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.
Invasive candidiasis is associated with significant morbidity and mortality in immune-compromised children. This proposal will address important questions about the frequency, risk factors, diagnosis, and best treatment strategies for children with this infection.
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