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

背景：大约70%的ICU患者接受抗生素治疗，因此这些患者中念珠菌的定植程度每天都在增加。与假丝酵母属(Candida spp.)从不同的身体部位检测到，在临床恶化的情况下开始抗真菌治疗的冲动很高，接受这种治疗的ICU患者中高达65%没有侵袭性真菌病(IFD)的记录。然而，不必要的抗真菌治疗与潜在的严重副作用有关，即增加多重耐药念珠菌。对医疗保健系统来说也是一个巨大的财政负担。(1-3)-β-D-葡聚糖(BDG)是多种医学相关真菌的主要细胞壁成分，可在IFD患者血清中检测到。BDG对IFD的诊断灵敏度高，阴性预测值高达99.9%。相比之下，特异度仅为中等，阳性预测价值较差。在过去，多项研究使用血清BDG测量来筛查有IFD风险的患者或开始对疑似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严重过度使用，并可能对患者产生严重的副作用。现在已经认识到，诊断策略应该利用BDG测量的高度阴性预测价值来排除IFD，并在BDG结果阴性的情况下停止抗真菌治疗。方法：我们计划进行一项前瞻性、随机干预研究，使用Fungitell试验测定BDG，以指导ICU患者尽早终止抗真菌治疗。所有在ICU开始接受抗真菌治疗且未证实IFD的患者都包括在这项研究中。患者将被随机分为干预组和对照组。两组患者均在抗真菌治疗的第1天和第2天测定血糖。如果两项检测结果均为阴性，干预组将停止抗真菌治疗，而对照组则不停止。在对照组中，何时停止抗真菌治疗由治疗医生在不知道BDG结果的情况下自行决定。将对患者进行为期28天的随访，并收集临床和微生物数据。主要终点是按每日规定的剂量使用抗真菌药物。次要终点是28天死亡率、经证实的IFD的发展、可归因于抗真菌治疗的副作用、在ICU的SOFA评分、在ICU的住院时间和住院时间。假设：通过使用连续两个负的BDG值的阴性预测值来停止对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使用，而不会对患者产生负面后果。

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.