title: A Multicenter Randomized Trial of Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis.
abstract: Continuous infusion of β-lactam antibiotics may improve outcomes because of time-dependent antibacterial activity compared with intermittent dosing.
  
  
  
  To evaluate the efficacy of continuous versus intermittent infusion in patients with severe sepsis.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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).
authors.affiliation: 1 Department of Intensive Care Medicine.|2 The Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, Australia.
authors.forename: Joel M
authors.identifier: 0000-0002-4524-0548
authors.initials: JM
authors.lastname: Dulhunty
authors.affiliation: 1 Department of Intensive Care Medicine.|3 Pharmacy Department, and.|2 The Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, Australia.
authors.forename: Jason A
authors.identifier: 0000-0001-6218-435X
authors.initials: JA
authors.lastname: Roberts
authors.affiliation: 4 Menzies School of Health Research, Charles Darwin University, Darwin, Australia.|5 Department of Infectious Diseases, John Hunter Hospital, Newcastle, Australia.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Davis
authors.affiliation: 6 Department of Intensive Care, Royal Perth Hospital, Perth, Australia.|7 School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
authors.forename: Steven A R
authors.initials: SA
authors.lastname: Webb
authors.affiliation: 8 Department of Intensive Care, Austin Hospital, Melbourne, Australia.|9 Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia.
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Bellomo
authors.affiliation: 10 Prince of Wales Hospital, Hong Kong.|11 Chinese University of Hong Kong, Hong Kong.
authors.forename: Charles
authors.initials: C
authors.lastname: Gomersall
authors.affiliation: 12 Department of Intensive Care, Blacktown Hospital, Blacktown, Australia.
authors.forename: Charudatt
authors.initials: C
authors.lastname: Shirwadkar
authors.affiliation: 8 Department of Intensive Care, Austin Hospital, Melbourne, Australia.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Eastwood
authors.affiliation: 13 Critical Care and Trauma Division, The George Institute for Global Health, Sydney, Australia.|14 St. George Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Myburgh
authors.affiliation: 15 Infectious Diseases Unit, Royal Brisbane and Women's Hospital, Brisbane, Australia.|16 The University of Queensland Centre for Clinical Research, Brisbane, Australia; and.
authors.forename: David L
authors.initials: DL
authors.lastname: Paterson
authors.affiliation: 1 Department of Intensive Care Medicine.|2 The Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, Australia.
authors.forename: Therese
authors.initials: T
authors.lastname: Starr
authors.affiliation: 17 Clinical Trials and Biostatistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Sanjoy K
authors.identifier: 0000-0003-0848-7194
authors.initials: SK
authors.lastname: Paul
authors.affiliation: 1 Department of Intensive Care Medicine.|2 The Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007902:Length of Stay / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018805:Sepsis / Q000188:drug therapy*; D016019:Survival Analysis; D016896:Treatment Outcome; D047090:beta-Lactams / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams
keywords: antibiotic; clinical outcome; intensive care; pharmacodynamics; pharmacokinetics