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Pharmacokinetics of imipenem-cilastatin in critically ill patients undergoing continuous venovenous hemofiltration. 1997

I Tegeder, and F Bremer, and R Oelkers, and H Schobel, and J Schüttler, and K Brune, and G Geisslinger
Department of Experimental and Clinical Pharmacology and Toxicology, University Erlangen/Nürnberg, Erlangen, Germany.

The pharmacokinetics of imipenem-cilastatin were investigated in 12 critically ill patients with acute renal failure (ARF) managed by continuous veno-venous hemofiltration (CVVH) while receiving a fixed combination of 500 mg of imipenem-cilastatin intravenously three or four times daily. No adverse drug reactions were observed. Plasma and hemofiltrate samples were taken at specified times during one dosing interval, and the concentrations of imipenem and cilastatin were determined by high-performance liquid chromatography. Pharmacokinetic variables were calculated by a first-order, two-compartment pharmacokinetic model for both substances. Total clearances of imipenem and cilastatin (mean +/- standard deviations) were 122.2 +/- 28.6 and 29.2 +/- 13.7 ml/min, respectively, with hemofiltration clearances of 22.9 +/- 2.5 and 16.1 +/- 3.1 ml/min, respectively, and nonrenal, nonhemofiltration clearances of 90.8 +/- 26.3 and 13.2 +/- 13.9 ml/min, respectively. Mean imipenem dosage requirements were approximately 2,000 mg/24 h (2,111.8 +/- 493.4 mg/24 h). They were calculated in order to achieve an average steady-state concentration of 12 mg/liter to ensure that concentrations in plasma exceeded the MICs at which 90% of intermediately resistent bacteria are inhibited (8 mg/liter) during the majority of the dosing interval. By contrast, the recommended dosage for patients with end-stage renal failure (ESRF) and infections caused by intermediately resistant bacteria is 1,000 mg/24 h. This remarkable difference may be due (i) to differences in the nonrenal clearance of imipenem between patients with ARF and ESRF and (ii) to the additional clearance by the hemofilter. Since the total clearance of cilastatin was low, marked accumulation occurred, and this was particularly pronounced in patients with additional liver dysfunction. Thus, in patients with ARF managed by CVVH, rather high imipenem doses are required, and these inevitably result in a marked accumulation of cilastatin. The doses of imipenem recommended for patients with ESRF, however, will lead to underdosing and inadequate antibiotic therapy.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008297 Male Males
D008875 Middle Aged An adult aged 45 - 64 years. Middle Age
D003198 Computer Simulation Computer-based representation of physical systems and phenomena such as chemical processes. Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004334 Drug Administration Schedule Time schedule for administration of a drug in order to achieve optimum effectiveness and convenience. Administration Schedule, Drug,Administration Schedules, Drug,Drug Administration Schedules,Schedule, Drug Administration,Schedules, Drug Administration
D004338 Drug Combinations Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture. Drug Combination,Combination, Drug,Combinations, Drug
D004359 Drug Therapy, Combination Therapy with two or more separate preparations given for a combined effect. Combination Chemotherapy,Polychemotherapy,Chemotherapy, Combination,Combination Drug Therapy,Drug Polytherapy,Therapy, Combination Drug,Chemotherapies, Combination,Combination Chemotherapies,Combination Drug Therapies,Drug Polytherapies,Drug Therapies, Combination,Polychemotherapies,Polytherapies, Drug,Polytherapy, Drug,Therapies, Combination Drug
D005069 Evaluation Studies as Topic Works about studies that determine the effectiveness or value of processes, personnel, and equipment, or the material on conducting such studies. Critique,Evaluation Indexes,Evaluation Methodology,Evaluation Report,Evaluation Research,Methodology, Evaluation,Pre-Post Tests,Qualitative Evaluation,Quantitative Evaluation,Theoretical Effectiveness,Use-Effectiveness,Critiques,Effectiveness, Theoretical,Evaluation Methodologies,Evaluation Reports,Evaluation, Qualitative,Evaluation, Quantitative,Evaluations, Qualitative,Evaluations, Quantitative,Indexes, Evaluation,Methodologies, Evaluation,Pre Post Tests,Pre-Post Test,Qualitative Evaluations,Quantitative Evaluations,Report, Evaluation,Reports, Evaluation,Research, Evaluation,Test, Pre-Post,Tests, Pre-Post,Use Effectiveness
D005260 Female Females

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