An antibiogram-based CentriCapillary system for neonatal sepsis PID and AST

基于抗菌谱的 CentriCapillary 系统，用于治疗新生儿败血症 PID 和 AST

基本信息

批准号：
9170096
负责人：
Vincent Jen-Jr Gau
金额：
$ 74.77万
依托单位：
GENEFLUIDICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9170096
关键词：
Address Adult Adverse event Agreement Algorithms Antibiotics Antimicrobial susceptibility Bacteremia Bacteria Bacterial Infections Beds Biosensor Birth Blood Blood Cells Blood Volume Blood specimen Blood-Borne Pathogens CDC7 gene Centers for Disease Control and Prevention (U.S.)Centrifugation Characteristics Clinical Clinical Microbiology Clinical Sensitivity Cytolysis Development Devices Diagnostic Diagnostic tests Emerging Communicable Diseases Feasibility Studies Goals Guidelines Health Hospitals Hour Hybrids Infant Infection Libraries Marketing Medical Microfluidics Minimum Inhibitory Concentration measurement Molecular Molecular Analysis Neonatal Neonatal Intensive Care Units Phase Premature Infant Procedures Publishing Recovery Regulation Research Risk Sampling Sepsis Small Business Innovation Research Grant Specificity System Systems Development Technology Testing Ultracentrifugation United States Urinary tract infection Urine Validation Whole Blood base blind design evidence base innovation neonatal sepsis neonate novel pathogen phase 2 study premature product development prototype screening validation studies

项目摘要

DESCRIPTION (provided by applicant): The key objective of this proposed product development effort is to optimize the treatment of infections and reduce adverse events associated with inappropriate antibiotic use according to each NICU's locally established antibiogram with a fully automated, evidence-based rapid PID/AST system. The ultimate goal of the proposed neonatal sepsis CentriCapillary system after successful completion of this SBIR fast track is to initially address analysis needs in NICU settings then in the entire blood culture market (currently estimated to total more than $3 billion in the United States alone). Neonates are not small adults. It is not practical to design a diagnostics system using 10 mL blood culture bottles for adults and only load 1 mL of blood sample for neonates. Undoubtedly, there is a risk of missing the target pathogen for extremely low-level bacteremia (e.g., below 1 CFU/mL) using small blood sample volume, but it is not practical or even possible to obtain more than 1 mL of blood routinely from neonates in the NICU for PID and AST lab tests. Currently, there is no commercial system or product development effort from major diagnostics companies to address neonatal sepsis screening specifically using smaller blood volume. We developed, demonstrated and published an innovative molecular-based genotypic-phenotypic-hybrid approach for multiplexed bacterial PID and AST profiling with 100% clinical sensitivity, 96% clinical specificity, 98% minimum inhibitory concentration (MIC) and 97% categorical agreement in our most recent ongoing clinical feasibility study on 73 raw clinical urine samples. In this fas track SBIR project, we will leverage our expertise in microfluidics, electrochemical biosensors, and clinical microbiology to develop an integrated CentriCapillary system. While our molecular analysis technology has been validated with multidrugresistant pathogens (MDR) that cause UTI, which is the most common bacterial infection, it is anticipated that the incorporation of the lysis-centrifugation and dynamic hybridization will have applicability for rapid neonatal sepsis PID/AST and other emerging infectious diseases. PHASE I STUDY (YEAR 1) Specific Aim 1: Transition the current PID/AST platform technology from urinary tract infection (UTI) to neonatal sepsis- Hypothesis: Lysis centrifugation can address the change of matrix effect from raw urine to whole blood samples and the issue of low abundant pathogen for neonatal sepsis by using a CentriCapillary cartridge for blood- pelleting assisted rapid blood culture on various low blood volumes from neonates (10 μL - 2 mL). Specific Aim 2: Demonstrate the feasibility of the electrochemical-based molecular analysis CentriCapillary cartridge - Hypothesis: Microfluidic cartridge-based blood pelleting can capture and recover all common pathogens on the YNHH NICU's antibiogram for rapid neonatal sepsis PID and AST. PHASE II STUDY (YEARS 2 AND 3). Specific Aim 3: Develop a dual-mode electrochemical-based dynamic hybridization analysis algorithm to expand the PID/AST panel - Hypothesis: Dynamic hybridization analysis can be utilized to expand the species-specific identification of common and emerging pathogens for neonatal sepsis. Specific Aim 4: Prototype, validate and manufacture the CentriCapillary cartridge (COGS<$15) and system (COGS<$25k) - Hypothesis: Ultracentrifugation (up to 50,000 g, gravitational force) can be incorporated into a multiplexed fluidic cartridge for a fully automated neonatal sepsis PID/AST from whole blood samples in 6 hours. Specific Aim 5: Clinically validate the rapid neonatal PID/AST CentriCapillary system according to CLSI guidelines - Hypothesis: Blood samples spiked with ATCC strain bacteria used in the analytical validation studies represent critical matrix characteristics of fresh whole blood samples from neonates The development and validation of neonatal sepsis will adhere to the ISO 13485 standards, FDA/CDC/CLSI guidelines on AST and federal regulation 21 CFR 866.1645. The ultimate goal of this study is to reduce adverse events associated with inappropriate antibiotic use in the NICU settings.

描述（由申请人提供）：本拟议产品开发工作的主要目标是根据每个 NICU 本地建立的抗菌谱以及全自动、基于证据的快速 PID/成功完成此 SBIR 快速通道后，拟议的新生儿败血症 CentriCapillary 系统的最终目标是首先满足 NICU 环境中的分析需求，然后满足整个血液培养中的分析需求。市场（目前估计仅在美国就超过 30 亿美元）为成人设计一个使用 10 mL 血培养瓶且仅加载 1 mL 血液样本的诊断系统是不切实际的。毫无疑问，对于极低水平的菌血症（例如低于1 CFU/mL），使用小血样量存在错过目标病原体的风险，但这是不切实际的，甚至不可能获得目前，主要诊断公司还没有专门使用较小血量进行新生儿败血症筛查的商业系统或产品开发工作。发表了一种创新的基于分子的基因型-表型-混合方法，用于多重细菌 PID 和 AST 分析，具有 100% 的临床敏感性、96% 的临床特异性、98% 的最小抑制浓度(MIC) 和我们最近对 73 个原始临床尿液样本进行的临床可行性研究中的 97% 绝对一致在这个 fas track SBIR 项目中，我们将利用我们在微流体、电化学生物传感器和临床微生物学方面的专业知识来开发集成的 CentriCapillary 系统。虽然我们的分子分析技术已针对导致 UTI（这是最常见的细菌感染）的多重耐药病原体 (MDR) 进行了验证，但预计将裂解离心和动态杂交将适用于快速新生儿败血症 PID/AST 和其他新出现的传染病第一阶段研究（第一年）具体目标 1：将当前的 PID/AST 平台技术从尿路感染 (UTI) 过渡到新生儿。脓毒症-假设：裂解离心可以解决原尿到全血样本基质效应的变化以及新生儿脓毒症病原体丰度低的问题用于血液沉淀的 CentriCapillary 试剂盒，用于对新生儿的各种低血容量（10 µL - 2 mL）进行快速血液培养。具体目标 2：证明基于电化学的分子分析 CentriCapillary 试剂盒的可行性 - 假设：基于微流体试剂盒的血液。颗粒化可以捕获并回收 YNHH NICU 抗菌谱上的所有常见病原体，用于快速新生儿败血症 PID 和 AST II 研究。（第 2 年和第 3 年）具体目标 3：开发基于双模式电化学的动态杂交分析算法以扩展 PID/AST 面板 - 假设：动态杂交分析可用于扩展常见和新兴物种的物种特异性识别。具体目标 4：原型设计、验证和制造 CentriCapillary 墨盒 (COGS < 15 美元) 和系统 (COGS < 25,000 美元) - 假设：超速离心（高达 50,000 g，重力）可合并到多重流体卡盒中，以实现完全离心 6 小时内从全血样本中自动检测新生儿败血症 PID/AST 具体目标 5：根据 CLSI 指南对快速新生儿 PID/AST CentriCapillary 系统进行临床验证 - 假设：分析验证研究中使用的添加了 ATCC 菌株细菌的血液样本至关重要。新生儿新鲜全血样本的基质特征新生儿败血症的开发和验证将遵守 ISO 13485 标准、FDA/CDC/CLSI 关于 AST 的指南和联邦法规21 CFR 866.1645。本研究的最终目标是减少 NICU 环境中与不当抗生素使用相关的不良事件。