{"id":5040,"date":"2025-08-21T12:51:36","date_gmt":"2025-08-21T18:51:36","guid":{"rendered":"https:\/\/allphasepharma.com\/dir\/?p=5040"},"modified":"2025-09-12T14:19:31","modified_gmt":"2025-09-12T20:19:31","slug":"an-intro-to-emblaveo-aztreonam-avibactam","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2025\/08\/21\/5040\/an-intro-to-emblaveo-aztreonam-avibactam\/","title":{"rendered":"An Intro to Emblaveo (aztreonam + avibactam)"},"content":{"rendered":"

\"\"<\/a><\/strong><\/h1>\n

The FDA web site usually provides label and review documents for approved drugs.[1]<\/a>\u00a0 Emblaveo, the combination of aztreonam and avibactam, was approved in February 2025, almost \u00bd year ago, but clinical review documents are still not posted at the site.[2]<\/a>\u00a0 Hence, we do not know how Regulators felt about the submission package for Emblaveo, but it is certain that LPAD considerations and other adjustments were made in light of medical need and prior data.<\/p>\n

Our information about Emblaveo is still quite limited; it is mainly based on the recent Carmeli publication in Lancet Infectious Diseases and the Package Insert, of course.[3]<\/a><\/p>\n

Here we will not discuss the logic of why combining aztreonam with avibactam makes sense.\u00a0 The rationale is well laid out in the literature and also cited in the Carmeli article.\u00a0 In essence, the combination of aztreonam, a unique monobactam antibiotic with activity against Class B metallo-\u03b2-lactamases, and avibactam, a DBO-type \u03b2-lactamase drug, confer coverage against Ambler Class A, B, C, and some D \u03b2-lactamase producers.<\/p>\n

Of course, both avibactam and aztreonam have been known compounds for some years.\"\"<\/a><\/p>\n

Avibactam is part of the ceftazidime+avibactam combination which has been on the market as Avycaz since 2015.\u00a0<\/p>\n

Aztreonam was approved in 1986 as \u00a0Azactam, and is by now generic.\u00a0 There is no question that aztreonam and avibactam are safe and effective.\u00a0 Hence, the ‘new’ combo of aztreonam plus avibactam is really not covering any new ground.\u00a0 We can assume activity and safety from prior clinical studies and years of clinical use.\u00a0 Of course, there is extensive microbiology information available to show continued activity against enterobacteriaceae, including MDR problem organisms with various resistance mechanisms.<\/p>\n

Even before the arrival of Emblaveo one could have co-administered Avycaz with Azactam and created a similar broad-spectrum combination; it would have included an unnecessary third component (ie, ceftazidime) but this would not have been a concern, but rather a benefit.<\/p>\n

Well, with this for a background, one may ask:
Q1:\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Is there actually a need for Emblaveo?
<\/span>A1:\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 We believe that Emblaveo is a \u2018nice to have\u2019 fixed dose combination but not a necessary new antibiotic.\u00a0
<\/span>Q2;\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Is there actually a need for clinical Phase 2\/3 studies with Emblaveo?\u00a0<\/span>
A2:\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 We would argue that historical data for both drugs plus microbiology of recent vintage should be sufficient.<\/span><\/p>\n

Let\u2019s state it upfront: we cannot think of any strong reason why new clinical efficacy \/ safety trials would be required to approve the AZT\/AVI combination, as both components are known and approved entities.\u00a0 With both drugs excreted by the renal route, significant drug-drug interactions are highly unlikely.\u00a0 We are not sure whether a new PK study is indicated as both components are so well-behaved.<\/p>\n

Regulators being regulators may not agree with our logic and demand some kind of clinical trial.\u00a0 In that case, the question becomes<\/p>\n

Q3:\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 How should one design a clinical program for Emblaveo?\u00a0 And<\/span><\/span>
Q4:\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 What would be the purpose of such a program and what kind of information should it provide?\u00a0<\/span><\/p>\n

A traditional registration program (in cUTI, cIAI, or HABP\/VABP patients) would only confirm the broad gram-negative coverage we already know about.\u00a0 However, looking for pathogens with specific resistance patterns (CRE, NDM, MBL, etc) in a prospective well-controlled clinical study is \u2018Mission Impossible\u2019 and doomed to fail.\u00a0 Such cases are simply too rare, short of outbreak situations.\u00a0<\/p>\n

Which approved antibiotic with a similar broad spectrum of activity could be chosen as comparator for a randomized prospective NI trial?\u00a0 We can only think of cefiderocol (not colistin!) which has a similar antimicrobial spectrum and is approved for cUTI and VABP.\u00a0 Still, if a comparative study were to be conducted, we would only expect confirmation of activity against common pathogens, not the group of pathogens for which a drug like Emblaveo is potentially life-saving and for which it was designed.<\/p>\n

We are not sure what kind of studies FDA mandated but the Agency certainly offered lenient LPAD-like conditions to make approval possible.\u00a0 After all, the REVISIT trial was not powered for NI testing or designed for formal hypothesis testing.<\/p>\n

Well, we know that Pfizer conducted 3 trials; the main trial being REVISIT, a hybrid cIAI \/ VABP \/ HABP study.\u00a0 This is surprising in light of the fact that the drug was ultimately only approved for cIAI, not for VABP.\u00a0 Why did Pfizer opt to include VABP patients, perhaps for possible label extension at a later time, after generating more data?<\/p>\n

But why would one chose cIAI as the first indication?\u00a0 Having run the ciprofloxacin nosocomial pneumonia and cIAI studies in the ’90s, we have some relevant experience in this area.\u00a0 Let me explain why cIAI is a poor choice.<\/p>\n

In cIAI patients, outcomes are largely a reflection of the surgical intervention, less so a result of antibiotic activity.\u00a0 Even in cases of peritonitis, antibiotics cannot claim to be the sole driver of clinical response.\u00a0 While we have culture results at the time of surgery, we are dealing with polymicrobial infections with a preponderance of anaerobes, whether cultured or not.\u00a0 As repeat cultures cannot be obtained, the microbiological outcome is either \u2018presumed eradication\u2019 or \u2018presumed persistence\u2019 at the EOT evaluation time point.\u00a0 In addition, the need for anerobic coverage further complicates evaluations as efficacy is now a function of the surgeon\u2019s skill and<\/u> of the concomitant administration of metronidazole.<\/p>\n

The REVISIT trial designers chose meropenem as a comparator.\u00a0 They permitted the addition of colistin, further complicating \/ compromising the interpretation of the results.<\/p>\n

They certainly did not enrich for Class B MBL-producers, the main group of infections we\u2019d like to see investigated with AZT\/AVI.\u00a0 In the micro-ITT population, there were only 10 MBL pathogens in the entire study, 7 treated with AZT\/AVI, and only 2 of them qualified as \u2018cures\u2019.\u00a0 The numbers are even smaller in the ME population.\u00a0 How is one supposed to interpret this and other data in the super-small MDR-cohorts that REVISIT was able to collect and study?<\/p>\n

IN SUMMARY, here is our take:<\/p>\n

    \n
  1. We feel rather strongly that there was no obvious need to conduct any kind of clinical outcome trials for Emblaveo. Updated micro data together with existing PK\/PD and clinical data should have sufficed. It would have saved much time and money; after all, REVISIT took a 5 year enrollment effort.<\/li>\n
  2. We would have liked to see the drug approved based on existing data for AZT and CTAZ\/AVI.<\/li>\n
  3. A single cUTI or VABP trial would have been more informative. There are fewer confounders with these indications. With easy microbiology sampling at EOT we would have learned about the true eradication of organisms, including a few MDR pathogens.<\/li>\n
  4. The MDR activity of this and other new drugs cannot be assessed properly within the standard prospective randomized trial format. A post-approval commitment for a study enriched in MDR \/ NDM \/ MBL pathogen infections would have provided more information than a REVISIT-like study.\u00a0 We will have more on this in an upcoming blog.<\/li>\n
  5. The REVISIT study confirmed on-par activity with meropenem against enterobacteriaceae (which we already knew)<\/li>\n
  6. The REVISIT study confirmed the safety issues associated with aztreonam (which we already knew)<\/li>\n<\/ol>\n

    The Roman poet Horace said it well: \u201cMontes geruntur, parietur ridiculus mus\u201c.\u00a0 Meaning: A huge effort for very little return.\u00a0 Or more freely: Could have told you so…<\/p>\n

    \n

    Please give us your thoughts and insights \u2013 we always appreciate reader comments and corrections.\u00a0 Thank you!<\/p>\n

    \n

    ABBREVIATIONS
    <\/strong>AVI\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 avibactam
    AZT\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 aztreonam
    cIAI\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 complicated intra-abdominal infection
    CTAZ\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 ceftazidime
    cUTI\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 complicated urinary tract infection
    EOT\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 end-of-therapy
    HABP\u00a0\u00a0\u00a0\u00a0\u00a0 hospital-acquired bacterial pneumonia
    LPAD\u00a0\u00a0\u00a0\u00a0\u00a0 Limited Population Pathway for Antibiotic Development
    MBL\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 metallo-\u03b2-lactamase
    MDR\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 multidrug resistant
    ME\u00a0 \u00a0 \u00a0 \u00a0 \u00a0 microbiologically evaluable population
    NDM\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 New Delhi metallo-\u03b2-lactamase
    NI\u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 non-inferiority
    VABP\u00a0\u00a0\u00a0\u00a0\u00a0 ventilator-associated bacterial pneumonia<\/p>\n

    REFERENCES
    <\/strong>    [1]<\/a> https:\/\/www.accessdata.fda.gov\/scripts\/cder\/daf\/
    [2]<\/a> Accessed Aug. 15, 2025
    [3]<\/a> Carmeli Y.\u00a0 Aztreonam-avibactam versus meropenem for the treatment of serious infections caused by Gram-negative bacteria (REVISIT): a descriptive, multinational, open-label, phase 3, randomised trial.\u00a0 Lancet Infect Dis 2024.\u00a0\u00a0<\/p>\n\n\n

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

    The FDA web site usually provides label and review documents for approved drugs.[1]\u00a0 Emblaveo, the combination of aztreonam and avibactam, was approved in February 2025, almost \u00bd year ago, but clinical review documents are still not posted at the site.[2]\u00a0 Hence, we do not know how Regulators felt about the Continue reading An Intro to Emblaveo (aztreonam + avibactam)<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":5050,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_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},"jetpack_post_was_ever_published":false},"categories":[227,3,18],"tags":[1271,403,974,1468,1955,288,354,42,2370,355,2366,727,2114,1279,1583,2121,2368,2369,2367,356],"class_list":["post-5040","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-recent_literature","category-the_news","category-the_viewpoint","tag-allphase-pharma-consulting","tag-antibiotic-blog","tag-avycaz","tag-aztreonamavibactam","tag-cefiderocol","tag-ceftazidimeavibactam","tag-ciai","tag-ciprofloxacin","tag-clinical-trials-for-mdr-pathogens","tag-cuti","tag-emblaveo","tag-fda-approval","tag-fetroja","tag-habp","tag-harald-reinhart","tag-lpad","tag-mbl","tag-metallo-beta-lactamase","tag-ndm-beta-lactamase","tag-vabp"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/Emblaveo-slider.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-1ji","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"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":5040,"position":0},"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 "Recent Literature"","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":5099,"url":"https:\/\/allphasepharma.com\/dir\/2025\/08\/23\/5099\/emblaveo-aztreonamavibactam-microbiology-testing-for-mdr-pathogens\/","url_meta":{"origin":5040,"position":1},"title":"EMBLAVEO (AZTREONAM+AVIBACTAM) Microbiology Testing for MDR Pathogens","author":"Harald","date":"August 23, 2025","format":false,"excerpt":"The discussion emphasizes challenges in clinical antibiotic trials which failed to effectively target multi-drug resistant (MDR) pathogens. 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