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

Project resources

Tools

Publications

Call

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

Publications

Call

Escherichia coli ST131: a model for high-risk transmission dynamics of antimicrobial resistance (ST131TS)

This project has connected many transnational academic resources to investigate the transmission success of the Escherichia coli ST131 clone. E. coli is the most common cause of urinary tract and bloodstream infections worldwide. Resistance to widely used antibiotics for the treating E. coli infections is common and widespread.

Completed project

A single E. coli clone, ST131, is mainly responsible for this global AMR pandemic causing millions of antibiotic-resistant infections annually. It remains unclear which features of ST131 had resulted in the biggest antimicrobial resistance succes of the 2000s.

The ST131TS project created a combined European-Canadian consortium that investigated the transmission dynamics of ST131. The study explored transmission of resistance and virulence genes and how they contributed to the success of ST131. The project also investigated transmission of ST131 among humans, animals and different environments.

The project has showed that ST131 is a public health concern in Canada and Europe and has provided information to better understand the spread and managing infections due to multidrug resistant E. coli. Only by understanding how antibiotic resistance evolves and spreads in bacterial populations, can we begin to overcome such resistance.

ST131 adapts rapidly to environmental changes; we need to know why and how. This project will serve as a model to predict what can possibly happen in the future with the continuing emergence of multidrug resistant clones among bacteria.

ST131TS project logo

Project partners

  • Johan Pitout,University of Calgary, Canada (Coordinator)
  • Neil Woodford, ARHI-UK, United Kingdom
  • Fernando Baquero, Ramón y Cajal Institute for Health Research (IRYCIS), Spain
  • Marie-Hélène Nicolas-Chanoine, Beaujon Hospital/ Paris VII University, France
  • Laurent Poirel, University of Fribourg, Switzerland
  • Alvaro Pascual, Fundación Púbica para la Gestión de la Investigación de Salud en Sevilla, Spain
  • Jean-Yves Madec, National Agency for Food, Environmental and Occupational Health & Safety (ANSES), France
  • Tarah Lynch, University of Calgary, Canada

Project resources

Tools

Publications

Call

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

Project resources

News articles

Publications

Call

A multi-scale approach to understanding the mechanisms of mobile DNA driven antimicrobial resistance transmission (JumpAR)

Antimicrobial resistance (AMR) is one of the greatest global health challenges. It spreads rapidly, constantly generating more dangerous bacteria.

Completed project

Mobile genetic elements (MGEs), segments of DNA that can move between bacterial cells, are a major route for resistance transfer in microbial communities. How often such ‘jumping genes’ move, which natural and man-made compounds influence them, and how they move at the molecular level is not understood.

In JumpAR, we surveyed MGEs in all bacteria, analysed their resistance cargos and transfer trends, and illuminated the molecular machinery that move them. Drawing on genome and metagenome sequences, we gained a global picture of the abundance and distribution of MGEs and revealed their profound impact on resistance transmission.

In a dedicated clinical study, we charted the effects of antibiotics on MGE-driven resistance spreading, and we identified human drugs and environmental compounds that can block AMR gene transfer in bacteria. We further delineated the structure and functioning of the molecular machinery, showing how MGEs build remarkably complex DNA shapes to promote insertion at diverse genomic sites, expanding gene transfer across diverse bacteria. Our collective results vastly expand knowledge on MGE-driven resistance spreading, opening doors to the development of novel strategies against resistance spreading.

JumpAR: Mechanism of AMR transmission

Project partners

  • Orsola Barabas, European Molecular Biology Laboratory, Germany (Coordinator)
  • Peer Bork, European Molecular Biology Laboratory, Germany
  • Maria Fällman, Umeå University, Sweden
  • Johan Normark, Norrlands University Hospital, Sweden
  • Gerard Wright, McMaster University, Canada

Project resources

Tools

Publications

Call

Prevention and Restriction of Antimicrobial Resistance in Pneumococci by Multi-Level Modelling (Restrict-Pneumo-AMR)

Microorganisms live in most parts of our body, including the inside of our nose. Most of the microbes are harmless and can even be beneficial to our health. However, some microbes can cause diseases – although they often go unnoticed, as our immune system can remove them before we show any symptoms.

Completed project

For example, the bacterium Streptococcus pneumoniae can cause diseases such as pneumonia and meningitis, but generally, it lives harmlessly in the nose, and is particularly common in children and the elderly. The longer the bacteria live in the nose before being killed by the immune system, the more likely they are to be transmitted to another person. The amount of time it takes for the immune system to clear the bacteria depends on various factors, such as the age of the person or the bacterium’s defense mechanism and its genetic material. A particularly important aspect is to what subtype, also known as serotype, a bacterium belongs to, which is characterized by differences in the structure of the sugar coating that surrounds the microbe. However, until now, it was not known how much each of these factors contributes.

This project provides new information for understanding the processes of evolution within the host and the mechanisms by which antibiotic treatment can influence the selection for antibiotic resistance.

Project partners

  • Stephen Bentley, The Wellcome Trust Sanger Institute, United Kingdom (Coordinator)
  • Nahuel Fittipaldi, Public Health Ontario Laboratories, Canada
  • James Kellner, University of Calgary, Canada
  • Bernd Schmeck, Philipps-University Marburg, Germany
  • Paul Turner, University of Oxford, United Kingdom
  • Tom van der Poll, Academic Medical Center University of Amsterdam, Netherlands
  • Nicolas Croucher, Imperial College London, United Kingdom

Project resources

Video

The Global Pneumococcal Sequencing (GPS) project: How can whole-genome sequencing be used to make vaccines more effective?

Publications

Call

Mechanisms for acquisition and transmission of successful antibiotic resistant pneumococcal clones pre- and postvaccination (PNEUMOSPREAD)

Pneumococcal infections are major contributors to morbidity and mortality world-wide, even though we have access to antibiotics and intensive care.

Completed project

Pneumococci are the major cause of common milder respiratory tract infections such as otitis and sinusitis, but also to more severe infections such as pneumonia with or without septicaemia and meningitis. Despite causing all these disease with even lethal outcome, pneumococci frequently colonize healthy children from where they may spread to susceptible individuals and cause disease. Resistance to antibiotics is emerging, threatening effective treatment.

In this project we have gained important insight into factors that affect transmission of pneumococcal strains, and into the pathogenesis of pneumococcal infections. We have unravelled factors both on the bacterial side and on the host side that are important for the spread and transmission of antimicrobial susceptible and resistant pneumococcal strains using in vitro and in vivo models. Based on this knowledge, potential novel treatment and preventive methods could be developed in the future.

Project partners

  • Birgitta Henriques Normark, Karolinska Institutet, Sweden (Coordinator)
  • Aras Kadioglu, University of Liverpool, United Kingdom
  • Tim Sparwasser, Institute for Medical Microbiology and Hygiene (IMMH), Germany
  • Jens Lagergren, KTH Royal Institute of Technology, Sweden

Publications

Call

Using collateral sensitivity to reverse the selection and transmission of antibiotic resistance (COLLATERALDAMAGE)

Urgent action is required to stem the apocalyptic spread of antimicrobial resistance (AMR). However, because the pace of novel drug development lags behind the evolution of novel AMR determinants, new strategies of containment are required.

Completed project

In this multinational proposal we develop a resistance-reversal strategy based on the concept of collateral sensitivity (CS). CS between a pair of antibiotics occurs when resistance to one antibiotic potentiates susceptibility to another. Thus, by exploiting CS relationships through sequential drug application, resistant strains can be specifically targeted which will reduce their frequencies in the community and arrest their transmission.

Our broad aim in this proposal is to realize the unique promise of CS-informed therapies. To do so, our work packages (WP) integrate theoretical biology, evolutionary and molecular microbiology, and in vivo modeling with a specific focus on arresting the transmission of resistant E. coli and S. pneumoniae.

The expected outcomes of the proposal are to provide pre-clinical recommendations for therapy to reduce the emergence and transmission of these two globally important bacterial pathogens and to provide a framework to develop CS-based strategies for other bacterial threats.

UiT, The Arctic University of Norway, coordinates the project and run two WPs in this JPI-EC-AMR project. One WP includes experimental work on E. coli where we test if general patterns of CS can be identified in clinical E. coli strains and how horizontal gene transfer affects these networks. The other WP aims to develop a modelling framework that furthers our understanding of sequential therapy within patients in the context of CS that is scalable to investigate transmission across patient populations.

Project partners

  • Pål Jarle Johnsen, The Arctic University of Norway, Norway (Coordinator)
  • Daniel Rozen, Leiden University, Netherlands
  • Pia Abel zur Wiesch, The Arctic University of Norway, Norway
  • Dan Andersson, Uppsala University, Sweden
  • Niels Frimodt-Møller, Rigshospitalet, Denmark

Project resources

Microbiology Research Group, The Arctic University of Norway, lead by project coordinator Pål Jarle Johnsen

Publications

Call

Phage Forward

Antibiotic resistant bacteria represent a major threat to public health and solutions to this problem require actions at several levels of society.

Completed project

This is particularly true for phage therapy, which was initially proposed in the early twentieth century. Following a period of worldwide expansion this treatment option became almost obsolete in western countries before finally being stopped. In France and Germany, phage treatments were still applied during the 70’s while in some eastern countries, especially in Georgia, Russia and Poland it was continuously and successfully used up to present.

The biology of bacteriophages (phages), the natural enemies of bacteria, is now much better known and scientifically described than in the past. However, some questions about the safety of phage preparations in the context of their production process and their reproducible efficacies require more intensive research and pre-clinical and clinical studies. Also the diffusion of appropriate documentation about phage therapy towards the public, the medical community as well as other various stakeholders is lacking.

Our initiative is to develop an integrated approach to overcome the hurdles that slow down the reintroduction of phage therapy as a regular treatment option and therapy concept for antibiotic resistant infections, focusing primarily on phage-adapted regulation, production and research-based awareness. To realize this, we aim at building on knowledge-based trust and several highly relevant recent publications that have been focusing on phage-adapted production and regulative requirements so that the tangible benefit becomes readily available for the patients who need it.

Network partners

  • Thomas Rose, Vrije Universiteit Brussel, Belgium (Coordinator)

This network includes 7 partners, please click on the following link to see complete network composition: Network composition Phage Forward 

Antibiotic resistant bacteria represent a major threat to public health. Phage therapy, the use of bacterial viruses (phages) to combat bacterial infections, is increasingly put forward as an alternative/addition to antibiotic therapy. However, the conventional medicinal product (drug) pathways are developed to cater for static drugs such as aspirin or antibiotics, but are less suitable for sustainable (evolving) page therapy products. As such, there are no phage medicinal products on the Western markets, and very few phages are available to conduct the necessary safety and efficacy studies. PhageForward’s aim was to overcome the hurdles that slow down the (re)introduction of phage therapy in Western medicine. In concrete, PhageForward facilitated a series of meetings, workshops and a scientific publication, which contributed to the awareness that there is a need for an adapted phage therapy regulatory framework and to the elaboration and implementation of such a regulation.

This lead to the implementation of a prototype phage therapy framework in Belgium, which is slowly spreading to other EU Member States such as France, Germany and The Netherlands.

Publications

Call

Network on quantification of veterinary Antimicrobial consumption at herd level and Analysis, CommunicaTion and benchmarking to improve responsible use (AACTING)

his network aims at developping guidelines and describing best practices for data collection systems of antimicrobials usage (AMU) in food-producing animals at farm level, applicable for herd level antibiotic stewardship, including benchmarking and result-communication to stakeholders and risk managers.

Completed project

To achieve this first a SWOT analysis of all currently available systems will be performed. Based on this strong and weak parts of the different systems will be identified and used to develop “best practice guidelines” adapted to the country specificities. The implementation of these guidelines also aim an improving comparability between results from various countries/ sectors/ species. Additionally, the up-to-date information on all currently available systems and the developed guidelines will be made publicly available through an online platform. This will aid interested people from various backgrounds to easily gain a comprehensive image of the work done on quantification of veterinary antimicrobial use at the herd level. Moreover, the platform will function as a discussion forum, where ideas, knowledge and experiences can be exchanged and discussed. Finally, a conference will be organized to gather all interested people active in the field of quantifying Veterinary Antimicrobial Consumption both to promote the guidelines and online platform as well as to discuss further developments and challenges.

Network partners

  • Jeroen Dewulf, Ghent University, Belgium (Coordinator)

This network includes 25 partners, please click on the following link to see complete network composition: Network composition Network on quantification of veterinary Antimicrobial consumption at herd level and Analysis, CommunicaTion and benchmarking to improve responsible use (AACTING)

AACTING, the “Network on quantification of veterinary Antimicrobial usage at herd level and Analysis, CommunicaTion and benchmarkING to improve responsible usage”, stems from the recognition that antimicrobial usage (AMU), as the main driver for the selection and spread of antimicrobial resistance, should be reduced. To be able to target the highest users and evaluate the effect of AMU reduction measures and responsible use campaigns, availability of adequate AMU data is vital.

Many countries have set up, are in the early stages of setting up or are planning to set up systems for monitoring farm-level AMU data in food animals. Such data have been shown to be powerful tools for antibiotic stewardship, e.g., stimulating a more responsible AMU through benchmarking farmers’ and veterinarians’ AMU. Due to a lack of standardisation among the systems, in terms of collection and analyses methodology (e.g., units of measurement and indicators) and benchmarking strategies (e.g., different benchmark criteria for acceptable or problematic use), the produced outcomes are typically not comparable. Furthermore, countries or organizations setting up a monitoring system will experience similar challenges and choices to solve.

The AACTING project has developed guidelines with practical advises on setting up AMU monitoring systems and their application to guide antimicrobial stewardship. These guidelines are disseminated through the AACTING-website. The website also contains a searchable database of monitoring systems, allowing to look per country or per animal species for farm-level AMU monitoring systems, currently containing information on 16 countries and 29 AMU data-collection systems.

Project resources

Call