Rapid Low Cost Phenotypic Antibiotic Susceptibility Testing.

快速低成本表型抗生素敏感性测试。

• 批准号: 9347745
• 负责人: PAUL RHODES
• 金额: $ 99.81万
• 依托单位: SPECIFIC DIAGNOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-07 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9347745
• 关键词: Affect; Agitation; Algorithms; Antibiotic Resistance; Antibiotic susceptibility; Antibiotics; Blood; Blood specimen; CLIA certified; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Chemicals; Clinical; Clinical Protocols; Clinical Research; Computer software; Consultations; Cyclosporine; Data; Dependence; Dependency; Detection; Development; Engineering; Environment; Evaluation; Future; Goals; Gold; Growth; Guidelines; Hand; Healthcare; Healthcare Systems; Hour; Incubators; International; Laboratories; Length of Stay; Liquid substance; Measures; Methods; Minimum Inhibitory Concentration measurement; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; Organism; Pathogenicity; Patients; Pattern; Performance; Phase; Phenotype; Pilot Projects; Preclinical Testing; Predictive Analytics; Predisposition; Preparation; Protocols documentation; Research; Research Design; Resistance; Sampling; Shock; Speed; System; Systems Development; Technology; Temperature; Testing; Time; Walking; cost; cost effective; disorder prevention; engineering design; image processing; instrument; mortality; pathogen; pathogenic bacteria; prototype; research clinical testing; response; seal; sensor; skills; software systems; targeted treatment

Project Summary Antibiotic resistance has recently emerged as a global threat for healthcare systems. An increasing number of pathogenic bacteria are acquiring antibiotic resistance, and new forms of resistance are continuously emerging with alarming speed across international boundaries.1 In the U. S. alone, the Center for Disease Control and Prevention (CDC) has estimated 2 million patients per year are directly affected by antibiotic-resistant pathogens, leading to more than 23,000 deaths.2 Providing rapid, definitive and cost effective antibiotic susceptibility testing (AST) will be of increasingly vital importance in controlling this burgeoning problem. While legacy methods generally require overnight culturing, the time-urgency of determining effective antibiotics has prompted a push for rapid AST that can perform in a few hours. Unfortunately, some of the newest rapid AST instruments are either not suited to multiplexing, or are an order of magnitude more costly than legacy methods, discouraging their widespread use. A rapid multiplexed AST platform that provides minimum inhibitory concentrations (MICs) within hours at comparable cost to current methods will enable rapid determination of effective targeted therapy, resulting in short hospital stays and fewer additional laboratory tests, and decreasing morbidity and mortality along with associated healthcare expenses. Specific Technologies has introduced and with NIAID support commercially developed a culture system that combines detection with organism ID.3, 4 Using a printed array of chemically responsive colorimetric indicators introduced into culture headspace, the species-specific pattern of volatiles emitted during growth produce a species-specific pattern, which we have shown to reduce detection time and enable Gram status and species ID to be determined hands-free during culture. Here, we present data showing that the use of this system can be extended to very rapidly, order 1 hour, ascertain phenotypic antibiotic susceptibility. The preliminary data demonstrate that introduction of antibiotic to positive blood culture prompts a susceptibility-dependent and antibiotic concentration-dependent shift in volatile sensor response within <60 minutes. Recognizing that a commercial AST instrument must be multi-well, we have performed pilot study in which the positive sample is removed from a blood culture bottle and divided into a multi-chamber setting, in which even at pilot study stage we demonstrate a < 2 ½ hrs phenotypic AST, measuring values matching the results of the CLIA-compliant Sensititre gold standard. Moreover, the disposable is inherently low cost, as it only depends upon an inexpensive printed sheet of CSA’s. Finally, not only is this method intrinsically low-cost but low-skill compatible, as there is no sample preparation from positive blood culture. It is thus very well-suited for both 24-hour/day developed world labs, where it will speed time-to-answer, as well as the low-skill environments of the developing world. In this direct-to-Phase II application, we propose to use our CSA technology to systematically quantify, and validate the parameter-dependence of this system and then engineer and produce a benchtop instrument suitable for preclinical and clinical testing, which will provide a low cost, highly automated multiplexed phenotypic susceptibility determination directly from a positive blood sample in less than 90 minutes. We propose to develop and commercialize an instrument that integrates our rapid AST capability with our Spec80 blood culture and species ID system that is being commercialized now, offering a uniquely streamlined and low cost system with by far the fastest yet proposed time from patient sample to detection, ID and phenotypic multiplexed quantitative AST.

项目概要 抗生素耐药性最近已成为医疗保健系统日益严重的全球威胁。 许多病原菌正在获得抗生素耐药性，并且新形式的耐药性正在出现 不断以惊人的速度跨越国际边界出现。1 仅在美国， 美国疾病控制与预防中心 (CDC) 估计每年有 200 万患者直接感染 受到抗生素耐药性病原体的影响，导致超过 23,000 人死亡。2 明确且具有成本效益的抗生素敏感性测试 (AST) 将变得越来越重要 虽然传统方法通常需要过夜培养，但 确定有效抗生素的时间紧迫性促使人们推动快速 AST，它可以在 不幸的是，一些最新的快速 AST 仪器不适合。 多路复用，或者比传统方法成本高一个数量级，从而阻碍了它们 广泛使用的快速多重 AST 平台，可提供最低抑制浓度。 （MIC）在数小时内以与当前方法相当的成本将能够快速确定有效性 靶向治疗，导致住院时间短，额外的实验室检查更少，并且减少 发病率和死亡率以及相关的医疗费用。 特定技术已引入并在 NIAID 支持下商业开发了一种培养系统 将检测与生物体 ID.3、4 结合起来使用化学响应比色印刷阵列 引入培养顶部空间的指标，在​​培养过程中排放的挥发物的特定物种模式 生长产生物种特异性模式，我们已证明这种模式可以减少检测时间并实现 在此，我们提供了显示数据，可在培养过程中免提确定革兰氏状态和物种 ID。 该系统的使用可以非常迅速地延长，订购1小时，确定表型抗生素 初步数据表明，引入抗生素可导致血培养呈阳性。 促使挥发性传感器发生药敏依赖性和抗生素浓度依赖性变化 认识到商用 AST 仪器必须是多孔的，我们有能力在 60 分钟内做出响应。 进行了初步研究，其中将阳性样本从血培养瓶中取出并分开 进入多室环境，即使在试点研究阶段，我们也展示了 < 2 ½ 小时的表型 AST，测量值与符合 CLIA 的 Sensititre 金标准的结果相匹配。 这种一次性产品本质上成本低廉，因为它仅依赖于廉价的 CSA 印刷片。 最后，这种方法不仅本质上成本低，而且技术含量低，因为没有样本 因此，它非常适合 24 小时/天的发达国家。 实验室，它将加快回答时间，以及发展中国家的低技能环境。 在这个直接进入第二阶段的应用中，我们建议使用我们的 CSA 技术来系统地量化， 并验证该系统的参数依赖性，然后设计和生产台式 适用于临床前和临床测试的仪器，这将提供低成本、高度自动化的 直接从阳性血样中进行多重表型敏感性测定，时间少于 90 分钟我们建议开发一种集成我们快速 AST 的仪器并将其商业化。 我们的 Spec80 血培养和物种 ID 系统现已商业化，提供 独特的简化且低成本的系统，具有迄今为止最快的患者样本建议时间 检测、ID 和表型多重定量 AST。