title: Penetration of piperacillin and tazobactam into pneumonic human lung tissue measured by in vivo microdialysis.
abstract: OBJECTIVE
  The pharmacokinetic profile of antibiotics at the site of anti-infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect. Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available. The aim of this study was to measure, using a new microdialysis-based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma.
  
  
  METHODS
  The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema. The condition was treated by decortication after lateral thoracotomy. Intra-, or post-operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values. Serum and microdialysis samples were collected at 20-min intervals for at last 8 h following i.v. administration of a single dose of 4 g piperacillin and 500 mg tazobactam.
  
  
  RESULTS
  The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 +/- 105.0 mg l-1 and 326.0 +/- 60.6 mg l-1, respectively. The mean AUC (area under the curve) for infected lung tissue was 288.0 +/- 167.0 mg.h l-1 and for serum 470.0 +/- 142.0 mg.h l-1. There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043). The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4-6 h. The procedure was well tolerated by all patients and no adverse events or microdialysis-associated side-effects were observed.
  
  
  CONCLUSIONS
  This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti-infective agents in the lung tissue of patients with pneumonia. The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.
authors.affiliation: Department of Surgery, Division of Thoracic and Hyperbaric Surgery, University Medical School of Graz, Graz, Austria. florian.tomaselli@uni-graz.at
authors.forename: Florian
authors.initials: F
authors.lastname: Tomaselli
authors.forename: Peter
authors.initials: P
authors.lastname: Dittrich
authors.forename: Alfred
authors.initials: A
authors.lastname: Maier
authors.forename: Michael
authors.initials: M
authors.lastname: Woltsche
authors.forename: Veronika
authors.initials: V
authors.lastname: Matzi
authors.forename: Johannes
authors.initials: J
authors.lastname: Pinter
authors.forename: Stephan
authors.initials: S
authors.lastname: Nuhsbaumer
authors.forename: Hans
authors.initials: H
authors.lastname: Pinter
authors.forename: Josef
authors.initials: J
authors.lastname: Smolle
authors.forename: Freyja M
authors.initials: FM
authors.lastname: Smolle-Jüttner
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D017551:Microdialysis / Q000379:methods; D008875:Middle Aged; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D010406:Penicillins / Q000493:pharmacokinetics*; D010878:Piperacillin / Q000493:pharmacokinetics*; D011014:Pneumonia / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism; D000078142:Tazobactam
chemical_list: D004791:Enzyme Inhibitors; D010406:Penicillins; D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin