Multiresistant bacteria are a severe problem to modern healthcare. The problem is increasing and development of novel technologies to cope with this critical situation is a necessity. Solutions include novel antibiotic drugs as well as reducing the spread of resistance genes in the environment.
Antimicrobial resistance is a worldwide problem, and many bacteria have now developed resistance towards even last-resort antibiotics. Despite significant attempts to limit this development more and more infections are identified as resistant to the treatment in hospitals. Much effort has been put into understanding the spread of resistance, and treatment thereof, within a hospital setting. It is only quite recently that an understanding that we need to also take in the environment, and development of resistance in such a setting in what now is called a One Health Approach has dawned.
Not only is the presence of resistance in hospitals important, but of equal importance is the presence of free antibiotics in nature, usage of antibiotics for food industry, handling of wastewater etc for the spread of antibiotic resistance. The wastewater treatment plants have been shown to be a hotspot for development of antibiotic resistance due to the high prevalence of bacteria and viruses there, as well as high levels of antibiotics. This will favor resistant bacteria, and exchange of resistance between microbes. A key player in this perspective are the bacterial viruses (bacteriophages) that can act as a transmission vehicle and transfer resistance between different bacteria. Our research aims at understanding the mechanisms underlying these transmission dynamics, and develop means to limit it.
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.
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.
While therapeutic antibiotic use directly impacts the evolution of AntiMicrobial Resistance (AMR), it has become increasingly clear that the environmental dimension of AMR is also of great importance. There is mounting concern that wastewater systems, which receive antibiotic residues and antibiotic resistant organisms and their antibiotic resistance genes, could facilitate the environmental dissemination of resistance.
DARWIN has examined the fate of clinically relevant antibiotic resistances along sewer catchments and receiving waters in three European cities. We found that hospitals sewers contain higher concentrations of resistant bacteria than sewers in residential areas. Many of the resistance genes, and especially those in hospital wastewater, were carried on genetic elements that have potential to transfer rapidly from one bacterium to another.
We collected several other indications of the potential for microbial communities in wastewater systems to exchange resistance genes, yet we did not find direct evidence of such transfer, possibly because of the difficulty of the task (enormous amounts of bacteria transit across sewers and wastewater treatment plants). Overall, our data suggests that our wastewater collection and treatment systems discharge only few antibiotic resistant organisms and genes in the environment but the question of the impact of this low-level pollution remains unanswered.
We proposed a standard way for scientists to report their findings to facilitate data interpretation and reuse and built mathematical models to understand the dynamics of antibiotic resistance that will contribute to further development of mitigation strategies.
Impact of the study: DARWIN, through the obtained evidence and through its partners, has significantly contributed to wider efforts aimed at mitigating the spread of antibiotic resistance around the world. Such involvement has included science-informed public information on AMR (e.g., an invited Insights piece for the Conversation), co-authoring international recommendations for the World Health Organisation aimed at promoting local National Action Plans and socio-technical AMR mitigation options for countries around the world.
We also co-wrote guidance for the Wellcome Trust and US Centre for Disease Control and Prevention on essential initiatives to mitigate AMR; have been invited input providers to the USA PACCARB (Presidential Advisory Council on Combating Antibiotic Resistant Bacteria); and are members of the technical advisory council of ICARS (International Centre for Antimicrobial Resistance Solutions).
Barth Smets, Technical University of Denmark, Denmark (Coordinator)
Søren Johannes Sørensen, University of Copenhagen, Denmark
David Graham, Newcastle University, United Kingdom
Jan-Ulrich Kreft, University of Birmingham, United Kingdom
Jesús L. Romalde, Universidade de Santiago de Compostela, Spain
Carlos García-Riestra, University Hospital Complex of Santiago de Compostela – CHUS (Carlos GarcíaRiestra), Spain
Mical Paul, Technion Israel Institute of Technology, Israel
The rise of antibiotic resistant infections is an imminent global public health threat, and Antibiotic resistance is a major health care concern worldwide. Wastewater (sewage) is considered an important source of dissemination of antibiotic resistant bacteria and resistance genes (ARB/ ARGs) to the environment.
AWARE investigated whether people working at wastewater treatment plants (WWTP) and people living in the vicinity of WWTP have an increased risk of carriage of ARB/ARGs through exposure to contaminated water or air. This was studied in Germany, the Netherlands and Romania.
The main conclusion was that WWTP workers and nearby-residents may be at greater risk of carriage of ABR than the general population in some (as was shown for Romania) but not in other countries (as was shown for Germany and the Netherlands). Also, the results suggest that elevated carriage in Romanian nearby residents were not likely to be directly caused by the WWTP. Further analyses will quantify exposure risks and shed light on the role of WWTP in selection of antibiotic resistance.
Heike Schmitt, National Institute for Public Health and the Environment (RIVM), Netherlands (Coordinator)
Carmen Chifiriuc, University of Bucharest, Romania
Antibiotic-resistant bacteria are not new, but in the last two to three decades antibiotic resistant bacteria have been constantly increasing and rapidly spreading. As a result, the emergence of antibiotic resistance is increasingly limiting treatment options for mild to moderate infections, which makes it of pivotal importance to control the emergence and spread of antibiotic resistant nacterial pathogens.
In the STARCS project we study the pathways by which resistant bacteria, particularly enterococci resistant to vancomycin and enterobacteriales resistant to extended-spectrum beta-lactamases, can emerge in complex ecosystems, such as the human intestinal tract, in which they can acquire genetic material that encodes resistance to antibiotics.
To this aim, we have developed a number of tools that are used to characterise the reservoir of resistant bacteria and resistance genes in microbial ecosystems. In addition, we perform research into the transfer of resistant bacteria and resistance genes between animals and humans. As antibiotic resistance can spread via horizontal gene transfer of mobile genetic elemenst (MGE) in addition to the spread of antibiotic resistant strains, we have developed in the STARCS consortium novel tools to identify and reconstruct MGE’s based on whole genome sequence data and to characterize with great precision the MGE-bacteria interaction networks of the microbiota in the mammalian gut using an approach called metaHi-C.
Using all these tools studies comparing bacteria found in humans and farm animals in the Netherlands by analysing their DNA revealed that resistant bacteria found in humans were different from those found in farm animals. This shows that humans are rarely infected by antibiotic resistant bacteria that come directly from farm animals.
Furthermore, three primary studies conducted in a community setting and two in hospital settings, using samples collected from different sources: patients, live and slaughtered food animals, and environmental samples in the slaughterhouses, taken from developing (Vietnam) and developed countries (Italy, Germany) with different antibiotic use and antibiotic resistance backgrounds, revealed, again, limited contribution of food-animal sources, particularly chickens and pigs, to causing urinary tract infections by ESBL-resistant enterobacteriaceae (ESBL-E) in Hanoi, Vietnam.
In hospital settings, actively screening and decolonising patients carrying ESBL-E are promising infection control strategies. Using simple mathematical models, we were able to show that the environment that is shared between farm animals and humans might be an important pathway for the transmission of antibiotic resistant bacteria as it can act as a reservoir between the two populations. Because of this, measures such as curtailing antibiotics in farm animals have much less impact on human health.
Furthermore, our modelling showed that the effect of curtailing of antibiotic resistance in farm-animals on human foodborne diseases is two-fold. By curtailing antibiotics is farm animals the proportion of human foodborne illnesses that is caused by a resistant pathogen will be decreased, but the number of food-borne illness cases is likely to increase due to this measure. However, further modelling showed that this can be mitigated by maintaining good farm bio-security (farm-to-fork and livestock health) and reducing transmission from animals to humans.
We furthermore looked at how (international) food imports affect the efficacy of antibiotic curtailment in livestock. For this we used a simple mathematical model. This shows that imports from non-domestic sources can reduce the efficacy of local livestock antibiotic curtailment.
Rob Willems, University Medical Center Utrecht, Netherlands (Coordinator)
Dik Mevius, Wageningen University & Research, Netherlands
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.
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.
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
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.
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.
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
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.
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.
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
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.
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.
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
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.
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).
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