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，其中最常见的是无并发症的念珠菌血症。 共同的演示。成人随机对照试验和儿童前瞻性观察研究 证明使用棘白菌素抗真菌药物进行初步治疗可改善预后。虽然这些数据告知 初始治疗选择，仍然缺乏有关适当治疗持续时间的数据。当前的 指南建议对念珠菌血症进行总共 14 天的抗真菌治疗，无论临床表现和情况如何 初步回应，但这只是基于意见而不是比较数据。多项研究证明，更短的 抗菌治疗的持续时间对于治疗多种严重细菌是安全有效的 感染。然而，还没有比较研究来评估较短疗程与标准疗程的治疗 对于任何侵袭性真菌病。儿童侵袭性念珠菌病很大一部分是无并发症的念珠菌血症 初级棘白菌素疗法的临床改善相对较快。据推测，这些患者 不需要 14 天的治疗，而是在更短的时间内得到有效治疗。初级 这项随机对照试验的目的是确定术后是否还需要再治疗 7 天。 完成儿童念珠菌血症的最初 7 天棘白菌素治疗。最初接受治疗的受试者 棘白菌素通过血培养清除显示出临床改善，将在第 7 天随机分为一组 两组：1) 停止治疗，或 2) 继续治疗总共 14 天。这一主要目标将包括 一种新颖的结果衡量标准，即结果排名的合意性 (DOOR)，它同时捕获收益 以及治疗的负面后果。我们将比较随机接受治疗的儿童的 DOOR 结果 仅使用棘白菌素治疗 7 天（短程）与使用棘白菌素治疗 7 天，然后再治疗 7 天 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，与随机接受标准疗程治疗的受试者相比，DOOR 测量值更高。二级 目标将评估新型生物标志物 T2Candida® 检测的效用，为以下方面提供支持证据： 短期疗法的有效性。我们之前证明了 T2Candida® 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 将比较具有阴性或阳性受试者的 14 天 DOOR 测量结果 每个研究组治疗第 7 天时的 T2Candida® 生物标志物。我们假设 T2Candida® 呈阴性 第 7 天的生物标志物将与第 14 天的较高 DOOR 测量值相关。本研究将利用 儿科真菌网络 (PFN) 是一个由美国 37 个站点组成的多学科小组，也是唯一一个这样的小组 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来定义 任何侵袭性真菌疾病的最佳治疗持续时间，并且是第一个探索真菌效用的人 生物标志物支持较短的疗程。结果可能会影响许多国家和国际准则。