Predicting Infections in Neutropenic Hosts Receiving Fluoroquinolone Prophylaxis

项目摘要/摘要 革兰氏阴性血流感染(BSI)在中性粒细胞减少的患者中会导致严重的发病率和死亡率。氟-- 在中性粒细胞减少症期间，罗喹诺酮(FQS)被用于预防革兰氏阴性BSI，但FQ的程度 耐药性威胁着FQ预防的有效性，目前尚不清楚。这项建议的目的是阻吓- 耐氟喹诺酮肠杆菌(FQRE)定植对儿童革兰氏阴性杆菌感染风险的影响 接受FQ预防的中性粒细胞减少患者以及FQRE定植密度和肠道微生物群如何变化 严酷程度会影响这一风险。假设FQ预防中性粒细胞减少患者的有效性是 在被FQRE定植的患者中显著减少，特别是如果定植在数量阈值以上， 而缺乏共生肠道细菌会增加患革兰氏阴性BSI的风险。这样做的理由是 建议是了解FQRE定植和肠道微生物群多样性对有效性影响 FQ预防可以导致个性化的感染预防策略。这个项目的具体目标是 1)确定中性粒细胞减少症患者FQRE定植的发生率及临床意义 细胞移植(HCT)接受者接受FQ预防；2)确定FQRE中FQRE BSI的危险因素- 在中性粒细胞减少期间接受FQ预防的定居的HCT接受者。这项提议将利用一种-- 在中性粒细胞减少期间接受FQ预防的350名HCT受者的LIST队列。大便样本已经被 在化疗开始时收集，此后每周收集，直到中性粒细胞减少症恢复。对于这位专业人士- 波萨尔，这些样本将被培养为FQRE。我们将确定FQRE的患病率和危险因素 移植入院时的定植情况，并比较移植期间发生革兰氏阴性细菌感染的风险。 接受FQRE治疗的患者与未接受FQRE治疗的患者的任务。然后我们会对血液进行测序 定植FQRE以确定在FQRE定植的HCT受者因其定植而发生BSI的频率 紧张。我们还将对FQRE进行定量培养，以确定是否存在定量阈值 容易导致BSI突破的FQRE殖民。然后我们将对粪便进行16S rRNA测序 来自FQRE定植患者的样本，比较发生和未发生的患者的微生物组多样性 FQRE BSI，并确定与FQRE BSI风险较低相关的细菌分类。然后我们将评估 在多变量模型中，这些变量是否与FQRE BSI独立相关。预期中的 这项提议的贡献是，我们将确定是否筛选和量化FQRE殖民， 结合肠道微生物组多样性的评估，可以确定中性粒细胞减少症的高危患者 尽管采取了FQ预防措施，但仍出现了革兰氏阴性BSI。这一贡献将是重大的和创新的- 因为这将为设计和评估一种个性化的抗菌方法奠定基础- 中性粒细胞减少患者的松弛，考虑FQRE定植和肠道的存在和密度 微生物多样性，而不是目前的“一刀切”的方法。

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.