title: Does prolonged β-lactam infusions improve clinical outcomes compared to intermittent infusions? A meta-analysis and systematic review of randomized, controlled trials.
abstract: BACKGROUND
  The emergence of multi-drug resistant Gram-negatives (MDRGNs) coupled with an alarming scarcity of new antibiotics has forced the optimization of the therapeutic potential of available antibiotics. To exploit the time above the minimum inhibitory concentration mechanism of β-lactams, prolonging their infusion may improve outcomes. The primary objective of this meta-analysis was to determine if prolonged β-lactam infusion resulted in decreased mortality and improved clinical cure compared to intermittent β-lactam infusion.
  
  
  METHODS
  Relevant studies were identified from searches of MEDLINE, EMBASE, and CENTRAL. Heterogeneity was assessed qualitatively, in addition to I2 and Chi-square statistics. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated using Mantel-Haenszel random-effects models.
  
  
  RESULTS
  Fourteen randomized controlled trials (RCTs) were included. Prolonged infusion β-lactams were not associated with decreased mortality (n=982; RR 0.92; 95% CI:0.61-1.37) or clinical cure (n=1380; RR 1.00 95% CI:0.94-1.06) compared to intermittent infusions. Subgroup analysis for β-lactam subclasses and equivalent total daily β-lactam doses yielded similar results. Most studies had notable methodological flaws.
  
  
  CONCLUSIONS
  No clinical advantage was observed for prolonged infusion β-lactams. The limited number of studies with MDRGNs precluded evaluation of prolonged infusion of β-lactams for this subgroup. A large, multicenter RCT with critically ill patients infected with MDRGNs is needed.
authors.affiliation: Department of Pediatric Infectious Diseases, Johns Hopkins Medical Institutions, Baltimore, MD, USA. ptamma1@jhmi.edu
authors.forename: Pranita D
authors.initials: PD
authors.lastname: Tamma
authors.forename: Nirupama
authors.initials: N
authors.lastname: Putcha
authors.forename: Yong D
authors.initials: YD
authors.lastname: Suh
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Van Arendonk
authors.forename: Michael L
authors.initials: ML
authors.lastname: Rinke
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D024901:Drug Resistance, Multiple, Bacterial; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D047090:beta-Lactams / Q000008:administration & dosage*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams