Virulence Typing of Pseudomonas Clinical Isolates

描述（由申请方提供）：铜绿假单胞菌是一种机会性细菌病原体，可引起相当大比例的严重医院获得性感染。该生物体对大多数类型的抗生素具有内在耐药性，并且可以容易地获得对所有临床可用的抗菌剂的耐药性，导致无法治疗的感染。铜绿假单胞菌定植发生在许多住院患者中，特别是那些经历了损害局部宿主免疫防御的程序（例如插管或膀胱导管插入术）的患者中。这些患者中的一些将发展为铜绿假单胞菌感染，并需要积极和适当的抗菌治疗才能生存;然而，其他人不会发展为侵袭性疾病，尽管铜绿假单胞菌反复从呼吸道分泌物或尿液中分离出来。尽管一些宿主因素与感染风险增加相关，但最近认识到铜绿假单胞菌分离株产生动物模型中毒力所需的毒力因子的不同补充，导致几个小组研究此类毒力因子是否也影响人类临床铜绿假单胞菌疾病。 两个研究小组确实已经确定了与铜绿假单胞菌III型分泌系统相关的毒力因子的这种相关性;然而，目前还没有临床上有用的测试来测量患者铜绿假单胞菌分离株中这些毒力因子的表达。 在该项目的第一阶段，我们开发了一种诊断测试，定量铜绿假单胞菌临床分离株的毒力因子产生。在第二阶段，我们的目标是获得该测试的前瞻性临床验证。我们计划测试从耶鲁-纽黑文医院获得的数千个分离株。我们将在两个特定的临床环境中，即急性假单胞菌呼吸道感染和慢性感染的囊性纤维化患者的疾病恶化，毒力因子的产生与严重疾病相关。这些信息可以通过揭示需要积极治疗的高毒力分离株的存在来改善个体患者的护理。我们还认为，这样的测试可能会减少携带无毒生物体且没有明显感染迹象的患者对广谱抗生素的不适当使用。这可能对公共卫生产生重大影响，通过限制我们医院中多重耐药病原体的出现，并控制医疗费用。

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa is an opportunistic bacterial pathogen responsible for a significant proportion of serious hospital acquired infections. The organism has intrinsic resistance to most types of antibiotics and can readily acquire resistance to all clinically available antimicrobials, resulting in infections that are impossible to treat. P. aeruginosa colonization occurs in many hospitalized patients, in particular amongst those who have undergone procedures (e.g. intubation or bladder catheterization) that impair local host immune defenses. Some of these patients will develop P. aeruginosa infections, and require aggressive and appropriate antimicrobial therapy to survive; others, however, will not develop invasive disease though P. aeruginosa is repeatedly isolated from respiratory secretions or urine. Although some host factors are correlated with an increased risk of infection, the recent recognition that P. aeruginosa isolates produce distinct complements of virulence factors that are required for virulence in animal models has led several groups to investigate whether such virulence factors also influence clinical P. aeruginosa disease in humans. Such a correlation has indeed been established by two research groups for virulence factors associated with the Type III secretion system of P. aeruginosa; however, no clinically useful test currently exists to measure expression of these virulence factors in patient P. aeruginosa isolates. In Phase I of this project, we developed a diagnostic test which quantitates virulence factor production by clinical isolates of P. aeruginosa. In Phase II, our aim will be to obtain prospective clinical validation of this test. We plan to test several thousand isolates obtained from Yale-New Haven Hospital. We will correlate production of virulence factors with severe disease in two specific clinical settings, namely acute Pseudomonas respiratory infection, and exacerbation of disease in chronically infected cystic fibrosis patients. Such information can improve the care of individual patients, by revealing the presence of highly virulent isolates that warrant aggressive therapy. We also believe that such a test may decrease the inappropriate use of broad-spectrum antibiotics in patients carrying avirulent organisms and showing no overt signs of infection. This can have significant consequences both for public health, by limiting the emergence of multi-drug resistant pathogens in our hospitals, and for containing the cost of medical care.