Rapid antimicrobial susceptibility testing directly from urine specimens

直接从患者标本中进行快速抗菌药物敏感性检测 摘要 每年有2000万患者被诊断出感染，导致超过10万人死亡， 医疗保健系统约700亿美元。抗生素耐药性感染越来越普遍， 感染和35，000人死亡，每年在美国。患者，即使是那些有生命危险的感染， 如果在感染开始时，可以用一种特异性靶向 导致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- 获得或确定的治疗方法。出于这个原因，医生必须根据经验使用广谱抗生素治疗患者。 抗生素通常不如确定性治疗有效，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。加剧了这种情况 事实上，至少30%的抗生素是不必要地开给实际上未感染的病人的。 目前用于确定最终治疗的抗菌药物敏感性测试方法需要数天才能交付 结果，因为它们需要多个冗长的步骤，包括长达一天的步骤来纯化大量的病原体细胞， 微生物培养的数量。这项提案开发了新的产品，检测患者是否在- 感染后，在30分钟内确定病原体，并在短短几个小时内确定最终的治疗方法， 比今天所需的时间更长。因此，拟议的测试有可能大大改善患者的外出- 来削弱抵抗的蔓延。新的测试识别（ID）病原体并进行抗菌 直接从患者标本中进行药敏试验（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， 灵敏度高，无需放大即可对单个显微镜下的细菌细胞进行计数。MultiPath AST 与其他新兴的快速传染病相比， 敏感性方法，因为它们可以确定具有细菌的标本的抗菌药物敏感性 细菌和患有多种微生物感染的患者。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MultiPath分析仪。本第二阶段提案开发快速ID， AST测试尿路感染（UTIs）。UTI约占所有感染的一半， 由耐药病原体引起的。拟议的工作建立在初步结果demon- 证明了直接从尿液标本中提取AST的可行性。具体而言，我们将（1）完成UTI ID/AST产品 开发;（2）完成α UTI/AST分析和临床前研究;和（3）完成外部β前 临床研究并准备监管申报。完成拟议项目将提供多路径 UTI ID/AST检测已准备好进行验证和确认研究，以供III期监管提交。

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.