title: Alveolar concentrations of piperacillin/tazobactam administered in continuous infusion to patients with ventilator-associated pneumonia.
abstract: OBJECTIVE
  To determine the steady-state serum and alveolar concentrations of piperacillin/tazobactam administered in continuous infusion to critically ill patients with ventilator-associated pneumonia and various degrees of renal failure.
  
  
  METHODS
  Prospective comparative study.
  
  
  METHODS
  An intensive care unit and research ward in a university hospital.
  
  
  METHODS
  Forty patients with microbiologically documented ventilator-associated pneumonia.
  
  
  METHODS
  Patients were randomized to receive piperacillin/tazobactam daily continuous infusions of 12/1.5 g or 16/2 g after a loading dose of 4/0.5 g. The serum and alveolar piperacillin/tazobactam concentrations were determined at steady-state with high performance liquid chromatography.
  
  
  RESULTS
  The median (interquartile) serum and alveolar piperacillin concentrations were respectively 25.3 mg/L (23.1-32.6) and 12.7 mg/L (6.7-18.0) for 12/1.5 g/day, and 38.9 mg/L (32.9-59.6) and 19.1 mg/L (14.0-21.5), respectively, for 16/2 g/day in patients with no/mild renal failure. In patients with moderate/advance renal failure, the median (interquartile) serum and alveolar piperacillin concentrations were 102.4 mg/L (97.4-112.6) and 44.1 mg/L (33.4-48.3), respectively, for 12/1.5 g/day, and 135.3 mg/L (119.5-146.2) and 54.9 mg/L (45.2-110.3), respectively, for 16/2 g/day. Our results show great variability in piperacillin/tazobactam concentrations, with an alveolar percentage penetration of 40-50% for piperacillin and 65-85% for tazobactam and a negative association between serum or alveolar concentrations and creatinine clearance.
  
  
  CONCLUSIONS
  A target piperacillin serum concentration of at least 35-40 mg/L is probably required to provide alveolar concentrations exceeding the susceptibility breakpoint for gram-negative bacteria (16 mg/L) during ventilator-associated pneumonia. In patients with no/mild renal failure, a continuous daily dose of piperacillin/tazobactam 16/2 g allows reaching this target concentration, which might be not observed with 12/1.5 g/day. In patients with moderate/advanced renal failure, both dosages achieve serum concentrations far above the 35-40 mg/L threshold, suggesting that in that case, therapeutic drug monitoring should be performed in order to adjust the daily dose.
authors.affiliation: Claude Bernard Lyon I University, Lyon, France. emmanuel.boselli@chu-lyon.fr
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Boselli
authors.forename: Dominique
authors.initials: D
authors.lastname: Breilh
authors.forename: Thomas
authors.initials: T
authors.lastname: Rimmelé
authors.forename: Christian
authors.initials: C
authors.lastname: Guillaume
authors.forename: Fabien
authors.initials: F
authors.lastname: Xuereb
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Saux
authors.forename: Lionel
authors.initials: L
authors.lastname: Bouvet
authors.forename: Dominique
authors.initials: D
authors.lastname: Chassard
authors.forename: Bernard
authors.initials: B
authors.lastname: Allaouchiche
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D053717:Pneumonia, Ventilator-Associated / Q000378:metabolism*; D011446:Prospective Studies; D011650:Pulmonary Alveoli / Q000378:metabolism*; D000078142:Tazobactam
chemical_list: D000900:Anti-Bacterial Agents; D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin