Last week, the European Commission approved the EMBLAVEO® drug, a combination of aztreonam and avibactam dedicated to fighting the serious infections caused by multidrug-resistant Gram-negative bacteria. Two of the EMBLAVEO® trials were supported by IMI’s COMBACTE-CARE project. We spoke to George Daikos, professor of medicine and infectious diseases at the National and Kapodistrian University of Athens and one of the academic leads of the IMI-supported Phase III REVISIT trial which took place across twenty countries in 81 hospitals.
Why do we need more drugs to tackle AMR?
The situation in several countries is very worrisome with the increasing number of multi-drug-resistant pathogens, mainly the carbapenem-resistant Gram-negative organisms - in particular those that produce metallo-β-lactamases (MBL). It is getting worse and worse and in some areas we don’t have any effective treatment available. There is no question that we desperately need new agents to act against these problematic pathogens.
The ATM-AVI combination (EMBLAVEO®) has now been approved for marketing authorisation in the EU. What impact do you think this will have?
The approval of aztreonam avibactam (ATM-AVI) known as EMBLAVEO® is exciting not only for infectious diseases specialists but also for intensivists and every physician who practices medicine in settings with high CRE (carbapenem resistant enterobacterales) prevalence. This new drug combination is expected to be a “game changer” in the treatment of infections caused by MBL-producing organisms and will save many human lives.
Can you tell us more about this specific ATM-AVI combination?
This is a combination of the well-established antibiotic aztreonam and the newer β-lactamase inhibitor avibactam. ATM-AVI tackles a type of protein known as ESBLs, as well as serine carbapenemases and MBLs. For the MBL-producing organisms we don’t have effective treatments, and there was very strong in vitro data supporting the activity of this drug combination against these particular organisms.
What’s the advantage of this treatment over existing treatments?
The advantage is that this new drug combination tackles MBL-producing bacteria that are not covered adequately by other treatments. For example, the older drug colistin damages the kidneys and is losing its efficacy against MBL-producing organisms. Also, a substantial percentage of MBL-producing organisms are resistant to the newer agent cefiderocol.
How was the REVISIT trial designed?
All the patients taking part in the trial were hospitalised patients. Some had intra-abdominal infections while others had hospital-acquired pneumonia or ventilator-associated pneumonia. Patients either received ATM-AVI ± metronidazole or a combination of meropenem ± colistin. Metronidazole was added to the group with intra-abdominal infections. The results were very encouraging; the clinical cure and the mortality rates were comparable in both treatment groups.
Did you encounter any challenges during this trial?
The problem with these kinds of trials is that it’s difficult to recruit patients. We had to adhere to strict recruitment protocols, and it took us more than 5 years to recruit over 422 patients from 81 centres in twenty different countries.
Why do you think a public-private partnership was the best setting for this trial?
The cost of developing new antimicrobial agents is enormous and the expected profit limited. Antibiotics are administered for a short time (10-14 days) and have short lifespans. Because of the emergence of bacterial resistance, antibiotics cannot be prescribed over a lifetime, unlike cholesterol or hypertensive drugs. Therefore, the support of the private sector by public funds is necessary to develop new antibiotics.
COMBACTE-CARE is supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry.