Impact of early gut microbiome features on risk of neutropenic fever and bloodstream infection in hematologic malignancy

早期肠道微生物组特征对血液恶性肿瘤中中性粒细胞减少性发热和血流感染风险的影响

• 批准号: 10335245
• 负责人: Matthew Ziegler
• 金额: $ 19.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-13 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10335245
• 关键词: Accounting; Address; Admission activity; Adult; Advanced Development; Adverse event; Advisory Committees; Affect; Anaerobic Bacteria; Antibiotic Prophylaxis; Antibiotic Therapy; Antibiotics; Benchmarking; Bioinformatics; Biological Markers; Biometry; Characteristics; Child; Clinical; Collection; Data; Development; Development Plans; Event; Exposure to; Fever; Foundations; Future; Goals; Gut Mucosa; Health; Hematologic Neoplasms; Hematology; Impairment; Infection prevention; Inflammation; International; Investigation; Knowledge; Length of Stay; Levaquin; Life; Link; Longitudinal cohort study; Measurement; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Methods; Microbe; Molecular Epidemiology; Monobactams; Morbidity - disease rate; Mucositis; Mucous Membrane; Neutropenia; Neutropenic Fever; Oncology; Outcome; Pathogenesis; Pathway interactions; Patients; Population; Populations at Risk; Prevention; Preventive measure; Prophylactic treatment; Prospective cohort study; Proteobacteria; Provider; Public Health; Research; Research Personnel; Research Support; Resistance; Resources; Risk; Risk Marker; Role; Sampling; Sepsis; Series; Serum; Stem cell transplant; Taxon; Time; Toll-like receptors; Training; Training and Education; Work; advanced analytics; bacterial community; bacteriome; base; care costs; career; career development; chemotherapy; cohort; colonization resistance; commensal bacteria; experience; gastrointestinal; gut bacteria; gut dysbiosis; gut microbiome; high risk; high risk population; individual patient; infection risk; microbiome; microbiome research; mortality; outcome prediction; patient oriented research; patient population; patient subsets; preference; prevent; programs; prophylactic; skills; statistics; symposium; therapy design; transplantation therapy; treatment duration; treatment strategy

PROJECT SUMMARY/ ABSTRACT Both neutropenic (NTP) fever and bloodstream infections (BSIs) are common complications in patients receiving treatment for hematologic malignancy and are associated with increased length of stay, cost of care, and mortality. Chemotherapy and neutropenia result in the disruption of the gastrointestinal mucosa, leading to translocation of commensal bacteria from the gut, causing NTP fever, and in some cases BSI. The study of the impact of the gut microbiome is critical to understanding the pathogenesis of, and risk for, NTP fever. To prevent BSIs and treat NTP fever, patients are exposed to both prophylactic and empiric broad-spectrum antibiotics. However, the decision for antibiotic prophylaxis and the choice of therapy with empiric antibiotics are typically based on provider preference. This is due to a lack of data to inform antibiotic treatment and selection of specific agents for individual patients. Utilizing the gut microbiome to predict NTP fever and BSI may allow for personalized antibiotic decisions, to determine which patients will benefit most from antibiotic prophylaxis while limiting excess antibiotic exposures in those at low risk of NTP fever and BSI. The candidate plans to study the ability of the early gut microbiome before and change after chemotherapy to predict NTP fever (Aim 1.1). This includes an investigation of the impact of the gut microbiome on measures of gut mucosal integrity and microbe-induced inflammation. This proposal also aims to discriminate microbiome features of patients with NTP fever who ultimately develop BSI from those patients who do not (Aim 1.2). This will be accomplished through longitudinal collection of patient samples, focusing on a broad patient population at risk of these events, specifically patients admitted for chemotherapy and stem cell transplantation for treatment of hematologic malignancy. In addition, the candidate will investigate the impact of specific antibiotic exposures on the gut microbiome over the course of admission to understand how specific antibiotic choices, including prophylaxis, impact the gut microbiome (Aim 2). The results of this study may allow future clinicians to utilize early gut microbiome features in patients receiving treatment for hematologic malignancy to predict NTP fever and BSI. This knowledge will help inform the decision for antibiotic prophylaxis using individual patient factors and will help guide selection of specific antibiotics used for the treatment of NTP fever that also reduce the risk of microbiome disruption. The aims are combined with a robust training plan that includes formal training and education in bioinformatics, molecular epidemiology, and biostatistics, the development of advanced analytic skills for microbiome data, formal benchmarks for progress including presentation at seminars and international conferences, and extensive research experience under the guidance of an expert mentoring and advisory team. This proposal will form a strong foundation for the candidate's continued development toward a career as an independent investigator with a program of research focused on the prevention of infection in patients with hematologic malignancy.

项目概要/摘要 中性粒细胞减少症 (NTP) 发热和血流感染 (BSI) 都是患者常见的并发症 接受血液恶性肿瘤治疗，并与住院时间、护理费用增加有关， 和死亡率。化疗和中性粒细胞减少症会导致胃肠粘膜破坏，从而导致 肠道内的共生细菌易位，引起 NTP 热，在某些情况下甚至引起 BSI。该研究的 肠道微生物组的影响对于了解 NTP 热的发病机制和风险至关重要。到 预防 BSI 并治疗 NTP 热，患者同时接触预防性和经验性广谱药物 抗生素。然而，抗生素预防的决定和经验性抗生素治疗的选择 通常基于提供商的偏好。这是由于缺乏数据来指导抗生素治疗和 为个别患者选择特定的药物。利用肠道微生物群预测 NTP 发烧和 BSI 可以允许个性化的抗生素决策，以确定哪些患者将从抗生素中受益最大 预防，同时限制 NTP 发热和 BSI 低风险人群的过量抗生素暴露。 候选人计划研究早期肠道微生物组之前和之后变化的能力 化疗预测 NTP 发热（目标 1.1）。这包括对肠道影响的调查 微生物组对肠粘膜完整性和微生物引起的炎症的测量。该提案还旨在 区分 NTP 发热患者和最终发展为 BSI 的患者的微生物组特征 谁不这样做（目标 1.2）。这将通过纵向收集患者样本来完成，重点是 广大患者群体面临这些事件的风险，特别是接受化疗和干细胞治疗的患者 移植治疗血液恶性肿瘤。此外，候选人将调查以下因素的影响： 在入院过程中对肠道微生物组进行特定抗生素暴露，以了解特定抗生素的具体情况 抗生素的选择（包括预防）会影响肠道微生物组（目标 2）。 这项研究的结果可能使未来的临床医生能够利用患者的早期肠道微生物组特征 接受血液恶性肿瘤治疗以预测 NTP 发热和 BSI。这些知识将有助于告知 根据患者个体因素做出抗生素预防性决定，并将有助于指导特定药物的选择 用于治疗 NTP 热的抗生素也可降低微生物组破坏的风险。目标是 结合强大的培训计划，包括生物信息学、分子生物学等方面的正式培训和教育 流行病学和生物统计学，微生物组数据高级分析技能的发展，正式 进展基准，包括在研讨会和国际会议上的演讲，以及广泛的 在专家指导和咨询团队的指导下获得研究经验。该提案将形成一个 为候选人继续发展成为独立调查员的职业奠定坚实的基础 一项研究计划的重点是预防血液恶性肿瘤患者的感染。