NEC05839 Chicken or the Egg: Is AMR in the Environment Driven by Dissemination of Antibiotics or Antibiotic Resistance Genes?

Lead Research Organisation: NERC Centre for Ecology and Hydrology
Department Name: Pollution (Wallingford)

Abstract

Antimicrobial resistance (AMR) in the environment is driven by antibiotics released in the urine of humans and animals into sewage and ultimately the receiving rivers. AMR is also released from within the gut bacteria that are shed in faeces of both humans and animals. In both cases, antibiotics and AMR-containing gut bacteria are released into the environment through sewage. Despite the continued release of both antibiotics and antibiotic-resistant bacteria into our rivers, we still don't know the relative role that they play in explaining the amount of antibiotic resistance that we see in our environment. This is a critically important knowledge gap as it prevents industry and policy makers from determining where to spend our time and resources so as to lower this 'environmental reservoir of antimicrobial resistance'.

Sewage contains thousands of chemicals, many of which are at concentrations sufficient to inhibit or kill bacteria. Microbes defend themselves from these chemicals with a range of strategies, all of which have genes that are broadly classified as 'resistance genes'. Hence, sewage is an excellent place to find bacteria rich in resistance genes. Many of these genes are known to be mobile, which allows for the genes to be shared, thereby increasing its abundance within the environment. This mobility of genes is key to why it is so difficult to know what is driving AMR in the environment-a bit like 'which came first, the chicken or the egg.' Are the concentrations of antibiotics present in sewage sufficiently high to select for resistance genes in the environment or are the genes for resistance simply spreading from the gut-derived bacteria into the native environmental microorganisms? The keys to answering this question lie in the following two questions: 1) Do genes released from sewage move into and persist in the natural microbial community without continued exposure to critical threshold concentrations of antibiotics; and 2) Are the critical threshold concentrations in the environment sufficiently high to maintain gut-derived AMR genes in the natural microbial community or select for them all on their own?

In the proposed research we aim to answer these two key questions using four innovative experimental systems: 1) a small laboratory microfluidic system for the precise control and manipulation of microbial biofilms; 2) an in situ river mesocosm and 3) ex situ macrocosm which can also control and manipulate microbial biofilms under controlled conditions with the addition of antibiotics and/or antibiotic resistance genes; and finally 4) the use of the freshwater shrimp, Gammarus pulex, as an indicator species of environments where the reservoir of antibiotic resistance is elevated. In the case of the Gammarus, we will study the microorganisms that live within this shrimp and determine if these microbes acquire similar antibiotic resistance traits as those found in identically-exposed biofilms. Modern molecular techniques (i.e, metagenomes, plasmid metagenomes, qPCR, meta-transcriptomes), will be used to quantify treatment effects within biofilms and Gammarus. The data from these studies will be used to parameterise a mathematical/statistical model that will be designed for use by regulators, industry and academia to better predict and understand the risks posed by AMR in the environment.

Planned Impact

This proposal will determine the degree to which antibiotics and antibiotic resistance genes are driving antimicrobial resistance (AMR) within the freshwater environment. There are a range of stakeholders for whom the research outputs could be valuable detailed below.

Regulators
Defra and the Environment Agency require sound science to inform their response to the European Water Framework Directive (WFD) and Urban Waste Water Treatment Directive (91/271/EEC) which has a major influence on the way chemical risks are assessed and chemical control measures might be considered. As described in the scientific case for support, antibiotic resistance gene prevalence could be mediated by antibiotics and antibiotic resistance genes, but to different degrees. Understanding the relative role of these drivers for AMR selection and maintenance in the environment, will help stakeholders and policy makers prioritise the most efficacious solution to minimising the risks to humans. CEH holds regular meetings with Defra Central Evidence group and the EA Evidence group, which represent opportunities for our science to be communicated across the agencies.

Water Industry
The central suggestion of this proposal could reasonably apply to the entire network of sewage treatment plants in the UK and is therefore potentially of great relevance to the Water Industry. If control measures for antibiotics or antibiotic resistance genes were required by the WFD it would be the Water Industry that would have to implement discharge controls to limit this risk (e.g. through enhanced waste water treatment). Thus, evidence from the proposed research will be critical for the industry's risk assessments and response. It may be that the minimum selective concentration for antibiotics are prohibitively low for the solution to lie with the water industry. We are liaising with Tony Griffiths of Southwest Water and Howard Brett of Thames Water, links that will be strengthened during the project.

Public Health
Public Health England are responsible to Government for clearly identifying and reporting on challenges to public health. AMR is a significant issue for PHE as evidenced by their 5 year Antimicrobial Resistance strategy, published in September 2013. Clarification on the potential for human exposure to a wide range of different antimicrobial resistance genes through wide-spread environmental prevalence will be important for their future review of the topic. As part of this project, we aim to engage with PHE, with particular reference to the further development of our statistical model that aims to predict high AMR exposure areas and the implications of our Gammarus 'sentinel' research for rapid monitoring of the environment.

We aim to conduct three seminar/workshops with an open panel discussion about the implications to policy, regulators, academics and industry of our research in light of changing national and international priorities on antibiotic use and regulation. The PI is very active on twitter (>1100 followers) and will use this to engage with the wider scientific community, along with the CEH twitter account. We will post blogs to the CEH website, which will be disseminated via Twitter and Press Releases. Our science outputs will be prepared for publication in high impact, open access journals. Our policy relevant messages will be communicated both through blogs and policy briefings and disseminated to the many relevant stakeholders already identified as well as CEH's wider stakeholder contacts. The PI will draw upon the expertise of the CEH Business Development and Engagement Section for advice on social media, events and workshops, public relations, media activities and science writing.

Publications

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Project Reference Relationship Related To Start End Award Value
NE/N019687/1 01/06/2016 30/11/2019 £620,155
NE/N019687/2 Transfer NE/N019687/1 01/12/2019 31/12/2020 £78,460
 
Description We have conducted research to understand the lower limit of impact that an antibiotic can have on a natural river system. The lowest concentration that can have a measurable impact on the prevalence of antibiotic resistance genes is extremely low. This has huge implications for setting protection targets for 'systems' that emit chemicals driving selection in the environment.
Exploitation Route Discussions are underway with policymakers to use this information to guide the most cost-effective mitigation measures.
Sectors Agriculture, Food and Drink,Chemicals,Environment,Leisure Activities, including Sports, Recreation and Tourism,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL https://www.ceh.ac.uk/our-science/projects/amr-environment
 
Description The aims of the study are key for informing UK and International policy on how to manage AMR and its drivers. Discussions with Department of Health, Defra, EA, SEPA and Irish EPA have resulted from work conducted as a result of this project.
First Year Of Impact 2016
Sector Agriculture, Food and Drink,Chemicals,Environment,Healthcare,Leisure Activities, including Sports, Recreation and Tourism,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Cultural,Policy & public services

 
Description Co-authored a box in Chief Medical Officers annual report
Geographic Reach National 
Policy Influence Type Citation in other policy documents
URL https://www.gov.uk/government/publications/chief-medical-officer-annual-report-2017-health-impacts-o...
 
Description Invited by Lee Slater (Senior Policy Advisor on AMR in the environment at Defra) to sit on a panel of academic experts in a series of workshops between the US, UK, China and India on antimicrobial resistance and antibiotic pollution in the environment. It's being co-ordinated by the UK Science and Innovation Network and the USA Centers for Disease Control and Prevention.
Geographic Reach Multiple continents/international 
Policy Influence Type Gave evidence to a government review
 
Description Invited to speak to Defra Antimicrobial Resistance Coordination (DARC) Group Autumn 2017 on AMR in the environment.
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact Talk to Defra and veterinary medicines directorate about antibiotics in the environment
 
Description Invited to speak to Defra Hazardous Substances Advisory committee about AMR in the environment
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Strategies for Addressing Antimicrobial Resistance - Future challenges for UK policy
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Rivers Trust Catchment Monitoring Cooperative Working Group 
Organisation Rivers Trust
Department Yorkshire Dales Rivers Trust
Country United Kingdom 
Sector Public 
PI Contribution Insights gained from this project were used to inform the development of a citizen science monitoring network for the UK. This is a major activity within the Rivers Trust Catchment Monitoring Cooperative Working Group to which I am a member.
Collaborator Contribution I am the only person from the project that is active with this group.
Impact A proposal to Ofwat has been drafted for submission.
Start Year 2019
 
Description "AMR in the Environment: An Agricultural Case Study" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Royal Society of Chemistry: Water Science Forum Workshop. Engaged in discussions with academics, policy and industry in person and online.
Year(s) Of Engagement Activity 2019
 
Description "Assessing AMR Risk in the Environment" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Department of Microbiology, Chulalongkorn University Bangkok, Thailand. October 11, 2018.
Raised awareness of the issue of AMR in the environment.
Year(s) Of Engagement Activity 2019
 
Description "Big Pharma has failed: the antibiotic pipeline needs to be taken under public ownership" 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Article in the online newspaper "The Conversation" on November 18, 2019 to highlight a paper on the same topic in Lancet ID. Discussions online and on social media resulted from its publication.
Year(s) Of Engagement Activity 2019
URL https://theconversation.com/big-pharma-has-failed-the-antibiotic-pipeline-needs-to-be-taken-under-pu...
 
Description "Considerations for Assessing AMR Risk in the Environment" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Halting Antimicrobial Resistance Dissemination in Aquatic Environments (HEARD2018), Congressi Stefano Franscini, Monte Verità, Ascona, Switzerland. September 16-19, 2018
Excellent networking meeting resulting in joint publications.
Year(s) Of Engagement Activity 2018
URL https://www.eawag.ch/fileadmin/Domain1/Agenda/2018/div/09/heard2018/program.pdf
 
Description "Constraints On And Reasons For Eliminating Sewage Pollution In Rivers" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Environmental Health 2019: Ensuring Safe And Healthy Environments To Support People And Prosperity. Westminster, London. September 18, 2019
Talk generated considerable interest and informed local civil servants about the impact of sewage on their local environment. Discussions online followed the talk.
Year(s) Of Engagement Activity 2019
URL https://10times.com/environmental-health-ensuring-safe-and-healthy
 
Description "Environment and AMR" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact London School of Tropical Medicine Antimicrobial Resistance: A Multidisciplinary Approach Short Course. Monday 15th July 2019
Training provided to a diverse range of people already employed in health sector internationally.
Year(s) Of Engagement Activity 2019
URL https://www.lshtm.ac.uk/study/courses/short-courses/antimicrobial-resistance
 
Description "Pollution: no river in England is safe for swimming" 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Served in an expert scientist capacity for the article "Pollution: no river in England is safe for swimming". 8/2/2019. The Times
Year(s) Of Engagement Activity 2019
URL https://www.thetimes.co.uk/article/pollution-no-river-in-england-is-safe-for-swimming-q8thdx678
 
Description "Rivers used as 'open sewers', says WWF charity" 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Served as expert scientist to help inform the discussion within the article "Rivers used as 'open sewers', says WWF charity" on 8/22/2019. BBC News
Year(s) Of Engagement Activity 2019
URL https://www.bbc.co.uk/news/uk-england-49131405
 
Description "Sewage: The New Freshwater" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gordon Research Conference on Urbanization, Water and Food Security held July 21- 26, 2019 at The Hong Kong University of Science and Technology in Hong Kong, China
Excellent discussions on the research during and after the talk and online. Collaborations resulted as well.
Year(s) Of Engagement Activity 2019
URL https://www.grc.org/urbanization-water-and-food-security-conference/2019/
 
Description "Wild swimmers driven from rivers by sewage spills" 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Provided an expert scientist perspective to help inform the article "Wild swimmers driven from rivers by sewage spills" by Ungoed-Thomas J, Taylor J, Calver T, inThe Sunday Times. 2019 Dec 22
Year(s) Of Engagement Activity 2019
URL https://www.thetimes.co.uk/article/wild-swimmers-driven-from-rivers-by-sewage-spills-wmmd5bmz6
 
Description 'Antibiotic Use in Humans and its Implications for Antimicrobial Resistance Selection in the Aquatic Environment' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact International Conference on Advances in Chemical Biology and Biologics, Indian Institute for Chemical Technology, Hyderabad, India. Feb 28-Mar 1, 2019.
Excellent networking resulted from this talk allowing for continued discussion online and through social media.
Year(s) Of Engagement Activity 2019
 
Description 'Challenges to Monitoring for AMR in the Environment' 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact ESRC-sponsored AMR policy evaluation workshop LSHTM, London. March 14-15th, 2019.
Enjoyed discussions with a diverse expert audience on AMR in the environment. Paper writing followed up the meeting.
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Description 'Driving Antimicrobial Resistance Selection in the Environment' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
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Year(s) Of Engagement Activity 2019
 
Description 'Overview of AMR in the Environment from the Perspective of How to Monitor for It' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Department of Pathology & Infectious Diseases, School of Veterinary Medicine, University of Surrey. Nov 21, 2018.
Enjoyable seminar to a keen room of academics who asked good questions.
Year(s) Of Engagement Activity 2019
 
Description 'What's in our Thames' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Pint of Science Festival - London. "Sewage: The New Freshwater". The George IV, 185 Chiswick High Rd, London. May 20, 2019.
Engaged with a general audience with an interest in pollution, resulting in some very informative and useful conversations with attendees. Good interactions online and social media.
Year(s) Of Engagement Activity 2019
URL https://pintofscience.co.uk/event/whats-in-our-thames
 
Description ? Attended a Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) workshop in Gothenburg 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Attended a Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) workshop in Gothenburg in September 2017 to explore and identify critical research needs that relate to the environmental dimensions of AMR, both in the longer term for providing input to an updated JPIAMR Strategic Research Agenda, but also in the shorter term to provide guidance for specific calls.
Year(s) Of Engagement Activity 2017
URL https://www.jpiamr.eu/wp-content/uploads/2017/11/Report-_JPIAMR-workshop-on-Environmental-dimensions...
 
Description ? Gaze WH. Co-selection for AMR by quaternary ammonium compounds. Royal Academy of Science. Stockholm. March 2016. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk at the Royal Academy of Science in Stockholm on AMR in the environment
Year(s) Of Engagement Activity 2016
 
Description ? Invited by MRC to work with Viadynamics to develop an AMR framework to map out research challenges and ways in which we are addressing those challenges. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Advise RCUK policy on research priorities on AMR
Year(s) Of Engagement Activity 2017
 
Description ? Invited to EA meeting on AMR in waste water to plan EA programme of investigation. March 2017 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Help inform water industry AMR research programme
Year(s) Of Engagement Activity 2017
 
Description ? NERC Planet Earth article "Have we opened the floodgates on antimicrobial resistance?" Winter 2016/17. 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact ?Article for Planet earth detailing role of flooding and climate change on environmental transmission of Amr
Year(s) Of Engagement Activity 2017
 
Description AMR in the Environment Module for: Antimicrobial Resistance: A Multidisciplinary Approach Short Course, led by the London School of Hygiene and Tropical Medicine & University of Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I raised the awareness of postgraduates who are interested in learning about combatting AMR. They had not been exposed to issues pertaining to AMR in the environment prior to my talk.
Year(s) Of Engagement Activity 2018
 
Description Constraints On and Reasons For, Eliminating Sewage Pollution In Riverswith a focus on AMR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Cardiff Seminar for School of Biosciences Departmental Seminar generated a good deal of discussion about the research area which continued on social media.
Year(s) Of Engagement Activity 2019
 
Description Expert Committee for the 2020 Antimicrobial Resistance Benchmark, Access to Medicine Foundation 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact My role on the expert panel was to highlight issues pertaining to the chemical drivers of AMR in the environment. My input helped put antifungals in the Access to Medicines AMR Benchmark. I also raised the issue that antivirals will need to be included, as well. I also highlighted the need to consider agricultural antimicrobial manufacturers.
Year(s) Of Engagement Activity 2017,2018
URL https://accesstomedicinefoundation.org/amr-benchmark
 
Description Invited to speak at Bolivian conference on AMR attended by the minister of health. Santa Cruz, June 2019. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact I had previously been invited to travel to Bolivia and speak to the AMR Action plan committee hosted by the British Embassy in La Paz, this was a follow up presentation to a similar group including the Minister of Health.
Year(s) Of Engagement Activity 2019
 
Description Irish EPA Research Programme - Project Steering Committee, "Antimicrobial Resistance and the Environment (AREST) - Sources, persistence, Transmission and risk management 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I shared my opinion on how to analyse and interpret environmental microbiology and pharmaceutical data.
Year(s) Of Engagement Activity 2018,2019
 
Description Joint FAO/WHO Expert Meeting on Foodborne Antimicrobial Resistance Role of Environment, Crops and Biocides, June 11-15 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact My contribution to the discussions helped to shape an FAO white paper that has since been published.
Year(s) Of Engagement Activity 2018
URL https://www.who.int/foodsafety/areas_work/antimicrobial-resistance/FAO_WHO_AMR_Summary_Report_June20...
 
Description Mentor for Newton Bhabha Fund's "UK-India AMR-Sanitation Workshop" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I provided mentorship to Indian researchers during the event. Facilitating discussions and providing talks on AMR in the environment.
Year(s) Of Engagement Activity 2018
 
Description Multilateral Scientific Committee for the "Impact of environmental contamination by antibiotic-resistant bacteria and antibiotics on human health," led by the United Kingdom Science and Innovation Network, the United States Centers for Disease Control and Prevention, in collaboration with Canada and the Wellcome Trust. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact I contributed a talk and provoked some discussions on how the WHO can better assist the need for global surveillance of the environment. The suggestion to use polio surveillance approaches was discussed and is now being piloted.
Year(s) Of Engagement Activity 2018
 
Description UK Parliament AMR Reception 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Representing UKRI funded research at the POSTnote event in Portcullis House, 25 Feb 2020
Year(s) Of Engagement Activity 2020
URL https://www.eventbrite.co.uk/e/superbugs-registration-92717521603#