The FDA web site usually provides label and review documents for approved drugs.[1] Emblaveo, the combination of aztreonam and avibactam, was approved in February 2025, almost ½ year ago, but clinical review documents are still not posted at the site.[2] 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.
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]
Here we will not discuss the logic of why combining aztreonam with avibactam makes sense. The rationale is well laid out in the literature and also cited in the Carmeli article. In essence, the combination of aztreonam, a unique monobactam antibiotic with activity against Class B metallo-β-lactamases, and avibactam, a DBO-type β-lactamase drug, confer coverage against Ambler Class A, B, C, and some D β-lactamase producers.
Of course, both avibactam and aztreonam have been known compounds for some years.
Avibactam is part of the ceftazidime+avibactam combination which has been on the market as Avycaz since 2015.
Aztreonam was approved in 1986 as Azactam, and is by now generic. There is no question that aztreonam and avibactam are safe and effective. Hence, the ‘new’ combo of aztreonam plus avibactam is really not covering any new ground. We can assume activity and safety from prior clinical studies and years of clinical use. Of course, there is extensive microbiology information available to show continued activity against enterobacteriaceae, including MDR problem organisms with various resistance mechanisms.
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.
Well, with this for a background, one may ask:
Q1: Is there actually a need for Emblaveo?
A1: We believe that Emblaveo is a ‘nice to have’ fixed dose combination but not a necessary new antibiotic.
Q2; Is there actually a need for clinical Phase 2/3 studies with Emblaveo?
A2: We would argue that historical data for both drugs plus microbiology of recent vintage should be sufficient.
Let’s 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. With both drugs excreted by the renal route, significant drug-drug interactions are highly unlikely. We are not sure whether a new PK study is indicated as both components are so well-behaved.
Regulators being regulators may not agree with our logic and demand some kind of clinical trial. In that case, the question becomes
Q3: How should one design a clinical program for Emblaveo? And
Q4: What would be the purpose of such a program and what kind of information should it provide?
A traditional registration program (in cUTI, cIAI, or HABP/VABP patients) would only confirm the broad gram-negative coverage we already know about. However, looking for pathogens with specific resistance patterns (CRE, NDM, MBL, etc) in a prospective well-controlled clinical study is ‘Mission Impossible’ and doomed to fail. Such cases are simply too rare, short of outbreak situations.
Which approved antibiotic with a similar broad spectrum of activity could be chosen as comparator for a randomized prospective NI trial? We can only think of cefiderocol (not colistin!) which has a similar antimicrobial spectrum and is approved for cUTI and VABP. 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.
We are not sure what kind of studies FDA mandated but the Agency certainly offered lenient LPAD-like conditions to make approval possible. After all, the REVISIT trial was not powered for NI testing or designed for formal hypothesis testing.
Well, we know that Pfizer conducted 3 trials; the main trial being REVISIT, a hybrid cIAI / VABP / HABP study. This is surprising in light of the fact that the drug was ultimately only approved for cIAI, not for VABP. Why did Pfizer opt to include VABP patients, perhaps for possible label extension at a later time, after generating more data?
But why would one chose cIAI as the first indication? Having run the ciprofloxacin nosocomial pneumonia and cIAI studies in the ’90s, we have some relevant experience in this area. Let me explain why cIAI is a poor choice.
In cIAI patients, outcomes are largely a reflection of the surgical intervention, less so a result of antibiotic activity. Even in cases of peritonitis, antibiotics cannot claim to be the sole driver of clinical response. 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. As repeat cultures cannot be obtained, the microbiological outcome is either ‘presumed eradication’ or ‘presumed persistence’ at the EOT evaluation time point. In addition, the need for anerobic coverage further complicates evaluations as efficacy is now a function of the surgeon’s skill and of the concomitant administration of metronidazole.
The REVISIT trial designers chose meropenem as a comparator. They permitted the addition of colistin, further complicating / compromising the interpretation of the results.
They certainly did not enrich for Class B MBL-producers, the main group of infections we’d like to see investigated with AZT/AVI. 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 ‘cures’. The numbers are even smaller in the ME population. How is one supposed to interpret this and other data in the super-small MDR-cohorts that REVISIT was able to collect and study?
IN SUMMARY, here is our take:
- 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.
- We would have liked to see the drug approved based on existing data for AZT and CTAZ/AVI.
- 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.
- 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. We will have more on this in an upcoming blog.
- The REVISIT study confirmed on-par activity with meropenem against enterobacteriaceae (which we already knew)
- The REVISIT study confirmed the safety issues associated with aztreonam (which we already knew)
The Roman poet Horace said it well: “Montes geruntur, parietur ridiculus mus“. Meaning: A huge effort for very little return. Or more freely: Could have told you so…
Please give us your thoughts and insights – we always appreciate reader comments and corrections. Thank you!
ABBREVIATIONS
AVI avibactam
AZT aztreonam
cIAI complicated intra-abdominal infection
CTAZ ceftazidime
cUTI complicated urinary tract infection
EOT end-of-therapy
HABP hospital-acquired bacterial pneumonia
LPAD Limited Population Pathway for Antibiotic Development
MBL metallo-β-lactamase
MDR multidrug resistant
ME microbiologically evaluable population
NDM New Delhi metallo-β-lactamase
NI non-inferiority
VABP ventilator-associated bacterial pneumonia
REFERENCES
[1] https://www.accessdata.fda.gov/scripts/cder/daf/
[2] Accessed Aug. 15, 2025
[3] Carmeli Y. 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. Lancet Infect Dis 2024.
