AMRflows: antimicrobials and resistance from manufacturing flows to people: joined up experiments, mathematical modelling and risk analysis

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Antibiotics and other pharmaceuticals are released into rivers from multiple manufacturing sites at concentrations high enough to select for antibiotic resistance genes (ARGs). Such mixtures of antibiotics may select for new combinations of resistance genes, which is particularly concerning as this will further limit antibiotic treatment options. In addition, bacteria from treating manufacturing waste or domestic sewage and raw sewage entering rivers will mingle, facilitating horizontal gene transfer (HGT) of resistance genes carried on plasmids. However, the antibiotics will be diluted while being transported downstream, and some will be quickly degraded, and resistant bacteria may not survive so the question is how long is resistance selected and how long does it survive? Is resistance transmitted to other bacteria before they are lost? How far are resistant bacteria transport and what is the exposure of humans or livestock?In order to ask these questions, evaluate mitigation strategies and develop evidence-based global environmental standards, we will pursue a unique combined experimental and mathematical modelling programme including the following streams:(1) Measure concentrations of antibiotics and heavy metals, water chemistry, water levels and flow rates, water sediment exchange, abundance and diversity of antibiotic resistance genes and antibiotic-resistant bacteria. (2) Quantify transmission of resistance genes in bench-scale reactors. (3) Study selection in the river samples in bench-scale reactors under realistic, controlled conditions. (4) Study the risk of infection by resistant bacteria in tissue culture and Zebrafish laboratory models and the antibiotic dose required for treatment. (5) Build and test a mathematical model of antimicrobial resistance (AMR) dynamics on the small scale of a water sample, including degradation of antibiotics, growth and death of sensitive and resistant bacteria, selection of resistance as a function of antibiotic concentration, HGT of resistance. (6) Build and test a model of water flow for the river network; this will be on the large scale of rivers. (7) Combine the small-scale AMR dynamics and large-scale transport models into a model that can calculate the dilution of the compounds and track how long the chemicals and bacteria have been in the river water, sediments and floodplains and how far they spread to downstream populations and ecosystems.The combined model can evaluate whether interventions such as separate treatment of antibiotic manufacturing waste and domestic sewage would be effective in reducing resistance levels before putting this into practice. The environmental AMR pathways will be examined across two river systems. The Musi (Hyderabad) is more polluted with antibiotics than the Adyar (Chennai). Both are polluted by sewage. Their pollution flows to people via irrigation, drinking water production and spiritual cleansing. These rivers have phases of low flow with concentrated industrial waste and sewage and limited bacterial spread and high flows in the monsoon season, flooding communities with resistant bacteria.(8) Analyse the human health risks based on the predictions of the combined model and the experimental study in (4) and other information. The risk analysis will include the level of uncertainty in those risks and will contribute to the development of international environmental standards.These will be the two main outcomes to improve human, animal and environmental health, specifically (i) quantitative evidence for resistance (co)selection and transfer under in situ conditions in a more and less polluted river system and (ii) a truly novel combined AMR dynamics and transport modelling framework that can be used globally as a tool to track AMRflows.