Development of a Novel Whole Genome Sequencing-based Platform for Rapid Identification and Antimicrobial Profiling of Uropathogens

开发基于全基因组测序的新型平台，用于尿路病原体的快速识别和抗菌谱分析

• 批准号: 10382740
• 负责人: Amanda Nicole Billings
• 金额: $ 30.39万
• 依托单位: DAY ZERO DIAGNOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382740
• 关键词: Address; Advanced Development; Algorithms; Antibiotic Resistance; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Antimicrobial Resistance; Antimicrobial susceptibility; Bacteria; Bacterial DNA; Blood; Blood specimen; Caring; Cells; Cessation of life; Characteristics; Clinical; Collection; Communicable Diseases; Coupled; Cytolysis; DNA; Data; Data Analyses; Data Compromising; Detergents; Development; Diagnosis; Diagnostic; Diagnostic Sensitivity; Economic Burden; Emergency department visit; Ensure; Evidence based treatment; Genomics; Goals; Health; Hospitalization; Hospitals; Hour; Human; Infection; Infective cystitis; Inpatients; Intervention; Length of Stay; Life; Machine Learning; Medical; Membrane; Microbiology; Modification; Molecular; Morbidity - disease rate; Morphology; Multi-Drug Resistance; Nucleotides; Patient Care; Patients; Performance; Phase; Physicians; Preparation; Process; Property; Protocols documentation; Quality of Care; Re 80; Reaction Time; Recovery; Research; Resistance profile; Resolution; Risk; Sampling; Source; Technology; Testing; Time; Urinary tract infection; Urine; Uropathogen; Viscosity; antimicrobial; base; care outcomes; clinically actionable; clinically relevant; cost; cost effective; data quality; design; diagnostic platform; diagnostic tool; diagnostic value; experience; genome sequencing; high risk; human DNA; improved; in-vitro diagnostics; infection management; mortality; nanopore; novel; novel diagnostics; pathogen; pathogenic bacteria; process optimization; research clinical testing; sample collection; standard of care; targeted treatment; validation studies; whole genome

Complicated urinary tract infections are severe or life-threatening infections that extend beyond a simple bladder infection and occur most frequently in hospitalized patients. There are over 2.8 million cases of complicated urinary tract infections in the U.S. each year, with 20% of cases progressing to urosepsis, leading to nearly 150,000 deaths each year. Effective management of complicated urinary tract infections requires the rapid identification of the causative bacterial pathogen(s) and the associated antibiotic resistance profile. The current standard of care, however, is urine culture, which requires 2-3 days from specimen collection until actionable information to guide patient treatment is generated. Hence, there is an urgent need for diagnostic tools that will allow for the rapid identification of uropathogens and their antimicrobial resistance/sensitivity profile(s). To address this unmet need, Day Zero Diagnostics (DZD) is developing a diagnostic workflow that leverages whole genome sequencing and machine learning to deliver high resolution species identification and antimicrobial resistance and susceptibility profiling from a patient sample without the need for urine culture. These data will guide evidence-based treatment decisions to improve patient care. The aims of this proposal are to (1) demonstrate ultra-high enrichment of bacterial DNA from a diverse range of species from urine samples and (2) optimize a sample preparation pipeline to deliver an actionable result in six hours or less, a clinically relevant timeframe for complicated urinary tract infection. The proposed Specific Aims, with quantifiable target metrics, are designed to demonstrate proof-of-concept in advance of the development of a commercial in vitro diagnostic. Upon Phase I completion, Phase II will focus on optimizing the workflow, expanding test capabilities, and analytical and clinical validation studies.

复杂性尿路感染是指超出简单膀胱范围的严重或危及生命的感染 感染，最常见于住院患者。复杂病例超过280万例 美国每年都会发生尿路感染，其中 20% 的病例进展为尿脓毒症，导致近 每年有 15 万人死亡。复杂尿路感染的有效治疗需要快速 鉴定致病细菌病原体和相关的抗生素耐药性。目前的 然而，护理标准是尿培养，从标本采集到可采取行动需要 2-3 天 生成指导患者治疗的信息。因此，迫切需要能够诊断的工具 允许快速识别尿路病原体及其抗菌药物耐药性/敏感性特征。到 为了解决这一未满足的需求，零日诊断 (DZD) 正在开发一个诊断工作流程，利用整个 基因组测序和机器学习可提供高分辨率物种识别和抗菌 无需尿培养即可从患者样本中进行耐药性和敏感性分析。这些数据将 指导循证治疗决策以改善患者护理。该提案的目的是 (1) 证明尿样中多种物种的细菌 DNA 具有超高富集度，并且 (2) 优化样品制备流程，在六小时或更短的时间内提供可操作的结果，这是临床相关的 复杂性尿路感染的时间表。拟议的具体目标以及可量化的目标指标， 旨在在开发商业体外诊断之前展示概念验证。 第一阶段完成后，第二阶段将重点优化工作流程、扩展测试能力和 分析和临床验证研究。