Advancing Analytical Methods for Investigating the Epidemiology of Antimicrobial Resistance using Campylobacter coli from Swine Populations as a Model System

项目总结/摘要 耐药病原菌的出现和持续存在对人类和动物造成了严重威胁 世界各地的人口。尽管已知抗菌剂的使用会选择抗菌剂耐药性（AMR）， 在没有抗菌剂暴露的情况下，耐药性通常持续存在。更好地理解 需要在自然病原体群体中进行AMR的流行病学研究。然而，传统的流行病学方法 不适合理解AMR风险因素，因为它们没有考虑到生态和 这一演变过程混淆了抗生素暴露与AMR之间的预期关联。 结合生态和进化原则的改进流行病学方法是必要的， 提供关于AMR的新见解，为更有效的AMR预防策略提供信息，并最终促进 抗生素治疗的未来效果。这项研究的长期目标是建立一个定量的 将生态学和进化原理与流行病学方法相结合的框架， 了解人类和动物群体中的AMR风险。该提案旨在利用 以商品猪群中的大肠弯曲杆菌种群为模型系统， AMR的演变和流行病学。先前的研究发现C.大肠杆菌从猪饲养在两个传统 无菌场对氟喹诺酮类和大环内酯类抗生素耐药，具有临床意义 因为这些药物用于治疗人类弯曲杆菌病。这项研究将建立在以前的基础上。 工作和完成以下目标：1）确定和量化宿主暴露和微生物基因型 与大肠杆菌对氟喹诺酮类和大环内酯类药物的表型耐药相关。猪大肠杆菌 使用概率图形模型（即链图）的畜群，以及2）量化选择和细菌适应性 与氟喹诺酮类和大环内酯类耐药相关的基因型在天然C.大肠杆菌种群 在存在和不存在抗菌剂使用的情况下，使用动态方法。预期的结果是， 研究是一个定量框架的发展，可应用于任何宿主-病原体系统， AMR是一种威胁，以阐明AMR选择和持久性的驱动因素。这个提案和指导团队 将提供培训申请人的发展作为一个独立的临床医生，科学家学习的关键 人与动物接触面的传染病流行病学。跨学科研究培训计划将 为申请人提供发展分子流行病学，计算生物学和 传染病流行病学比较临床培训计划将使申请人获得 在指导下的人类和动物群体传染病管理经验 传染病医生和兽医流行病学家。北卡罗来纳州的培训环境 大学非常适合申请人跨学科的培养目标，因为申请人还可以获得 资源和机会在杜克大学和北卡罗来纳大学教堂山。

PROJECT SUMMARY/ABSTRACT The emergence and persistence of antimicrobial resistant pathogens are a serious threat to human and animal populations worldwide. Although antimicrobial use is known to select for antimicrobial resistance (AMR), resistance often persists in the absence of antimicrobial exposure. An improved understanding of the epidemiology of AMR in natural pathogen populations is needed. However, traditional epidemiological methods are not well-suited for understanding AMR risk factors because they do not account for the ecological and evolutionary processes that confound the expected association between antimicrobial exposure and AMR. Improved epidemiological methods that incorporate ecological and evolutionary principles are necessary for providing new insights on AMR, informing more effective AMR prevention strategies, and ultimately promoting the future efficacy of antimicrobial therapies. The long-term goal of this research is to develop a quantitative framework integrating ecological and evolutionary principles with epidemiological methods to advance existing knowledge of AMR risk among human and animal populations. This proposal aims to use commensal Campylobacter coli populations in commercial swine herds as a model system to investigate the ecology, evolution, and epidemiology of AMR. Prior studies found that C. coli from pigs reared under both conventional and antibiotic-free farms were resistant to fluoroquinolone and macrolide antibiotics, which is clinically significant as these drugs are used to treat human campylobacteriosis. The proposed research will build upon this previous work and accomplish the following aims: 1) identify and quantify host exposures and microbial genotypes associated with phenotypic resistance to fluoroquinolone and macrolide drugs among commensal C. coli in swine herds using probabilistic graphical models (i.e. chain graphs), and 2) quantify selection and bacterial fitness costs of genotypes associated with fluoroquinolone- and macrolide-resistance among natural C. coli populations in presence and absence of antimicrobial use, using phylodynamic methods. The expected outcome of this research is the development of a quantitative framework that can be applied to any host-pathogen system in which AMR is a threat to elucidate drivers of AMR selection and persistence. This proposal and mentorship team will provide training critical for the applicant’s development as an independent clinician-scientist studying infectious disease epidemiology at the human-animal interface. The interdisciplinary research training plan will provide the applicant opportunities to develop skills in molecular epidemiology, computational biology and infectious disease epidemiology. The comparative clinical training plan will enable the applicant to gain experience in infectious disease management among both human and animal populations under the guidance of infectious disease physicians and veterinary epidemiologists. The training environment at North Carolina State University is ideal for the applicants cross-disciplinary training goals, as the applicant also has access to resources and opportunities at Duke University and University of North Carolina-Chapel Hill.