Improving rational prescribing for UTI in frail elderly (ImpresU)

Frail elderly, particularly those receiving home care or living in a care home, constitute a vulnerable and under researched population. They are frequently diagnosed with urinary tract infection (UTI) and almost 60% of the antibiotics (AB) used in this population are for UTI. However, a substantial part of these prescriptions might not be necessary, because presenting signs and symptoms (S&S) are erroneously ascribed to a UTI.

Ongoing project

Diagnosing UTI is challenging in frail elderly, due to atypical illness presentation, the lack of reliable diagnostics and the high prevalence of (asymptomatic) bacteriuria. Combined with the influence of contextual factors, such as beliefs and expectations of patients and caregivers, these factors increase the risk of AB overuse. This applies especially to AB courses that are prescribed for UTI with non-specific S&S, i.e. S&S not directly related to the urinary tract (e.g. mental status change, agitation, altered consciousness, lack of appetite).

Another driver of AB overuse in this population of frail elderly is recurrent UTI, which may lead to monthly courses of AB. Previous studies have shown that antimicrobial resistance is a growing problem in long term care and that the risk of transmission of resistant organisms between health care settings is increasing. Therefore, antibiotic stewardship interventions (ASI) are much needed in the continuum of home care and institutional care settings for frail elderly. For this purpose, the studies proposed here aim to reduce AB overuse for UTI in this population through implementation of a new algorithm – developed by an international Delphi panel – to support clinical decision making on signs and symptoms that justify a ‘watchful waiting’ approach in cases of suspected UTI in frail elderly.

As a first step, we will develop a conceptual model of factors that contribute to the prescribing decision in this population. Next, using a modified participatory action research approach, we will develop and implement a tailored ASI. Core of this intervention will be the implementation of the decision support algorithm. This will be combined with complementary interventions, selected together with the study participants (care staff, nurses, physicians) using the conceptual model and applying this to their specific setting and care practice. In addition, we will conduct a double blinded RCT on the safety and effectivity of prophylactic treatment with methenamine hippurate in older women with recurrent UTI. The results of this trial will help to further strengthen ASI in this group of patients.

Project partners

  • Cees Hertogh, VU University Medical Center, Netherlands (Coordinator)
  • Theo Verheij, University Medical Center Utrecht, Netherlands
  • Pär-Daniel Sundvall, Västra Götaland och Regionala Strama Södra Älvsborgs Sjukhus, Sweden
  • Morten Lindbaek, Antibiotic Centre for primary care, dept of general practice, University of Oslo, Norway
  • Maciek Godycki-Cwirko, Medical University of Lodz, Poland

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A digital antimicrobial stewardship smartphone application to combat AMR: the AB-assistant (AB-assistant)

Antimicrobials are an indispensable part of modern medicine. However, optimal prescription of these agents is becoming increasingly challenging because of the growing complexity of guidelines, and constantly changing epidemiology. Moreover, due to local variations in the prevalence of certain pathogens and antimicrobial resistance, antimicrobial choices need to be tailored to local epidemiology.

Ongoing project

Improvement of antimicrobial use, in particular prevention of overuse of (broadspectrum) antibiotics, through antimicrobial stewardship (AMS) programs is increasingly regarded as indispensable, both to optimize therapy for the individual patients as well as to reduce emergence of resistance. With the widespread use of electronic health records and handheld electronic devices in hospitals, informatics-based AMS interventions hold great promise as tools to improve antimicrobial prescribing. However, they are still underdeveloped, understudied and underutilized. We propose the development and evaluation of AB-assistant, a smartphone based digital stewardship app that is customizable to local guidelines and therefore has the potential to be used worldwide, including in low- and middleincome countries.

AB-assistant will build on the significant experience in the development and implementation of electronic tools for AMS by the partners participating in this proposal. Furthermore, the app will be available for the two most common mobile operating systems: iOS and Android.

In this project we propose to 1) develop an AB-assistant app based on the existing Spectrum app (Calgary; www.thespectrumapp.com) with improvements to enhance AMS in large parts of the world 2) test the usability of this app in different countries to determine barriers and facilitators 3) evaluate the AB-assistant in an international, multicentre, randomized clinical trial involving centres in 4 countries in different settings with appropriate antimicrobial use as a primary outcome and 4) use factors identified in this study to facilitate further customization and worldwide implementation of AB-assistant.

This unique proposal aims to develop a digital steward for use in different countries worldwide which will increase adherence to prescription guidelines and reduce antimicrobial resistance.

Project partners

  • Annelies Verbon, Erasmus MC University Medical Center, Netherlands (Coordinator)
  • Thomas Tängdén, Uppsala University, Sweden
  • Benedikt Huttner, University Hospitals Geneva, Switzerland
  • John Conly, University of Calgary, Canada
  • Marlies Hulscher, Radboud University Medical Center, Netherlands
  • Christina Grosu, University of Medicine and Pharmacy, Romania
  • Helena Zemlickova, Charles University, Czech Republic
  • Johan Mouton, Erasmus MC University Medical Center, Netherlands

Background: Antimicrobials are an indispensable part of modern medicine. However, optimal prescription of these agents is becoming increasingly challenging because of the growing complexity of guidelines, and constantly changing epidemiology. With the widespread use of electronic health records and handheld electronic devices in hospitals, informatics-based AMS interventions hold great promise as tools to improve antimicrobial prescribing.

Methods: In this study, we aim to develop and evaluate the AB-assistant, a smartphone based digital stewardship app that is customizable to local guidelines of hospitals. The project is a collaboration between hospitals in the Netherlands, Switzerland, Sweden, and Canada and has started at February 1, 2018. A pilot study determining the potential barriers and facilitators for using the app in different languages and cultures is part of the project. The impact of the AB assistant on appropriate antibiotic prescribing will be evaluated in a large randomized study in the Netherlands, Sweden and Switzerland. Hospitals in the Caribbean and Africa will also participate in (part of) the study.

Results: 1) An existing app (Spectrum MD) has been adapted to the AB assistant in a project with partners in the Netherlands, Canada, Sweden and Switzerland. The app is now available for use in all these countries. 2) A content management system was added so that changes can be easily made in the app by participating hospitals. 3) A pilot study with this app in the Netherlands, Switzerland and Sweden to determine barriers and facilitators for its use has been done and data were used to improve the app and to develop a quantitative questionnaire. 4) Preparations for the evaluation of the AB-assistant in an clinical trial such as IRB approval; selection of participating wards; a study record form tested with vignet patients; randomization program and whitelisting system
for users are in place. The actual trial has been started. 5)approached African and Caribbean countries agreed to participate in the study 6) the app has been presented at national SWAB symposia and the protocol has been published in a Medical Journal.

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Comparative assessment of social-ecological resilience and transformability to limit AMR in one health systems (AMResilience)

Resilience captures the ability of systems to respond to surprise while maintaining vital functions and is an important attribute for health systems in the context of rising global risks such as emerging infectious diseases and growing antimicrobial resistance (AMR).

Ongoing project

The theoretical and empirical foundation underpinning one-health systems’ resilience to AMR, is largely undeveloped. This includes the aspect of transformability; the capacity to undertake fundamental change to achieve a more sustainable or desirable state. In the area of AMR, a transformative intervention could e.g. be the transformation to livestock production without antimicrobial use (AMU) for growth promotion or classes relevant for human use as well as other interventions to ensure human health and sustainable food production systems.

We recently introduced and formalized resilience and transformation frameworks for AMR at the global level. Here, we extend these to assess the resilience and transformability of national and regional one health systems and interventions. With the specific focus on resistant Enterobacteriaceae and MRSA, we assess factors governing resilience and transformations in selected high-income (HIC) and lowermiddle income countries (LMIC, focusing on South and East Asia), explicitly considering the link between both agriculture, aquaculture and human health.

Using a multi-method approach, we undertake a systematic literature review, case study analysis (WP1) and participatory assessment (WP2) to build a database describing factors determining resilience and transformability. This database is cross-validated by quantitative time-series analyses (WP3). We then seek to identify indicators of resilience and transformability (WP4) with the aim to be able to predict these dynamics in the future. Together, these analyses feed information into a set of integrated assessment models (WP5), which explore the system dynamics of interventions and future scenarios. Together, and through a comprehensive set of outreach activities to practitioners and decision makers these activities will inform future management and policy to better limit AMU and AMR across animal and human health.

Project partners

  • Peter Jørgensen Søgaard, Royal Swedish Academy of Sciences, Sweden (Coordinator)
  • Shannon Majowicz, University of Waterloo, Canada
  • Didier Wernli, University of Geneva, Switzerland
  • Jane Parmley, University of Guelph, Canada
  • Stephan Harbarth, University Hospitals Geneva, Switzerland

The project aims to understand the factors that enhances resilience of society to the challenge of AMR using interventions as a study object. Resilience captures the ability of systems to respond to surprise while maintaining vital functions and is an important attribute for health systems in the context of rising global risks such as emerging infectious diseases and growing threat of AMR. Aspects of interventions and resilience studied in the project include success factor and obstacles of interventions, understanding social and ecological aspects of intervention settings, and modelling systems dynamics of new types of interventions.

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Intervention of antimicrobial resistance transfer into the food chain (INART)

Soil and water have been identified as reservoirs of antimicrobial resistance (AMR) and the food chain as the most likely mode of AMR transfer into human and animal pathogens. Manure is reused as soil fertiliser in which food plants grow and is a source of AMR.

Ongoing project

We hypothesise that pre-treatment of manure will reduce and remove the abundance and diversity of AMR genes and pathogenic bacteria of high priority from entering the food chain. Alleviating AMR elements from entering the food chain will reduce the transfer and uptake of mobile AMR genes and pathogens by human and animals.

This project will focus on chicken and pig manure as both have been demonstrated to carry a wide variety and abundance of mobile AMR genes of clinical relevance. Our intervention is to pre-treat the manure in order to reduceor remove the burden of AMR in the manure prior to reuse as fertiliser. The microbiomes of chicken and pig manure differ, but the AMR genes and mobile elements overlap. Our study will investigate if the same pre-treatments will reduce or remove AMR prior to application and if these reductions or removal are maintained on the food plants or grass, and in the soil.

We will also identify the main microbiome changes mediated by the intervention and analyse if these bacterial changes are important in the mitigation of AMR. Reducing or removing thethreat of AMR at the start of the food chain will reduce the potential for selection and transfer of such AMR genes and pathogens further along the food chain. By stopping or reducing the continuous transfer of AMR genes and mobile elements along the food chain we will reduce the burden of AMR in pathogenic bacteria.

Project partners

  • Fiona Walsh, Maynooth University, Ireland (Coordinator)
  • Edward Topp, University of Western Ontario, Canada
  • Magdalena Popowska, University of Warsaw, Poland
  • Eddie Cytryn, Agriculture Research Organisation, Israel
  • David Drissner, Albstadt-Sigmaringen University, Germany
  • Fiona Brennan, Teagasc Environmental Research Centre, Ireland
  • Xavier Sidler, University of Zurich, Switzerland

Antimicrobial resistance can be passed from animal and human waste to the environment through pollution and using it as fertilisers to help crops and grass growth. Our research wants farmers to be still able to use this useful waste to give nutrients to the crops and grass but to remove the chance of antimicrobial resistance being passed on to bacteria in the soil or on the plants.

This project is looking at ways to treat farm manure before it’s added to the field. We have used three different and cost-effective ways to treat animal manures and compared these with untreated manures. The manures are then spread on crops or grass and we measure if antibiotic resistance is present, if bacteria that cause disease are present and if both of these stay on the plant and in the soil for weeks afterwards. We will be able to say if the treatments reduce or stop the antibiotic resistant bacteria being passed onto the soil and grass and which treatments work best. We’ll also be able to say if some of these bacteria and antibiotic resistances don’t survive on the plants or in the soil for very long and then also the bacteria and antibiotic resistances that can survive and that are most important to look for on the plants before animals or humans eat them.

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Preventing transmission of MRSA from livestock to humans through competitive exclusion (ExcludeMRSA)

Pig farms act as reservoir of Livestock-Associated Methicillin-resistant Staphylococcus aureus (LA-MRSA). Through occupational exposure to farm dust and contact with pigs, farm workers are at risk for acquiring LA-MRSA.

Ongoing project

Although health care institutions can cope with the current situation, it is a burden for patients, health care staff, and finances. In addition, the recent observed adaptation of LA-MRSA originating from pigs to humans in Denmark further highlights the need to reduce LA-MRSA colonization in pigs and subsequent transmission to humans. In a pilot study of the nasal microbiome we observed that piglets become LA-MRSA positive after a few days of birth. The presence of several other bacterial species, including coagulase-negative staphylococci was negatively associated with the presence of LA-MRSA. More evidence is needed regarding which bacterial species and/or strains compete with LAMRSA.

The project aims to establish the effect of colonization resistance (bacterial competition) on the transmission of LA-MRSA from pigs to humans by i) identifying bacterial species that compete with LA-MRSA (S. aureus in general) in a systematic way using state of the art bioinformatics and metagenomics methods at strain level, ii) studying the efficacy of applying a nasal microflora for piglets which will be produced under GMP conditions by the industrial partner in the project and tested under field conditions at conventional farms, and iii) to estimate the risk reduction as a result from limiting MRSA transmission to humans by reducing shedding and consequently a more limited environmental contamination.

Communication with farmers, veterinarians, public health workers and other stakeholders, with the help of our supporting organizations, will prepare the stakeholders for the outcome of the project, bringing it close to immediate use in practice. Exclude MRSA will deliver a reduction of MRSA colonization or will lead to complete prevention of MRSA colonization by precolonization of piglets with microflora. The efficacy will be assessed in two countries by using proven environmental risk models for human exposure and evaluating changes in the exposure risk association. Because of the earlier performed successful pilot studies, the experience of the partners and the inclusion of an industrial partner experienced in production of live strains, this project is feasible in three years’ time.

Project partners

  • Jaap Wagenaar, Utrecht University, Netherlands (Coordinator)
  • Marcus Claesson, University College Cork, Ireland
  • Peadar Lawlor, Teagasc Environmental Research Centre, Ireland
  • Dick Heederik, University Medical Center Utrecht, Netherlands
  • Thilo Borchardt, EW Nutrition GmbH, Germany

Pig farms act as reservoir of Livestock-Associated Methicillin-resistant Staphylococcus aureus (LA-MRSA). Through occupational exposure, farm workers are at risk for acquiring LA-MRSA. In countries with low-prevalent health care associated MRSA and community acquired MRSA, LA-MRSA adds considerably to the MRSA-burden for patients, health care staff, and finances. The recent observed adaptation of LA-MRSA to humans in Denmark highlights the need to reduce LA-MRSA colonization in pigs.

The project aims to establish the effect of colonization resistance on the transmission of LA-MRSA from pigs to humans by i) identifying bacterial species that compete with LA-MRSA, ii) studying the efficacy of applying a nasal microflora for piglets, and iii) to estimate the risk reduction for MRSA transmission to humans due to a reduced shedding and environmental contamination. Currently, we analyzed our pilot study data in which the nasal microbiome of piglets was followed over a period of 42 days. We detected in total 15 bacterial species negatively correlated with Staphylococcus aureus and/or MRSA colonization. Because samples were not collected for culturing in the pilot, it functions primarily as a method to determine which timepoint is optimal to find competing bacteria. We completed the sampling phase of the full study and these samples are being analyzed. The strains will be isolated from samples of the investigated piglets. We will produce a nasal microflora carrying a mix of competing micro-organisms that will either prevent or strongly reduce colonization of MRSA in piglets. Finally we will use this microflora in a farm setting, the level of colonization of MRSA will be tracked in treated and untreated animals to assess the reduction in spread.

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Understanding and modelling reservoirs, vehicles and transmission of ESBL-producing Enterobacteriaceae in the community and long term care facilities (MODERN)

MODERN is an international collaborative project investigating the reservoirs and transmission of Enterobacteriaceae producing extended-spectrum β-lactamases, a group of antibiotic-resistant bacteria that has spread worldwide recently.

Completed project

The study is centered in transmission in non-hospital environment such as households and nursing homes, and include food products, environmental reservoirs and wastewater. Advanced epidemiological methods and whole genome sequencing are being used to identify the rate and risk factors for transmission of these bacteria among residents in these environments in order to produce the information needed to build mathematical models explaining their spread, which will allow to estimate the impact of potential control measures.

Very exhaustive and state-of-the-art studies have been carried out to see the characteristics of these bacteria and their way of transmission, which is different in different species. Knowing this, and adding all the demographic characteristics and risk factors collected from each participant, using advanced mathematical methodology, a model is developed that allows predicting transmission. The ultimate goal is to be able to act at critical points in order to end the problem of antibiotic resistance.

Project partners

  • Jesús Rodríguez-Baño, Hospital Universitario Virgen Macarena, Spain (Coordinator)
  • Evelina Tacconelli, University Hospital Tübingen, Germany
  • Stephan Harbarth, University of Geneva, Switzerland
  • Jan Kluytmans, University Medical Center Utrecht, Netherlands
  • Didier Hocquet, University Hospital, France
  • Ben Cooper, University of Oxford, United Kingdom

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The rates and routes of transmission of multidrug resistant Klebsiella clones and genes into the clinic from environmental sources (SpARK)

The rise of antimicrobial resistance is a pressing public health crisis on a global scale, but the use of antibiotics in humans only represents a small part of the problem.

Completed project

Effective management strategies need to incorporate antibiotics in agriculture, as well as the release of these drugs, and resistant bacteria, into the environment. This project conforms to this “One-Health” framework by discovering how frequently antibiotic resistant bacteria move between humans, animals and different settings in the environment such as river water and soil.

The project focusses on a group of bacterial species called Klebsiella which are common in the environment and in animals, but also cause infections in humans and livestock that are resistant to antibiotics. One species in particular, Klebsiella pneumoniae, is a very common cause of resistant infections in hospitals and is recognised by the WHO as critically high priority. Northern Italy is a ‘hotspot’ for these infections, but it is not clear whether these bacteria are confined to hospitals, or are also present elsewhere.

To address this, we took 3500 Klebsiella strains from hospital patients, wild and domesticated animals and multiple environmental sources. Importantly, all the strains were taken from a single city, Pavia, in Lombardy. By sequencing the genomes of these bacteria, combined with mathematical modelling, we could tell which resistant genes were present, and how the strains were moving. We found that resistant genes are strains were uncommon outside of hospitals, and that the vast majority (around 75%) of Klebsiella in humans comes from other humans. However, we did find some risk of transmission from companion animals (dogs and cats) and water sources.

Project partners

  • Edward Feil, University of Bath, United Kingdom (Coordinator)
  • Piero Marone, Fondazione IRCCS Policlinico San Matteo, Italy
  • Sylvain Brisse, Pasteur Institute, France
  • Louise Matthews, University of Glasgow, United Kingdom
  • Jukka Corander, University of Oslo, Norway
  • David Aanensen, Big Data Institute, Oxford, United Kingdom
  • Alan McNally, University of Birmingham, United Kingdom

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Genomic approach to transmission and compartmentalization of extended-spectrum cephalosporin resistance in Enterobacteriaceae from animals and humans (TransComp-ESC-R)

This project studied the epidemiology of resistance to a critically important group of antibiotics called extended-spectrum cephalosporins (ESCs) in humans, animals and food. It showed that the multiplication, transmission and host adaptation of major bacterial strains such as the famous E. coli ST131 is only one method by which resistance to ESCs spreads.

Completed project

The study has identified specific types of ESC resistance plasmids (genetic elements which can move from one bacterium to another), which are spreading very actively in bacterial populations from humans and animals (including wildlife), from the local to the international level and even between Europe and North America.

By comparing bacteria with and without ESC-resistance plasmids the researchers have discovered new interactions between plasmids and their host bacterium. In one case, these interactions may be associated with the regulation of chromosomal genes by plasmid genes not related to antimicrobial resistance. In another case, an antimicrobial resistance gene (mcr) other than for ESC but frequently located on the same plasmid was shown to facilitate the establishment and colonization of the gut by bacteria. In both cases, these interactions are thought to increase the success of ESC resistance plasmids in bacterial populations.

Finally, the researchers also showed that the use of antimicrobials increases the persistence of ESC-resistant bacteria in cattle. They developed mathematical models which allow to predict and quantify this effect. Overall, this study has generated new information on the epidemiology of ESC resistance and mathematical models which will be of great use for both scientists and policy makers in the fight against antimicrobial resistance.

Project partners

  • Patrick Boerlin, University of Guelph, Canada (Coordinator)
  • Richard Bonnet, Université d’Auvergne, France
  • Jean-Yves Madec, National Agency for Food, Environmental and Occupational Health & Safety (ANSES), France
  • Michael Mulvey, University of Manitoba, Canada
  • Stefan Schwarz, Friedrich-Loeffler-Institut, Germany
  • James Wood, University of Cambridge, United Kingdom
  • Alison Mather, University of Cambridge, United Kingdom
  • Heike Kaspar, Federal Office of Consumer Protection and Food Safety, Germany

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Predicting the Persistence of Resistance Across Environments (PREPARE)

Antimicrobial resistance poses a serious challenge to health care worldwide. One common approach to tackling resistance is to stop using a particular antimicrobial for a period of months or years, in the hope that resistance will decrease.

Completed project

However, such attempts to control resistance by stopping antimicrobial use have met with mixed success. Failures of a critical assumption underlying such strategies – that resistant strains suffer a disadvantage in the absence of drug (the “cost of resistance”) – may be responsible for difficulties in controlling resistance by cessation of drug use.

The PREPARE consortium was convened to develop an experimental and theoretical framework for understanding, and ultimately predicting, the conditions under which resistance will persist. Specifically, we set out to address the roles of host genetic background and environment in determining the costs of resistance. That is, we asked whether there are particular environments, or particular bacterial strains, in which we would expect to see resistance persist.

We found that there are indeed strains, environments, and combinations thereof, where resistance confers no cost. This suggests that resistance could persist in some real-world settings, even when antimicrobial usage has been stopped or paused. Unfortunately, we found that it is very difficult to predict which environments or strains might act as reservoirs for resistance. Novel mathematical models do show promise in increasing our ability to predict persistence. The ability to make such predictions will assist policy-makers in formulating strategies for controlling the spread of resistance.

Project partners

  • Alex Wong, Carleton University, Canada (Coordinator)
  • Claudia Bank, Instituto Gulbenkian de Ciência, Portugal
  • Thomas Bataillon, University of Aarhus, Denmark
  • Isabel Gordo, Instituto Gulbenkian de Ciência, Portugal
  • Rees Kassen, University of Ottawa, Canada

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Risk of companion animal to human transmission of antimicrobial resistance during different types of animal infection (PET-Risk)

The close contact of pets with humans provides excellent opportunities for interspecies transmission of resistant bacteria and their resistance genes in either direction. Infections in humans due to antimicrobial resistant bacteria originating from pets are becoming a concern.

Completed project

The PET-Risk consortium evaluated the frequency and the public health importance of the sharing of resistant bacteria between dogs, cats and humans living in close contact.

How was this done?

  • Study case enrolment – Dogs, cats and humans living in contact were recruited. The enrolment of participants took place in Portugal and the United Kingdom.
  • Sharing of bacteria – The samples collected from companion animals and their owners were used to evaluate the presence of multi-resistant bacteria as well as the occurrence of transmission between humans and animals.
  • Risk analysis – Established control measures that might help to limit the dissemination of resistant bacteria from companion animals.

What questions were answered?

  • Is there transmission of similar bacteria and/or antibiotic resistance genes to humans during companion animal with UTI? NO
  • Is there transmission of similar bacteria and/or antibiotic resistance genes to humans during companion animal with SSTI? YES
  • What is the extent of the risk of human colonization? As far as we have learned it exists but is LOW!
  • Does the transfer of antimicrobial resistance from companion animals to humans in contact occur more frequently during animal infection? YES
  • Which types of infection promote a higher risk of transmission, skin and soft tissue infections (SSTIs) or urinary tract infections (UTIs)? SSTIs
  • What measures are advised to control the transfer of antimicrobial resistance from companion animals to humans in contact? Wash hands after contact with your pet if is sick with a resistant bacteria and under antimicrobial treatment, were gloves for procedures, clean surfaces, avoid direct contact during the treatment (no kissing, no sleeping in the same bed).

Project partners

  • Constança Ferreira Pomba, University of Lisbon, Portugal (Coordinator)
  • Stefan Schwarz, Friedrich-Loeffler-Institut, Germany
  • Scott Weese, Ontario Veterinary College at the University of Guelph, Canada
  • Anette Loeffler, The Royal Veterinary College, United Kingdom
  • Vincent Perreten, University of Bern, Switzerland

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