The use of mass spectrometry for rapid detection of carbapenemase-producing bacte

使用质谱法快速检测产碳青霉烯酶细菌

• 批准号: 8454979
• 负责人: MICHAEL E HODSDON
• 金额: $ 22.47万
• 依托单位: MZ DIAGNOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454979
• 关键词: Accounting; Address; Adoption; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Appearance; Back; Bacteria; Bacterial Infections; Biological Assay; Blinded; Blood; Carbapenems; Caring; Cephalosporins; Cessation of life; Characteristics; Chemotherapy-Oncologic Procedure; Chronic; Clinical; Clinical Microbiology; Clinical Research; Clinical Sensitivity; Clinical Trials; Clinical effectiveness; Complication; DNA; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Outbreaks; Early Diagnosis; Early identification; Effectiveness; Ensure; Environment; Enzymes; Epidemiology; Equipment and supply inventories; Europe; Freezing; Future; Genetic Identity; Genetic Variation; Gold; Gram-Negative Bacterial Infections; Growth; Guidelines; Health Personnel; Healthcare Systems; Hospitalization; Hospitals; Hour; Hydrolysis; Immunosuppressive Agents; Incidence; Infection; Inflammatory; Laboratories; Lactamase; Lactams; Length of Stay; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Medical; Methods; Modern Medicine; Molecular; Monitor; Monobactams; Multi-Drug Resistance; Nosocomial Infections; Operative Surgical Procedures; Organism; Patient Care; Patients; Penicillins; Performance; Phase; Plasmids; Predisposition; Preparation; Production; Protocols documentation; Public Health; Randomized; Regimen; Reproducibility; Research; Resistance; Risk; Sampling; Sensitivity and Specificity; Specificity; Specimen; Substrate Specificity; Swab; Technology; Testing; Time; TimeLine; Transplant Recipients; Treatment Protocols; Validation; analytical method; assay development; bacterial resistance; base; beta-Lactamase; beta-Lactams; carbapenem resistance; carbapenemase; clinical care; combat; commercialization; cost; effective therapy; global health; member; mortality; novel; prevent; prospective; public health relevance; rapid detection; rectal; resistance factors; resistance mechanism; response; retinal rods; transmission process

DESCRIPTION (provided by applicant): The practice of modern medicine relies heavily on effective antibiotic therapy to combat bacterial infections. In their absence, many surgeries and chemotherapeutic regimens used to combat cancer and suppress chronic inflammatory conditions would simply not be possible. Development of multidrug-resistant (MDR) bacterial strains threatens to undermine these advances and represents a major global health challenge. A common resistance mechanism in "gram negative rod" (GNR) bacteria is secretion of a beta-lactamase that hydrolyzes the beta-lactam ring common to all members of the penicillin class. Hundreds of diverse beta-lactamases, which vary in their catalytic mechanism and substrate specificity, have evolved in response to treatment of infections with multiple b-lactam antibiotics Carbapenems represent the last line of effective defense against MDR GNRs expressing extended spectrum beta-lactamases (ESBLs) capable of hydrolyzing all non-carbapenem beta-lactams. However, their effectiveness has been compromised by the recent emergence of plasmid-encoded carbapenemases. To effectively contain and/or prevent outbreaks of carbapenem resistant bacterial infections and to offer optimal patient care, rapid detection of carbapenemase activity in clinical specimens is imperative. We have pioneered a rapid, phenotypic method relying on mass spectrometry to detect carbapenemase activity, by selectively monitoring for the appearance of carbapenem hydrolysis products. In the first aim of this application, we will refine and optimize our current MS- based assay to detect ¿-lactam ring hydrolysis of carbapenem antibiotics. We will define necessary kit components and assay protocols for detection of carbapenem hydrolysis activity in bacterial isolates. In the second aim of this application, we will perform a blinded clinical study using selected retrospective and prospective clinical specimens from Yale-New Haven Hospital in order to establish biologic sensitivity and specificity of the overall protocol. Future phases of development will apply the technology to primary specimens, which will be followed by multicenter clinical trials in pursuit o FDA 510(k) clearance of the final product.

描述（由申请人提供）：现代医学的实践在很大程度上依赖于有效的抗生素治疗来对抗细菌感染。如果没有它们，许多用于对抗癌症和抑制慢性炎症的手术和化疗方案将根本不可能。多药耐药（MDR）菌株的发展可能会破坏这些进展，并代表着一个重大的全球健康挑战。“革兰氏阴性杆菌”（GNR）细菌中的常见耐药机制是分泌β-内酰胺酶，所述β-内酰胺酶水解青霉素类的所有成员共有的β-内酰胺环。数百种不同的β-内酰胺酶，其催化机制和底物特异性不同，在多种β-内酰胺抗生素治疗感染的反应中进化而来，碳青霉烯类代表了针对MDR GNR的最后一道有效防线，这些MDR GNR表达能够水解所有非碳青霉烯类β-内酰胺的超广谱β-内酰胺酶（ESBL）。然而，它们的有效性受到最近出现的质粒编码的碳青霉烯酶的影响。为了有效控制和/或预防碳青霉烯类耐药细菌感染的爆发，并提供最佳的患者护理，必须快速检测临床标本中的碳青霉烯酶活性。我们开创了一种依靠质谱法的快速表型方法，通过选择性监测碳青霉烯水解产物的出现来检测碳青霉烯酶活性。在本申请的第一个目的中，我们将改进和优化我们目前的基于MS的检测碳青霉烯类抗生素的<$-内酰胺环水解的方法。我们将定义检测细菌分离株中碳青霉烯水解活性所需的试剂盒组分和测定方案。在本申请的第二个目的中，我们将使用耶鲁-纽黑文医院选定的回顾性和前瞻性临床标本进行盲法临床研究，以确定整体方案的生物学灵敏度和特异性。未来的开发阶段将把该技术应用于主要标本，随后将进行多中心临床试验，以获得最终产品的FDA 510（k）批准。