Screening for Resistant Enteric Bacteria to Personalize Infection Prevention Strategies in Neutropenic Patients

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。 氟喹诺酮类(FQS)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 耐药性威胁着FQ预防的有效性，目前尚不清楚。这项提案的目标是减少- 终止中性粒细胞减少患者耐氟喹诺酮肠杆菌(FQRE)定植的流行 FQRE定植密度和肠道微生物群对革兰氏阴性杆菌感染风险的影响。 接受FQ预防的患者，并开发一种快速诊断试验来检测耐药的定植情况 肠道细菌。中心假设是FQRE通过多种方法快速识别密集定植。 复合聚合酶链式反应确定中性粒细胞减少的患者发生FQRE BSI的风险很高，尽管进行了FQ预防。这个 这项建议的理由是，对FQRE定植和肠道微生物群影响的了解 FQ预防的有效性将导致新的个性化感染预防策略。具体的 本项目的目的是：1)确定FQRE在中性粒细胞中的定植情况及其临床意义 跨不同地理位置的大型癌症中心的患者；2)确定哪些FQRE殖民患者 在接受FQ预防的同时发生革兰氏阴性BSI的风险最高；以及3)开发和验证 建立了一种快速鉴定耐FQS和其他POS的肠道细菌定植的分子方法。 预防性抗生素。在这项研究中，900名急性白血病患者接受了强化化疗 或在四个癌症中心进行造血细胞移植筛查FQRE的定植情况 每周一次的肛周拭子培养。将确定FQRE定植的流行率和革兰氏菌的风险- 将FQRE定植患者和非定植患者的BSI阴性进行比较。一种预测性风险模型 对于革兰氏阴性，然后将为FQRE定植的患者构建合并FQRE定植的BSI。 肠道微生物多样性、共生菌丰度和寄主因素。此外，每个- 鉴定FQS和β-内酰胺类药物遗传抗性决定因素的多重聚合酶链式反应平台的建立 这些试剂将与选择性培养和抗菌药敏感性测试的黄金标准进行比较。这个 这项提案的贡献是，我们将确定全国范围内FQRE殖民的流行率，并 接受FQ预防的定植中性粒细胞减少患者发生革兰氏阴性血友病的风险，建立模型 确定哪些FQRE定植的患者患FQRE BSI的风险最高，并制定一种快速、易于使用的 FQRE和β-内酰胺类耐药肠道细菌定植的分子检测这些贡献 将具有重大意义和创新性，因为它们将直接导致一种潜在的实践改变的设计 中性粒细胞减少的患者随机接受个体化抗菌治疗的临床试验- Laxis，基于对FQRE和对其他潜在耐药性的肠道细菌的定植筛选 预防药物，或目前普遍使用FQ预防的“一刀切”方法。

PROJECT SUMMARY/ABSTRACT Gram-negative bloodstream infections (BSIs) cause severe morbidity and mortality in neutropenic patients. Fluoroquinolones (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 objectives of this proposal are to de- termine the prevalence of colonization with FQ-resistant Enterobacteriaceae (FQRE) in neutropenic patients and the impact of FQRE colonization density and the gut microbiome on the risk of Gram-negative BSI in pa- tients who receive FQ prophylaxis, and to develop a rapid diagnostic test to detect colonization with resistant enteric bacteria. The central hypothesis is that rapid identification of dense colonization with FQRE via multi- plexed PCR identifies neutropenic patients at high risk of developing FQRE BSI despite FQ prophylaxis. The rationale for this proposal is that knowledge of the impact of FQRE colonization and the gut microbiome on the effectiveness of FQ prophylaxis would lead to novel personalized infection prevention strategies. The specific aims of this project are: 1) Determine the prevalence and clinical significance of FQRE colonization in neutro- penic patients across large geographically-diverse cancer centers; 2) Identify which FQRE-colonized patients are at highest risk for developing Gram-negative BSI while receiving FQ prophylaxis; and 3) Develop and verify a molecular assay to rapidly identify colonization with enteric bacteria that are resistant to FQs and other po- tential prophylactic antibiotics. In this study, 900 patients receiving intensive chemotherapy for acute leukemia or hematopoietic cell transplantation at four cancer centers will be screened for colonization with FQRE by weekly perianal swab cultures. The prevalence of FQRE colonization will be identified and the risk of Gram- negative BSI in FQRE-colonized patients and non-colonized patients will be compared. A predictive risk model for Gram-negative BSI will then be constructed for FQRE-colonized patients that incorporates FQRE coloniza- tion density, gut microbial diversity, abundance of commensal bacteria, and host factors. Additionally, the per- formance of a multiplexed PCR platform that identifies genetic resistance determinants to FQs and β-lactam agents will be compared to the gold standards of selective culture and antimicrobial susceptibility testing. The contributions of this proposal are that we will determine the nationwide prevalence of FQRE colonization and the risk of Gram-negative BSI in colonized neutropenic patients who receive FQ prophylaxis, develop a model to identify which FQRE-colonized patients are at highest risk of FQRE BSI, and develop a rapid, easy-to-use molecular test to diagnose colonization with FQRE and β-lactam-resistant enteric bacteria. These contributions will be significant and innovative because they will directly lead to the design of a potentially practice-changing clinical trial in which neutropenic patients are randomized to an individualized strategy of antibacterial prophy- laxis, based on screening for colonization with FQRE and enteric bacteria that are resistant to other potential prophylactic agents, or to the current “one-size-fits-all” approach of universal administration of FQ prophylaxis.