title: Is continuous infusion of imipenem always the best choice?
abstract: 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>MICand 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>MICtarget, only continuous infusion was associated with nearly optimal exposures. Higher PTAs for the targets of 40%fT>MICand 100%fT>MICwere 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, Palacký University in Olomouc, Hněvotínská 3, Olomouc 775 15, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Suchánková
authors.affiliation: Department of Anaesthesiology and Intensive Care, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, U Nemocnice 2, Prague 2 128 08, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Lipš
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, Palacký University in Olomouc, Hněvotínská 3, Olomouc 775 15, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Urbánek
authors.affiliation: Laboratory of Applied Pharmacokinetics and Bioinformatics, Division of Pediatric Infectious Diseases, University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Neely
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, Palacký University in Olomouc, Hněvotínská 3, Olomouc 775 15, Czech Republic. Electronic address: jan.strojil@upol.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Strojil
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016638:Critical Illness; D003428:Cross Infection / Q000188:drug therapy; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous / Q000379:methods; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D018410:Pneumonia, Bacterial / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D015378:Imipenem
keywords: Critically ill; Extended infusion; Monte Carlo simulation; Pharmacodynamics; Pharmacokinetics; Pneumonia