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We present the findings of a prospective, bi-center study to establish the appropriate duration of antibiotic therapy for acute, uncomplicated bone and joint infections in children. Historically, patients have been treated with prolonged courses of intravenous and oral therapy. Our hypothesis was that children could be safely treated with 3 days of high-dose intravenous therapy followed by 3 weeks of oral therapy.We prospectively collected data from children presenting to Birmingham Children's Hospital and The Royal Children's Hospital, Melbourne who fitted our diagnostic criteria for septic arthritis and osteomyelitis over a 52-month period. Inclusion criteria for entry into the database were children ≤16 years of age who had no underlying disease or medical therapy predisposing to infection, and who had symptoms for less than 14 days before presentation. They were all started on intravenous antibiotics and a predetermined treatment algorithm was followed. All patients with septic arthritis also underwent joint washout. The patients were converted to oral antibiotics once they improved clinically and hematologically. Regular outpatient follow-up continued for 1 year with blood tests and x-rays.Our database included 70 consecutive, eligible children aged 2 weeks to 14 years. Staphylococci were the only organisms isolated in cases of osteomyelitis, whereas Streptococcal infection was more prevalent in patients with septic arthritis. Using our treatment protocol, we found that 59% of children could be converted to oral therapy after 3 days of intravenous therapy and 86% after 5 days. The median duration of inpatient stay was 5 days. We established that 3 weeks of oral therapy was appropriate for those patients who received 5 days or less intravenous treatment. We have identified temperature and C-reactive protein as the best quantitative means of monitoring response to therapy. All patients were clinically, hematologically, and radiologically normal before discharge 1 year post-presentation.We have found that a shortened course of intravenous and oral antibiotic therapy is effective in the management of acute uncomplicated bone and joint sepsis in children.Prospective cohort study investigating diagnostic tests and the results of treatment.