Detection of Antibiotic Resistance Genes in Bacterial Agents of Hospital-Acquired

医院感染细菌中抗生素耐药基因的检测

• 批准号: 7619621
• 负责人: Andrew E. Levin
• 金额: $ 30万
• 依托单位: IMMUNETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2011-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619621
• 关键词: Academic Medical Centers; Acinetobacter; Acute; Affect; AmpC Genes; Antibiotic Resistance; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Area; Aspirate substance; Bacteremia; Bacteria; Bacterial Infections; Biological Assay; Blood; Blood Circulation; Blood specimen; Carbapenems; Cells; Cephalosporin Resistance; Cephalosporins; Cephamycins; Citrobacter; Clinical; Collaborations; Communicable Diseases; Critical Illness; DNA; Data; Detection; Development; Devices; Diagnosis; Diagnostic; Diagnostic tests; Drug resistance; Early Diagnosis; Enterobacter; Enterobacteriaceae; Enterococcus; Environment; Escherichia coli; Exhibits; Fluoroquinolones; Gene Components; Generations; Genes; Genetic; Genetic Determinism; Glycopeptides; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Grant; Growth; Hafnia; Healthcare; Hospitals; Infection; Infection Control; Integrons; Intensive Care Units; Klebsiella; Laboratories; Lactamase; Lactams; Length of Stay; Liquid substance; Lung; Measures; Methicillin; Methods; Microbe; Modification; Molecular; Morbidity - disease rate; Mutation; New England; Nosocomial Infections; Nosocomial pneumonia; Organism; Oropharyngeal; Outcome; Oxacillin; Patients; Performance; Pharmaceutical Preparations; Phase; Phenotype; Physicians; Piperacillin-Tazobactam; Plasmids; Pneumonia; Predisposition; Prospective Studies; Proteus; Pseudomonas; Pseudomonas aeruginosa; Recording of previous events; Research; Research Ethics Committees; Research Personnel; Resistance; Resistance profile; Sampling; Science of Microbial Genetics; Sensitivity and Specificity; Sepsis; Serratia; Simulate; Site; Specificity; Specimen; Sputum; Staging; Staphylococcus aureus; Sterility; Streptococcus; Survival Rate; Teaching Hospitals; Test Result; Testing; Treatment Failure; United States National Institutes of Health; Universities; Urine; Validation; Vancomycin; Vancomycin Resistance; Variant; Yeasts; antimicrobial; assay development; base; clinically relevant; design; drug resistant bacteria; effective therapy; endotracheal; fluoroquinolone resistance; improved; inhibitor/antagonist; methicillin resistant Staphylococcus aureus; microbial; microorganism; mortality; novel; pathogen; patient population; prototype; public health relevance; resistance mutation; respiratory; success; tool

DESCRIPTION (provided by applicant): Hospital-acquired pneumonia (HAP) and sepsis are leading causes of morbidity and mortality in critically ill patients, especially in hospital intensive care units. These acute conditions are caused by infection with a range of Gram-positive and Gram-negative bacteria commonly found in the hospital environment. Treatment of patients with suspected HAP or sepsis is often initiated based on presumptive evidence. The presence and identity of the pathogen are generally not established until culture results are available (usually days after samples are obtained), followed by a further delay for completion of antibiotic susceptibility testing. Therefore broad-spectrum antibiotics are commonly administered by default. However, an increasing proportion of bacterial pathogens exhibit drug resistance to these antibiotics, and conventional testing may miss clinically relevant resistances, resulting in treatment failures and increased patient mortality. Thus, determining as early as possible both the identity of bacteria causing HAP or sepsis and their drug resistance profiles is critical to making treatment decisions, and modifying or de-escalating antibiotic usage. The aim of the proposed project is to develop a molecular test for concurrent detection and identification of microorganisms and genetic determinants of antibiotic resistance, including resistance to ¿-lactams and fluoroquinolones in Gram-negative bacteria, and to methicillin and vancomycin in Gram-positive bacteria. The diagnostic test will be based on a reverse line blot assay developed by investigators, which enables detection and identification of a wide range of common bacterial pathogens. In contrast with the 2-4 day delay required for culture-based methods, it will offer same-day turnaround by obtaining genetic information directly from clinical samples without need for bacterial growth. In Phase I, the assay will be developed based on respiratory and blood samples from patients with suspected HAP or sepsis obtained from intensive care units at two hospital sites. Results of the reverse line blot method will be compared with those of conventional culture-based ID and antibiotic susceptibility testing. In Phase II, a commercial version of the assay will be completed and its accuracy in predicting antibiotic resistant phenotypes, and thereby potentially improving treatment decisions and healthcare outcomes for affected patients in hospital intensive care units, will be evaluated in a prospective study. Overall, this novel molecular diagnostic assay will provide a powerful tool in efforts to improve treatment and limit the emergence and spread of drug resistant bacteria by appropriate antimicrobial use and infection control measures. PUBLIC HEALTH RELEVANCE: Hospital-acquired pneumonia (HAP) and sepsis resulting from bacterial infection are leading causes of morbidity and mortality in hospital intensive care units, and the emergence of antibiotic resistance in many bacteria is a major threat to effective treatment. This application will result in the development of a rapid test for simultaneous identification of bacterial species and drug resistance genes in bacteria causing these conditions. Earlier detection of the bacteria and their antibiotic resistances than is now possible will enable clinicians to select more effective antibiotic therapy, improving the survival rate for affected patients and deterring the spread of drug resistant bacteria.

描述（由适用提供）：医院获得的肺炎（HAP）和败血症是重症患者的发病率和死亡率的主要原因，尤其是在医院重症监护病房中。这些急性疾病是由于在医院环境中通常发现的一系列革兰氏阳性和革兰氏阴性细菌的感染引起的。经常根据假定证据开始对怀疑HAP或败血症患者的治疗。通常在培养结果获得（通常在样品后几天）之前，通常无法确定病原体的当前和身份，然后进一步延迟完成抗生素易感性测试。因此，默认情况下通常给予广谱抗生素。然而，越来越多的细菌病原体暴露于这些抗生素的耐药性以及常规测试可能会错过临床上相关的抗药性，从而导致治疗失败和患者死亡率增加。这是尽早确定引起HAP或败血症的细菌的身份及其耐药性特征对于做出治疗决策，修饰或降低抗生素的使用至关重要。拟议项目的目的是开发一种分子检测，以同时检测和鉴定抗生素耐药性的微生物和遗传确定剂，包括对革兰氏阴性细菌中的 - lactams和氟喹诺酮类的耐药性，以及甲基甲苯蛋白质和甲基甲霉素的氟喹诺酮类药物。诊断测试将基于研究人员开发的反线印迹分析，该测定能够检测和鉴定多种常见细菌病原体。与基于培养的方法所需的2-4天延迟相反，它将通过直接从临床样本中获得遗传信息而无需细菌生长来提供当天的周转。在第一阶段，将根据呼吸道和血液样本进行制定，并从两个医院的重症监护病房获得的疑似HAP或败血症患者的血液样本进行开发。反向线印迹方法的结果将与常规培养物ID和抗生素易感性测试的结果进行比较。在第二阶段，将完成该测定法的商业版本，并在一项前瞻性研究中评估该测定法的准确性，从而有可能改善医院重症监护病人的治疗决策和医疗保健结果。总体而言，这种新颖的分子诊断测定法将提供一种强大的工具，以改善治疗并限制通过适当的抗菌使用和感染控制措施限制耐药细菌的出现和扩散。公共卫生相关性：细菌感染引起的医院获得的肺炎（HAP）和败血症是医院重症监护病房发病和死亡率的主要原因，许多细菌中抗生素耐药性的出现是对有效治疗的主要威胁。该应用将导致在细菌中同时鉴定细菌的迅速测试，从而导致这些疾病。比现在可能的较早发现细菌及其抗生素耐药性将使临床医生能够选择更有效的抗生素疗法，从而提高患者的生存率并确定耐药细菌的扩散。