COMBACTE-CARE

Combatting Bacterial Resistance in Europe - Carbapenem Resistance

Summary

In 2019 alone, it’s estimated that 1.27 million people died because of bacterial antimicrobial resistance (AMR). The rise of AMR is particularly concerning in a hospital setting, where dangerous infections can spread rapidly amongst vulnerable people, and routine medical procedures can become too risky to perform without effective antimicrobials. The COMBACTE-CARE project focused on learning more about severe infections caused by bacteria known as ‘carbapenem-resistant Enterobacterales’ (CRE) which are considered to be the most dangerous drug-resistant bacteria in the world. These bacteria have become resistant to many conventionally used antimicrobials, and cases of CRE are on the rise in Europe and globally. The project contributed to several clinical trials observing the clinical management of patients with infections from CRE, and the potential of a new antibiotic treatment.

The EURECA trial was an observational study that examined the risk factors for acquiring CRE and the impact of these infections – for instance, how many people did these infections kill over a given timeframe. The study compared those factors to patients without any infections and to another group of patients that had infections caused by carbapenem-susceptible enterobacteria (CSE). The study involved 235 patients with CRE infections, 235 patients with CSE infections and 705 patients that were infection-free. The results of this study inform site footprint and recruitment assumptions for the subsequent REJUVENATE and REVISIT clinical trials to recruit better suited patients more rapidly.

The REJUVENATE trial was a Phase II trial examining the potential of a new antibiotic combination of aztreonam-avibactam (ATM-AVI) for patients with severe intrabdominal complications caused by Gram-negative bacteria for which there are limited or no treatment options. The people who took part in the trial were hospitalised adult patients with these infections who had had or were planning to have a surgery within 24 hours of taking the first dose of ATM-AVI. They had also previously received antibacterials to try to treat their infections, but those antibacterials had failed. The participants were divided into three cohorts, with varying doses to establish which dosage was most beneficial. The trials took place in France, Spain and Germany and 40 patients were enrolled overall. The Spanish sites were particularly successful in enrolling patients and their methods of recruitment served as lessons learned for the following COMBACTE trials.

Building on the results of the REJUVENATE trial, the REVISIT Phase III trial enrolled 422 hospitalised patients with a complicated intra-abdominal infection (cIAI) or pneumonia (either ventilator- or hospital-acquired) caused by or presumed to be caused by Gram-negative bacteria at the time of enrolment. The participants in the trial were given either the ATM-AVI combination with/without metronizadole (another antibiotic, given to patients with cIAI only), or meropenem with/without colistin (another combination of antibiotics). COMBACTE-CARE was a key contributor to the study, which was held in approximately 165 sites across Europe, the Americas and Asia. More than half of all the randomised patients involved in the trial were from clinical sites that were part of the COMBACTE CLIN-Net network and four of the top six recruitment sites were from the network.

The results were largely positive, showing that ATM-AVI was effective and generally well-tolerated, with no new safety concerns arising. This result was especially welcome because treating these infections caused by Gram-negative bacteria has proved extremely challenging in hospitals. Results of the REJUVENATE and REVISIT clinical trials contributed to the data package that led to the approval of a new antibiotic in Europe.

The results of COMBACTE-CARE proved to be pivotal in helping us to better understand and treat the growing threat of antimicrobial resistance, now and in years to come. Overall, the COMBACTE projects as part of IMI’s New Drugs for Bad Bugs have contributed to a wealth of new information in the fight against antimicrobial resistance.

The work that COMBACTE-MAGNET, COMBACTE-NET and COMBACTE-CARE carried out will be continued by ECRAID, a non-profit foundation led by academic investigators that will continue to strengthen Europe’s capacity to fight antimicrobial resistance. EPI-NET and the other three networks fostered by COMBACTE form the pillarstones of this foundation, which is based in Utrecht, in the Netherlands, and has 80 employees at present. At the time of writing, ECRAID was involved in 11 international studies at 269 study sites in 24 EU countries. The network involves more than 250 primary care sites, more than 1200 hospital sites and 900 clinical laboratories.

 

Achievements & News

COMBACTE-CARE completes recruitment for major antimicrobial resistance study

COMBACTE-CARE has recruited 2 266 patients to its EURECA study on infections that are resistant to antibiotics called carbapenems, which are considered to be among the most difficult to treat. ###In a statement, the project said: ‘Excellent collaboration between the central team and the study sites has ensured that the study has run smoothly, and in future will lead to results that have a significant impact on the practice of infectious diseases in Europe and elsewhere.’ Cases of infections caused by bacteria known as carbapanem-resistant enterobacteriaceae (CRE) are on the rise, and are most common in healthcare settings. They are extremely hard to treat (very often the only treatment options are combinations of old, toxic antibiotics) and can be fatal. The EURECA study is investigating the risk factors for CRE infection and things that influence treatment outcomes. The samples collected during the study are now being sent to a central site for analysis.

COMBACTE-CARE study recruits first patient

Antimicrobial resistance (AMR) project COMBACTE-CARE has recruited the first patient in the REJUVENATE study, a clinical trial of a novel antibiotic designed to tackle drug-resistant infections that are particularly hard to treat.### The goal of the REJUVENATE study is to assess the workings and safety of a novel antibiotic combination product called Aztreonam-Avibactam (ATM-AVI) in 40 hospitalised adults with ‘complicated intra-abdominal infections’. The first patient was enrolled at the University Hospital Virgen del Rocio in Seville, Spain. Other study sites recruiting patients are based in Germany and France. The COMBACTE-CARE project focuses on tackling bacteria known as ‘carbapenem-resistant enterobacteriaceae’ (CRE), which are resistant to most available antibiotics and are so difficult to treat they are considered to be an urgent global threat. Worryingly, cases of CRE infections are on the rise in Europe and globally.

COMBACTE-CARE antibiotic study forges US link

Antibiotic research and development was given a boost recently by the announcement that the US Biomedical Advanced Research and Development Authority (BARDA) would fund clinical studies of a novel antibiotic combination product called Aztreonam-Avibactam (ATM-AVI). ###ATM-AVI is designed to tackle certain antibiotic infections that are particularly tough to treat. In Europe, IMI is supporting clinical studies of ATM-AVI through the COMBACTE-CARE project. The funding from BARDA will support additional studies needed to advance the development of this urgently-needed treatment.

Meet COMBACTE at ECCMID!
IMI’s COMBACTE family of antimicrobial resistance projects will have a stand at the exhibition of the 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Vienna, Austria on 22-25 April. ###The project team will be at booth 29 at the exhibition. Partners in the COMBACTE-MAGNET project will also present results from their RESCUING study at the conference. RESCUING gathered observational data on the treatment of some 1 000 patients with complicated urinary tract infections in 8 countries where the prevalence of multidrug-resistant Gram-negative bacteria is seen to be high. That includes Bulgaria, Greece, Hungary, Israel, Italy, Romania, Turkey and Spain. In a blog post on the COMBACTE website, COMBACTE-NET’s Bruno François explains why COMBACTE is going to ECCMID: ‘Since ECCMID is one of the biggest, most important microbiology and infectious diseases congresses, I would say it is really ‘the place to be’ for our project. Without a doubt it also creates more visibility. Next to that, the event itself fits with the purpose of COMBACTE.’
(March 2017)

IMI antimicrobial resistance programme expands with new project
IMI’s antimicrobial resistance programme New Drugs for Bad Bugs has acquired a new project with the launch of COMBACTE-CARE. With 18 academic partners and 3 pharmaceutical companies , the project will bring highly innovative studies and activities related to the treatment of patients with infections caused by Carbapenem-Resistant Enterobacteriaceae (CRE). ###Tough to treat and sometimes deadly, CRE are considered to be one of the most dangerous resistant bacteria in the world. Specifically, the €83 million project aims to understand how patients with CRE infections are managed, with a focus on best available treatment and clinical outcomes. The project will develop new tools to detect CRE and conduct clinical trials with AstraZeneca’s antibiotic combination product Aztreonam-Avibactam (ATM-AVI), in development for the treatment of serious infections due to a difficulty to treat sub-type of CRE infections called metallo‐β‐lactamase producing Gram‐negative pathogens. All clinical and microbiological studies will be conducted in South-Eastern Europe, where infection rates with MDR-GNB are expected to be high. The phase III study is intended to include investigation sites outside Europe to ensure the global assessment of the ATI-AVI combination product. - Read the project’s press release  
(March 2015)

Participants

  Show participants on map
EFPIA companies
  • Basilea Pharmaceutica International AG, Basel, Switzerland
  • Glaxosmithkline Research & Development Limited, Brentford, Middlesex, United Kingdom
  • Pfizer Limited, Sandwich, Kent , United Kingdom
Universities, research organisations, public bodies, non-profit groups
  • Academisch Medisch Centrum Bij De Universiteit Van Amsterdam, Amsterdam, Netherlands
  • Cardiff University, Cardiff, United Kingdom
  • Centre hospitalier universitaire de Limoges, Limoges, France
  • Ethniko Kai Kapodistriako Panepistimio Athinon, Athens, Greece
  • Fundacion Privada Instituto De Salud Global Barcelona, Barcelona, Spain
  • Institut National De La Sante Et De La Recherche Medicale, Paris, France
  • Klinikum Der Universitaet Zu Koeln, Cologne, Germany
  • Servicio Andaluz De La Salud, Sevilla, Spain
  • St George'S Hospital Medical School, London, United Kingdom
  • Stichting European Clinical Research Alliance On Infectious Diseases, Utrecht, Netherlands
  • The Foundation For Medical Research Infrastructural Development And Health Services Next To The Medical Center Tel Aviv, Tel Aviv, Israel
  • The Health Corporation - Rambam, Haifa, Israel
  • Universitaet Ulm, Ulm, Germany
  • Universitaetsklinikum Freiburg, Freiburg, Germany
  • Universitair Medisch Centrum Utrecht, Utrecht, Netherlands
  • Universite De Geneve, Genève 4, Switzerland
  • Universiteit Antwerpen, Antwerp, Belgium
Third parties
  • Centre Hospitalier Universitaire De Poitiers, Poitiers, France
  • Universite De Poitiers, Poitiers , France
Non EFPIA companies
  • MINISTRIA E SHENDETESISE (National Institute of Public Health of Kosovo), Pristina, Kosovo * UN resolution
  • Servicio Madrileno De Salud, Madrid, Spain

Participants
NameEU funding in €
Academisch Medisch Centrum Bij De Universiteit Van Amsterdam325 000
Cardiff University173 539
Centre hospitalier universitaire de Limoges2 124 060
Ethniko Kai Kapodistriako Panepistimio Athinon755 750
Fundacion Privada Instituto De Salud Global Barcelona233 962
Institut National De La Sante Et De La Recherche Medicale317 550
Klinikum Der Universitaet Zu Koeln2 173 221
MINISTRIA E SHENDETESISE (National Institute of Public Health of Kosovo)45 000
Servicio Andaluz De La Salud3 722 506
Servicio Madrileno De Salud199 080
St George'S Hospital Medical School216 250
Stichting European Clinical Research Alliance On Infectious Diseases410 000
The Foundation For Medical Research Infrastructural Development And Health Services Next To The Medical Center Tel Aviv893 092
The Health Corporation - Rambam522 200
Universitaet Ulm76 000
Universitaetsklinikum Freiburg234 250
Universitair Medisch Centrum Utrecht10 210 563
Universite De Geneve250 164
Universiteit Antwerpen903 063
 
Third parties
NameFunding in €
Centre Hospitalier Universitaire De Poitiers15 750
Universite De Poitiers70 500
 
Total Cost23 871 500