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.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...

Novel Approach To Optimize Synergistic Carbapenem-Aminoglycoside Combinations against Carbapenem-Resistant Acinetobacter baumannii

“…A tobramycin concentration of 4 mg/liter and isepamicin concentrations of 8 to 16 mg/liter represent the average unbound plasma concentrations in humans over a 24-h dosing interval for tobramycin at 7 mg/kg of body weight and 15 or 25 mg/kg isepamicin given once daily (17,26). Additional experimental arms with 12 mg/ liter tobramycin and 64 mg/liter isepamicin represent the average free plasma concentration of aminoglycosides during the first 6 h. For the highest clinically approved imipenem doses of 4 g per day, our Monte Carlo simulations predicted the unbound average steady-state concentrations to range from 7.61 to 22.6 mg/liter in adult critically ill patients (27).…”

Efficacy of Lysophosphatidylcholine in Combination with Antimicrobial Agents against Acinetobacter baumannii in Experimental Murine Peritoneal Sepsis and Pneumonia Models

“…Concentrations of colistins A and B and their prodrugs, colistin methanesulfonate A and colistin methanesulfonate B, as well as tigecycline and imipenem, were measured using high-pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) (19)(20)(21). The maximum concentration of drug in serum (C max ), the area under the concentration-time curve from 0 h to 24 h (AUC 0 -24 ), the AUC 0 -ϱ for the free, unbound fraction of drug (fAUC 0 -24 ), the half-life (t 1/2 ), the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%T MIC ), the AUC over 24 h in the steady state divided by the MIC for the free, unbound fraction of drug (fAUC/MIC), and the AUC/MIC value were obtained by a computer-assisted method (22).…”

Population pharmacokinetics and Monte Carlo dosing simulations of imipenem in patients with ventilator-associated pneumonia

“…A previous PD study in critically ill patients with VAP found that a 90% PTA achieving 40% T >MIC was observed at a MIC of 1-2 μg/mL when imipenem was administered by a 40 min infusion of 1 g q8h, whereas a continuous infusion of a daily dosage of 2 g of imipenem had a 90% PTA for achieving a target of 40% T >MIC at a MIC of 2-4 μg/ mL [8]. In the current study, the probability of a 4-h infusion regimen achieving a target of 40% fT >MIC were superior to a 1-h infusion regimen in an equivalent daily dosage of imipenem, therefore, a prolonged 4-h infusion regimen was a more effective strategy to achieve optimal PD exposure for pathogens with higher MIC than a 1-h infusion regimen.…”

“…It was found that a two-compartment model is adequate for describing distribution phase of imipenem [7,8], so it was employed in this study. Due to the high values of the rate constants in the differential equations, computation instabilities were expected, hence Taylor series expansion method [9] was used to solve the differential equations to avoid this problem by computing them until convergence of the final results was achieved.…”