MOSAR - Mastering hospital antimicrobial resistance and its spread into the community

EC contribution: : € 10.000.000
Duration: : 60 months
Starting date: : 01/02/2007
Funding scheme: : Integrated Project
Keywords: : antimicrobial resistance, cross-transmission, diagnostic tests, infection control, prevention, typing, statistical models
Contract/Grant agreement number: : LSHM-CT-2007-037941
Project web-site: : http://www.mosar-sic.org

Background:

Infections caused by antimicrobial-resistant bacteria (AMRB) account for an increasing proportion of healthcare-associated infections in European hospitals, particularly in high-risk units like intensive care units (ICUs)and surgery. Patients discharged to rehabilitation care units often remain long-term carriers of AMRB, contributing to their dissemination into other care areas and within the community. Increased prevalence of resistance to antibiotics of major hospital pathogens is associated with adverse outcomes of patients affected, and includes delayed appropriate therapy or even failure of therapy, prolonged length of hospital stay, and increased mortality.

While the optimal strategies for control of AMRB remain debated, understanding the dynamics of resistance and the relative contribution of the most important determinants of dissemination of AMRB (cross-transmission via contacts and antimicrobial selective pressure), is needed to better define these strategies. The integration in these approaches of rapid molecular diagnostic testing for AMRB carriage may improve the timeliness and efficacy of control measures.

Problem:

The prevalence of AMRB has been rising worldwide during the past decades. Data gathered within the European surveillance system (EARSS project) show that resistance rates for major nosocomial pathogens have increased up to alarming levels in many countries, despite persistently low rates among a few others, mostly from northern Europe. Each of the AMRB listed below can colonise hospitalised patients in its specific niche, who then become occult carriers and may contribute to the further dissemination of AMRB within facilities or upon transfer to other facilities and into the community. Rehabilitation centres could serve as a large reservoir of AMRB, with the potential for amplification and dissemination into the community. Indeed, there is growing concern with e.g., community-acquired methicillin-resistant Staphylococcus aureus (MRSA), causing small outbreaks in specific populations. Exchange of genetic material and resistance traits can also occur between related or unrelated species, further worsening the problem. For example, co-colonization with MRSA and vancomycin-resistant enterococci (VRE), which frequently occurs in patients with prolonged stay, facilitates horizontal transfer of vancomycin-resistance genes, transforming MRSA into vancomycin-resistant S. aureus (VRSA). Several outbreaks with VRE and multi-resistant Acinetobacter spp have been described recently in many European hospitals. There is clearly a need for recommendations to combat the emergence of these organisms in Europe with respect to recognition, detection, and prevention of transmission.
Although most authorities agree that control of AMRB such as MRSA, VRE, extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae, and Acinetobacter spp. is desirable, the most appropriate strategies for control remain elusive. While interventions to reduce patient-to-patient transmission are considered the cornerstone of infection prevention, their feasibility and cost-effectiveness have not been determined rigorously. Evidence from prospective, multi-facility studies regarding the relative efficacy and cost-effectiveness of different control strategies is lacking. The lack of strong scientific support to recommendations for control of AMRB substantially weakens their impact and contributes to the marked heterogeneity of preventive practices across institutions.

Aim:

The overall objective of MOSAR is to provide advanced knowledge in the dynamics of transmission of AMRB, and address the controversies surrounding control measures by testing different strategies to combat the emergence and spread of antimicrobial resistance, focusing on endemic or emerging AMRB in hospitals, now spreading into the community.

Microbial genomics and human response to carriage of AMRB will be integrated in MOSAR with health sciences research, including interventional controlled clinical studies of strategies for control of AMRB in ICUs, surgical wards and rehabilitation centers, incorporating the use of new molecular diagnostic tools for rapid detection of carriage; medico-economic evaluation of the strategies tested will be conducted in parallel to inform policy makers. The data gathered during the clinical trials will be used to advance our understanding of the dynamics of resistance through mathematical modelling, integrating several factors contributing to the spread of AMR strains to inform on: 1) The real-time analysis of the relative contribution of exposure to antibiotics and resulting selective pressure; 2) The intrinsic characteristics of epidemic clones that contribute to inter-individual transmission ('epidemicity' of strains); 3) The identification of factors contributing to the transmission of strains between individuals in the hospital population and community (e.g., "transmission hubs" linked to caregivers and direct contacts between patients).
To achieve these objectives, MOSAR brings together experts in basic laboratory sciences, hospital epidemiology, clinical medicine, behavioural sciences, quantitative analysis and modelling, and health economics. MOSAR involves 11 institutions recognized for their leadership in these fields from 10 EU Member or Associated States, as well as 6 SMEs to develop and validate high-throughput automated molecular tools for detection of AMRB.

Expected and obtained results:

The results anticipated by the MOSAR partners include the following:

development of standards for conventional methods for detection of AMRB in screening samples;
development and validation in the clinical setting of high-throughput molecular-based methods for detection of resistant bacteria in screening for carriage of AMRB in clinical samples, and assessment of their cost-utility;
establishment of a bank of well-characterised clinical isolates of MRSA, VRE, and ESBL-producing Enterobacteriaceae and Acinetobacter spp.
characterisation of subtypes of the MRSA and VRE associated with hospital outbreaks, and analysis the molecular basis of the epidemicity of corresponding MRSA and VRE strains.
assessment from prospective, multi-centre studies in areas with high prevalence of antimicrobial resistance (ICUs, surgical units, rehabilitation centers), of the relative efficacy and cost-effectiveness of different control strategies including enhanced standard precautions, screening for carriage using conventional or high-throughput molecular methods, and decolonisation in surgical patients;
definition of the cost-effectiveness and applicability of strategies for control of AMRB in high-risk areas in the hospital setting.
development of mathematical models to assess the potential value of the tested control measures in various environments and their long-term effects, allowing prediction of the efficacy of interventions in different populations, settings, timescales, and variants of interventions.
development of mathematical models integrating the contribution of the intrinsic epidemicity of MRSA, of cross-transmission and of antibiotic use in the dynamics of resistance, to be translated into user-friendly interfaces for use by infection control personnel.

Potential applications:

Results from MOSAR will inform healthcare workers and decision-makers on strategies for forecasting and mastering antimicrobial resistance. The project's results should increase awareness of nosocomial pathogens such as vancomycin-resistant enterococci (VRE) as an emerging cause of hospital acquired infections.

MOSAR will contribute to developing the next generation state-of-the-art technologies of diagnostic tests. Existing molecular tests and the newly developed technologies will be adapted to the different needs of the laboratories and countries participating in MOSAR.

In addition, the standardisation of conventional tests and high throughput assays for the detection of AMR will facilitate a common approach to microbiological practice, and allow the meaningful comparison of results from different settings. The results of the observational and interventional studies contained within the MOSAR integrated project will provide evidence to base additional support for, or the modification of, the standards on which to base interventions to combat dissemination of antibiotic resistance within healthcare facilities, against which local practices can be audited. Mathematical modelling will facilitate the generalisability and implementation of these interventions to make these standards relevant to all healthcare systems across Europe. These interventions will enhance infection control practices and are likely to subsequently impact on antibiotic use and resistance. Initiatives for change in practice can be directed towards these standards. Knowledge gained through MOSAR will help format education and training of healthcare personnel and beyond.
Through development of models forecasting levels of antimicrobial resistance, accounting for the major players (control measures, antibiotic pressure and strains involved), MOSAR will provide healthcare staff and infection control personnel with user-friendly instruments designed to provide short-term and real-time forecasting of antimicrobial resistance within a given setting. These instruments will be developed to interpret outcomes from intervention studies and help design future strategies for control.

Coordinator:

Prof. Christian Brun-Buisson
Institut National de la Santé et de la Recherche Médicale (INSERM)
INSERM U657 & Université Paris Val de Marne (UVPM)
Hôpital Henri Mondor, Assistance Publique-Hopitaux de Paris
51, Ave Mal De Lattre de Tassigny
Créteil, France
Tel. +33 1 4981 2391
Fax +33 1 4207 9943
E-mail: christian.brun-buisson@hmn.aphp.fr

European Commission