{"id":5099,"date":"2025-08-23T22:21:36","date_gmt":"2025-08-24T04:21:36","guid":{"rendered":"https:\/\/allphasepharma.com\/dir\/?p=5099"},"modified":"2025-09-20T19:03:40","modified_gmt":"2025-09-21T01:03:40","slug":"emblaveo-aztreonamavibactam-microbiology-testing-for-mdr-pathogens","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2025\/08\/23\/5099\/emblaveo-aztreonamavibactam-microbiology-testing-for-mdr-pathogens\/","title":{"rendered":"EMBLAVEO (AZTREONAM+AVIBACTAM) Microbiology Testing for MDR Pathogens"},"content":{"rendered":"

\"\"<\/a><\/p>\n

In our last blog we discussed strategic and regulatory issues related to Emblaveo\u2019s clinical development, without commenting much on the REVISIT study results [1]<\/a>.<\/p>\n

Today we want to highlight a recurrent problem seen in almost all clinical studies of anti-infectives that no one makes a serious attempt to tackle.<\/p>\n

New antibiotics are supposed to be used preferentially against MDR pathogens, not against\u00a0 the majority of infecting bugs which are susceptible to any number of antibiotics.\u00a0 We really would like new antibiotics to be tested in infections caused by a particular MDR pathogen as their \u2018claim to fame\u2019 efficacy feature.\u00a0 As it stands, our Phase 3 trials do the opposite: they collect information predominantly on pathogens commonly involved in a given indication, but hardly tell us anything about activity against the rarer problem isolates that we actually would need to learn more about.<\/p>\n

Let\u2019s revisit the MDR organism yield of the REVISIT trial.\u00a0 The effort was impressive. This was a multinational trial conducted at 81 centers in 20 countries.\u00a0 Most patients were recruited in China, Turkey, Spain, and the Ukraine; the single participating US center recruited an amazing 21 patients.\u00a0 So far so good.<\/p>\n

After 5 (!) years and screening 461 patients with cIAI or nosocomial pneumonia, 422 were actually enrolled.\u00a0 Here is the yield for \u2018organisms-of-interest\u2019:<\/p>\n

\"\"<\/a><\/p>\n

As obvious from the table, the study found hardly any MBL producers, the main reason for existence of Emblaveo.\u00a0 In addition, how should we interpret the data given the extremely small number of microbiologically evaluable cases?\u00a0 Outcome was adjudicated by blinded reviewers, an important quality marker of the study; hence, we can trust their assessment.\u00a0 That said, the rather high percentage of clinical failures in the MBL and carbapenemase-positive subgroups is nothing to be proud of.\u00a0 Again, the numbers are too small to draw any conclusions.<\/p>\n

\n
This effort contrasts with the ease with which Falcone et al. were able to prospectively find and enroll MBL patients.\u00a0 At a single center in Pisa they prospectively collected 343 patients with various infections over 3 years.[2]<\/strong><\/a>\u00a0 <\/span><\/em><\/h6>\n
In an earlier publication, the same group of authors reported on the treatment of MBL bloodstream infections with various regimens.\u00a0 Within 13 months they identified 102 cases of infections caused by MBL producing Enterobacterales prospectively at 3 centers in Italy and Greece.<\/span>[3]<\/strong><\/a><\/em><\/h6>\n<\/blockquote>\n

\"\"<\/a><\/p>\n

Remember this next time you visit Tuscany, Pisa, the Torre Pendente and the Piazza dei Miracoli and try not to end up in a local hospital \u2013 you\u2019re in an MBL-endemic area.2<\/sup> \u00a0<\/span><\/p>\n<\/div>\n

Did the REVISIT study at least succeed in showing comparable efficacy to meropenem in cIAI?\u00a0 The answer is a clear and resounding NO.\u00a0 The study was not powered to show NI even if we were to add the 34 cases of cIAI infections from the uncontrolled REJUVENATE trial to the mix.[4]<\/a><\/p>\n

Let’s get back to MDR pathogen-centered studies.\u00a0 As it stands, clinical trials and guidelines are not really suitable to verify antibiotic activity in any kind of MDR infections.\u00a0 We still enroll based on clinical presentation without knowing anything about the causative organism and its resistance genotype.\u00a0 Our indication-focused registration studies are good at selecting the right patients in a given disease category, like UTI, IAI, skin infection or pneumonia, but agnostic regarding organism species and their all-important resistance-patterns.<\/p>\n

\n
In cancer trials we are able to select patients with certain MSI mutations for study.\u00a0 There is sufficient time to do this and other specific testing to preselect patients and assign to treatment.\u00a0 Antimicrobial studies are fundamentally different; sponsors rarely make use of rapid molecular testing to identify organisms of interest and their resistance profiles.\u00a0 <\/em><\/span><\/h6>\n<\/blockquote>\n

In this age of PCR and genomic testing, the time-honored culture approach should be abandoned whenever possible.\u00a0 We should not have to wait 3 days to obtain culture and susceptibility results, using empiric therapy in the meantime.\u00a0 Rapid diagnostics have come a long way and can provide critical information within hours to select (1) the right antibiotic for our patients, and (2) the right patients for our clinical studies.<\/p>\n

We believe Sponsors have a role to play in adapting the newer technologies.\u00a0 Regulators will follow and amend the Guidances and regulatory statutes in light of the \u2018new science\u2019.<\/p>\n

Rapid PCR based diagnostics are getting cheaper.\u00a0 They are offered as kits by various manufacturers.\u00a0 We are not endorsing any particular product or technology but had a good experience with the bioMerieux BioFire system for identifying CRAB in a recently published trial [5]<\/a><\/p>\n

Using PCR-based rapid diagnostics makes especially good sense for clinical trials of new antibiotics.\u00a0 This will streamline our enrollment efforts and eliminate the diluting effect of non-contributing pan-susceptible pathogens.\u00a0 Honing in on patients with \u2018problem pathogens\u2019, we can then randomize our new antibiotic to existing SOC or BAT.\u00a0 We believe such an approach is vastly preferable to the way clinical trials are mostly done today.<\/p>\n

Organism-specific indications have always existed; drugs for malaria and TB, for Helicobacter and C. difficile infections, all have organism-specific labeling.\u00a0 Daptomycin was approved for Staph. aureus bacteremia and right-sided endocarditis.\u00a0 Clearly, these are still exceptions.\u00a0 Truth be told, regulators had a very hard time with the wording of the daptomycin label, as it broke the mold of indication-driven approvals.\u00a0 Nowadays, we have regulatory support for the development of organism-specific antibiotics like P. aeruginosa and A. baumannii.<\/p>\n

We\u2019d like to move away from the time-consuming testing sequence (detection of pathogens in specimens \u2013 growing them to density for speciation – resistance testing against a panel of antibiotics).\u00a0 This all was fine and good in the days of Robert Koch, but today we should make use of newer technologies not only in hospitals but also when it comes to clinical trials.<\/p>\n

\n

ABBREVIATIONS
\n<\/strong>BAT\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 best alternative therapy
\nBSI\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 blood-stream infections
\nCDI\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Clostridium difficile infection
\nCPE\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 carbapenem-producing enterobacteriaceae
\nCRAB\u00a0 \u00a0 \u00a0 carbapenem-resistant Acinetobacter baumannii
\nESBL\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 extended-spectrum beta-lactamase
\nMBL\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 metallo-beta-lactamase
\nMDR\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 multi-drug resistance
\nMSI\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 micro-satellite instability
\nSOC\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 standard of care<\/p>\n

REFERENCES
\n<\/strong>[1]<\/a> Carmeli Y.\u00a0 Aztreonam\u2013avibactam 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\u00a0 2025; 25: 218
\n[2]<\/a> Falcone M. Clinical Features and Outcomes of Infections Caused by Metallo-\u03b2-Lactamase\u2013Producing Enterobacterales: A 3-Year Prospective Study From an Endemic Area. Clin Infect Dis 2024;78:1111
\n[3]<\/a> Falcone M.\u00a0 Efficacy of Ceftazidime-avibactam Plus Aztreonam in Patients With Bloodstream Infections Caused by Metallo-\u03b2-lactamase\u2013Producing Enterobacterales.\u00a0 Clin Infect Dis 2021; 72:1871
\n[4]<\/a> Cornely O.\u00a0 Pharmacokinetics and safety of aztreonam\/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study. J Antimicrob Chemother 2020; 75: 618
\n[5]<\/a> Kaye K.\u00a0 Efficacy and safety of sulbactam\u2013durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii\u2013calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).\u00a0 Lancet Infect Dis 2023; 9:1072<\/p>\n","protected":false},"excerpt":{"rendered":"

The discussion emphasizes challenges in clinical antibiotic trials which failed to effectively target multi-drug resistant (MDR) pathogens. It advocates for using rapid PCR diagnostics to streamline trials, ensuring focus on pathogens of concern, and calls for regulatory adaptations to enhance study design and antibiotic testing efficacy. Continue reading EMBLAVEO (AZTREONAM+AVIBACTAM) Microbiology Testing for MDR Pathogens<\/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_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":[227,3,18],"tags":[198,1271,403,974,1468,691,2372,2375,2380,75,288,2377,1915,229,228,2366,1583,1977,590,2368,181,2378,2379,295,2376,2374,196,2373],"class_list":["post-5099","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-recent_literature","category-the_news","category-the_viewpoint","tag-acinetobacter","tag-allphase-pharma-consulting","tag-antibiotic-blog","tag-avycaz","tag-aztreonamavibactam","tag-bacteremia","tag-biomerieux-biofire","tag-bsi","tag-c-difficile-infection","tag-cdi","tag-ceftazidimeavibactam","tag-clinical-trial-design","tag-crab","tag-cubicin","tag-daptomycin","tag-emblaveo","tag-harald-reinhart","tag-helicobacter","tag-malaria","tag-mbl","tag-mdr","tag-microsatellite-instability","tag-msi","tag-mtb","tag-multi-drug-resistance","tag-pcr-pathogen-identification","tag-pseudomonas","tag-rapid-diagnostics"],"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-1kf","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":5040,"url":"https:\/\/allphasepharma.com\/dir\/2025\/08\/21\/5040\/an-intro-to-emblaveo-aztreonam-avibactam\/","url_meta":{"origin":5099,"position":0},"title":"An Intro to Emblaveo (aztreonam + avibactam)","author":"Harald","date":"August 21, 2025","format":false,"excerpt":"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\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\/2025\/08\/avibactam-Stick-Model.jpg?resize=350%2C200&ssl=1","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/avibactam-Stick-Model.jpg?resize=350%2C200&ssl=1 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/avibactam-Stick-Model.jpg?resize=525%2C300&ssl=1 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/avibactam-Stick-Model.jpg?resize=700%2C400&ssl=1 2x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/avibactam-Stick-Model.jpg?resize=1050%2C600&ssl=1 3x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/avibactam-Stick-Model.jpg?resize=1400%2C800&ssl=1 4x"},"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":5099,"position":1},"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 - 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Our inofficial list has 61 drugs, of which we believe only 57 are still in active clinical development.\u00a0 So we are in fairly close agreement. 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