Rapid antimicrobial susceptibility testing directly from urine specimens

直接从患者标本中进行快速药敏试验 摘要 每年有2000万名患者被诊断出感染，导致超过10万人死亡，并在美国造成损失 医疗保健系统约700亿美元。抗生素耐药感染日益常见，造成约300万人死亡 在美国，每年有35,000人感染和死亡。患者，即使是那些有生命危险的感染，也可能是 如果在感染发生的时候，可以用一种专门针对 引起感染的病原体。不幸的是，今天的诊断方法需要2-4天来确定焦油- 接受或确定的治疗。出于这个原因，医生必须使用广谱技术对患者进行经验性治疗 抗生素的效果往往不如确凿的治疗方法，有时甚至完全无效。 此外，使用这些强效药物治疗会导致抗生素耐药性的传播。这加剧了这种情况 事实上，至少有30%的抗生素是不必要地开给实际上没有感染的患者的。 目前用于确定最终治疗方法的药物敏感性测试方法需要数天时间才能交付使用 结果是因为它们需要多个漫长的步骤，包括一天的步骤来纯化大量的病原体细胞 通过微生物培养获得的数字。这项提议开发了新的产品，可以检测患者是否在- 感染，在30分钟内鉴定病原体，并在短短几个小时内确定最终的治疗方法 比今天所需的天数还多。因此，拟议的测试有可能显著改善患者的门诊率- 并减弱抗药性的传播。新的测试识别(ID)病原体并进行抗菌 直接从患者样本中进行药敏试验(AST)，消除了 目前的方法。作为测试基础的新型多路径技术使用廉价的数字成像来快速、 无需放大即可灵敏且经济实惠地计数单个微小细菌细胞。多路径AST 与其他新出现的快速检测相比，检测可以确定对更广泛范围的感染的最终治疗 药敏方法，因为它们可以确定共生样本的抗菌药敏感性 细菌和多重微生物感染的患者。易于使用的测试运行在自动随机- 访问目前正在接受监管审查的多路径分析器。此第二阶段提案开发快速ID和 尿路感染(UTIs)的AST测试。尿路感染约占所有感染的一半，而这些感染正在不断增加 由耐药病原体引起。拟议的工作建立在初步结果中提出的工作基础上-- 从尿标本中直接检测AST的可行性。具体来说，我们将(1)完成UTI ID/AST产品 开发；(2)完成阿尔法UTI/AST分析和临床前研究；以及(3)完成外部贝塔试验前 临床研究，并为提交监管机构做准备。拟议项目的完成将提供多路径 UTI ID/AST测试准备好进行验证和验证研究，以便在第三阶段提交监管机构。

Rapid antimicrobial susceptibility testing directly from patient specimens Abstract Each year, 20 million patients are diagnosed with infections leading to over 100,000 deaths and costing the US healthcare system about $70B. Antibiotic resistant infections are increasingly common, causing about 3 million infections and 35,000 deaths annually in the US. Patients, even those with life-threatening infections, can be quickly cured if, near the onset of infection, they can be treated with an antibiotic that specifically targets the pathogen causing the infection. Unfortunately, today’s diagnostic methods require 2-4 days to determine tar- geted, or definitive, therapies. For this reason, physicians must treat patients empirically using broad-spectrum antibiotics that are often less effective than definitive treatments and sometimes even completely ineffective. Furthermore, treatment with these powerful drugs causes the spread of antibiotic resistance. This is exacerbated by the fact that at least 30% of antibiotics are prescribed unnecessarily to patients that are in fact uninfected. Current antimicrobial susceptibility testing methods for determining the definitive therapies take days to deliver results because they require multiple lengthy steps including a day-long step to purify the pathogen cells in large numbers by microbiological culture. This proposal develops novel products that detect whether patients are in- fected, identify the pathogen in 30 minutes, and determine the definitive treatment in just a few hours rather than the days required today. The proposed tests thus have the potential to dramatically improve patient out- comes and attenuate the spread of resistance. The new tests identify (ID) pathogens and perform antimicrobial susceptibility testing (AST) directly from patient specimens, eliminating the lengthy culture steps required by the current methods. The novel MultiPath technology underlying the tests uses inexpensive digital imaging to rapidly, sensitively, and affordably count individual microscopic bacterial cells without magnification. The MultiPath AST tests can determine the definitive treatment for a much broader range of infections than other emerging rapid susceptibility methods because they can determine antimicrobial susceptibility for specimens with commensal bacteria and from patients with polymicrobial infections. The easy-to-use tests run on the automated random- access MultiPath analyzer that is currently under regulatory review. This Phase II proposal develops rapid ID and AST tests for urinary tract infections (UTIs). UTIs account for about half of all infections which are increasingly caused by resistant pathogens. The proposed work builds on work presented in the preliminary results demon- strating the feasibility of AST directly from urine specimens. Specifically, we will (1) Complete UTI ID/AST product development; (2) Complete alpha UTI/AST analytical and preclinical studies; and (3) Complete external beta pre- clinical studies and prepare for regulatory submission. Completion of the proposed project will deliver MultiPath UTI ID/AST tests ready for verification and validation studies for regulatory submission in Phase III.