AstraDx: Sub-Hour AST Via Computational Image Processing

AstraDx：通过计算图像处理实现不到一小时的 AST

• 批准号: 10547198
• 负责人: Jonathan Florez
• 金额: $ 29.96万
• 依托单位: ASTRADX, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547198
• 关键词: Acinetobacter baumannii; Address; Agreement; American; Antibiotics; Antimicrobial Resistance; Antimicrobial susceptibility; Area; Bacteria; Behavior; Biotechnology; Blood; Boston; Caring; Categories; Centers for Disease Control and Prevention (U.S.); Cessation of life; Code; Communicable Diseases; Complex; Dangerousness; Data; Data Set; Detection; Devices; Disease; Drug Combinations; ESKAPE pathogens; Engineering; Ensure; Enterococcus; Eye; Fostering; Genus staphylococcus; Goals; Gold; Growth; Guidelines; Health; Home; Hospitals; Hour; Human; Image; Incubators; Infection; Intelligence; Lead; Legal patent; Life; Measures; Mechanics; Methods; Microbiology; Minimum Inhibitory Concentration measurement; Mission; Modernization; Morbidity - disease rate; Optics; Organism; Outcome; Patients; Performance; Pharmaceutical Preparations; Phase; Phenotype; Process; Pseudomonas aeruginosa; Public Health; Resistance; Resolution; Resources; Running; Scientist; Sepsis; Side; Small Business Innovation Research Grant; Sum; Technology; Testing; Time; Training; United States National Institutes of Health; Validation; Vancomycin resistant enterococcus; Work; biosafety level 2 facility; carbapenem resistance; computational pipelines; cost; disease diagnostic; drug standard; experimental study; image processing; improved; innovation; member; methicillin resistant Staphylococcus aureus; mortality; mortality risk; multidrug-resistant Pseudomonas aeruginosa; normal microbiota; optical imaging; pathogen; personalized diagnostics; prevent; priority pathogen; routine Bacterial stain; serial imaging

PROJECT SUMMARY/ABSTRACT Antimicrobial susceptibility testing (AST) for bacterial bloodstream infections (BSIs) is dangerously slow. Starting from a positive blood culture, AST currently takes a median of 15 hours, and often takes days. Until results are available, there is no choice but to treat patients with empiric antibiotics and hope the pathogen is susceptible. This is unacceptable. BSIs are serious, rapidly fatal infections that kill a quarter-million Americans each year, including a third of all hospital deaths. Empiric antibiotics destroy patients’ normal flora, predisposing them to additional, untreatable infections. Every hour a patient is on the wrong antibiotic increases risk of death by 7.6%. This key problem has made rapid, affordable AST a global priority. To address this problem, AstraDx has developed a low-cost new AST device that we hypothesize can perform AST in under an hour. The purpose of this proposal is to test this hypothesis. Preliminary studies involving multiple experiments on 19 strains vs. 8 standard antibiotics have demonstrated growth detection in 31±18 minutes (95% range, 20-63 minutes). Strains tested included methicillin-resistant S. aureus (MRSA), vancomycin-resistant Enterococci (VRE), carbapenem-resistant A. baumannii (CRAB), carbapenem-resistant Enterobacterales (CRE), multidrug-resistant P. aeruginosa—all high priority per the CDC—as well as corresponding susceptible strains. The innovation that makes these results possible is a new computational image-processing pipeline, which enables extremely sensitive and robust detection of an antibiotic’s effect on growth, often in less than the strain’s doubling time. A second innovation is the use of inexpensive standard components, leading to an affordable device and consumables. These innovations support our long-term goal of making rapid AST universally available. We will test our hypothesis through three tightly focused specific aims. Aim 1 will generate training data on diverse bug-drug combinations, with bacteria from simulated- positive blood cultures grown in the presence of doubling dilutions of antibiotic on 384-well plates, similar to the current phenotypic gold standard, with multiple antibiotics on each plate. Aim 2 will use the images from Aim 1 to create a unified picture of each strain’s behavior in the presence of each antibiotic, which we will use to refine how we determine minimum inhibitory concentrations (MICs) in order to maximize categorical agreement with the CLSI gold standard. Finally, Aim 3 will validate the method from Aim 2 by testing additional bacterial strains and measuring categorical agreement with the gold standard, per FDA standard guidelines. The expected outcome is a device proven to achieve sub-hour AST with FDA-level performance on a wide variety of pathogens, establishing technical merit, feasibility, and commercial potential for an SBIR Phase II. Our advanced technology, a clearly identified product, will help meet the critical need for rapid, highly sensitive infectious-disease diagnostics to address antimicrobial resistance for life-threatening BSIs and sepsis.

项目摘要/摘要 细菌血液感染（BSIS）的抗菌敏感性测试（AST）危险缓慢。 从积极的血液培养开始，AST目前的中位数为15小时，并且通常需要几天。直到 结果可用，别无选择，只能治疗经验性抗生素的患者，并希望病原体是 易受影响的。这是不可接受的。 BSI是严重的，迅速致命的感染，杀死了250万美国人 每年，包括所有医院死亡的三分之一。经验性抗生素破坏患者的正常菌群， 使它们诱发其他不可治疗的感染。每小时患者使用错误的抗生素 将死亡风险增加7.6％。这个关键问题使快速，负担得起的AST成为全球优先事项。 为了解决这个问题，Astradx开发了一种低成本的新AST设备，我们假设可以执行该设备 不到一个小时的时间。该建议的目的是检验该假设。涉及的初步研究 19株和8种标准抗生素的多次实验表明31±18的生长检测 分钟（范围95％，20-63分钟）。测试的菌株包括耐甲氧西林的金黄色葡萄球菌（MRSA）， 抗性霉素肠球菌（VRE），抗碳青霉烯抗苯甲酸杆菌（CRAB），耐碳青霉烯 肠杆菌（CRE），抗多药的铜绿假单胞菌 - 每个CDC的所有优先级 - 相应的易感菌株。使这些结果成为可能的创新是一种新的计算 图像处理管道，可以极为敏感且强大地检测抗生素对 增长，通常比应变的两倍时间不足。第二种创新是使用便宜的标准 组件，导致负担得起的设备和消耗品。这些创新支持我们的长期目标 普遍可用的快速AST。我们将通过三个紧密集中的特定于三个的假设来检验我们的假设 目标。 AIM 1将生成有关潜水虫子组合的培训数据，并与模拟的细菌一起生成培训数据。 在384孔板上抗生素稀释稀释液的情况下，阳性血液培养物与 电流表型金标准，每个板上都有多种抗生素。 AIM 2将使用AIM 1中的图像 在每种抗生素存在下，创建每种菌株行为的统一图片，我们将使用 优化我们如何确定最低抑制浓度（MIC），以最大程度地达成分类协议 使用CLSI黄金标准。最后，AIM 3将通过测试其他细菌从AIM 2验证该方法 根据FDA标准指南，应变和测量与黄金标准的分类一致。 预期的结果是一种被证明可以在宽阔的FDA级别实现次小时的设备 SBIR II期的各种病原体，建立技术优点，可行性和商业潜力。 我们的先进技术是一种清晰可识别的产品，将有助于满足快速，高度敏感的关键需求 传染性疾病诊断，以解决威胁生命的BSI和败血症的抗菌素耐药性。