Is continuous infusion of imipenem always the best choice?

• Published in: International journal of antimicrobial agents Vol. 49; no. 3; pp. 348 - 354
• Main Authors: Suchánková, Hana, Lipš, Michal, Urbánek, Karel, Neely, Michael N., Strojil, Jan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2017
• Subjects: Acinetobacter; Aged; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; bacteria; Critical Illness; Critically ill; Cross Infection - drug therapy; data collection; Escherichia coli; Extended infusion; Female; Gram-Negative Bacteria - drug effects; Humans; imipenem; Imipenem - administration & dosage; Imipenem - pharmacokinetics; Infectious Disease; Infusions, Intravenous - methods; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Monte Carlo method; Monte Carlo simulation; pathogens; patients; Pharmacodynamics; Pharmacokinetics; Plasma - chemistry; Pneumonia; Pneumonia, Bacterial - drug therapy; prediction; Pseudomonas aeruginosa; risk factors; Staphylococcus aureus; Staphylococcus aureus - drug effects; Time Factors; Pneumonia; Pharmacodynamics; Pharmacokinetics; Critically ill; Extended infusion; Monte Carlo simulation
• ISSN: 0924-8579; 1872-7913; 1872-7913
• DOI: 10.1016/j.ijantimicag.2016.12.005

•Imipenem volume of distribution is approximately doubled in patients with hospital-acquired pneumonia.•Extended infusions of imipenem provide better probability of target attainment (PTA).•Continuous infusion carries a risk of failing to reach bacteriostatic targets.•Cumulative PTA is very sensitive to local susceptibility patterns and epidemiology. Monte Carlo simulations allow prediction and comparison of concentration–time profiles arising from different dosing regimens in a defined population, provided a population pharmacokinetic model has been established. The aims of this study were to evaluate the population pharmacokinetics of imipenem in critically ill patients with hospital-acquired pneumonia (HAP) and to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) using EUCAST data. A two-compartment model based on a data set of 19 subjects was employed. Various dosage regimens at 0.5-h and 3-h infusion rates and as continuous infusion were evaluated against the pharmacodynamic targets of 20%fT>MIC, 40%fT>MIC and 100%fT>MIC. For the target of 40%fT>MIC, all 0.5-h infusion regimens achieved optimal exposures (CFR ≥ 90%) against Escherichia coli and Staphylococcus aureus, with nearly optimal exposure against Klebsiella pneumoniae (CFR ≥ 89.4%). The 3-h infusions and continuous infusion exceeded 97% CFR against all pathogens with the exception of Pseudomonas aeruginosa and Acinetobacter spp., where the maximum CFRs were 85.5% and 88.4%, respectively. For the 100%fT>MIC target, only continuous infusion was associated with nearly optimal exposures. Higher PTAs for the targets of 40%fT>MIC and 100%fT>MIC were achieved with 3-h infusions and continuous infusion in comparison with 0.5-h infusions; however, continuous infusion carries a risk of not reaching the MIC of less susceptible pathogens in a higher proportion of patients. In critically ill patients with HAP with risk factors for Gram-negative non-fermenting bacteria, maximum doses administered as extended infusions may be necessary.