title: Population pharmacokinetics and pharmacodynamics of continuous versus short-term infusion of imipenem-cilastatin in critically ill patients in a randomized, controlled trial.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller-University of Jena, Jena, Germany.
authors.forename: Samir G
authors.initials: SG
authors.lastname: Sakka
authors.forename: Anna K
authors.initials: AK
authors.lastname: Glauner
authors.forename: Jürgen B
authors.initials: JB
authors.lastname: Bulitta
authors.forename: Martina
authors.initials: M
authors.lastname: Kinzig-Schippers
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Pfister
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
authors.forename: Fritz
authors.initials: F
authors.lastname: Sörgel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D015377:Cilastatin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016638:Critical Illness; D003428:Cross Infection / Q000188:drug therapy* / Q000382:microbiology; D004338:Drug Combinations; D005260:Female; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009010:Monte Carlo Method; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D011480:Protease Inhibitors; D015377:Cilastatin; D015378:Imipenem