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Antimicrobial Agents and Chemotherapy, September 2007, p. 3304-3310, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.01318-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics and Pharmacodynamics of Continuous versus Short-Term Infusion of Imipenem-Cilastatin in Critically Ill Patients in a Randomized, Controlled Trial{triangledown}

Samir G. Sakka,1,{dagger} Anna K. Glauner,1 Jürgen B. Bulitta,2,{ddagger} Martina Kinzig-Schippers,2 Wolfgang Pfister,3 George L. Drusano,4 and Fritz Sörgel2,5*

Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller-University of Jena, Jena, Germany,1 Institute for Biomedical and Pharmaceutical Research (IBMP), Nürnberg-Heroldsberg, Germany,2 Institute of Medical Microbiology, Friedrich-Schiller-University of Jena, Jena, Germany,3 Ordway Research Institute, Inc., Albany, New York 12208,4 Department of Pharmacology, University of Duisburg-Essen, Essen, Germany5

Received 22 October 2006/ Returned for modification 14 January 2007/ Accepted 2 July 2007

Beta-lactams are regularly administered in intermittent short-term infusions. The percentage of the dosing interval during which free drug concentrations exceed the MIC (fT>MIC) is the measure of drug exposure that best correlates with clinical outcome for beta-lactams. Therefore, administration by continuous infusion has gained increasing interest recently. We studied 20 critically ill patients with nosocomial pneumonia and investigated whether continuous infusion with a reduced total dose, compared to the standard regimen of intermittent short-term infusion, results in a superior probability of target attainment as assessed by the fT>MIC value of imipenem. In this prospective, randomized, controlled clinical study, patients received either a loading dose of 1 g/1 g imipenem and cilastatin (as a short-term infusion) at time zero, followed by 2 g/2 g imipenem-cilastatin per 24 h as a continuous infusion for 3 days (n = 10), or 1 g/1 g imipenem-cilastatin three times per day as a short-term infusion for 3 days (total daily dose, 3 g/3 g; n = 10). Imipenem concentrations in plasma were determined by using a validated liquid chromatography-tandem mass spectrometry assay. A two-compartment open model was employed for population pharmacokinetic modeling. We simulated 10,000 intensive-care-unit patients via Monte Carlo simulations for pharmacodynamic evaluation using the target 40% fT>MIC. The probability of target attainment by MIC for intermittent infusion was robust (>90%) up to MICs of 1 to 2 mg/liter. The corresponding value for continuous infusion was 2 to 4 mg/liter. Although all 20 patients had an fT>MIC of 100%, 3 patients died. Patient survival was best described by employing a sepsis-related organ failure assessment score as a covariate in a logistic regression analysis. Larger clinical trials are warranted for evaluation of continuous infusions at a reduced dose of imipenem for critically ill patients.

* Corresponding author. Mailing address: Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Str. 19, D-90562 Nürnberg-Heroldsberg, Germany. Phone: 49-911-518290. Fax: 49-911-5182920. E-mail: ibmp{at}osn.de

{triangledown} Published ahead of print on 9 July 2007.

{dagger} Present address: Department of Anesthesiology and Intensive Care Medicine, Medical Center Cologne-Merheim, University Witten/Herdecke, Cologne, Germany.

{ddagger} Present address: State University of New York at Buffalo, Buffalo, NY 14260.

Antimicrobial Agents and Chemotherapy, September 2007, p. 3304-3310, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.01318-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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