Development of a diagnostic test for hypervirulent Klebsiella pneumoniae

高毒力肺炎克雷伯菌诊断测试的开发

• 批准号: 9087528
• 负责人: THOMAS A RUSSO
• 金额: $ 23.93万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087528
• 关键词: Abscess; Affect; Animals; Antibiotics; Antimicrobial Resistance; Asians; Autoantibodies; Biological Markers; Clinical; Clinical Microbiology; Clinical Research; Communities; Comorbidity; Comparative Study; Country; Data; Derivation procedure; Development; Diagnostic tests; Distant; Drainage procedure; Endophthalmitis; Epidemiologic Studies; Epidemiology; Ethnic group; Evolution; Extended-spectrum β-lactamase; Extrahepatic; Eye; Generations; Genes; Genetic Predisposition to Disease; Gold; Hand; Healthcare; Hepatic; Host Defense; Immunocompromised Host; Individual; Infection; Infectious Agent; Institution; Klebsiella pneumonia bacterium; Knowledge; Laboratories; Laboratory Study; Lead; Life; Literature; Modeling; Nature; Neuraxis; Operative Surgical Procedures; Organ; Patient Care; Patients; Phenotype; Prevalence; Production; Resistance; Risk; Scientific Advances and Accomplishments; Sensitivity and Specificity; Siderophores; Site; Staining method; Stains; Syndrome; Testing; Validation; Variant; Virulence; Vitrectomy; aerobactin; animal data; antimicrobial; base; cohort; improved; in vivo; phenotypic biomarker; public health relevance; rim 1; trait; vigilance

 DESCRIPTION (provided by applicant): The emergence and global dissemination of a hypervirulent pathotype of Klebsiella pneumoniae (hvKP) is concerning. In contrast to the usual healthcare-associated venue for "classical" K. pneumoniae (cKP) infections in the West, hvKP causes serious, life and organ threatening infections in younger, healthy individuals from the community and has the ability to metastatically spread from sites of infection. Further, what makes this variant outright scary is its potential to acquire extreme and pan-resistant antimicrobial resistance, a reality that has already begun. Few laboratories are studying hvKP and none in the US that we are aware of. Many significant knowledge gaps exist. Importantly, a reliable and efficient means to differentiate hvKP strains from cKP strains is lacking. This deficiency has resulted in under-recognition of hvKP, impeded scientific advances, and has adversely affected patient care. Identification of hvKP as the offending agent will inform the clinician to seek out occult abscesses for drainage as needed, maintain vigilance for the development of endophthalmitis (which requires immediate institution of intravitreal antibiotics & vitrectomy), optimize conditions for successful percutaneous drainage of abscesses (and thereby avoid open surgical drainage), and modify the nature and duration of systemic antimicrobial therapy as dictated by site(s) of infection. The objective of this proposal is to identify a specific genotypic and/or phenotypic marker for hvKP. Although a hypermucoviscous phenotype, as defined by a positive string test, has been used to discriminate hvKP, this test is NOT optimally sensitive or specific, especially in regions of lower hvKP prevalence. Presently, the most reliable means to identify hvKP is from the clinical syndrome of serious infection in ambulatory, healthy hosts plus/minus metastatic spread of infection. Although not all patients infected with hvKP can be identified in this manner (infection in patients with co-morbidities also occurs), using this definition will enable the generation of hvKP-rich and cKP-rich strain cohorts for comparative study. Preliminary data from our group and the literature, has identified genotypic markers (e.g. iucA (aerobactin synthesis) and 2 new potential gene markers identified by our lab) and phenotypic markers (total siderophore production and virulence in an animal infection model) that we hypothesize can be used to reliably and efficiently identify hvKP. Initial studies on hvKP-rich and cKP-rich strain derivation cohorts will identify the optimal marker, which will be subsequently assessed in independent validation cohorts. Animal data will be used to support the specificity and sensitivity of an hvKP marker that can be practically employed in both clinical microbiology and research laboratories. Data generated from this proposal will result in the development of a test for use by the clinical microbiology and research laboratories to reliably and efficiently identify hvKP. This ability will enable the needed translational advancs in the field and most importantly improved patient care.

 描述（由适用提供）：涉及肺炎克雷伯氏菌（HVKP）的高呼吸病病原体的出现和全球传播。与西方“古典” K.肺炎（CKP）感染的通常与医疗保健相关的场所相反，HVKP引起严重，生命和器官威胁来自社区的年轻健康个体的感染，并具有从感染部位转移的能力。此外，使这种变体的彻底磨损的原因在于它具有获得极端和抗药性抗菌抗性的潜力，这是现实已经开始的。很少有实验室正在研究HVKP，而在美国没有实验室。存在许多重要的知识差距。重要的是，缺乏将HVKP菌株与CKP菌株区分HVKP菌株的可靠和有效手段。这种缺陷导致HVKP的识别低下，阻碍了科学进步，并对患者的护理产生了不利影响。将HVKP识别为有问题的代理人，将通知临床寻找脓肿，保持对内脑炎的发展（需要立即建立玻璃体内抗生素和玻璃体切除术），以优化条件，以成功地进行临时排水（并在此避免露出的效果），并避免进行临时的临时（并避免进行修改），并对其进行修改的疗效，并具有更高的疾病，并且对造成的性质进行了修改），并且对造成了修改的疗效），并且对造成了造成的自然流动），并且可以避免使用），并且可以造成自然流失），并且可以造成自然流失），并且可以进行造成的自然流失），并进行了造成的自然流失），并进行了造成的自然流失），并避免了造成的自然流失。如感染部位所决定的。该建议的目的是确定HVKP的特定基因型和/或表型标记。尽管由阳性弦测试定义的超敏化表型已用于区分HVKP，但该测试并不是最佳敏感或特异性的，尤其是在较低的HVKP患病率的区域。目前，鉴定HVKP的最可靠手段是来自卧床健康宿主的严重感染临床综合征，以及感染的转移性传播。尽管并非所有感染HVKP的患者都可以以这种方式识别（合并症患者的感染也 发生），使用此定义将使富含HVKP的富含HVKP和富含CKP的菌株队列进行比较研究。来自我们小组和文献的初步数据已经鉴定了基因型标记（例如IUCA（拟南芥合成）和我们实验室鉴定的2个新的潜在基因标记物）和表型标记（在动物感染模型中的总副磷和病毒），我们可以将我们推测可用于可靠并有效地识别HVKP。最初的 对富含HVKP和CKP的富菌株衍生队列的研究将确定最佳标记，随后将在独立的验证队列中进行评估。动物数据将用于支持HVKP标记的特异性和敏感性，该标记实际上可以在临床微生物学和研究实验室中使用。该提案产生的数据将导致开发临床微生物学和研究实验室使用的测试，以可靠有效地识别HVKP。这种能力将使该领域所需的翻译冒险，最重要的是改善了患者护理。