Predicting Infections in Neutropenic Hosts Receiving Fluoroquinolone Prophylaxis

预测接受氟喹诺酮预防的中性粒细胞减少宿主的感染

• 批准号: 10057041
• 负责人: Michael Joseph Satlin
• 金额: $ 8.48万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057041
• 关键词: 16S ribosomal RNA sequencing; Admission activity; Anti-Bacterial Agents; Bacteria; Biological Models; Blood Circulation; Cessation of life; Data; Effectiveness; Enterobacteriaceae; Experimental Models; Extended-spectrum β-lactamase; Fluoroquinolones; Foundations; Goals; Gram-Negative Bacteria; Hematologic Neoplasms; Infection; Infection prevention; Integration Host Factors; Knowledge; Lead; Life; Mentored Patient-Oriented Research Career Development Award; Mission; Modeling; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; Neutropenia; Oncology; Patients; Prevalence; Prevention strategy; Prophylactic treatment; Public Health; Recovery; Research; Resistance; Resistance profile; Risk; Risk Factors; Sampling; Sepsis; Testing; Transplant Recipients; Transplantation; Vulnerable Populations; chemotherapy; clinically significant; cohort; commensal bacteria; density; design; efficacy evaluation; fluoroquinolone resistance; gastrointestinal; gastrointestinal bacteria; genome sequencing; gut bacteria; gut microbiome; gut microbiota; hematopoietic cell transplantation; high risk; innovation; microbiome; microbiome composition; mortality; novel; pathogen; patient population; personalized approach; personalized strategies; prevent; prophylactic; screening; stool sample; whole genome

PROJECT SUMMARY/ABSTRACT Gram-negative bloodstream infections (BSIs) cause severe morbidity and mortality in neutropenic patients. Fluo- roquinolones (FQs) are used to prevent Gram-negative BSI during neutropenia, but the extent to which FQ resistance threatens the effectiveness of FQ prophylaxis is unknown. The objective of this proposal is to deter- mine how colonization with FQ-resistant Enterobacterales (FQRE) impacts the risk of Gram-negative BSI in neutropenic patients who receive FQ prophylaxis and how FQRE colonization density and gut microbiome di- versity influence this risk. The hypothesis is that the effectiveness of FQ prophylaxis in neutropenic patients is markedly diminished in patients colonized with FQRE, particularly if colonized above a quantitative threshold, and that absence of commensal gut bacteria increases the risk of Gram-negative BSI. The rationale for this proposal is that knowledge of the impact of FQRE colonization and gut microbiome diversity on the effectiveness of FQ prophylaxis could lead to individualized infection prevention strategies. The specific aims of this project are: 1) Determine the prevalence and clinical significance of FQRE colonization in neutropenic hematopoietic cell transplant (HCT) recipients who receive FQ prophylaxis; 2) Identify risk factors for FQRE BSI in FQRE- colonized HCT recipients who receive FQ prophylaxis during neutropenia. This proposal will utilize an estab- lished cohort of 350 HCT recipients who received FQ prophylaxis during neutropenia. Stool samples have been collected upon initiation of chemotherapy and weekly thereafter until recovery from neutropenia. For this pro- posal, these samples will be cultured for FQRE. We will determine the prevalence of and risk factors for FQRE colonization on admission for transplant, and compare the risk of Gram-negative BSI during the transplant ad- mission between patients colonized and not colonized with FQRE. We will then sequence the bloodstream and colonizing FQRE to determine how frequently FQRE-colonized HCT recipients develop BSI from their colonizing strain. We will also perform quantitative cultures for FQRE to determine whether there is a quantitative threshold of FQRE colonization that predisposes to breakthrough BSI. We will then perform 16S rRNA sequencing of stool samples from FQRE-colonized patients, compare the microbiome diversity of patients who do and do not develop FQRE BSI, and identify bacterial taxa that are associated with a lower risk of FQRE BSI. We will then assess whether these variables are independently associated with FQRE BSI in a multivariate model. The expected contribution of this proposal is that we will determine whether screening for and quantifying FQRE colonization, combined with an assessment of gut microbiome diversity, can identify neutropenic patients at high risk of de- veloping Gram-negative BSI despite FQ prophylaxis. This contribution would be significant and innovative be- cause it would set the foundation for designing and evaluating an individualized approach to antibacterial prophy- laxis in neutropenic patients that takes into account the presence and density of FQRE colonization and gut microbiome diversity, instead of the current “one-size-fits-all” approach.

项目总结/摘要 革兰氏阴性血流感染（BSI）导致严重的发病率和死亡率在血小板减少症患者。荧光- 氟喹诺酮类药物（FQs）用于预防中性粒细胞减少症期间的革兰氏阴性BSI，但FQs在多大程度上 耐药性威胁FQ预防的有效性尚不清楚。这项建议的目的，是遏止─ 我如何殖民与耐药肠球菌（ESTRE）影响革兰氏阴性BSI的风险， 接受FQ预防治疗的贫血患者以及FQ定植密度和肠道微生物组如何改变 风险影响这种风险。假设FQ预防性治疗在血小板减少症患者中的有效性 在定植有ESTRE的患者中显著减少，特别是如果定植高于定量阈值， 并且肠道细菌的缺乏增加了革兰氏阴性BSI的风险。这样做的理由 建议是了解肠道菌群定植和肠道微生物组多样性对有效性影响 FQ的预防可能导致个体化的感染预防策略。该项目的具体目标 主要有：1）确定贫血造血干细胞中BRE定植的患病率和临床意义， 接受FQ预防的细胞移植（HCT）接受者; 2）确定在BRE中BRE BSI的风险因素- 在中性粒细胞减少症期间接受FQ预防的定植HCT接受者。该提案将利用一个建立- 在中性粒细胞减少症期间接受FQ预防的350名HCT接受者的队列。粪便样本已经 在开始化疗时收集，此后每周收集一次，直至从中性粒细胞减少症中恢复。对于这个亲- 因此，将对这些样本进行培养，以进行细菌培养。我们将确定EMPRE的患病率和风险因素， 移植入院时的定植，并比较移植期间革兰氏阴性BSI的风险， 定植和未定植的患者之间的使命。然后我们会对血流进行测序 定殖HCTRE以确定HCTRE定殖的HCT接受者从其定殖中发展BSI的频率 株我们还将进行定量培养，以确定是否存在定量阈值 会导致严重的脑脊髓损伤然后我们将对粪便进行16S rRNA测序， 从大肠杆菌定植患者的样本中，比较发生和不发生大肠杆菌定植患者的微生物组多样性。 检测BSI，并鉴定与较低的BSI风险相关的细菌分类群。我们将评估 在多变量模型中，这些变量是否独立地与BRE BSI相关。预期 该建议的贡献在于，我们将确定是否筛选和量化ESTRE定植， 结合肠道微生物组多样性的评估，可以确定处于高风险的脱 尽管FQ预防，但仍发生革兰氏阴性BSI。这一贡献将是重大的和创新的- 因为这将为设计和评估个性化的抗菌预防方法奠定基础- 在考虑到大肠杆菌定植和肠道菌群的存在和密度的情况下， 微生物组多样性，而不是目前的"一刀切"的方法。