Dynamics of Antimicrobial Resistance in the Urban Water Cycle in Europe

Resistance of pathogenic bacteria to antibiotics and other antimicrobials is increasing everywhere on Earth. This is making progressively our current antibiotics useless, potentially placing patient's lives at risk as some can no longer be treated by available treatment options. Resistance is not only selected inside the human body when antibiotics are used to treat people, but also selected after the antibiotics from patients in hospitals or ill people at home are entering the sewage. Moreover, the resistance genes can transfer to other bacteria, where they can persist and eventually transfer back to pathogenic bacteria. This transfer also happens in the sewage.

We postulate that urban water systems, that is, sewers, sewage treatment plants and receiving waters, are central places of exchange of resistance genes between pathogenic bacteria and environmental bacteria because these systems continuously receive excreted antimicrobials, resistant bacteria and resistance genes from many sources. Further, the high numbers of bacteria in these systems increases the transfer of resistance genes between different bacteria. The mixing of different wastes (e.g., hospital and community sewage) increases the selection for bacteria carrying multiple resistance genes due to the simultaneous presence of various antibiotics, biocides, and heavy metals.

DARWIN (Dynamics of Antimicrobial Resistance in the Urban Water Cycle in Europe) will be the first project to perform a cross-European examination of the fate of key resistant bacteria and resistance genes in UWSs resulting from discharged hospital and community wastes, including mechanisms of resistance gene transfer in different stages of sewer catchments and receiving waters. We will focus on the spread of resistance genes that are amongst the most problematic now because they confer resistance to the latest generation of antibiotics available (genes for extended spectrum beta-lactamases (ESBL) and carbapenemases). Specifically, we will investigate these resistance classes in three countries that differ in their use of antibiotics and sewage management practices: Denmark, Spain and the UK. We postulate that resistance genes readily transmit in urban water systems from pathogenic and non-pathogenic "gut" bacteria in human wastes (after antibiotic use) to environmental bacteria better adapted to the sewer environment. The environmental bacteria then carry the resistance genes across the wider environment, increasing community exposure.

Hence, we will, for the first time, determine which specific bacteria carry the resistance genes across the urban water systems and identify where resistance gene transfer events occur. Our ultimate goal is to assess the relative risk of resistance genes returning back to humans due to environmental exposure. To guide risk assessments, a predictive dynamic mathematical model for the urban water systems will be developed to assist in health and sewage management decisions.

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. We postulate that urban water systems (UWS), which are our receptacle for excreted antimicrobials, AMR organisms and AMR genes, are central conduits of AMR to and from pathogens and environmental strains. This is because of high microbial densities and the co-mingling of different wastes, which promotes accelerated AMR gene transfer (HGT) and multi-resistance due to the co-occurrence of antibiotics, biocides, metals and microbes.

In DARWIN, we will undertake a never-previously-performed pan-European examination of the fate of key AMR organisms and genetic determinants in UWSs resulting from discharged hospital and community wastes, including transmission mechanisms in different stages of sewer catchments and receiving waters. We focus on the spread of AMR genes encoding clinically relevant extended spectrum b-lactam (ESBL) and carbapenem resistance in three countries with differing AMR profiles and sewage management practices. We posit that AMR genes readily transmit in UWSs from pathogens and commensal hosts in human wastes (after antibiotic use) to environmental strains better adapted to migrate through the sewer environment, which is driven by local ecologies, conjugal plasmid transfer and phage-mediated transduction.

Hence, we will, for the first time, determine specific bacterial hosts that carry AMR genes across UWSs, and identify where key HGT events occur with the ultimate goal of assessing the relative risk of AMR genes returning back to humans due to environmental exposure to AMR in urban environments. To guide risk assessments, a predictive dynamic mathematical model for UWSs will be developed to assist in health and sewage management decisions.

Our project combines diverse expertise and access to urban water systems in three different countries to quantify patterns, pathways and mechanisms that drive AMR dissemination in urban environments. Central to project impact will be active involvement of our three industrial partners (major water companies in the UK, Denmark and Spain); our international External Advisory Board (EAB); and our strong links with European-wide AMR surveillance networks. Through these partners and connections, DARWIN has clear pathways to influence national, European and international policy. Specifics include:

i) Water industry partners: Active industrial partners are Northumbrian Water Ltd (NWL, UK), VIAQUA S.A. (ESP), and VandcenterSyd Denmark (VCS, DK). All three companies will provide complete cooperation, including access to their catchments and long-term data sets. However, each partner also has proactive relationships with their public and private stake-holders, and each will use their channels to support DARWIN outreach activities. For example, industrially-supported PhD students will be promoted and each company will help champion wider water issues within each national industry network.

ii) Industry impacts beyond project partners: Through each active partner, DARWIN will have wider influence across the EU water industry. For example, VIAQUA is active across Europe, having offices in ten countries. VIAQUA's philosophy is to invest in innovation to improve access to clean water, which they espouse across their corporate network. As such, DARWIN via VIAQUA will have pan-European influence, including water industries in countries outside of DARWIN. Further, NWL is an active partner in UKWIR; a research network spanning all UK water companies. UKWIR brokers novel approaches to wastewater management, which provides a path for DARWIN to impact the whole UK water industry. Finally, Danish colleagues have active collaborations with BIOFOS (the organisation responsible for sewage treatment across Copenhagen), and Veolia Water (FR), which is among the largest water companies in the world, creating global influence.

iii) Impact through the EAB: Our EAB includes Prof R Singer (US Presidential Advisory Committee on ARB), Prof Y-G Zhu (Director of the Chinese Academy of Science Institute of the Urban Environment), and Prof FB Mochales (Director of Instituto Ramon y Cajal de investigación Sanitaria). All three advisors are influential leaders on links between environmental and clinical AMR, and health in their countries. They provide a direct path for DARWIN to guide AMR decisions in each country and across the EU, which are all influential to global AMR policy.

iv) AMR awareness networks: DARWIN will link with ECDC, COMBACTE and EPI-NET under the new drugs for bad bugs - ND4BB program, ESCMID and its affiliated study groups on Antimicrobial Resistance Surveillance; Food- and Water-borne Infections; and Epidemiological Markers. These leading epidemiological networks on AMR will expand the impact of our project, including contextualising DARWIN efforts to help combat AMR spread in Europe.

v) The public-at-large: DARWIN will be use Press Offices of each academic partner to promote results to their local and national press, stakeholder organisations, and public interest groups. We have a strong track record in the public access to AMR work, including coverage on BBC World News and Danish TV, especially the role of the environment on AMR in healthcare systems. To further promote access, a multi-lingual webpage will be developed as well as a regularly updated Twitter feed, which allows rapid dissemination of outputs. We will, however, pay careful attention to reporting of results so as not to create undue concern about AMR detected during the work. Finally, Citizen Science will be encouraged throughout he project via access to our webpage, including an "invitation to share and collaborate" on the wider use of our databases.