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.In critically ill patients, intensive care unit (ICU)-acquired pneumonia has been shown to be associated with a significant increase in the length of stay and mortality (27). Besides other factors, early and adequate antibiotic treatment has a major prognostic impact and is therefore of particular clinical relevance (12,14). Furthermore, adequacy of antibiotic treatment is also determined by sufficient distribution to the site of action. Since antibiotic concentrations at the site of action are often difficult to determine, concentrations in plasma are most commonly used as a surrogate measure.Broad-spectrum -lactam antibiotics are considered appropriate in the treatment of ICU-acquired pneumonia. However, the optimal method for administration of -lactam antibiotics is currently under investigation. Although they are usually administered in clinical practice in regular intermittent shortterm infusions following the manufacturers' instructions, the administration of -lactam antibiotics by continuous infusion has been proposed (4,15,21). Previous studies (3,7,17,28) repeatedly emphasized that the t...
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