title: Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials.
abstract: Optimization of β-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis.
  
  
  
  In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of β-lactam antibiotics.
  
  
  
  We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of β-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis.
  
  
  
  We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6% versus 26.3% (relative risk, 0.74; 95% confidence interval, 0.56-1.00; P = 0.045) and 55.4% versus 46.3% (relative risk, 1.20; 95% confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent β-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous β-lactam administration was not independently associated with clinical cure.
  
  
  
  Compared with intermittent dosing, administration of β-lactam antibiotics by continuous infusion in critically ill patients with severe sepsis is associated with decreased hospital mortality.
authors.affiliation: 1 Department of Intensive Care Medicine and.|3 Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, Australia.|2 Burns, Trauma & Critical Care Research Centre and.|4 School of Pharmacy, The University of Queensland, Brisbane, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
authors.affiliation: 2 Burns, Trauma & Critical Care Research Centre and.|5 School of Pharmacy, International Islamic University Malaysia, Kuantan, Malaysia.
authors.forename: Mohd-Hafiz
authors.initials: MH
authors.lastname: Abdul-Aziz
authors.affiliation: 6 Menzies School of Health Research, Charles Darwin University, Darwin, Australia.|7 Department of Infectious Diseases, John Hunter Hospital, Newcastle, Australia.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Davis
authors.affiliation: 1 Department of Intensive Care Medicine and.|2 Burns, Trauma & Critical Care Research Centre and.|8 Redcliffe Hospital, Brisbane, Australia.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Dulhunty
authors.affiliation: 1 Department of Intensive Care Medicine and.|3 Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, Australia.|2 Burns, Trauma & Critical Care Research Centre and.|4 School of Pharmacy, The University of Queensland, Brisbane, Australia.
authors.forename: Menino O
authors.initials: MO
authors.lastname: Cotta
authors.affiliation: 9 Critical Care and Trauma Division, The George Institute for Global Health, Sydney, Australia.|10 St. George Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Myburgh
authors.affiliation: 11 Department of Intensive Care, Austin Hospital, Melbourne, Australia; and.|12 Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia.
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Bellomo
authors.affiliation: 1 Department of Intensive Care Medicine and.|2 Burns, Trauma & Critical Care Research Centre and.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality; D047090:beta-Lactams / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams
keywords: antibiotic; meropenem; pharmacodynamics; pharmacokinetics; piperacillin-tazobactam