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(1-3)-beta-D-glucan guided early termination of antifungal therapy in ICU patients

(1-3)-β-D-葡聚糖指导 ICU 患者提前终止抗真菌治疗

基本信息

批准号：
400727961
负责人：
Privatdozent Dr. Jürgen Held
金额：
--
依托单位：
Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2018
资助国家：
德国
起止时间：
2017-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/400727961?language=en
关键词：
beta glucan guided early termination

项目摘要

Background: Approximately 70 % of ICU patients receive antibiotics and as a consequence the extent of Candida colonization in these patients increases daily. With Candida spp. detected from various body sites the urge to start antifungal treatment in case of a clinical deterioration is high and up to 65 % of ICU patients receiving such therapy have no documented invasive fungal disease (IFD). However, unnecessary antifungal treatment is associated with potentially severe side effects, an increase in multiresistent Candida spp. and a significant financial burden for the health care system. (1-3)-beta-D-glucan (BDG) is a main cell wall component of various medically relevant fungi and can be detected in serum of patients with IFD. BDG has a high sensitivity and a negative predictive value of up to 99.9 % for the detection of IFD. In contrast, the specificity is only moderate and the positive predictive value is poor. In the past, multiple studies have used serum BDG measurement for screening of patients at risk of IFD or to initiate antifungal treatment in patients with suspected IFD. However, this approach has led to a significant overuse of antifungal drugs with potentially severe side effects for the patients. It is now recognized, that diagnostic strategies should utilize the high negative predictive value of BDG measurement to rule out IFD and to discontinue antifungal therapy in case of negative BDG results. Methods: We plan to conduct a prospective, randomized intervention study using the Fungitell assay for BDG measurement to guide an early termination of antifungal therapy in ICU patients. All patients with an antifungal therapy that was started in the ICU and without proven IFD are included in the study. The patients will be randomized to an intervention group and a control group. In both groups serum BDG will be determined on day 1 and 2 of antifungal therapy. If both measurements are negative the antifungal therapy will be discontinued in the intervention group but not in the control group. The decision when to stop the antifungal treatment in the control group is made at the discretion of the treating physician without knowledge of the BDG results. The patients will be followed-up for 28 days and clinical as well as microbiological data will be collected. The primary endpoint is antifungal drug usage in daily defined doses. Secondary endpoints are 28 day mortality, development of a proven IFD, side effects attributable to antifungal therapy, SOFA score in the ICU, length of stay in the ICU and length of hospitalization. Hypothesis: By using the negative predictive value of two consecutive negative BDG-values to discontinue antifungal therapy in patients without proven fungal infection we will be able to significantly reduce antifungal consumption without negative consequences for the patient.

背景资料：大约70%的ICU患者接受抗生素治疗，因此这些患者中念珠菌定植的程度每天都在增加。念珠菌属（Candida spp.）从各种身体部位检测到，在临床恶化的情况下开始抗真菌治疗的迫切性很高，并且高达65%的接受这种治疗的ICU患者没有记录的侵袭性真菌病（IFD）。然而，不必要的抗真菌治疗与潜在的严重副作用有关，多重耐药念珠菌的增加。这对医疗保健系统来说是一个沉重的财政负担。（1-3）-β-D-葡聚糖（BDG）是各种医学相关真菌的主要细胞壁成分，可在IFD患者的血清中检测到。BDG对于IFD的检测具有高灵敏度和高达99. 9%的阴性预测值。相比之下，特异性仅为中等，阳性预测值较差。在过去，多项研究使用血清BDG测量筛查有IFD风险的患者或对疑似IFD患者进行抗真菌治疗。然而，这种方法导致了抗真菌药物的过度使用，对患者有潜在的严重副作用。现在人们认识到，诊断策略应该利用BDG测量的高阴性预测值来排除IFD，并在BDG结果阴性的情况下停止抗真菌治疗。研究方法：我们计划进行一项前瞻性随机干预研究，使用Fungitell测定BDG，以指导ICU患者早期终止抗真菌治疗。所有在ICU开始抗真菌治疗且未证实IFD的患者均纳入本研究。患者将被随机分配到干预组和对照组。在两组中，将在抗真菌治疗的第1天和第2天测定血清BDG。如果两项测量结果均为阴性，干预组将停止抗真菌治疗，但对照组不停止。在不了解BDG结果的情况下，由治疗医生决定何时停止对照组的抗真菌治疗。将对患者进行28天随访，并收集临床和微生物学数据。主要终点是每日规定剂量的抗真菌药物使用。次要终点是28天死亡率、已证实的IFD的发展、抗真菌治疗引起的副作用、ICU中的SOFA评分、ICU中的住院时间和住院时间。假设：通过使用连续两个阴性BDG值的阴性预测值来停止未证实真菌感染的患者的抗真菌治疗，我们将能够显着减少抗真菌药物的消耗，而不会对患者产生负面影响。