Short Course Versus Standard Course Antifungal Therapy for Pediatric Candidemia: A Multi-Center Randomized Controlled Trial

儿童念珠菌血症的短期疗程与标准疗程抗真菌治疗：一项多中心随机对照试验

• 批准号: 10487627
• 负责人: Brian T Fisher
• 金额: $ 146.86万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2029-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487627
• 关键词: Adult; Americas; Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Antifungal Therapy; Automobile Driving; Bacteremia; Bacterial Infections; Benefits and Risks; Biological Assay; Biological Markers; Blood; Candida; Candidiasis; Child; Childhood; Clinical; Cohort Studies; Communicable Diseases; Communities; Comparative Study; Complication; Data; Disease; Drug Interactions; Early Diagnosis; Effectiveness; Expert Opinion; Fluconazole; Foundations; Funding; Future; Guidelines; Human Resources; Infection; International; Knowledge; Laboratories; Lead; Length of Stay; Measures; Methodology; Molds; Morbidity - disease rate; Multicenter Studies; Mycoses; Observational Study; Otitis Media; Outcome; Outcome Measure; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pneumonia; Prospective Studies; Publishing; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Recommendation; Research; Research Personnel; Resolution; Site; Societies; United States National Institutes of Health; Update; Urinary tract infection; Yeasts; arm; base; biomarker performance; candidemia; clinical epidemiology; comparative effectiveness study; design; effective therapy; improved; improved outcome; molecular marker; mortality; multidisciplinary; novel; novel marker; optimal treatments; prospective; randomized trial; rapid diagnosis; response; standard of care; therapy duration

Invasive candidiasis is the most common invasive fungal disease, and uncomplicated candidemia is the most common presentation. Randomized controlled trials in adults and a prospective observational study in children demonstrated primary treatment with an echinocandin antifungal improved outcomes. While these data inform initial therapy choice, there remains a paucity of data regarding appropriate duration of therapy. Current guidelines recommend 14 total days of antifungal therapy for candidemia regardless of clinical presentation and initial response, yet this is based on opinion and not comparative data. Several studies have proven that shorter durations of antibacterial therapy are safe and effective for the treatment of numerous serious bacterial infections. However, there has been no comparative study to assess shorter versus standard duration therapy for any invasive fungal disease. A large proportion of pediatric invasive candidiasis is uncomplicated candidemia with relatively rapid clinical improvement on primary echinocandin therapy. It is hypothesized that these patients do not require 14 days of therapy and instead would be effectively treated with a shorter duration. The primary objective of this randomized controlled trial is to determine whether 7 more days of therapy is necessary after completing an initial 7days of echinocandin therapy for pediatric candidemia. Subjects initially treated with an echinocandin showing clinical improvement with blood culture clearance will be randomized at 7 days into one of two arms: 1) cessation of therapy, or 2) continuation of therapy for 14 total days. This primary aim will include a novel outcome measure, the desirability of outcome ranking (DOOR), which simultaneously captures benefits and negative consequences of treatment. We will compare the DOOR outcome in children randomized to receive 7 days of an echinocandin only (short-course) versus 7 days of echinocandin therapy followed by 7 more days of antifungal therapy (standard-course). We hypothesize that subjects randomized to short-course therapy will on average have a higher DOOR measure than subjects randomized to standard-course therapy. The secondary objective will assess utility of a novel biomarker, the T2Candida® assay, to provide supporting evidence for effectiveness of short course therapy. We previously demonstrated the T2Candida® assay can rapidly diagnose invasive candidiasis in children. However, there are no data on the utility of a negative biomarker to support cessation of therapy. Aim 2 will compare the 14-day DOOR measure for subjects with a negative or positive T2Candida® biomarker at day 7 of therapy within each study group. We hypothesize that a negative T2Candida® biomarker at day 7 will be associated with a higher DOOR measure at day 14. This study will leverage the Pediatric Fungal Network (PFN), a multidisciplinary group composed of 37 sites across the US and the only such group dedicated to pediatric invasive fungal disease. This will be the first randomized controlled trial to define the optimal duration of therapy for any invasive fungal disease, and the first to explore the utility of a fungal biomarker to support a shorter course. Results could impact numerous national and international guidelines.

侵袭性念珠菌病是最常见的侵袭性真菌病， 共同介绍。成人随机对照试验和儿童前瞻性观察性研究 表明棘白菌素抗真菌药物的初步治疗改善了结局。虽然这些数据表明 尽管最初的治疗选择，但关于适当的治疗持续时间的数据仍然很少。电流 指南建议对念珠菌血症进行14天的抗真菌治疗，无论临床表现如何， 初步答复，但这是基于意见，而不是比较数据。多项研究表明， 抗菌治疗的持续时间是安全和有效的治疗许多严重的细菌 感染.然而，目前还没有比较研究来评估较短与标准持续时间治疗 任何侵袭性真菌病很大一部分儿童侵袭性念珠菌病是单纯性念珠菌血症 在棘白菌素治疗的基础上有相对快速的临床改善。据推测，这些患者 不需要14天的治疗，而是可以在较短的时间内有效治疗。主 这项随机对照试验的目的是确定是否有必要再治疗7天， 完成最初7天的棘白菌素治疗儿童念珠菌血症。最初接受治疗的受试者 在第7天时，将显示临床改善且血培养清除的棘白菌素随机分为1组 两组：1）停止治疗，或2）继续治疗共14天。这一主要目标包括 一种新的结局指标，即结局排序（DOOR）的期望性，它同时捕获了获益 治疗的负面后果。我们将比较随机接受DOOR治疗的儿童的结局， 棘白菌素单药治疗7天（短期）与棘白菌素治疗7天后再治疗7天的比较 抗真菌治疗（标准疗程）。我们假设随机接受短期治疗的受试者将 平均而言，DOOR指标高于随机接受标准疗程治疗的受试者。次级 目的是评估一种新的生物标志物T2 Candida ®检测的效用，为以下方面提供支持性证据： 短期治疗的有效性。我们之前证明了T2 Candida ®检测可以快速诊断 儿童侵袭性念珠菌病。然而，没有关于阴性生物标志物的效用的数据来支持 停止治疗。目标2将比较阴性或阳性受试者的14天DOOR指标 在每个研究组内治疗第7天的T2念珠菌®生物标志物。我们假设阴性T2念珠菌 在第7天的生物标志物将与在第14天的更高DOOR测量相关。这项研究将利用 儿科真菌网络（PFN），一个由美国37个站点组成的多学科小组，也是唯一一个 致力于儿科侵袭性真菌病的小组。这将是第一个随机对照试验， 任何侵袭性真菌病的最佳治疗持续时间，以及第一个探索真菌治疗的效用的人。 生物标志物，以支持更短的过程。结果可能会影响许多国家和国际准则。