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Temporal dynamics of MDRO eradication after FMT

FMT 后 MDRO 根除的时间动态

基本信息

批准号：
10598519
负责人：
Michael Holmes Woodworth
金额：
$ 19.15万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598519
关键词：
16S ribosomal RNA sequencing AR gene Active Sites Address Anaerobic Bacteria Antibiotics Antimicrobial Resistance Bacteria Bacterial Antibiotic Resistance Bacterial Drug Resistance Bacteriophages Benchmarking Biomedical Research Centers for Disease Control and Prevention (U.S.)Cessation of life Clinical Clinical Research Clinical Trials Clostridium difficile Collaborations Collection Complement Control Groups Data Data Science Data Scientist Development Disease Dryness Educational workshop Enterobacteriaceae Environment Extended-spectrum β-lactamase Feces Frequencies Funding Future Genes Goals Infection Institution Intestines Investigation K-Series Research Career Programs Kidney Transplantation Link Mentors Mentorship Metabolic Pathway Metabolism Metagenomics Methods Microbiology Morbidity - disease rate Multi-Drug Resistance Organism Participant Patients Persons Pharmaceutical Preparations Prevalence Process Public Health Pythons Randomized Randomized Controlled Clinical Trials Recurrence Refractory Research Resources Risk Safety Sampling Techniques Testing Therapeutic Time Training Translating Transplant Recipients United States Viral Virulence Virus World Health Organization antimicrobial peptide antimicrobial resistant infection apprenticeship bacteriocin carbapenem-resistant Enterobacteriaceae career career development clinical application colonization resistance design drug development effective therapy fecal transplantation genome sequencing global health gut colonization gut microbiota improved infection risk knowledge base microbial microbiome mortality multi-drug resistant pathogen nephrotoxicity next generation sequencing novel operational taxonomic units pre-clinical programs public health intervention resistance gene therapeutic development tool virome virulence gene whole genome

项目摘要

PROJECT SUMMARY The World Health Organization and U.S. Centers for Disease Control and Prevention have designated antimicrobial resistance a major threat to Global Health with over 23,000 annual deaths related to antimicrobial resistant infections in the U.S. alone. However, the drug pipeline to develop new antibiotics is dry. Small studies support the safety and efficacy of fecal microbiota transplantation (FMT) to eliminate intestinal colonization with antibacterial resistant organisms but its mechanisms are not well understood. We will leverage patient-linked samples from a clinical trial PREMIX (NCT02922816) to test our overarching hypothesis that anaerobic bacteria, viruses, and their gene-predicted functions are causally associated with decreased MDRO colonization after FMT. The Specific Aims of this proposal include: Aim 1: Use the clinical gold standard of bacterial culture to estimate efficacy of FMT in MDRO eradication. Aim 2A: Establish a novel metagenomic analytic pipeline (MAP) to quantify abundance of bacterial and viral taxa, AR, virulence, and colonization resistance genes. Aim 2B: Use 16S rRNA sequencing to estimate temporal dynamics of difficult to culture bacterial taxa in FMT vs controls. Aim 2C: Use metagenomic whole-genome sequencing and the MAP to estimate temporal dynamics of AR, virulence, and colonization resistance genes in FMT vs controls. Aim 3: Use environmental virome NGS techniques to test the association of viral (including bacteriophage) taxa with abundance of MDRO after FMT. We expect that completion of these aims and related training will lead to clinically applicable preliminary data and next steps in translational microbial therapeutic development for MDRO colonization. My long-term career goal is to become a collaborative leader in ID microbiome data science focusing on: 1) mechanisms of microbial therapeutics such as FMT in reducing colonization with multi- drug resistant organisms (MDRO), and 2) translating these findings into clinical and public health interventions to reduce MDRO colonization and infection. Emory and Georgia Tech are ideal and highly-collaborative research environments, which are both national leaders in biomedical research. Both institutions provide rich resources to complete the described aims and progress in career development to become an independent translational ID microbiome data scientist. In addition, Emory is an active site of microbial therapeutic investigation with 7 clinical trials of microbial therapeutics and a clinical FMT program that has completed over 300 treatments for refractory Clostridioides difficile.

项目概要世界卫生组织和美国疾病控制与预防中心已指定抗菌药物耐药性是全球健康的主要威胁，每年有超过 23,000 人因抗菌药物死亡仅在美国就有耐药性感染。然而，开发新抗生素的药物渠道却很枯竭。小的研究支持粪便微生物群移植（FMT）消除肠道疾病的安全性和有效性细菌耐药性微生物定植，但其机制尚不清楚。我们将利用来自临床试验 PREMIX (NCT02922816) 的患者相关样本来测试我们的总体假设厌氧细菌、病毒及其基因预测的功能与 FMT 后 MDRO 定植减少。该提案的具体目标包括：目标 1：使用临床评估 FMT 根除 MDRO 功效的细菌培养金标准。目标 2A：创作一部小说宏基因组分析流程 (MAP)，用于量化细菌和病毒类群的丰度、AR、毒力和定植抗性基因。目标 2B：使用 16S rRNA 测序来估计难以预测的时间动态 FMT 与对照中培养细菌分类群。目标 2C：使用宏基因组全基因组测序和 MAP 评估 FMT 与对照中 AR、毒力和定植抗性基因的时间动态。目标 3：使用环境病毒组 NGS 技术来测试病毒（包括噬菌体）分类群与 FMT 后 MDRO 丰度。我们期望完成这些目标和相关培训将导致临床适用的初步数据和转化微生物治疗开发的后续步骤 MDRO定植。我的长期职业目标是成为 ID 微生物组数据领域的协作领导者科学重点关注：1）微生物疗法（例如 FMT）减少多种微生物定植的机制耐药微生物 (MDRO)，以及 2) 将这些发现转化为临床和公共卫生干预措施减少多重耐药菌定植和感染。埃默里大学和佐治亚理工学院是理想且高度合作的大学研究环境，在生物医学研究方面均处于国家领先地位。两个机构都提供了丰富的资源来完成所描述的目标并在职业发展中取得进展，成为独立的转化 ID 微生物组数据科学家。此外，埃默里大学还是微生物治疗的活跃场所 7 项微生物疗法临床试验和已完成超过 10 项临床 FMT 项目的调查治疗难治性艰难梭菌 300 次。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fecal Microbiota Transplantation Is Safe and Effective in Patients With Clostridioides difficile Infection and Cirrhosis.

DOI：
10.1016/j.cgh.2020.06.051
发表时间：
2021-08
期刊：
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
影响因子：
0
作者：
Cheng YW;Alhaffar D;Saha S;Khanna S;Bohm M;Phelps E;Ghabril M;Orman E;Sashidhar S;Rogers N;Xu H;Khoruts A;Vaughn B;Kao D;Wong K;Cammarota G;Ianiro G;Dhere T;Kraft CS;Mehta N;Woodworth MH;Allegretti JR;Nativ L;Marcus J;El-Nachef N;Fischer M
通讯作者：
Fischer M

mSphere of Influence: Microbiome-Associated Phenotypes Are Modifiable.

影响范围：微生物组相关表型是可修改的。

DOI：
10.1128/msphere.00508-20
发表时间：
2020
期刊：
mSphere
影响因子：
4.8
作者：
Woodworth,MichaelH
通讯作者：
Woodworth,MichaelH

Critical Care Management of the Patient with Clostridioides difficile.

DOI：
10.1097/ccm.0000000000004739
发表时间：
2021-01-01
期刊：
Critical care medicine
影响因子：
8.8
作者：
Adelman MW;Woodworth MH;Shaffer VO;Martin GS;Kraft CS
通讯作者：
Kraft CS

Haemophagocytic lymphohistiocytosis associated with bartonella peliosis hepatis following kidney transplantation in a patient with HIV.

HIV 患者肾移植后与肝紫癜性巴尔通体相关的噬血细胞淋巴组织细胞增多症。

DOI：
10.1016/s1473-3099(22)00276-6
发表时间：
2022-10
期刊：
LANCET INFECTIOUS DISEASES
影响因子：
56.3
作者：
Steed, Danielle;Collins, Jeffrey;Farris, Alton B.;Guarner, Jeannette;Yarar, Dilek;Friedman-Moraco, Rachel;Doane, Tristan;Pouch, Stephanie;Lyon, G. Marshall, III;Woodworth, Michael H.
通讯作者：
Woodworth, Michael H.

Changes in treatment of community-onset Clostridioides difficile infection after release of updated guidelines, Atlanta, Georgia, 2018.