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

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。 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。本提案的目的是： 确定贫血患者中耐甲氧西林肠杆菌科细菌（ESTRE）定植的患病率 以及大肠杆菌定植密度和肠道微生物组对PA中革兰氏阴性BSI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菌的定植。 肠道细菌中心假设是，通过多重PCR快速鉴定密集定植的BMPRE， 复合PCR鉴定出尽管FQ预防但仍处于发生BRE BSI的高风险的血小板减少症患者。的 这一建议基本原理是了解了大肠杆菌定殖和肠道微生物组对 FQ预防的有效性将导致新的个性化感染预防策略。具体 本项目的目的是：1）确定中性粒细胞中ESTRE定植的患病率和临床意义， 2）确定哪些患者是在地理上不同的大型癌症中心中的贫血患者; 在接受FQ预防时发生革兰氏阴性BSI的风险最高;和3）开发和验证 一种快速鉴定对FQs和其他口服药物耐药的肠道细菌定植的分子测定， 潜在的预防性抗生素在这项研究中，900名接受强化化疗的急性白血病患者， 或四个癌症中心的造血细胞移植将通过以下方法筛选CRAMRE的定殖： 每周肛周拭子培养。将确定革兰氏阳性菌定植的患病率，并评估革兰氏阳性菌定植的风险。 将比较在BRE定殖患者和非定殖患者中的阴性BSI。预测风险模型 对于革兰氏阴性BSI，然后将构建用于合并有ERARE定植的ERARE定植患者的BSI， 密度、肠道微生物多样性、肠道细菌丰度和宿主因素。此外，每- 鉴定对FQs和β-内酰胺的遗传抗性决定因素的多重PCR平台的开发 将与选择性培养和抗菌药物敏感性测试的金标准进行比较。的 这项提案的贡献是，我们将确定全国范围内的反种族主义殖民化的普遍性， 在接受FQ预防性治疗的定植性血小板减少症患者中发生革兰氏阴性BSI的风险，开发了一个模型 以确定哪些CRE定植患者发生CRE BSI的风险最高，并开发一种快速，易于使用的 分子检测，以诊断大肠杆菌和β-内酰胺类耐药肠道细菌的定植。这些贡献 将是重要的和创新的，因为它们将直接导致一个潜在的实践改变的设计， 在一项临床试验中，贫血患者被随机分配到一个个性化的抗菌预防策略， 根据对耐药菌和对其他潜在耐药菌具有耐药性的肠道细菌的定植筛查， 预防剂，或目前的“一刀切”的FQ预防的普遍施用方法。

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.