Call: Prevention and Intervention Strategies to control AMR infections

5th call, 2017

An Online Platform for Expanding Antibiotic Stewardship (OPEN Stewardship)

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Call

Antibiotic resistance is a mounting public health threat calling for action on global, national and local levels. Antibiotic use has been a major driver of increasing rates of antibiotic resistance. This has given rise to the practice of antibiotic stewardship, which seeks to reduce unnecessary antibiotic use across different care settings.

Ongoing project

Antibiotic stewardship has been increasingly applied in hospital settings, but adoption has been slow in many ambulatory care settings including primary care of humans. Uptake of antibiotic stewardship in veterinary care has been similarly limited. Audit and feedback systems of antibiotic use coupled with patterns of antibiotic use and best practice guidelines have proven useful in outpatient settings, but scale-up is limited by heterogeneous systems of care and limited resources.

We aim to develop an open web-based system that allows for advanced stewardship interventions in the form of feedback and benchmarking as well as sharing of best practice guidelines and antibiotic resistance patterns. The proposed model can be rapidly expanded across health systems, countries, and sectors (animal vs. human), with minimal resource expenditures. We will build upon an existing platform for monitoring antibiotic resistance, and pilot these interventions with international providers in both medicine and veterinary medicine, in the form of an interrupted time series analysis. Outcomes will focus on platform development, interface usability, and prescription patterns during the study.

Project partners

  • David Fisman, University of Toronto, Canada (Coordinator)
  • Sonja Löfmark, Public Health Agency of Sweden, Sweden
  • Amy Greer, University of Guelph, Canada
  • Nadav Davidovitch, Ben-Gurion University, Israel
  • Moriah Ellen, Jerusalem College of Technology, Israel
  • John Brownstein, Harvard Medical School, USA
  • Derek MacFadden, Boston Children’s Hospital, USA

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Impact of Prescription Quality, Infection Control and Antimicrobial Stewardship on Gut Microbiota Domination by Healthcare-Associated Pathogens (PILGRIM)

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Vancomycin-resistant enterococci (VRE), extended-spectrum beta-lactamase producing Enterobacteriaceae (EPE), and Clostridium difficile have become an immediate threat to hospitalized patients worldwide. Although surveillance and control programmes are in place in many countries to mitigate transmission of these drug-resistant organisms in the healthcare setting, the impact of the VRE/EPE/C. difficile epidemic on individual patients entering the healthcare system is poorly understood.

Ongoing project

There is a scarcity of trials defining the impact of the VRE/EPE/C. difficile epidemic on individual patients newly entering the healthcare-system. It is unknown to what degree infection control (IC) and antimicrobial stewardship (AMS) interventions can disrupt the presumed chain of events (acquisition, colonization, antibiotic selective pressure, and intestinal domination) leading to infections with these microorganisms. Herein, we describe a comprehensive, multinational, multi-centre clinical study programme to elucidate the impact of the VRE/EPE/C. difficile epidemic on patients at high risk of healthcare-associated infections, during which we will observe the clinical and pathophysiological events leading to infection, analyse the preventative potential of IC and AMS, establish the preventable burden of these microorganisms, and better understand when and why AMS/IC measures are not always effective.

Centrepieces of the study will be rating of adequateness of antibiotic treatments by an international AMS-board and in-depth analysis of intestinal microbiota before and after antibiotic exposure. We hypothesize that receiving inadequate treatment places patients at high risk of intestinal domination and thus infection by these microorganisms. Further analyses will address costeffectiveness of specific interventions, behavioural analyses of the decision process leading to inadequate antibiotic treatment, and the rate of undetected previous colonization by EPE/VRE/C. difficile falsely attributed as hospital-acquired when conventional screening methods are used.

Project partners

  • Jörg Janne Vehreschild, University Hospital of Cologne, Germany (Coordinator)
  • Noa Eliakim Raz, Rabin Medical Center, Israel
  • Uga Dumpis, University of Latvia, Latvia
  • Gunnar Skov Simonsen, University Hospital of North Norway , Norway
  • Christian Giske, Karolinska Institutet, Sweden
  • Makeda Semret, McGill University Health Centre (MGU), Canada

The gut flora includes millions of bacteria and other microorganisms which naturally contribute to keep the human body healthy. It is mainly located in the colon (large intestine). Alimentary habits, diseases, and the use of antibiotics or other drugs may modify the number and type of bacteria in the gut flora. Antibiotics save many lives by curing patients with bacterial infections such as pneumonias or urinary infections. After oral or intravenous administration, antibiotics enter the bloodstream, are transported to the site of infection (for example, in the lungs or in urine) and kill the bacteria causing the infection. Small amounts of antibiotics also reach the colon and the bacteria of the gut flora. There, some bacterial species may be killed; other species may abnormally overgrow, resulting in domination of the flora, or become resistant to antibiotics.

The number of antimicrobial resistant bacteria has increased dramatically among patients worldwide. So-called vancomycin-resistant enterococci (VRE) and extended-spectrum beta-lactamase producing Enterobacteriaceae (EPE) are a large threat for hospitalised patients worldwide. Similarly, the burden of “healthcare associated” infectious diarrhoea caused by a Clostridium difficile infection (CDI) has increased as well, resulting in longer treatments and higher risks for re-hospitalisation. For these reasons, it is important to use antibiotics only when they are really needed. If an antibiotic is required, it should be carefully selected to be effective against the bacteria causing the infection while preserving the healthy gut flora as much as possible.

There are initiatives that support doctors in choosing the best antibiotic by training, educational materials and prescription regulations, called Antimicrobial Stewardship. Another approach to reduce the spread of multi-resistant bacteria are hygiene and infection control measures. However, these measures come with considerable cost and effort during a time of limited healthcare resources. It remains unknown which measures are the most effective to prevent spread of resistance bacteria and ensure optimal antibiotic treatment. We also need more information on how much antibiotics contribute to spread of EPE, VRE and C. difficile and whether appropriate, rational antibiotic use could help improving the current situation.

The objective of the present PILGRIM study is to – determine the impact of antimicrobial prescription on the gut flora by EPE or VRE or infection with C. difficile – determine how often and when gut colonization by EPE or VRE and/or C. difficile occurs in-hospital or before admission – determine what measures (e.g. Infection Control or Antimicrobial Stewardship) are the most effective strategies to prevent healthcare-acquired colonization and infection by VRE, EPE, and C. difficile.

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Piloting on-site interventions for reducing antimicrobial use in livestock farming emerging economies (REDUCE AMU)

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Increasing intensification and expansion of the livestock sector in emerging economies is a large user of antimicrobials, driving the global emergence of antimicrobial resistant bacteria in livestock, humans and the environment.

Ongoing project

The objective here is to test interventions aimed to reduce antimicrobial use (AMU) in livestock in emerging economies using the pig production in Thailand as a study case. Regulations may not be sufficient to reduce AMU in the livestock sector and can therefore have limited impact on the resulting development of AMR in the biota. Thus, there is a need to find interventions that do not depend solely on regulation.

The novelty is that we will test interventions by computer simulations based on primary data generated through a One Health approach. Based on known distributions of pig production we will record knowledge, attitudes and practices related to AMU and animal management among pig farmers. Then we will collect samples from pigs, pig farmers and control human subjects who are not in contact with pigs and perform phenotypic and molecular analysis of the AMR profiles.

Using these data-sets, we will do spatial analyses and model the impacts of altering variables for practices related to AMU, animal management and farm structure, with emphasis on farmers’ incentives, to explore whether these would be expected to lead to a reduction in AMU. Ultimately, we will assess if such a reduction can be related to the burden of AMR in pigs, pig farmers and non-exposed humans. Finally, we will assess the economic and social feasibility of the tested interventions.

Project partners

  • Ulf Magnusson, Swedish University of Agricultural Sciences, Sweden (Coordinator)
  • Josef Järhult, Uppsala University, Sweden
  • Thomas P. Van Boeckel, ETH Zurich, Switzerland
  • Marianne Sunde, The Norwegian Veterinary Institute, Norway
  • Jatesada Jiwakanon, Khon Kaen University, Thailand
  • Karl M Rich, International Livestock Research Institute, Vietnam

Countries with emerging economies experience an intensification in livestock production. As a consequence, the consumption of antibiotics increases, and with that, the problem of antibiotic resistance that can spread from livestock to humans and the environment. A significant part of the antibiotic use in the world today goes to pig and poultry production in Asia. A country with such a growing economy is Thailand.

This project will use pig production in Thailand as a case and by modelling test measures that can help reduce the use of antibiotics in livestock production. The project is highly multi-disciplinary and includes veterinarians, doctors, modelers, economists and microbiologists. The consortium will through a One Health-approach test the impact of various measures. Input data for the modelling are collected in the field in North eastern Thailand and comprise mapping and documenting what kind of knowledge and attitudes the pig producers have, how pig production is performed and organized. Furthermore, mapping presence of several kinds of resistant bacteria in samples from pigs, pig farmers and from a control group of people who have not been in contact with pigs has been performed. In-depth analyzes of the resistant bacteria will be performed, using whole genome sequencing.

Interviews and sampling of pig farms and humans in Thailand started in late September 2018 and ended in January 2020. The initial laboratory work was carried out at the University of Khon Kaen, and was followed-at the Veterinary Institute in Oslo, Uppsala University and the Swedish University of Agricultural Science. Further work on data analyses is ongoing. The data generated from field and laboratory work will thus serve as input for the modelling work that will be carried out at ETH.

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Improving rational prescribing for UTI in frail elderly (ImpresU)

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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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Antimicrobial Resistance Manure Intervention Strategies (ARMIS)

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Manure is one of the major sources of antimicrobial resistance (AMR) in the environment, since livestock animals consume the majority of antibiotics produced globally. Antibiotics together with antibiotic resistant bacteria are excreted to the environment via manure, and may significantly contribute to the transmission of and exposure to AMR in food, water, and air as exemplified for methicillin-resistant Staphylococcus aureus (MRSA).

Ongoing project

Techniques for nutrient reduction in manure, such as composting and anaerobic digestion, exist and are started to be applied in a number of countries. These techniques can also reduce antibiotic resistance. However, to date, no studies simultaneously studied the reduction of all AMR components (antibiotics, bacteria and genes) by different manure interventions.

In this project, we will measure the effectiveness of different manure treatment techniques on AMR reduction throughout the manure chain and analyse process parameters of influence. Both large-scale (centralised) treatment systems and small-scale (farm) systems will be evaluated in different national contexts with varying AMR prevalence. With culture dependent and culture independent methods, the abundance of antibiotic resistance and its mobility at different steps of the manure treatment processes is evaluated.

We will focus on ESBLproducing Enterobacteriaceae, vancomycin-resistant Enterococci (VRE) and MRSA, as well as metagenomic and qPCR analyses of antibiotic resistance genes, and quantification of antibiotic residues. Emissions of AMR from manure and manure treatment systems will be assessed, in order to determine risks of exposure. With input from workshops on risk perception with relevant stakeholders, these risk assessment outcomes will be communicated to improve awareness on antibiotic usage, to guide prioritising intervention initiatives, and to further comprehend exposure risks. Knowledge on the effectiveness of manure interventions on AMR transmission may contribute to reducing the AMR impact caused by the livestock industry.

Project partners

  • Ana Maria De Roda Husman, National Institute for Public Health and the Environment (RIVM), Netherlands (Coordinator)
  • Edward Topp, University of Western Ontario, country
  • Patrick Boerlin, University of Guelph, Canada
  • Carmen Chifiriuc, University of Bucharest, Romania
  • Peter Kämpfer, Justu-Liebig University, Germany
  • Paul Hoeksma, Wageningen Livestock Research, Netherlands 

In Europe and Canada, animal manure is increasingly often processed before it is spread on land for fertilisation. Treatment for example exists of composting or digestion.

In the ARMIS project, international partners are investigating to what extent these manure processing techniques can reduce antibiotic resistance. Sampling campaigns in Canada, Romania, Germany and the Netherlands are used to measure and model the presence of antibiotic resistance in manure, manure treatment products and manure processing plants.

The risks that people are exposed to are also investigated: how big are these risks, how are they seen through the eyes of those involved and how can the risks be clearly communicated.

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

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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)

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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)

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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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Aligning industry incentives with AMR control goals: Exploring the feasibility of an antibiotic susceptibility bonus for drugs to treat Gram-negative infection (ASB)

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High prices create incentives for industry to develop new antibiotics, but also incentivize firms to promote their products to maximize sales volume. Similarly, the Market Entry Rewards proposed by the O’Neill Commission and others will, if introduced, help to get new drugs to market but do not directly address the problem of antibiotic overuse leading to emergence and spread of antimicrobial resistance (AMR) (O’Neill 2016).

Ongoing project

The multidisciplinary study proposed here explores the feasibility of a finance-based intervention intended to directly re-align pharmaceutical industry interests with the minimization of AMR and with the overall prolongation of antibiotic efficacy through time. The proposed intervention allows pharmaceutical companies to qualify for staged bonuses if pathogen susceptibility to their antibiotic remains above a given threshold, despite a certain minimum volume of usage. This Antibiotic Susceptibility Bonus may help maximize efforts towards good prescribing practice and towards minimizing the risk of acquisition, development and transmission of antibiotic-resistant Gram-negative bacteria. The lure of a bonus greater than expected revenues from unit sales could help align efforts behind antibiotic stewardship and infection prevention efforts in hospitals, communities, agriculture, and the environment, bolstering public and private AMR initiatives across One Health sectors.

This project will evaluate the feasibility and potential impact of the Antibiotic Susceptibility Bonus. It will address the difficulties involved in: i) developing a general measure of susceptibility; ii) calculating optimal bonuses based on realistic market considerations; iii) assessing product utility and accessibility. This will be done through 2-3 case studies of actual late stage (Phase III) candidate antibiotics and an existing product with particular antimicrobial features – each targeting multi-resistant Gram-negative bacteria.

Project partners

  • Aidan Hollis, University of Calgary, Canada (Coordinator)
  • Stephan Harbarth, University of Geneva, Switzerland
  • Olof Lindahl, Uppsala University, Sweden

Resistance to antibiotics makes them less effective over time. The preservation of antibiotics requires efforts from all stakeholders. Thus far numerous initiatives have been put in place to improve prescribing by physicians, enhance formalities surrounding dispensing by pharmacists, and encourage regimen adherence by patients, inter alia. The last stakeholder to come on-board are the developers who make these badly needed products. Due to a very traditional marketplace these companies are still incentivized to sell as many units of antibiotics as possible – even of the newest ones that we so badly need to conserve.

This multidisciplinary study explored the feasibility of a finance-based intervention intended to directly re-align pharmaceutical industry interests with the minimization of antimicrobial resistance and with the overall prolongation of antibiotic efficacy through time. The proposed scheme allows pharmaceutical companies to qualify for staged bonuses if pathogen susceptibility to their antibiotic remains above a given threshold, despite a certain minimum volume of usage. Entitled the Antibiotic Susceptibility Bonus (ASB), this scheme would in theory help maximize efforts towards good prescribing practice and towards minimizing the risk of acquisition, development and transmission of antibiotic-resistant bacteria. The lure of a bonus greater than expected revenues from unit sales could help align efforts behind antibiotic stewardship and infection prevention efforts in hospitals, communities, agriculture, and the environment.

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

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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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