RATIONALE: Continuous infusion of beta-lactam antibiotics may improve outcomes due to time-dependent antibacterial activity compared to intermittent dosing. OBJECTIVES: To evaluate the efficacy of continuous versus intermittent infusion in patients with severe sepsis. METHODS: We conducted a randomized controlled trial in 25 intensive care units (ICUs). Participants commenced on piperacillin-tazobactam, ticarcillin-clavulanate or meropenem were randomized to receive the prescribed antibiotic via continuous or 30-minute intermittent infusion for the remainder of the treatment course or until ICU discharge. The primary outcome was the number of alive ICU-free days at day 28. Secondary outcomes were 90-day survival, clinical cure 14 days post antibiotic cessation, alive organ failure-free days at day 14 and duration of bacteremia. MEASUREMENTS AND MAIN RESULTS: We enrolled 432 eligible participants with a median age of 64 years and an Acute Physiology and Chronic Health Evaluation II score of 20. There was no difference in ICU-free days: 18 days (IQR: 2-24) and 20 days (IQR 3-24) in the continuous and intermittent groups (P = 0.38). There was no difference in 90-day survival: 74.3% (156/210) and 72.5% (158/218); HR 0.91 (95% CI 0.63-1.31, P = 0.61). Clinical cure was 52.4% (111/212) and 49.5% (109/220); OR 1.12 (95% CI 0.77-1.63, P = 0.56). There was no difference in organ-failure free days (6 days, P = 0.27) and duration of bacteremia (0 days, P = 0.24). CONCLUSIONS: In critically ill patients with severe sepsis, there was no difference in outcomes between beta-lactam antibiotic administration by continuous and intermittent infusion. Clinical trial registration available at www.anzctr.org.au, ID ACTRN12612000138886.
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