Developing a conceptual framework to improve understanding of AMR in livestock systems: translating research into policy and practice

It is estimated that by 2050 AMR infections will be the leading cause of death globally with a total economic cost of $100 trillion, with the overwhelming burden placed on LMICs (O'Neill report, 2016). Antimicrobial usage (AMU) in livestock has been shown to be an important driver of antimicrobial resistance (AMR) in animals and is associated with resistance in the clinical setting, with a recent review attributing 24% of AMR in humans to AMU in animals. Impacts on the wider environment are also well documented as is the potential for human exposure and transmission; although the latter are poorly quantified for livestock rearing scenarios. Agriculture's share of global antibiotic consumption is high and rising, as the demand for animal protein increases, especially in low and middle-income countries. Without considering the important role that the farmed and natural environment plays in contributing to the overall burden of AMR infection, and taking steps to reduce environmental AMR, efforts in other sectors may not prevent the post-antibiotic era that threatens modern medicine. We will consider the issue of AMR using a DPSEEA framework (Drivers-Pressure-State- Exposure-Effect-Action). This framework was designed to allow complex problems to be broken down into logical components, it also allows Actions and critical control points to be identified which lends itself to the application of control theory modelling approaches. We will produce a "blueprint" for an integrated surveillance, analysis, interpretation, modelling and policy translation approach that can be utilised for any livestock system in any LMIC to facilitate decision making, implementation of incentives and informing new policy around interventions to reduce AMU, AMR and risk to human health. This will reduce the economic and societal burden of AMR whilst ensuring associated economic costs of interventions are considered.

Rather than trying to generate as much surveillance data, in as many livestock rearing systems, under as many management strategies as possible, we have instead taken an interdisciplinary approach to studying the impacts of feedlot production on antimicrobial usage and AMR in beef cattle as well as feedlot impacted environments. The rationale being that we can investigate this single livestock system, as an exemplar, in detail, including the impacts of cattle breeding and rearing systems combined with specific interventions including reduction of use of antibiotics as growth promoters, cessation of metaphylaxis at the point of recruitment to the feedlot and vaccination as an additional intervention. The use of dairy sourced calves as an additional risk factor due to increased antimicrobial usage (AMU) on dairy farms will also be investigated. Feedlot beef production is increasingly used instead of grassland production in much of Latin America and other parts of the world including LMICs in Latin America and beyond. It is ironic that as international efforts to tackle AMR increase (eg. the FAO, OIE and WHO Memorandum of Understanding, signed on the 30 May 2018) one of the remaining largely extensive, low AMU livestock systems is moving towards intensive, high AMU production systems. The impacts of this will be felt most keenly in LMICs where demand is increasingly most rapidly for affordable animal protein.

The project aims to generate new ways of considering AMR in farmed and natural environments, focusing on a Driving Force-Pressure-State-Exposure-Effect-Action (DPSEEA) framework to explore the linkages between selection for and dissemination of antimicrobial resistance (AMR) and the processes that drive this phenomenon. We will focus on feedlot beef production systems, as an exemplar, which are increasingly being used in Argentina and low and middle income countries (LMICs) in Latin America to replace less intensive, grass fed, low antimicrobial usage (AMU) systems. With thousands of animals kept within small areas large amounts of manure are generated which can impact surrounding soil and water resources with the potential for wider dissemination and risk of human exposure and environmental transmission of AMR pathogens. The research consortium is made up of AMR experts from Argentina and the UK, from government institutions and universities and includes clinical, veterinary and environmental microbiologists, specialists in bioinformatics and genomics, agricultural economics, evidence synthesis, mathematical modelling and AMR policy. This interdisciplinary team will enable a holistic approach to the problem, integrating understanding of 1) economic and human behaviours that drive AMU and livestock management practice, 2) evolutionary and ecological processes that lead to increased AMR in animal faeces and environmental matrices such as soil and water 3) mechanistic insights into resistance mechanisms and evolution of resistance within impacted environments and 4) human exposure risk associated with environmental and food borne human exposure. This data will be used to populate the conceptual framework, highlighting where knowledge gaps exist, and in development of an underpinning mathematical model using critical control, info-gap and adaptive management theories.

The proposed research will make an important contribution to efforts to tackle AMR within Argentina, other LMICs and in a global context. We will produce a "blueprint" for an integrated surveillance, analysis, interpretation, modelling and policy translation approach that can be used in any livestock system in any LMIC to facilitate decision making, implementation of incentives and inform new policy around interventions to reduce AMU, AMR and risk to human health. This will reduce the economic and societal burden of AMR whilst ensuring associated economic costs of interventions are considered. We will focus on beef feedlot systems as they pose an emerging threat through increased antimicrobial usage, relative to conventional grassland production systems, and the potential for environmental contamination from large amounts of waste. The research project will benefit livestock producers by identifying the most cost-effective mitigation
strategies to reduce AMR and will benefit consumers and society by reducing the risk of human AMR infection. The project will also benefit researchers studying AMR as we will investigate new ways of thinking about AMR in a holistic way, and will ensure impact through engagement with policy makers through a dedicated policy work package and through knowledge exchange via an extensive network of contacts throughout the world including the WHO, OIE, FAO and UNEP who lead the Tripartite Plus response to AMR.