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: 10206034
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206034
• 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.

项目概要/摘要 革兰氏阴性血流感染（BSI）会导致中性粒细胞减少症患者严重发病和死亡。氟- 罗喹诺酮类 (FQ) 用于预防中性粒细胞减少症期间的革兰氏阴性 BSI，但 FQ 的程度 耐药性是否威胁 FQ 预防的有效性尚不清楚。该提案的目的是阻止 探究耐 FQ 肠杆菌 (FQRE) 的定植如何影响革兰氏阴性 BSI 的风险 接受 FQ 预防的中性粒细胞减少症患者以及 FQRE 定植密度和肠道微生物组如何变化 多样性影响这种风险。假设 FQ 预防对中性粒细胞减少症患者的有效性是 在 FQRE 定植的患者中显着减少，特别是如果定植超过定量阈值， 肠道共生细菌的缺乏会增加革兰氏阴性 BSI 的风险。这样做的理由 建议了解 FQRE 定植和肠道微生物组多样性对有效性的影响 FQ 预防的研究可能会导致个体化的感染预防策略。该项目的具体目标 是： 1) 确定中性粒细胞减少性造血系统中 FQRE 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 FQRE 中 FQRE 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。该提案将利用建立 列出了 350 名 HCT 接受者的队列，他们在中性粒细胞减少症期间接受了 FQ 预防。粪便样本已 在化疗开始时收集，此后每周收集一次，直至中性粒细胞减少症恢复。对于这个亲 posal，这些样本将被培养用于 FQRE。我们将确定 FQRE 的患病率和风险因素 移植入院时定植，并比较移植期间革兰氏阴性 BSI 的风险 FQRE 定植和未定植患者之间的任务。然后我们将对血流进行测序并 定植 FQRE 以确定定植 FQRE 的 HCT 接受者因定植而发生 BSI 的频率 拉紧。我们还将对FQRE进行定量培养，以确定是否存在定量阈值 FQRE 定植易于突破 BSI。然后我们将对粪便进行 16S rRNA 测序 来自 FQRE 定植患者的样本，比较发生和未发生 FQRE 定植的患者的微生物组多样性 FQRE BSI，并识别与 FQRE BSI 风险较低相关的细菌分类群。然后我们将评估 这些变量是否与多变量模型中的 FQRE BSI 独立相关。预期的 该提案的贡献在于我们将确定是否筛选和量化 FQRE 定植， 结合肠道微生物组多样性的评估，可以识别中性粒细胞减少症高风险患者 尽管采用 FQ 预防，但仍发展出革兰氏阴性 BSI。这一贡献将是重大且创新的 因为它将为设计和评估个性化抗菌预防方法奠定基础 中性粒细胞减少症患者的松弛，考虑到 FQRE 定植和肠道的存在和密度 微生物组多样性，而不是当前的“一刀切”方法。

项目成果

Reply to Caldwell et al.

回复考德威尔等人。

• DOI: 10.1093/cid/ciab1001
• 发表时间: 2022
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Satlin,MichaelJ;Chen,Liang;Douglass,Claire;Hovan,Michael;Davidson,Emily;Soave,Rosemary;LaSpina,Marisa;Gomez-Arteaga,Alexandra;vanBesien,Koen;Mayer,Sebastian;Phillips,Adrienne;Hsu,JingMei;Malherbe,Rianna;Small,CatherineB;Je
• 通讯作者: Je