Multi-center studies to improve diagnosis and treatment of pediatric candidiasis

描述(由申请人提供)：侵袭性念珠菌病是高危住院儿童的一种常见且经常致命的感染。协调努力改善了成人患者侵袭性念珠菌病的预防和治疗，但在改善儿童预后方面做的工作很少。因此，解决侵袭性念珠菌病治疗的实践指南包含的儿童数据有限且验证效果不佳。这种缺乏儿科专科的 信息令人担忧，因为这两个群体之间存在重大差异。我们的首要目标是为儿童侵袭性念珠菌病制定新的循证治疗指南。我们将前瞻性地招募600名儿童参加一项多国家队列研究 对儿童侵袭性念珠菌病进行研究，比较目前儿童抗真菌治疗(两性霉素B、三氮唑和棘球菌素)的有效性。我们还将验证在儿科重症监护病房期间发生念珠菌血症的患者的临床预测模型。这一验证将使我们能够确定经验性抗真菌治疗的最佳临床方案。这项建议将集中在两个特定的目标：1)比较棘球菌素与两性霉素B或三氮唑抗真菌治疗儿童侵袭性念珠菌病的有效性。儿童的最佳抗真菌治疗目前尚不清楚。我们假设，与接受两性霉素B或三唑类抗真菌药物治疗的儿童相比，接受棘球菌素治疗的侵袭性念珠菌病儿童的总体反应将高出10%。2)验证儿科重症监护中念珠菌血症的临床预测模型 单位。我们小组以前的工作是从单个中心导出预测模型，我们的目标是验证该模型并评估其在多个中心的泛化能力。我们假设临床预测模型将准确地对风险最高的儿童进行分类，识别出有10%的风险发展为念珠菌症的患者，从而提供适当和有针对性的预防性或经验性治疗策略。我们的研究团队正准备进行这项研究。十多年来，调查人员作为许多项目的合作者一起发挥了作用。这个研究团队将利用我们组建的独特的多中心联盟，即国际儿科真菌网络(PFN)。PFN由32个全球站点组成，由传染病、血液学/肿瘤学和造血干细胞移植方面的儿科专家领导。这项研究的影响将是确定治疗儿童侵袭性念珠菌病最有效的抗真菌疗法，并验证一个模型，以准确识别重症监护病房中那些患念珠菌症风险最高的儿童。完成后，我们将有新的数据来推进美国传染病学会关于念珠菌病的治疗指南，将儿童侵袭性念珠菌病管理的关键组成部分的建议强度从C级提高到B级，证据质量从III级提高到II级。这将改善儿童的结局。

DESCRIPTION (provided by applicant): Invasive candidiasis is a common and frequently fatal infection in high-risk hospitalized children. Coordinated efforts have improved the prevention and treatment of invasive candidiasis in adult patients, but little work has been done to improve outcomes in children. As a result, practice guidelines addressing the treatment for invasive candidiasis contain limited and poorly validated data for children. This lack of pediatric-specific information is concerning as major differences exist between the two populations. Our overarching objective is to develop new evidence-based treatment guidelines for invasive candidiasis in children. We will prospectively enroll 600 children in a multi-national cohort study of pediatric invasive candidiasis to compare the effectiveness of current pediatric antifungal treatments (amphotericin B, triazoles, and echinocandins). We will also validate our previously derived clinical prediction model for patients developing candidemia while in the pediatric intensive care unit. This validation will allow us to define the optimal clinical scenario for empirical antifungal therapy. This proposal will focus on two specific aims: 1) Compare the effectiveness of echinocandin versus amphotericin B or triazole antifungal therapy for pediatric invasive candidiasis. Optimal antifungal therapy for children is currently unknown. We hypothesize that children with invasive candidiasis treated an echinocandin will have a 10% greater global response compared to children treated with either amphotericin B or triazole antifungals. 2) Validate a clinical prediction model for candidemia in the pediatric intensive care unit. Previous work by our group has derived a prediction model from a single center and we aim to validate the model and assess its generalizability in multiple centers. We hypothesize that the clinical prediction model will accurately classify children at highest risk, identifying patients with a > 10% risk of developing candidemia, and therefore inform appropriate and targeted preventative or empirical treatment strategies. Our study team is uniquely poised to conduct this research. The investigators have functioned together as collaborators on numerous projects for over a decade. This research team will leverage the unique multi- center consortium we have assembled known as the International Pediatric Fungal Network (PFN). The PFN is composed of 32 worldwide sites led by pediatric subspecialists in infectious diseases, hematology/oncology, and hematopoietic stem cell transplantation. The impact of this research will be to define the most effective antifungal therapy for pediatric invasive candidiasis and validate a model to accurately identify those children in the intensive care unit at highest risk fr developing candidemia. Upon completion, we will have new data to advance the Infectious Diseases Society of America treatment guidelines for candidiasis strength of recommendation from C to B and the quality of evidence from level III to II for the key components of management of invasive candidiasis in children. This will lead to improved outcomes in children.