Consortium for drug-resistant Gram-negative pathogen detection

 描述(申请人提供)：这项名为“耐药革兰氏阴性病原体检测联盟”的项目是一个学术和产业合作伙伴关系，旨在应对RFA“解决特定细菌病原体抗药性的诊断伙伴关系”所带来的挑战。该项目将重点关注两组革兰氏阴性细菌(GNB)病原体--碳青霉烯类耐药肠杆菌科(CRE)和耐药铜绿假单胞菌(PA)，这两种病原体已被疾病控制和预防中心(CDC)分别指定为“紧急威胁”和“严重威胁”病原体。这些微生物是医疗保健相关感染(HAI)的主要原因，但Cres也正在成为社区感染(CoI)的威胁生命的原因。它们的治疗非常复杂，特别是当它们表达使常用抗菌剂失活的酶(β-内酰胺酶)时。该项目将开发和验证一种综合诊断系统，旨在直接检测GNBs，并从血液和尿样中将其区分为Cres和PA。同样的系统将被设计来检测所有临床上重要的β-内酰胺酶，这样临床医生就可以更知情和更迅速地决定开始使用哪种抗生素。因此，集成系统被设计成在一个设备中模拟临床微生物学实验室中检测Cres和PA的大部分步骤。拟议的诊断系统之所以成为可能，是因为两项重要的创新。一种是集成分子诊断系统(IMDX)，旨在从临床样本中快速分离GNBs，并捕获目标GNBs以进行物种鉴定。另一种是自加速二聚化(SAD)法，它可以促进细菌酶的扩增，从而在不到10分钟的时间内检测到目标酶的活性。SAD检测将被整合到iMDx中。总之，这些创新将针对从世界不同地区的血液(BSI)和尿路感染(UTI)获得的大量GNBs临床分离株进行改进和验证。旧金山总医院还将对因BSI或败血症以及导管相关尿路感染住院的患者进行前瞻性的系统准确性评估。该系统的成功开发不仅将改善患者的临床管理，还将有助于减少昂贵的新一代抗生素的不必要使用，并防止在医疗保健和社区环境中选择新的抗药性GNB病原体。

 DESCRIPTION (provided by applicant): This project called "Consortium for drug-resistant Gram-negative pathogen detection" is an academic-industrial partnership established to address the challenges posed by the RFA "Partnerships for Diagnostics to Address Antimicrobial Resistance of Select Bacterial Pathogens". The project will focus on two groups of Gram-negative bacterial (GNB) pathogens-carbapenem-resistant Enterobacteriaceae (CRE) and drug-resistant Pseudomonas aeruginosa (PA), which have been designated by the Centers for Disease Control and Prevention (CDC) as "urgent threat" and "serious threat" pathogens, respectively. These organisms are major causes of healthcare-associated infections (HAIs), but CREs are also emerging as life-threatening causes of community-onset infections (COIs). They are enormously complicated to treat, especially when they express enzymes (ß-lactamases) that inactivate commonly-used antimicrobial agents. This project will develop and validate an integrated diagnostic system designed to directly detect and differentiate GNBs into CREs and PA from blood and urine samples. The same system will be designed to detect all of the clinically important ß- lactamases, so that clinicians can make a more informed and rapid decision about which antibiotics to initiate. The integrated system is thus designed to mimic in one device most of the steps involved in a clinical microbiology laboratory to detect CREs and PA. The proposed diagnostic system is made possible because of two important innovations. One is an integrated molecular diagnostics system (iMDx) designed to rapidly separate GNBs from clinical sample and capture target GNBs for species identification. The other is called self-accelerated dimerization (SAD) assay that facilitates bacterial enzyme amplification so that the target enzyme activity can be detected in less than 10 minutes. The SAD assay will be integrated into iMDx. Together, these innovations will be refined and validated against a large panel of clinical isolates of GNBs obtained from blood stream (BSI) and urinary tract infections (UTI) in different regions of the world. The accuracy of the system will also be prospectively assessed at San Francisco General Hospital among patients hospitalized for BSI or sepsis, and catheter-associated UTI. A successful development of this system will not only improve patient clinical management, but help reduce unnecessary use of expensive, later-generation antibiotics and prevent the selection of new drug-resistant GNB pathogens in healthcare and community settings.