title: Plasma concentrations might lead to overestimation of target site activity of piperacillin in patients with sepsis.
abstract: OBJECTIVE
  Pharmacokinetic (PK)/pharmacodynamic (PD) models have become increasingly important in optimizing antimicrobial therapy. This approach is highly recommended by regulatory authorities intending to force the evaluation of antimicrobial action at the site of infection.
  
  
  METHODS
  Clinical isolates of Pseudomonas aeruginosa and Staphylococcus aureus with MICs of 4, 8 and 16 mg/L for piperacillin were used in an in vivo PK/in vitro PD model. Bacteria were exposed in vitro to the concentration-versus-time profiles of piperacillin in plasma and subcutaneous adipose tissue measured in vivo in septic patients. Samples were withdrawn at defined intervals and the numbers of bacteria per mL were counted and plotted against time.
  
  
  RESULTS
  Piperacillin levels determined in plasma were able to effectively inhibit bacterial growth of all bacterial strains used in the present study (MIC ranged from 4-16 mg/L). In contrast, concentration-versus-time profiles of subcutaneous adipose tissue were effective in killing isolates with MICs of 4 and 8 mg/L only, while bacterial growth of S. aureus and P. aeruginosa with MICs of 16 mg/L was not inhibited.
  
  
  CONCLUSIONS
  Bacteria with MICs < 16 mg/L were effectively inhibited in subcutaneous adipose tissue in patients with sepsis. The prediction of microbiological outcome based on concentrations of piperacillin in plasma resulted in a marked overestimation of antimicrobial activity at the site of infection.
authors.affiliation: Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna, Vienna, Austria.
authors.forename: M A
authors.initials: MA
authors.lastname: Zeitlinger
authors.forename: B M
authors.initials: BM
authors.lastname: Erovic
authors.forename: R
authors.initials: R
authors.lastname: Sauermann
authors.forename: A
authors.initials: A
authors.lastname: Georgopoulos
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: C
authors.initials: C
authors.lastname: Joukhadar
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008954:Models, Biological; D009928:Organ Specificity; D010878:Piperacillin / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011552:Pseudomonas Infections / Q000188:drug therapy; D018805:Sepsis / Q000188:drug therapy*; D013203:Staphylococcal Infections / Q000188:drug therapy; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D010878:Piperacillin