/avicaz-approval-and-labeling-restrictions\/","url_meta":{"origin":653,"position":2},"title":"Avycaz Approval and Labeling Restrictions","author":"Harald","date":"August 26, 2015","format":false,"excerpt":"On Feb 25, 2015 the combination of ceftazidime\/avibactam (Avycaz) was approved by FDA for cUTI and cIAI infections in\u00a0patients \u2018who have limited or no alternative treatment options\u2019.\u00a0 As a QIDP drug, Avycaz\u00a0received priority review.\u00a0 Its label states that it is indicated for infections caused by pathogens proven or \u2018suspected 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":"Avycaz - slider","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/08\/Avycaz-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/08\/Avycaz-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/08\/Avycaz-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":2563,"url":"https:\/\/allphasepharma.com\/dir\/2016\/06\/22\/2563\/progress-report-new-antibacterials-in-the-fight-against-mdr-bacteria\/","url_meta":{"origin":653,"position":3},"title":"Progress Report: New Antibacterials In the Fight against MDR Bacteria","author":"Harald","date":"June 22, 2016","format":false,"excerpt":"Since the beginning of this millennium we have seen antibiotic R&D dwindle year after year. There are many reasons for this; while economics are often cited for this decline, the FDA and the \u2018Guideline Wars\u2019, i.e., those never ending discussions about regulatory requirements, have contributed to this trend in a\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"Pipeline - slider","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/06\/Pipeline-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/06\/Pipeline-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/06\/Pipeline-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":561,"url":"https:\/\/allphasepharma.com\/dir\/2014\/07\/10\/561\/the-difficult-transition-into-phase-3\/","url_meta":{"origin":653,"position":4},"title":"The Difficult Transition Into Phase 3","author":"Harald","date":"July 10, 2014","format":false,"excerpt":"Preclinical and early clinical development is expensive enough already for VC companies but it gets really expensive in Phase 3.\u00a0 Hence, not surprisingly, few small companies tackle Phase 3 programs on their own.\u00a0 Unless an 'angel investor' with deep pockets commits to the compound and assures continuity of development, the\u2026","rel":"","context":"In "The Viewpoint"","block_context":{"text":"The Viewpoint","link":"https:\/\/allphasepharma.com\/dir\/category\/the_viewpoint\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/07\/DrugDevProcess.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\/07\/DrugDevProcess.jpg?fit=640%2C200&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/07\/DrugDevProcess.jpg?fit=640%2C200&ssl=1&resize=525%2C300 1.5x"},"classes":[]},{"id":157,"url":"https:\/\/allphasepharma.com\/dir\/2014\/04\/22\/157\/antibiotics-with-qidp-designation\/","url_meta":{"origin":653,"position":5},"title":"Antibiotics with QIDP Designation – – – Updated 9-30-14","author":"Harald","date":"April 22, 2014","format":false,"excerpt":"For the latest QIDP listing, please click HERE \u00a0 Since\u00a0FDA issued the QIDP designation in 2012, many companies have requested this important 'label'. \u00a0Which should not come as a surprise: QIDP status confers significant benefits - and there is no downside. While an official FDA list of drugs that have\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\/2014\/04\/FDA-GAIN-LPAD-banner-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\/04\/FDA-GAIN-LPAD-banner-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/04\/FDA-GAIN-LPAD-banner-copy.jpg?fit=640%2C200&ssl=1&resize=525%2C300 1.5x"},"classes":[]}],"jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/653","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=653"}],"version-history":[{"count":11,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/653\/revisions"}],"predecessor-version":[{"id":2016,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/653\/revisions\/2016"}],"wp:attachment":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media?parent=653"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/categories?post=653"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/tags?post=653"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}