Molecular Detection of Blood Stream Infections in Women with Gynecologic Cancer

描述（由申请人提供）：估计每年医院感染的发生率超过200万例。其中，血流感染（BSI）占病例的最大比例，为28%。感染是癌症患者的主要并发症，也是化疗相关死亡的主要原因。许多因素导致了感染风险的增加，包括患者接受的化疗方案会损害和削弱他们的免疫系统，他们必须经历漫长的手术过程来切除肿瘤，以及使用血管内装置，这会破坏皮肤的防御屏障。事实上，较新的用于治疗癌症患者的腹腔内疗法在短期内比静脉内疗法有更高的发病率。在发热性嗜中性粒细胞减少的癌症患者中，BSI实际上占记录感染的80-90%；90%的病例与细菌有关，10%与酵母菌或真菌有关。临床怀疑BSI通常难以确认，因为血培养通常为阴性。因此，疑似BSI的患者通常经验性地使用广谱抗生素治疗。目前的黄金标准是用血液培养生物体，这需要时间；细菌需要1-3天才能生长到可检测的水平，而酵母和真菌需要更多的时间。一旦一种生物繁殖到可检测的水平，就需要几天的时间来分离和鉴定该生物，并进行抗菌药物敏感性试验。利用更快速的手段，如基于分子的方法，在更短的时间内检测和识别生物体，将对患者产生积极的影响；更快的检测可以降低死亡率。抗菌疗法可以更快地改进，减少广谱抗生素的使用，这反过来可以降低抗生素相关结肠炎的风险，药物引起的毒性，以及选择更耐药的生物的压力。在本研究中，我们将验证以下假设：在有BSI风险的妇科恶性肿瘤患者中，实时PCR和快速DNA测序（焦磷酸测序）将允许一种更快速，但与培养一样准确的检测和识别生物体的方法。结合这些技术直接筛选全血，以及从孵育的血液培养瓶中筛选培养液，将是学习如何改进用于诊断高风险患者人群中危及生命的血流感染的算法的关键的第一步，包括更新和强大的基于分子的诊断工具。

DESCRIPTION (provided by applicant): The estimated incidence of nosocomial infections exceeds 2 million cases per year. Of those, bloodstream infections (BSI) constitute the largest percentage of cases at 28%. Infections are a major complication in cancer patients and are the leading cause of chemotherapy-related mortality. Many factors contribute to this increased risk of infection including the chemotherapeutic regimens received by the patient that damage and weaken their immune system, the lengthy surgical procedures that they must undergo to remove their tumors, and the use of intravascular devices, which breach the skin's defensive barrier. In fact, the newer intraperitoneal therapies used to treat cancer patients have higher morbidities in the short term, than do intravenous therapies. In the febrile neutropenic cancer patient BSI actually accounts for 80-90% of documented infections; bacteria are associated with 90% of cases, and yeast or fungi with 10%. Clinical suspicion of BSI is often difficult to confirm because blood cultures are often negative. As a result, patients with suspected BSI are often treated empirically with broad-spectrum antibiotics. Culturing organisms out of blood, the current gold standard, takes time; bacteria require 1-3 days to grow to detectable levels, while yeast and fungi require even more time. Once an organism multiplies to detectable levels, several more days are needed to isolate and identify the organism and to perform antimicrobial susceptibility testing. Utilizing a more rapid means, such as a molecular-based approach to detect and identify the organism in less time would have a positive impact on the patient; quicker detection could result in reduced mortality. Antimicrobial therapies could be modified sooner, reducing the use of broad-spectrum antibiotics, which in turn could reduce the risk of antibiotic associated colitis, drug-induced toxicity, and the pressure to select more resistant organisms. In this study, we will test the following hypothesis: In women with a gynecologic malignancy at risk for BSI, real-time PCR and rapid DNA sequencing (pyrosequencing) will permit a more rapid, yet as accurate a means of detecting and identifying organisms as that of culture. Combining these techniques to screen whole blood directly as well as screening culture fluid from incubating blood culture bottles will be a critical first step in learning how to improve the algorithms used to diagnose life-threatening bloodstream infections in high-risk patient populations, by encompassing the newer and powerful tools of molecular-based diagnostics.