title: Meropenem dosing requirements against Enterobacteriaceae in critically ill patients: influence of renal function, geographical area and presence of extended-spectrum β-lactamases.
abstract: The aim of this study was the evaluation of the influence of the susceptibility patterns of Escherichia coli and Klebsiella pneumoniae isolates, specifically the presence of extended-spectrum β-lactamases and the geographical area (Europe and USA), on the meropenem dosing requirements in critically ill patients with different degrees of renal function by estimation of the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Additionally, estimation of the PK/PD breakpoints according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) approach was also an objective. Six dosing regimens were evaluated: 0.5 g, 1 g and 2 g every 8 h given as 0.5-h or 3-h infusions. Pharmacokinetic data were obtained from the literature, and susceptibility data to meropenem for E. coli and K. pneumoniae were collected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) surveillance study. For the same dose level, the 3-h infusion provided a probability of target attainment (PTA) ≥90 % for minimum inhibitory concentration (MIC) values up to two-fold dilution higher than those obtained with the 0.5-h infusion. For E. coli, the cumulative fraction of response (CFR) was 100 % in most cases, and neither the dose nor the infusion length nor the geographical area significantly affected the probability to reach the target. With regards to K. pneumoniae, the CFR increased when increasing the dose and decreasing the creatinine clearance (CLCR). The CFR for Spanish and USA strains was higher than that calculated for European strains. Meropenem PK/PD breakpoints are dependent on the dose, infusion length and CLCR, ranging from 2 to 32 mg/L. Based on our results, meropenem administered as a extended infusion is the best option to treat infections due to E. coli and K. pneumoniae.
authors.affiliation: Pharmacokinetics, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.|Centro de Investigación Lascaray Ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Isla
authors.affiliation: Microbiology Service, Hospital Universitario de Álava (HUA), Servicio Vasco de Salud Osakidetza, Vitoria-Gasteiz, Spain.|Instituto de Investigación Sanitaria de Álava (BIOARABA), Servicio Vasco de Salud Osakidetza, Vitoria-Gasteiz, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Canut
authors.affiliation: Microbiology Service, Hospital Clínico Universitario, Zaragoza, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Arribas
authors.affiliation: Pharmacokinetics, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.|Centro de Investigación Lascaray Ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Asín-Prieto
authors.affiliation: Pharmacokinetics, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain. alicia.rodriguez@ehu.eus.|Centro de Investigación Lascaray Ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain. alicia.rodriguez@ehu.eus.
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez-Gascón
mesh_terms: D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016638:Critical Illness / Q000628:therapy*; D024881:Drug Resistance, Bacterial; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000235:genetics; D004756:Enterobacteriaceae Infections / Q000188:drug therapy* / Q000382:microbiology*; D005060:Europe; D005260:Female; D005843:Geography; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D012307:Risk Factors; D013845:Thienamycins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014481:United States; D001618:beta-Lactamases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D001618:beta-Lactamases; D000077731:Meropenem