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R-GNOSIS Résumé de rapport

Project ID: 282512
Financé au titre de: FP7-HEALTH
Pays: Netherlands

Periodic Report Summary 2 - R-GNOSIS (Resistance in Gram-Negative Organisms: Studying Intervention Strategies)

Project Context and Objectives:

The European community and health care settings are facing a dramatic increase in infections caused by MDR-GNB, with few effective therapeutic options remaining in the armamentarium of clinicians. There are no truly new antimicrobial agents against MDR-GNB expected on the market in the short or medium term. Even if new agents were to come to market, on their own, they could not solve the resistance problem. Effective measures to contain resistance and limit the spread of MDR-GNB are therefore urgently needed to protect the health and well-being of the people in Europe and world-wide. We are confronted with a formidable enemy, equipped with sophisticated molecular methods to express and exchange resistance genes, capable of colonizing multiple reservoirs, and harbouring a bewildering array of virulence factors to infect any suitable host, both the hospitalised frail and healthy people living in the community.

The R-GNOSIS (Resistance in Gram-Negative Organisms: Studying Intervention Strategies) project combines five international clinical intervention studies, all supported by highly innovative microbiology and mathematical modelling, to determine – in the most relevant patient populations – the efficacy and effectiveness of cutting-edge interventions to reduce acquisition, carriage, infection and spread of Multi-Drug Resistant Gram-negative Bacteria (MDR-GNB).

The five clinical studies will investigate the following interventions:

- A Point-Of-Care-Testing guided management strategy to improve appropriate antibiotic prescription for uncomplicated UTI in primary care
- Gut decolonization in outpatients with intestinal carriage of MDR-GNB
- A “test and prescribe” strategy, based on rapid diagnostic testing of faeces for MDR-GNB to optimize antibiotic prophylaxis in colo-rectal surgery
- Contact Isolation of patients with ESBL-producing Enterobacteriaceae in general hospital wards
- Three Decolonization strategies in ICUs.

All clinical studies will progress science beyond the state-of-the-art in generating new and translational clinically relevant knowledge, through hypothesis-driven studies with a focus on patient-centred outcomes that matter to the people of Europe and beyond.

The studies and analyses proposed in R-GNOSIS will generate a step-change in identifying evidence-based preventive measures and clinical guidance for primary care and hospital-based physicians, as well as health-care authorities, to combat the spread and impact of the unprecedented rise of infections caused by MDR-GNB in Europe.

The overall structure and interactions of the WPs are demonstrated in the figure (see PDF). WP1 and WP10 are support packages and interact with all other WPs.

R-GNOSIS partners: the proposed research program involves patients and clinicians, microbiologists and epidemiologists, infectious disease specialists, caregivers in inpatient care and mathematical modellers. The R-GNOSIS consortium is made of 20 partners from 9 countries which include Belgium, Denmark, France, Germany, Israel, Netherlands, Spain, Switzerland and United Kingdom.

In October 2012, a new partner joined the project, Partner 22 – HUMFRYX.

- UMC Utrecht, Utrecht, Netherlands – Prof. Dr. M.J.M. Bonten
- Université de Genève, Geneva, Switzerland – Prof. Stephan Harbarth
- University of Antwerp, Antwerp, Belgium – Prof. Herman Goossens
- TASMC, Tel Aviv, Israel – Prof. Yehuda Carmeli
- Health Protection Agency, London, United Kingdom – Dr. Julie Robotham
- Université Paris XII – Val de Marne, Paris, France – Prof. Christian Brun-Buisson
- Université Paris Sud XI, Paris, France – Prof. Patrice Nordmann
- Cardiff University, Cardiff, United Kingdom – Prof. Chris Butler
- University of Southampton, Southampton, United Kingdom – Prof. Paul Little
- Spanish Society and Family Medicine, Barcelona, Spain – Dr. Carl Llor
- Charite - Universitaetsmedizin Berlin, Berlin, Germany – Prof. Petra Gastmeier
- Da Volterra, Paris, France – Dr. Florence Séjourné
- Servicio Madrileno de Salud, Madrid, Spain – Prof. Rafael Cantón Moreno
- Statens Serum Institut, Copenhagen, Denmark – Prof. Niels Frimodt-Møller
- University of Oxford, Oxford, United Kingdom – Dr. Ben Cooper
- ARTTIC, Paris, France – Carlos Triay
- Check-Points Health, Wageningen, the Netherlands – Dr. Pieter Vos
- GENEWAVE, Paris, France – Dr. Yann Marcy
- Assistance Publique Hôpitaux de Paris, Paris, France – Prof. Antoine Andremont
- HUMFRYX S.C, Barcelona, Spain – Josep Maria Cots, PhD

Project Results:

During the first 24 months of the R-GNOSIS programme, efforts have been focused on the preparation of the lab and study protocols, receiving ethical approval for the clinical studies, and – eventually - starting the clinical studies.

Progress on the preparation of the five clinical trials is as follows:

- WP2 – “Primary care”, has started in all 4 study sites.
- WP3 – “Decolonisation of ESBL carriers” underwent significant changes in its design, which was needed as the development program of the proposed investigational products was discontinued. The original plan was to decolonize patients with high concentrations of topical antibiotics and subsequently to recolonize them with an antibiotic-susceptible E. coli strain. Yet, recent studies suggested carcinogenic effects of the intended recolonisation strain. It was agreed to change the intervention to faecal transplantation, a procedure recently demonstrated to be highly effective for preventing recurrent infections with Clostridium difficile. During the second year of R-GNOSIS new laboratory and study protocols have been developed and the study is now ready for IRB submission.
- WP4 – “Surgical prophylaxis” received IRB approval for the three study sites and patient enrolment started in each of these sites.
- WP5 – “Isolation of ESBL carriers” has adapted study methods as per IRB issues. This necessitated a change in the microbiological procedures (from centralized to local testing), which necessitated considerable budget reallocations in the program. Study and laboratory protocols were finalized and IRB approval was obtained in all four study sites. The clinical study will start in M26, with the kick-off meeting in Berlin.
- WP6 – “Decolonisation in ICU” finalized the study protocol including the data safety committee protocol, as well as all logistical/financial arrangements for medication and culture methods. Interested study sites have been evaluated and IRB approval procedures have been initiated in 8 countries. IRB approval has been obtained in 6 countries. The kick-off meeting was on October 16th 2013 (M25) and the first 3 sites will start with the clinical study on December 1st 2013 (M26).
- WP7 – “Microbiology” has supported the development of microbiologic protocols for WP2/3/4/5 and 6. They have also worked on refining novel essays for the rapid detection of MDR-GNB to be used in WP2 and WP4 clinical trials.
- WP8 – “Mathematical modelling” work in this period consisted in the coordination with the other WPs in order to ensure that the data to be collected is relevant and several analyses, using data from external sources, have been started.
- WP9 – “Data Coordination Centre”, has been established and the collection portal website has been taken into production. Data management implementation has been defined with data capture adapted to the requirements of the R-Gnosis studies. All clinical studies (except WP3) have been implemented onto Research Online.
- WP10 - "Dissemination" has taken care of disseminating widely all the news and outputs which have been produced by all the partners and WPs within the frame of the R-GNOSIS project.

The activities of all WPs were closely monitored by the coordinator, with the support of the Project Office (acting through WP1). Cooperation between the WPs has been ensured and supported. There were regular teleconferences and numerous bilateral contacts between partners. Follow-up meetings of the consortium were held in September 2012 in Cardiff (UK) and in September 2013 in Amsterdam-Schiphol (NL). Close contacts between R-GNOSIS and other EU-funded projects (EvoTAR) were maintained.

The plans for the promotion of the project had already been laid out in a project dissemination plan through WP10. The website was launched on the 29/11/2012 under It contains, among other promotional material of the project, a section which displays the R-GNOSIS related scientific publications and outputs as they become available for public exposure and the scientific community.

Potential Impact:

The European Centre for Disease Prevention and Control and the European Medicines Agency estimated that 193,300 patients were infected with MDR-GNB in 2007, and that these infections caused 18,200 excess deaths and 1,375,000 additional hospital days in EU Member States, Iceland and Norway. Moreover, the rate of infections caused by MDR-GNB is still increasing. Today, ‘more of the same’ research is therefore no longer an option. An “out-of-the-box” conceptual step-change is necessary. Evidence base needs to be optimised for “well known but inadequately researched” infection prevention strategies through innovative and state-of-the-art study designs. Counterintuitive and highly innovative, solutions need to be identified and rigorously evaluated.

The R-GNOSIS programme will concentrate on:

- the reduction of the prescription of antibiotics by family practitioners;
- preventive administration of antibiotics to IC patients;
- the usefulness of isolating patients who are carriers of ESBL bacteria and;
- the prevention of infections following abdominal operations.

R-GNOSIS will perform five pivotal international clinical intervention studies, each yielding a clear-cut solution, readily implementable in clinical practice, if proven effective. R-GNOSIS proposes innovative technology and a beyond state-of-the-art hypothesis-driven clinical approach.

Furthermore, R-GNOSIS will apply a ‘bedside-to-bench’ translational approach to study the impact of antibiotics and gut decolonization on MDR-GNB pathogens and commensals in the community or hospital utilizing state-of-the-art microbiological tools. Results from the diagnostic interventions planned here will revolutionize current screening practices for MDR-GNBs in hospitals and introduce the use of point-of-care testing in primary care.

Finally, R-GNOSIS will facilitate ground-breaking modelling studies, in which nosocomial transmission capacities for different species of MDR-GNB during different interventions will be quantified. Within-host models of bacterial dynamics and gene transfer (based on in vivo and in vitro experiments) will be combined with between-host models, both for hospitals and the community. These integrated models will be used to provide projections of long-term impacts of interventions.

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