The R-GNOSIS (Resistance in Gram-Negative Organisms: Studying Intervention Strategies) project combines 5 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).
All clinical work-packages (WPs) 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. Separate horizontal WPs will deliver transformational project-management, data-management and dissemination. 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 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 is a striking lack of new antimicrobial agents against MDR-GNB. Even if new agents were to be discovered, the lead in time is considerable as there are no truly new agents 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 of 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.
To identify the most effective measures for controlling selection and transmission of MDR-GNB and their genes, the most effective measures to reduce infections caused by MDR-GNB in relevant patient populations in the community and healthcare settings, to optimize treatment and prophylaxis strategies to avoid the detrimental consequences of these bacteria on patient outcome and to investigate the critical molecular aspects for persistence and transfer of resistance genes in the human gut.
The scope of the problem (an estimated 25,000 people dying from infections caused by multiresistant bacteria in Europe in 2007, with infections caused by MDR-GNB increasing exponentially) means that 'more of the same' research is simply not an option. An "out-of-the-box" conceptual step-change is necessary, in which the evidence base is optimised for "well known but inadequately researched" infection prevention strategies through innovative and state-of-the-art study designs, and in which counterintuitive and highly innovative, solutions are identified and rigorously evaluated.
The R-GNOSIS project is built on 5 clinical WPs (WP2-6), all interacting with WPs on microbiology (WP7) and mathematical modelling (WP8). SMEs will participate in two of the clinical WPs. Separate horizontal WPs will lead and deliver high-quality project-management, (WP1) data-management (WP9) and transformational dissemination (WP10). The scientific contents of the clinical WPs will be hypothesis-driven, with clear and ambitious outcomes that matter to the health and well-being of the people in Europe and beyond. Each primary outcome addresses "reduction of infections with or spread of MDR-GNB".
R-GNOSIS will perform 5 pivotal international clinical intervention studies (2 RCTs, 2 cluster-RCTs (cRCT) and 1 interrupted longitudinal study), each yielding a clear-cut solution, readily implementable in clinical practice, if proven effective. Each study will be innovative; because of technology used and/or because of its hypothesis-driven clinical approach.
The five clinical WPs will provide the required evidence for optimizing antibiotic prescription for a wide range of relevant infections, both in primary care and in health care settings. 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.
Transmission of MDR-GNB or their resistance genes (Dashed arrows are not studied in R-GNOSIS)
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 (reproductive number per hospital admission, RA) for different species of MDR-GNB during different interventions (contact isolation, standard precautions and decolonization strategies) will be quantified, and in which 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 tested and not tested in R-GNOSIS.