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JAC Advance Access published online on August 24, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki284
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Received April 27, 2005
Revised July 10, 2005
Accepted July 24, 2005

Original article

Plasma concentrations might lead to overestimation of target site activity of piperacillin in patients with sepsis

M. A. Zeitlinger 1, B. M. Erovic 2, R. Sauermann 1, A. Georgopoulos 3, M. Müller 1, and C. Joukhadar 4*

1 Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna, Vienna, Austria
2 Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria
3 Department of Internal Medicine I, Division of Infectious Diseases and Chemotherapy, Medical University of Vienna, Vienna, Austria
4 Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna, Vienna, Austria; Department of Internal Medicine I, Division of Infectious Diseases and Chemotherapy, Medical University of Vienna, Vienna, Austria

* To whom correspondence should be addressed.
C. Joukhadar, E-mail: christian.joukhadar{at}meduniwien.ac.at


  Abstract

Objectives: 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 Samples were withdrawn at defined intervals and the numbers of bacteria per mL were counted and plotted against time.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.

Keywords: pharmacokinetics; pharmacodynamics; PK/PD; {beta}-lactams; in vitro.
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