PROJECT SUMMARY With more than 300,000 new cases of Lyme disease each year in the U.S., approximately half of new cases occur in children. Children with Lyme meningitis, a clinical manifestation of Lyme disease, present with headache, fever and fatigue. Previously, an intravenous antibiotic (ceftriaxone) was the recommended first treatment for Lyme meningitis, but it is associated with a high rate of complications related either to the long- term intravenous catheter placed for medication delivery or to complications from the medicine itself. Based on European trials conducted in adults and small observational pediatric studies, some clinicians have begun treating Lyme meningitis in children with an oral antibiotic (doxycycline), avoiding the complications associated with intravenous ceftriaxone and reducing health care costs. Our first goal is to compare oral doxycycline to intravenous ceftriaxone for the treatment of Lyme meningitis, with a focus on both short-term recovery and long-term quality of life. Our second goal is to examine patient, parent and clinician preferences to inform shared decision-making about Lyme meningitis treatments. To accomplish our goals, we propose a comprehensive pediatric Lyme meningitis study, enrolling children at 20 U.S. centers located in regions of the U.S. where Lyme disease is endemic. Treatment decisions will be made by the child?s doctors, per usual practice, and we will obtain informed consent to follow the outcomes over the following six months. We will enroll a total of 210 children with Lyme meningitis to determine whether oral doxycycline is not inferior to intravenous ceftriaxone for the treatment of Lyme meningitis in children. We will interview patients, parents and clinicians to gain a nuanced understanding of the factors that shape treatment decisions. The overall impact of this study will be to inform the best practices for the treatment of children with Lyme meningitis accounting for the preferences of key stake holders.