GRACE - Genomics to combat resistance against antibiotics in community-acquired LRTI in Europe

EC contribution: : € 11.500.000
Duration: : 60 months
Starting date: : 01/03/2006
Funding scheme: : Network of Excellence
Keywords: : antimicrobial resistance, community-acquired lower respiratory tract infections, genomics, health education
Contract/Grant agreement number: : LSHM-CT-2005-518226
Project web-site: : www.grace-lrti.org

Background:

GRACE is a NoE focusing on the complex and controversial field of community-acquired lower respiratory tract infections (CA-LRTI), which is one of the leading reasons for seeking medical care. The promiscuous use of antibiotics to treat LRTI accounts for a major part of the community burden of antibiotic use and contributes dramatically to the rising prevalence of resistance among major human pathogens. The overall objective of GRACE is to combat antimicrobial resistance through integrating centres of research excellence and exploiting genomics in the investigation of CA-LRTI. Microbial and human genomics will be integrated with health sciences research consisting of clinical observational and intervention studies, health economics and health education to change practice in managing CA-LRTI. In the jointly executed research programme, 28 academic groups, spread across 14 EU Member States and 4 SMEs will participate. GRACE will organise professional education, including web-based teaching and practical courses through two leading European scientific societies (European Society of Clinical Microbiology and Infectious Diseases and European Respiratory Society).

Problem:

CA-LRTIs are the leading reason for seeking medical care. Yet, there are few conditions in medicine that are so controversial. These uncertainties have resulted in prescriptive promiscuity, which largely explains the escalating antibiotic resistance of common bacterial respiratory pathogens in the community. Invasive S. pneumoniae represent a major threat of serious morbidity and mortality. The continued development of antibiotic resistance by this organism has made the treatment of CA-LRTI more difficult. There are no good studies of sufficient size on detecting bacterial aetiology of LRTI and on diagnosis of CAP in primary care. The epidemiological situation of infections, especially in the outpatient sector is almost completely unknown, because microbiological testing with an appropriate quality is almost never performed. Nucleic acid amplification based molecular diagnostic methods could be used to identify the causative organisms or to study the prevalence of these pathogens, such as the "atypical" bacterial and viral organisms. There has been no comprehensive, in-depth qualitative study identifying the perspective of patients and clinicians on management of CA-LRTI. Specifically, no study has sought to achieve a deep understanding of the variation in presentation, investigation and management across a range of European cultures and clinical setting. Very few, if any, interventions aimed to enhance clinical care have been based on thorough development work that incorporates a deep understanding of clinicians' and patients' perspectives. Most patients with acute bronchitis receive antibiotics, because there is still uncertainty about the indications for antibiotics in important subgroups of patients and often the distinction between viral and bacterial infections and between pneumonia and bronchitis is difficult. There is a tendency to "over-treat" and unnecessarily admit relatively mild cases to hospitals but also to inappropriately treat severely compromised and other high-risk patients. Some patients develop severe CAP, despite appropriate antimicrobial treatment and this could be related to host genetic susceptibility. Prediction rules for poor outcome in patients with CA-LRTI in primary care, that could help to restrict antibiotic treatment to high-risk patients, are lacking. Costs will become an important issue for the reimbursement of diagnostic tests and for new antimicrobials, which will depend upon their benefit and effectiveness. Technologies and solutions are available to address these issues, and the individual areas of expertise do exist in Europe, but the problem is in integrating these. It is obvious that the expected achievements of applicable microbial and genomic deliverables for improved patient care require the joint efforts of a multidisciplinary consortium.

Aim:

GRACE aims to strengthen European human and microbial genomic research excellence, focussing on an infection, which is a leading reason for seeking medical care and consuming antibiotics. This antibiotic consumption leads to a potent selective force for antimicrobial resistance among common bacterial respiratory pathogens in the community. There has been considerable fragmentation in European research efforts into CA-LRTI and this project represents a unique opportunity to address this head-on. GRACE will develop a durable network established over an initial five-year time frame. We aim to integrate research groups and organisations on a large pan-European with an ambitious scale. The close collaboration that will flow from GRACE aims to generate comprehensive, creative and more practical thinking through novel integration of cutting edge basic genomic science with research practitioners working in the community at the bedside and training such that the evidence informs future generations of practitioners. The hallmark of the network of excellence created by GRACE will be the integration of research platforms creating a European-wide infrastructure to investigate and improve the management of CA-LRTI.

Expected and obtained results:

First results

An Internet web portal under a common corporate identity is delivered which integrates all IT functions.
To this end workpacakge 2 developed a platform GOS (GRACE Online System). The portal serves for GRACE internal purposes as well as for dissemination of results to the public.
Workpackage 3 established a microbial diagnostic network of laboratories to develop novel rapid genome-based diagnostic testes for the detection of pathogens and performed. It did preparatory work for WP5, WP6, and WP7 and produced preliminary results based on the first samples collected from LRTI and control patients included in WP9-10. All these subjects were tested for known bacteria and viruses to establish a link between pathogens and disease. This material will be used to establish a European repository of specimens and strains linked to a database including microbial and patient information.
Workpackage 4 is responsible for studying the host genetic factors affecting the susceptibility to CA-LRTI. The susceptibility genes will be identified first by using candidate genes as well as genome-wide association approach in more severe LRTI, invasive pneumococcal disease, cases. As a result of candidate gene studies, the list of known susceptibility genes has been extended to 8 in total, including MBL, CD32, CRP, PTPN22, TLR1-6-10, MAL/TIRAP, NFKBIA, and NFKBIE.
Workpackage 5 will analyze "negative" patient samples with the aim of detecting new viruses. To do so, two partners of this WP, LUMC and AMC-Amsterdam, employ complementary state-of-art techniques, one exploiting the genome conservation among viruses and another relying on the ubiquitous presence of restriction sites in virus genomes. Results of these analyses are expected to contribute to our understanding of the mechanisms of the LRTI, and development of methods that may be applicable for analysis of the etiology of other infectious diseases.
Workpackage 6 is responsible for collecting the pneumococcal isolates from the clinical platforms within GRACE and to characterize these isolates with genomic molecular techniques. Antibiotic resistance types, serotypes, genotypes, and virulence characteristics will be correlated to clinical pictures of CA-LRTI. The first years have been focused on establishing and evaluating the molecular methods that will be used using an existing collection of pneumococcal isolates.
Workpackage 7 is responsible for investigating the prevalence, mechanism and evolution of antibiotic resistance in Haempohilus influenzae. The firs two years of the consortium have been focused on the preparation of the work to be conducted in the last 3 years.
Workpackage 8 has completed the registration study (GRACE-01) and shown the variability in both prescribing and antibiotic choice across Europe, which is only partially explained by variation in presenting symptoms and clinical signs. A qualitative interview study with clinicians has also been completed and analysed (GRACE-02). A similar study in patients is nearing completion. Finally it has also completed literature reviews and a consensus process to agree on definitions of common LRTI in primary care (GRACE-03). WP 8 data and results have also contributed to the design of WP9 and WP10 and also to the work of WP11.
Workpackage 9 is responsible for the observational clinical studies in GRACE. All necessary study documents and materials were prepared in close collaboration with
WP 10 and the workpackages 3, 4, 5, 6 and 7. In total 13 primary care networks in 10 EU countries were initiated and trained to start data collection. The networks were monitored and supported on a weekly basis. At this moment 1533 subjects (LRTI patients and controls) are included. Currently, the first Randomised Controlled Trial of workpackage 10 is running. It aims to assess the effect of amoxicillin 1g three times a day or placebo in altering symptom duration and severity, and whether deterioration in illness is prevented. The first winter recruitment phase neared completion and the emphasis is now on improving recruitment for the remainder of the trial.
Workpackage 11 is responsible for the economics element of GRACE. At this stage only preliminary results from the analysis of resource use (at the level of individual items of resource use) and health outcome data collected during WP8 are available. Results obtained to date may therefore change as further analysis (including application of additional unit cost data, imputation of data etc) is conducted. Early results suggest considerable variation in resource use across networks (for example, the number of GP consultations over four weeks and associated costs) and in improvement in health status over the four weeks as measured by the EQ-5D.
Workpackage 12 is responsible for education and training in GRACE. In the first two years, the overall Education and Training Curriculum was elaborated, the first three one-day postgraduate courses and the first two three-day workshops delivered. The next educational events are scheduled (https://www.grace-lrti.org/portal/en-GB/Training+Course.htm). All educational material is made freely available at the GRACE e-learning portal (http://www.ersnet.org/grace/).

Coordinator:

Prof. Herman Goossens
University of Antwerp
Department of Medical Microbiology
Universiteitsplein 1 S3
B-2610 Wilrijk-Antwerp, Belgium
Tel. +32 38213789
Fax +32 38254281
herman.goossens@uza.be

Manager
Dr. Katherine Loens
University of Antwerp
Department of Medical Microbiology
Universiteitsplein 1 S009a
B-2610 Wilrijk-Antwerp, Belgium
Tel. +32 38202418
Fax +32 38202752
katherine.loens@ua.ac.be

SMEs:

Guido Krupp
AmpTec GmbH
Hamburg, Germany

Jan Schouten
MRC-Holland
Amsterdam, Netherlands

Guus Simons
PathoFinder
Maastricht, Netherlands

Thierry Leclipteux
Coris BioConcept
Gembloux, Belgium

Scientific societies:

Javier Garau
European Society for Clinical Microbiology and Infectious Diseases (ESCMID)
University of Barcelona
Terrassa, Spain

Séverin Tania
European Respiratory Society (ERS)
Lausanne, Switzerland

European Commission