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

项目摘要/摘要 抗菌素耐药病原体的出现和持续存在严重威胁着人类和动物 世界各地的人口。虽然已知抗菌剂的使用选择抗菌素耐药性(AMR)， 在缺乏抗菌剂暴露的情况下，耐药性往往持续存在。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 不适合于理解AMR风险因素，因为它们没有考虑到生态和 抗菌素暴露和AMR之间的预期关联的进化过程。 有必要改进流行病学方法，纳入生态学和进化论原则 提供有关AMR的新见解，提供更有效的AMR预防策略，并最终推动 抗菌疗法的未来疗效。这项研究的长期目标是开发一种量化的 将生态和进化原理与流行病学方法相结合的框架，以促进现有的 人类和动物群体中AMR风险的知识。这项提议旨在利用共生关系 商业猪群中的结肠弯曲杆菌种群作为一个模型系统来研究生态， AMR的演变和流行病学。先前的研究发现，在两种常规饲养条件下饲养的猪的大肠埃希菌 不含抗生素的农场对氟喹诺酮类和大环内酯类抗生素耐药，这具有临床意义。 因为这些药物是用来治疗人类弯曲杆菌病的。拟议的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类型 猪共生性大肠埃希菌对氟喹诺酮类和大环内酯类药物的表型耐药性 使用概率图形模型(即链图)的牛群，以及2)量化选择和细菌适合度 天然大肠埃希菌对氟喹诺酮类药物和大环内酯类药物耐药的基因分型成本 在有或没有使用抗菌剂的情况下，使用系统动力学方法。这样做的预期结果是 研究正在开发一种定量框架，该框架可以应用于任何寄主-病原体系统 哪种AMR是一种威胁，以阐明AMR选择和持久性的驱动因素。此建议书和指导团队 将提供对申请人作为独立临床医生-科学家研究的发展至关重要的培训 人-动物界面的传染病流行病学。跨学科研究培训计划将 为申请者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者能够获得 在指导下开展人畜共患传染病管理的体会 传染病内科医生和兽医流行病学家。北卡罗来纳州的培训环境 大学是申请者跨学科培养目标的理想之地，因为申请者还可以获得 杜克大学和北卡罗来纳大学教堂山分校的资源和机会。

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.