Impacts of Antibiotic Residues in the Environment on Bacterial Resistance and Human Health in Eastern China: An Interdisciplinary Mixed-Methods Study Protocol. - Related Documents




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671901.0000Impacts of Antibiotic Residues in the Environment on Bacterial Resistance and Human Health in Eastern China: An Interdisciplinary Mixed-Methods Study Protocol. Antibiotic resistance is a global health challenge that threatens human and animal lives, especially among low-income and vulnerable populations in less-developed countries. Its multi-factorial nature requires integrated studies on antibiotics and resistant bacteria in humans, animals, and the environment. To achieve a comprehensive understanding of the situation and management of antibiotic use and environmental transmission, this paper describes a study protocol to document human exposure to antibiotics from major direct and indirect sources, and its potential health outcomes. Our mixed-methods approach addresses both microbiological and pathogen genomics, and epidemiological, geospatial, anthropological, and sociological aspects. Implemented in two rural residential areas in two provinces in Eastern China, linked sub-studies assess antibiotic exposure in population cohorts through household surveys, medicine diaries, and biological sampling; identify the types and frequencies of antibiotic resistance genes in humans and food-stock animals; quantify the presence of antibiotic residues and antibiotic resistance genes in the aquatic environment, including wastewater; investigate the drivers and behaviours associated with human and livestock antibiotic use; and analyse the national and local policy context, to propose strategies and systematic measurements for optimising and monitoring antibiotic use. As a multidisciplinary collaboration between institutions in the UK and China, this study will provide an in-depth understanding of the influencing factors and allow comprehensive awareness of the complexity of AMR and antibiotic use in rural Eastern China.202235805804
672010.9999Human, animal and environmental contributors to antibiotic resistance in low-resource settings: integrating behavioural, epidemiological and One Health approaches. Antibiotic resistance (ABR) is recognized as a One Health challenge because of the rapid emergence and dissemination of resistant bacteria and genes among humans, animals and the environment on a global scale. However, there is a paucity of research assessing ABR contemporaneously in humans, animals and the environment in low-resource settings. This critical review seeks to identify the extent of One Health research on ABR in low- and middle-income countries (LMICs). Existing research has highlighted hotspots for environmental contamination; food-animal production systems that are likely to harbour reservoirs or promote transmission of ABR as well as high and increasing human rates of colonization with ABR commensal bacteria such as Escherichia coli However, very few studies have integrated all three components of the One Health spectrum to understand the dynamics of transmission and the prevalence of community-acquired resistance in humans and animals. Microbiological, epidemiological and social science research is needed at community and population levels across the One Health spectrum in order to fill the large gaps in knowledge of ABR in low-resource settings.201829643217
670020.9999Antimicrobial Resistance in Diverse Ecological Niches-One Health Perspective and Food Safety. Antimicrobial resistance (AMR) is a multi-sectoral, systemic, and global issue worldwide. Antimicrobial use (AMU) is a key factor in the selection of resistant bacteria within different ecological niches, from agriculture to food-producing animals to humans. There is a question regarding the extent to which the use of antibiotics in livestock production and the primary food production sector influences the selection and transmission of resistant bacteria and/or resistant genes throughout the food chain and thus contributes to the complexity in the development of AMR in humans. Although the trends in the prevalence of foodborne pathogens have changed over time, the burden of ecological niches with resistance genes, primarily in commensal microorganisms, is of concern. The implementation of the harmonized surveillance of AMU and AMR would provide comprehensive insights into the actual status of resistance and further interventions leading to its reduction. Tracking AMR in different ecological niches by applying advanced genome-based techniques and developing shared AMR data repositories would strengthen the One Health concept.202540426510
670630.9999Antimicrobial Resistance Development Pathways in Surface Waters and Public Health Implications. Human health is threatened by antibiotic-resistant bacteria and their related infections, which cause thousands of human deaths every year worldwide. Surface waters are vulnerable to human activities and natural processes that facilitate the emergence and spread of antibiotic-resistant bacteria in the environment. This study evaluated the pathways and drivers of antimicrobial resistance (AR) in surface waters. We analyzed antibiotic resistance healthcare-associated infection (HAI) data reported to the CDC's National Healthcare Safety Network to determine the number of antimicrobial-resistant pathogens and their isolates detected in healthcare facilities. Ten pathogens and their isolates associated with HAIs tested resistant to the selected antibiotics, indicating the role of healthcare facilities in antimicrobial resistance in the environment. The analyzed data and literature research revealed that healthcare facilities, wastewater, agricultural settings, food, and wildlife populations serve as the major vehicles for AR in surface waters. Antibiotic residues, heavy metals, natural processes, and climate change were identified as the drivers of antimicrobial resistance in the aquatic environment. Food and animal handlers have a higher risk of exposure to resistant pathogens through ingestion and direct contact compared with the general population. The AR threat to public health may grow as pathogens in aquatic systems adjust to antibiotic residues, contaminants, and climate change effects. The unnecessary use of antibiotics increases the risk of AR, and the public should be encouraged to practice antibiotic stewardship to decrease the risk.202235740227
671840.9999Agroecosystem exploration for Antimicrobial Resistance in Ahmedabad, India: A Study Protocol. INTRODUCTION: Antimicrobial resistance (AMR) has emerged as one of the leading threats to public health. AMR possesses a multidimensional challenge that has social, economic, and environmental dimensions that encompass the food production system, influencing human and animal health. The One Health approach highlights the inextricable linkage and interdependence between the health of people, animal, agriculture, and the environment. Antibiotic use in any of these areas can potentially impact the health of others. There is a dearth of evidence on AMR from the natural environment, such as the plant-based agriculture sector. Antibiotics, antibiotic-resistant bacteria (ARB), and related AMR genes (ARGs) are assumed to present in the natural environment and disseminate resistance to fresh produce/vegetables and thus to human health upon consumption. Therefore, this study aims to investigate the role of vegetables in the spread of AMR through an agroecosystem exploration in Ahmedabad, India. PROTOCOL: The present study will be executed in Ahmedabad, located in Gujarat state in the Western part of India, by adopting a mixed-method approach. First, a systematic review will be conducted to document the prevalence of ARB and ARGs on fresh produce in South Asia. Second, agriculture farmland surveys will be used to collect the general farming practices and the data on common vegetables consumed raw by the households in Ahmedabad. Third, vegetable and soil samples will be collected from the selected agriculture farms and analyzed for the presence or absence of ARB and ARGs using standard microbiological and molecular methods. DISCUSSION: The analysis will help to understand the spread of ARB/ARGs through the agroecosystem. This is anticipated to provide an insight into the current state of ARB/ARGs contamination of fresh produce/vegetables and will assist in identifying the relevant strategies for effectively controlling and preventing the spread of AMR.202338644926
670150.9999Current Insights Regarding the Role of Farm Animals in the Spread of Antimicrobial Resistance from a One Health Perspective. Antimicrobial resistance (AMR) represents a global threat to both human and animal health and has received increasing attention over the years from different stakeholders. Certain AMR bacteria circulate between humans, animals, and the environment, while AMR genes can be found in all ecosystems. The aim of the present review was to provide an overview of antimicrobial use in food-producing animals and to document the current status of the role of farm animals in the spread of AMR to humans. The available body of scientific evidence supported the notion that restricted use of antimicrobials in farm animals was effective in reducing AMR in livestock and, in some cases, in humans. However, most recent studies have reported that livestock have little contribution to the acquisition of AMR bacteria and/or AMR genes by humans. Overall, strategies applied on farms that target the reduction of all antimicrobials are recommended, as these are apparently associated with notable reduction in AMR (avoiding co-resistance between antimicrobials). The interconnection between human and animal health as well as the environment requires the acceleration of the implementation of the 'One Health' approach to effectively fight AMR while preserving the effectiveness of antimicrobials.202236136696
670760.9998Investigating the occurrence of antimicrobial resistance in the environment in Canada: a scoping review. Antimicrobial resistance is an environmental, agricultural, and public health problem that is impacting the health of humans and animals. The role of the environment as a source of and transmission pathway for antibiotic resistant bacteria and antibiotic resistance genes is a topic of increasing interest that, to date, has received limited attention. This study aimed to describe the sources and possible pathways contributing to antimicrobial resistance dissemination through bioaerosols, water, and soil in Canada using a scoping review methodology and systems thinking approach. A systems map was created to describe the occurrence and relationships between sources and pathways for antimicrobial resistance dissemination through water, soil, and bioaerosols. The map guided the development of the scoping review protocol, specifically the keywords searched and what data were extracted from the included studies. In total, 103 studies of antimicrobial resistance in water, 67 in soil, and 12 in air were identified. Studies to detect the presence of antimicrobial resistance genes have mainly been conducted at wastewater treatment plants and commercial animal livestock facilities. We also identified elements in the systems map with little or no data available (e.g., retail) that need to be investigated further to have a better understanding of antimicrobial resistance dissemination through different Canadian environments.202540279669
670470.9998Gut microbiota research nexus: One Health relationship between human, animal, and environmental resistomes. The emergence and rapid spread of antimicrobial resistance is of global public health concern. The gut microbiota harboring diverse commensal and opportunistic bacteria that can acquire resistance via horizontal and vertical gene transfers is considered an important reservoir and sink of antibiotic resistance genes (ARGs). In this review, we describe the reservoirs of gut ARGs and their dynamics in both animals and humans, use the One Health perspective to track the transmission of ARG-containing bacteria between humans, animals, and the environment, and assess the impact of antimicrobial resistance on human health and socioeconomic development. The gut resistome can evolve in an environment subject to various selective pressures, including antibiotic administration and environmental and lifestyle factors (e.g., diet, age, gender, and living conditions), and interventions through probiotics. Strategies to reduce the abundance of clinically relevant antibiotic-resistant bacteria and their resistance determinants in various environmental niches are needed to ensure the mitigation of acquired antibiotic resistance. With the help of effective measures taken at the national, local, personal, and intestinal management, it will also result in preventing or minimizing the spread of infectious diseases. This review aims to improve our understanding of the correlations between intestinal microbiota and antimicrobial resistance and provide a basis for the development of management strategies to mitigate the antimicrobial resistance crisis.202338818274
671680.9998Wastewater surveillance of antibiotic-resistant bacteria for public health action: potential and challenges. Antibiotic resistance is an urgent public health threat. Actions to reduce this threat include requiring prescriptions for antibiotic use, antibiotic stewardship programs, educational programs targeting patients and healthcare providers, and limiting antibiotic use in agriculture, aquaculture, and animal husbandry. Wastewater surveillance might complement clinical surveillance by tracking time/space variation essential for detecting outbreaks and evaluating efficacy of evidence-based interventions, identifying high-risk populations for targeted monitoring, providing early warning of the emergence and spread of antibiotic-resistant bacteria (ARBs), and identifying novel antibiotic-resistant threats. Wastewater surveillance was an effective early warning system for SARS-CoV-2 spread and detection of the emergence of new viral strains. In this data-driven commentary, we explore whether monitoring wastewater for antibiotic-resistant genes (ARGs) and/or bacteria resistant to antibiotics might provide useful information for public health action. Using carbapenem resistance as an example, we highlight technical challenges associated with using wastewater to quantify temporal/spatial trends in ARBs and ARGs and compare with clinical information. While ARGs and ARBs are detectable in wastewater enabling early detection of novel ARGs, quantitation of ARBs and ARGs with current methods is too variable to reliably track space/time variation.202539475072
651390.9998Antibiotic Resistance Dissemination and Mapping in the Environment Through Surveillance of Wastewater. Antibiotic resistance is one of the major health threat for humans, animals, and the environment, according to the World Health Organization (WHO) and the Global Antibiotic-Resistance Surveillance System (GLASS). In the last several years, wastewater/sewage has been identified as potential hotspots for the dissemination of antibiotic resistance and transfer of resistance genes. However, systematic approaches for mapping the antibiotic resistance situation in sewage are limited and underdeveloped. The present review has highlighted all possible perspectives by which the dynamics of ARBs/ARGs in the environment may be tracked, quantified and assessed spatio-temporally through surveillance of wastewater. Moreover, application of advanced methods like wastewater metagenomics for determining the community distribution of resistance at large has appeared to be promising. In addition, monitoring wastewater for antibiotic pollution at various levels, may serve as an early warning system and enable policymakers to take timely measures and build infrastructure to mitigate health crises. Thus, by understanding the alarming presence of antibiotic resistance in wastewater, effective action plans may be developed to address this global health challenge and its associated environmental risks.202539676299
6703100.9998Foodborne Microbial Communities as Potential Reservoirs of Antimicrobial Resistance Genes for Pathogens: A Critical Review of the Recent Literature. Antimicrobial resistance (AMR) is a global and increasing threat to human health. Several genetic determinants of AMR are found in environmental reservoirs, including bacteria naturally associated with widely consumed fermented foods. Through the food chain, these bacteria can reach the gut, where horizontal gene transfer (HGT) can occur within the complex and populated microbial environment. Numerous studies on this topic have been published over the past decades, but a conclusive picture of the potential impact of the non-pathogenic foodborne microbial reservoir on the spread of AMR to human pathogens has not yet emerged. This review critically evaluates a comprehensive list of recent experimental studies reporting the isolation of AMR bacteria associated with fermented foods, focusing on those reporting HGT events, which represent the main driver of AMR spread within and between different bacterial communities. Overall, our analysis points to the methodological heterogeneity as a major weakness impairing determination or a causal relation between the presence of AMR determinants within the foodborne microbial reservoir and their transmission to human pathogens. The aim is therefore to highlight the main gaps and needs to better standardize future studies addressing the potential role of non-pathogenic bacteria in the spread of AMR.202337512869
6694110.9998Interconnected microbiomes and resistomes in low-income human habitats. Antibiotic-resistant infections annually claim hundreds of thousands of lives worldwide. This problem is exacerbated by exchange of resistance genes between pathogens and benign microbes from diverse habitats. Mapping resistance gene dissemination between humans and their environment is a public health priority. Here we characterized the bacterial community structure and resistance exchange networks of hundreds of interconnected human faecal and environmental samples from two low-income Latin American communities. We found that resistomes across habitats are generally structured by bacterial phylogeny along ecological gradients, but identified key resistance genes that cross habitat boundaries and determined their association with mobile genetic elements. We also assessed the effectiveness of widely used excreta management strategies in reducing faecal bacteria and resistance genes in these settings representative of low- and middle-income countries. Our results lay the foundation for quantitative risk assessment and surveillance of resistance gene dissemination across interconnected habitats in settings representing over two-thirds of the world's population.201627172044
6717120.9998Updated research agenda for water, sanitation and antimicrobial resistance. The emergence and spread of antimicrobial resistance (AMR), including clinically relevant antimicrobial-resistant bacteria, genetic resistance elements, and antibiotic residues, presents a significant threat to human health. Reducing the incidence of infection by improving water, sanitation, and hygiene (WASH) is one of five objectives in the World Health Organization's (WHO) Global Action Plan on AMR. In September 2019, WHO and the Health-Related Water Microbiology specialist group (HRWM-SG) of the International Water Association (IWA) organized its third workshop on AMR, focusing on the following three main issues: environmental pathways of AMR transmission, environmental surveillance, and removal from human waste. The workshop concluded that despite an increase in scientific evidence that the environment may play a significant role, especially in low-resource settings, the exact relative role of the environment is still unclear. Given many antibiotic-resistant bacteria (ARB) can be part of the normal gut flora, it can be assumed that for environmental transmission, the burden of fecal-oral transmission of AMR in a geographical area follows that of WASH-related infections. There are some uncertainties as to the potential for the propagation of particular resistance genes within wastewater treatment plants (WWTPs), but there is no doubt that the reduction in viable microbes (with or without resistance genes) available for transmission via the environment is one of the goals of human waste management. Although progress has been made in the past years with respect to quantifying environmental AMR transmission potential, still more data on the spread of environmental AMR within human communities is needed. Even though evidence on AMR in WWTPs has increased, the reduction in the emergence and spread of AMR by basic sanitation methods is yet unresolved. In order to contribute to the generation of harmonized One Health surveillance data, WHO has initiated an integrated One Health surveillance strategy that includes the environment. The main challenge lies in rolling it out globally including to the poorest regions.202033328358
4297130.9998Predicting clinical resistance prevalence using sewage metagenomic data. Antibiotic resistance surveillance through regional and up-to-date testing of clinical isolates is a foundation for implementing effective empirical treatment. Surveillance data also provides an overview of geographical and temporal changes that are invaluable for guiding interventions. Still, due to limited infrastructure and resources, clinical surveillance data is lacking in many parts of the world. Given that sewage is largely made up of human fecal bacteria from many people, sewage epidemiology could provide a cost-efficient strategy to partly fill the current gap in clinical surveillance of antibiotic resistance. Here we explored the potential of sewage metagenomic data to assess clinical antibiotic resistance prevalence using environmental and clinical surveillance data from across the world. The sewage resistome correlated to clinical surveillance data of invasive Escherichia coli isolates, but none of several tested approaches provided a sufficient resolution for clear discrimination between resistance towards different classes of antibiotics. However, in combination with socioeconomic data, the overall clinical resistance situation could be predicted with good precision. We conclude that analyses of bacterial genes in sewage could contribute to informing management of antibiotic resistance.202033244050
6702140.9998Reservoirs of antimicrobial resistance in the context of One Health. The emergence and spread of antimicrobial resistance (AMR) and resistant bacteria, are a global public health challenge. Through horizontal gene transfer, potential pathogens can acquire antimicrobial resistance genes (ARGs) that can subsequently be spread between human, animal, and environmental reservoirs. To understand the dissemination of ARGs and linked microbial taxa, it is necessary to map the resistome within different microbial reservoirs. By integrating knowledge on ARGs in the different reservoirs, the One Health approach is crucial to our understanding of the complex mechanisms and epidemiology of AMR. Here, we highlight the latest insights into the emergence and spread of AMR from the One Health perspective, providing a baseline of understanding for future scientific investigations into this constantly growing global health threat.202336913905
6604150.9998The spread of antimicrobial resistance in the aquatic environment from faecal pollution: a scoping review of a multifaceted issue. Antimicrobial resistance (AMR) is a major global health concern accelerated by the misuse and mismanagement of antibiotics in clinical and veterinary settings, leading to longer treatment times, increased costs and greater mortality rates. The environment can play a major role as a source and disseminator of AMR, with faecal pollution, from both anthropogenic and non-anthropogenic sources making a significant contribution. The review aimed to identify how faecal pollution contributes to AMR in surface water, focusing on current methods of source tracking faecal pollution. The databases used were Medline Ovid® and Scopus. From the search, 744 papers from January 2020 to November 2023 were identified, and after the screening, 33 papers were selected that reported on AMR, aquatic environments and faecal pollution and were published in English. The studies were from six different continents, most were from Europe and Asia indicating faecal pollution is influenced by spatiotemporal differences such as population and sanitation infrastructure. Multiple different methodologies were used with a lack of standardised methods making comparability challenging. All studies identified AMR strains of faecal indicator bacteria showing resistance to a wide variety of antibiotics, particularly beta-lactams and tetracyclines. Few studies investigated mobile gene elements with class 1 integrons being the most frequently studied. Wastewater treatment plants were significant contributors, releasing large amounts of AMR bacteria into the environment. Environmental factors such as seasonal differences, temperature, rainfall and UV exposure, along with local antibiotic usage influenced the local resistome. Animals, both wild and domestic, introduced antimicrobial resistance genes and potential pathogens into the aquatic environment. Overall, faecal pollution is a complicated issue with multiple factors contributing to and facilitating the spread of AMR. Standardisation of methods and surveillance, robust wastewater management and further research into AMR dissemination are needed to address the human health, animal health and environmental concerns.202540131552
6601160.9998Use of Wastewater to Monitor Antimicrobial Resistance Trends in Communities and Implications for Wastewater-Based Epidemiology: A Review of the Recent Literature. Antimicrobial resistance (AMR) presents a global health challenge, necessitating comprehensive surveillance and intervention strategies. Wastewater-based epidemiology (WBE) is a promising tool that can be utilized for AMR monitoring by offering population-level insights into microbial dynamics and resistance gene dissemination in communities. This review (n = 29 papers) examines the current landscape of utilizing WBE for AMR surveillance with a focus on methodologies, findings, and gaps in understanding. Reported methods from the reviewed literature included culture-based, PCR-based, whole genome sequencing, mass spectrometry, bioinformatics/metagenomics, and antimicrobial susceptibility testing to identify and measure antibiotic-resistant bacteria and antimicrobial resistance genes (ARGs) in wastewater, as well as liquid chromatography-tandem mass spectrometry to measure antibiotic residues. Results indicate Escherichia coli, Enterococcus spp., and Pseudomonas spp. are the most prevalent antibiotic-resistant bacterial species with hospital effluent demonstrating higher abundances of clinically relevant resistance genes including bla, bcr, qnrS, mcr, sul1, erm, and tet genes compared to measurements from local treatment plants. The most reported antibiotics in influent wastewater across studies analyzed include azithromycin, ciprofloxacin, clindamycin, and clarithromycin. The influence of seasonal variation on the ARG profiles of communities differed amongst studies indicating additional factors hold significance when examining the conference of AMR within communities. Despite these findings, knowledge gaps remain, including longitudinal studies in multiple and diverse geographical regions and understanding co-resistance mechanisms in relation to the complexities of population contributors to AMR. This review underscores the urgent need for collaborative and interdisciplinary efforts to safeguard public health and preserve antimicrobial efficacy. Further investigation on the use of WBE to understand these unique population-level drivers of AMR is advised in a proposed framework to inform best practice approaches moving forward.202541011405
3899170.9998Overview of Evidence of Antimicrobial Use and Antimicrobial Resistance in the Food Chain. Antimicrobial resistance (AMR) is a global health problem. Bacteria carrying resistance genes can be transmitted between humans, animals and the environment. There are concerns that the widespread use of antimicrobials in the food chain constitutes an important source of AMR in humans, but the extent of this transmission is not well understood. The aim of this review is to examine published evidence on the links between antimicrobial use (AMU) in the food chain and AMR in people and animals. The evidence showed a link between AMU in animals and the occurrence of resistance in these animals. However, evidence of the benefits of a reduction in AMU in animals on the prevalence of resistant bacteria in humans is scarce. The presence of resistant bacteria is documented in the human food supply chain, which presents a potential exposure route and risk to public health. Microbial genome sequencing has enabled the establishment of some links between the presence of resistant bacteria in humans and animals but, for some antimicrobials, no link could be established. Research and monitoring of AMU and AMR in an integrated manner is essential for a better understanding of the biology and the dynamics of antimicrobial resistance.202032013023
3900180.9998Antimicrobial resistance pattern in domestic animal - wildlife - environmental niche via the food chain to humans with a Bangladesh perspective; a systematic review. BACKGROUND: Antimicrobial resistance (AMR) is a growing concern globally, but the impact is very deleterious in the context of Bangladesh. Recent review article on the AMR issue demonstrates the scenario in human medicine; unfortunately, no attempt was taken to address this as One Health issue. The antimicrobial resistance bacteria or genes are circulating in the fragile ecosystems and disseminate into human food chain through direct or indirect ways. In this systematic review we are exploring the mechanism or the process of development of resistance pathogen into human food chain via the domestic animal, wildlife and environmental sources in the context of One Health and future recommendation to mitigate this issue in Bangladesh. RESULTS: Tetracycline resistance genes were presenting in almost all sample sources in higher concentrations against enteric pathogen Escherichia coli. The second most significant antibiotics are amino-penicillin that showed resistant pattern across different source of samples. It is a matter of concerns that cephalosporin tends to acquire resistance in wildlife species that might be an indication of this antibiotic resistance gene or the pathogen been circulating in our surrounding environment though the mechanism is still unclear. CONCLUSIONS: Steps to control antibiotic release and environmental disposal from all uses should be immediate and obligatory. There is a need for detailed system biology analysis of resistance development in-situ.202032838793
6695190.9998'Disperse abroad in the land': the role of wildlife in the dissemination of antimicrobial resistance. Antimicrobial resistance (AMR) has been detected in the microbiota of many wildlife species, including long-distance migrants. Inadequately treated wastes from humans and livestock dosed with antimicrobial drugs are often assumed to be the main sources of AMR to wildlife. While wildlife populations closely associated with human populations are more likely to harbour clinically important AMR related to that found in local humans and livestock, AMR is still common in remote wildlife populations with little direct human influence. Most reports of AMR in wildlife are survey based and/or small scale, so researchers can only speculate on possible sources and sinks of AMR or the impact of wildlife AMR on clinical resistance. This lack of quantitative data on the flow of AMR genes and AMR bacteria across the natural environment could reflect the numerous AMR sources and amplifiers in the populated world. Ecosystems with relatively simple and well-characterized potential inputs of AMR can provide tractable, but realistic, systems for studying AMR in the natural environment. New tools, such as animal tracking technologies and high-throughput sequencing of resistance genes and mobilomes, should be integrated with existing methodologies to understand how wildlife maintains and disperses AMR.201627531155