Joel M Dulhunty1,2, Jason A Roberts1,3,2, Joshua S Davis4,5, Steven A R Webb6,7, Rinaldo Bellomo8,9, Charles Gomersall10,11, Charudatt Shirwadkar12, Glenn M Eastwood8, John Myburgh13,14, David L Paterson15,16, Therese Starr1,2, Sanjoy K Paul17, Jeffrey Lipman1,2. 1. 1 Department of Intensive Care Medicine. 2. 2 The Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, Australia. 3. 3 Pharmacy Department, and. 4. 4 Menzies School of Health Research, Charles Darwin University, Darwin, Australia. 5. 5 Department of Infectious Diseases, John Hunter Hospital, Newcastle, Australia. 6. 6 Department of Intensive Care, Royal Perth Hospital, Perth, Australia. 7. 7 School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. 8. 8 Department of Intensive Care, Austin Hospital, Melbourne, Australia. 9. 9 Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia. 10. 10 Prince of Wales Hospital, Hong Kong. 11. 11 Chinese University of Hong Kong, Hong Kong. 12. 12 Department of Intensive Care, Blacktown Hospital, Blacktown, Australia. 13. 13 Critical Care and Trauma Division, The George Institute for Global Health, Sydney, Australia. 14. 14 St. George Clinical School, University of New South Wales, Sydney, Australia. 15. 15 Infectious Diseases Unit, Royal Brisbane and Women's Hospital, Brisbane, Australia. 16. 16 The University of Queensland Centre for Clinical Research, Brisbane, Australia; and. 17. 17 Clinical Trials and Biostatistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Abstract
RATIONALE: Continuous infusion of β-lactam antibiotics may improve outcomes because of time-dependent antibacterial activity compared with 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 (interquartile range, 2-24) and 20 days (interquartile range, 3-24) in the continuous and intermittent groups (P = 0.38). There was no difference in 90-day survival: 74.3% (156 of 210) and 72.5% (158 of 218); hazard ratio, 0.91 (95% confidence interval, 0.63-1.31; P = 0.61). Clinical cure was 52.4% (111 of 212) and 49.5% (109 of 220); odds ratio, 1.12 (95% confidence interval, 0.77-1.63; P = 0.56). There was no difference in organ failure-free days (6 d; P = 0.27) and duration of bacteremia (0 d; P = 0.24). CONCLUSIONS: In critically ill patients with severe sepsis, there was no difference in outcomes between β-lactam antibiotic administration by continuous and intermittent infusion. Australian New Zealand Clinical Trials Registry number (ACT RN12612000138886).
RCT Entities:
RATIONALE: Continuous infusion of β-lactam antibiotics may improve outcomes because of time-dependent antibacterial activity compared with 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 (interquartile range, 2-24) and 20 days (interquartile range, 3-24) in the continuous and intermittent groups (P = 0.38). There was no difference in 90-day survival: 74.3% (156 of 210) and 72.5% (158 of 218); hazard ratio, 0.91 (95% confidence interval, 0.63-1.31; P = 0.61). Clinical cure was 52.4% (111 of 212) and 49.5% (109 of 220); odds ratio, 1.12 (95% confidence interval, 0.77-1.63; P = 0.56). There was no difference in organ failure-free days (6 d; P = 0.27) and duration of bacteremia (0 d; P = 0.24). CONCLUSIONS: In critically illpatients with severe sepsis, there was no difference in outcomes between β-lactam antibiotic administration by continuous and intermittent infusion. Australian New Zealand Clinical Trials Registry number (ACT RN12612000138886).
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