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Our overall goal is to reduce the impact of antibiotic use on commensal bacteria and thereby reduce the risks posed to public health by antibiotic resistant pathogenic bacteria. We will pursue six objectives to achieve this goal: <OL> <LI> Perform a structured review of the quality of evidence supporting relevant university curricula, beef and dairy quality assurance programs, and professional prudent-use guidelines to identify plausible and practical antibiotic resistance (AR) interventions, <LI> Develop, evaluate and improve dairy and beef cattle systems-based mathematical models of AR, <LI> Employ molecular microbiology to discover the mechanisms underlying several paradoxical responses of resistant strains to antibiotic selection pressures, <LI> Field-test practical interventions designed to effectively manage AR levels in production as well as near-slaughter phases of beef and dairy cattle systems, <LI> Develop and test sensitive and accurate methods for enhancing surveillance to better detect and characterize early resistance to critically important antibiotics, <LI> Revise AR curricula, quality assurance guidelines and prudent-use guidelines and effectively disseminate these to appropriate individuals and organizations while monitoring, evaluating and improving the rate of adoption. </OL> The expected outputs from each of these objectives, respectively, are as follows: <OL> <LI> A database of the major sources of contemporary AR intervention recommendations, categorization of recommendations according to the strength of evidence, and a ranked list of the most promising interventions for study in subsequent research objectives, <LI> An integrated model to assess the temporal dynamics of AR in cattle systems and evaluate the effectiveness of interventions to mitigate AR dissemination in cattle systems. This model will also be available for education and extension purposes as a very effective demonstration tool, <LI> A comprehensive understanding of the dynamics of co- and counter-selection in vitro and in vivo will have been provided, which will support the design of innovative antibiotic-use practices to protect and salvage the use of these agents, <LI> We will have experimentally evaluated the efficacy and effectiveness of multiple AR interventions under field conditions. Scientifically proven interventions will be shared with interested parties and decision-makers in the cattle industry who will be encouraged to further evaluate those methods in their production systems. Decision-makers also will be warned of ineffective interventions, <LI> We will greatly enhance our detection of early-resistant E. coli, and we will be able to better estimate animal-level prevalence of resistance carriage through enhanced surveillance. We expect that our new approach will yield earlier detection and characterization of resistance to critically important antibiotics, <LI> Influence leaders within industry and academia will - when presented with current information about AR interventions - effectively disseminate that information to peers and subordinates within their circle of influences leading to wide-scale adoption on an industry-wide level.
NON-TECHNICAL SUMMARY: The dissemination of antibiotic resistance among normal cattle gut bacteria such as commensal Escherichia coli can yield vast pools of resistance elements which may then be transferred to pathogens such as Salmonella. If pathogenic bacteria resistant to antibiotics enter the food chain, treatment of humans can be complicated. Our overall goal is to identify, evaluate, and implement practical interventions for managing antibiotic resistance in beef and dairy cattle systems. We focus on the longstanding problem of resistance emergence, dissemination, and persistence among commensal enteric bacteria; that is, among beneficial and non-pathogenic bacteria naturally present in the gut of healthy livestock. We will employ a variety of methods to assess and then improve the quality of evidence contained in education and extension materials such as veterinary curricula and commodity specific prudent-use guidelines. We will improve the research base of this knowledge through a series of laboratory and field studies built on a framework of theoretical, basic and applied research. These will culminate in a series of recommended practices best suited to manage resistance in beef and dairy cattle systems. The results of our work will fill a knowledge gap that has been identified by stakeholders as critical: the potential impact of commensal bacteria on antibiotic resistance across host and environmental ecosystems. Our systems-based approach for achieving practical and proven interventions against this pressing problem will address a highly significant applied food safety problem.
<P>APPROACH: The approaches used to achieve each of our six objectives and to evaluate our success in disseminating their results, respectively, will be as follows: 1) a priori criteria will be used to screen content including abstracts and documents for inclusion eligibility and study quality. Information from publications of acceptable quality will be extracted and summarized with respect to each candidate intervention in a form conducive to analysis for quality and type of evidence. The evaluation will include formative and summative evaluation of program effectiveness. Indicators and data sources will include: the external steering committee, participating faculty and project personnel, project records and documents, and identified stakeholders, 2) our current ecological model describing the growth and death of a bacterial population in four habitats within the farm as well as the movements of bacteria among these habitats will be expanded to include additional elements specific to the study of AR among commensal enteric bacteria including: a) multiple strains, b) transmission of resistance genes among bacteria, c) the effect of antibiotic selection pressure, and d) biological fitness of the different strains, 3) we will assess the effect of different tet genes on the fitness of E. coli strains under the selective pressure of tetracycline, both in vitro and in vivo. The association of the respective tet genes with the blaCMY-2 gene responsible for ceftiofur resistance and their effects on growth will be assessed in vitro both independently and concomitantly with the blaCMY-2 plasmid present, 4) in both flow-through systems (i.e., beef feedlots) and non-flow-through systems (i.e., dairy farms), a favorable change in the flora of the bovine gut will be achieved by adding an end-stage management component to the life of intensively reared cattle. For a second set of intervention trials (beef and dairy) we aim to achieve more sustained animal- and environment-level AR outcomes in the growth (beef) and milk production (dairy) periods, 5) using historical samples and isolates, we will combine the use of selective media, along with further phenotypic and molecular characterization of isolated strains and comparisons with strains arising from non-selective approaches, to better understand and track the emergence, fitness shifts, and rise of ceftiofur-resistant E. coli over the past decade and during the next four years, and 6) having determined prior conditions of the targeted audience we will then identify the most likely opinion leaders in the various industry segments of this study. Using Rogers' (2003) innovation-decision process, we will design and deliver a mass media message aimed at the opinion leaders of each education and industry segment. Specific benchmarks related to this objective for evaluation include: a) recommendations for improved curriculum, guidelines, and extension materials, b) communication and dissemination of project results, c) adoption prediction model and adoption information, d) suggested changes for national and local policy regarding AR, and e) recommendations for surveillance system design.