title: Meropenem population pharmacokinetics in critically ill patients with septic shock and continuous renal replacement therapy: influence of residual diuresis on dose requirements.
abstract: Meropenem dosing in critically ill patients with septic shock and continuous renal replacement therapy (CRRT) is complex, with the recommended maintenance doses being 500 mg to 1,000 mg every 8 h (q8h) to every 12 h. This multicenter study aimed to describe the pharmacokinetics (PKs) of meropenem in this population to identify the sources of PK variability and to evaluate different dosing regimens to develop recommendations based on clinical parameters. Thirty patients with septic shock and CRRT receiving meropenem were enrolled (153 plasma samples were tested). A population PK model was developed with data from 24 patients and subsequently validated with data from 6 patients using NONMEM software (v.7.3). The final model was characterized by CL = 3.68 + 0.22 · (residual diuresis/100) and V = 33.00 · (weight/73)(2.07), where CL is total body clearance (in liters per hour), residual diuresis is the volume of residual diuresis (in milliliters per 24 h), and V is the apparent volume of distribution (in liters). CRRT intensity was not identified to be a CL modifier. Monte Carlo simulations showed that to maintain concentrations of the unbound fraction (fu ) of drug above the MIC of the bacteria for 40% of dosing interval T (referred to as 40% of the ƒ uT >MIC), a meropenem dose of 500 mg q8h as a bolus over 30 min would be sufficient regardless of the residual diuresis. If 100% of the ƒ uT >MIC was chosen as the target, oligoanuric patients would require 500 mg q8h as a bolus over 30 min for the treatment of susceptible bacteria (MIC < 2 mg/liter), while patients with preserved diuresis would require the same dose given as an infusion over 3 h. If bacteria with MICs close to the resistance breakpoint (2 to 4 mg/liter) were to be treated with meropenem, a dose of 500 mg every 6 h would be necessary: a bolus over 30 min for oligoanuric patients and an infusion over 3 h for patients with preserved diuresis. Our results suggest that residual diuresis may be an easy and inexpensive tool to help with titration of the meropenem dose and infusion time in this challenging population.
authors.affiliation: Fundació Privada Clínic per la Recerca Biomèdica, Barcelona, Spain Critical Care Department, Sabadell Hospital, University Institute Parc Taulí-Universitat Autònoma de Barcelona (UAB), Sabadell, Spain Universitat de Barcelona (UB), Barcelona, Spain marta.ulldemolins@gmail.com DSOY@clinic.ub.es.
authors.forename: Marta
authors.initials: M
authors.lastname: Ulldemolins
authors.affiliation: Fundació Privada Clínic per la Recerca Biomèdica, Barcelona, Spain Universitat de Barcelona (UB), Barcelona, Spain Pharmacy Department, Hospital Clínic de Barcelona, Barcelona, Spain Centro de Investigación Biomédica En Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain marta.ulldemolins@gmail.com DSOY@clinic.ub.es.
authors.forename: Dolors
authors.initials: D
authors.lastname: Soy
authors.affiliation: Nursing Department, Universitat Rovira i Virgili (URV), Tarragona, Spain Critical Care Department, Joan XXIII University Hospital, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Tarragona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Llaurado-Serra
authors.affiliation: Critical Care Department, Sabadell Hospital, University Institute Parc Taulí-Universitat Autònoma de Barcelona (UAB), Sabadell, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Vaquer
authors.affiliation: Universitat de Barcelona (UB), Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Medical Critical Care Unit, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Castro
authors.affiliation: Centro de Investigación Biomédica En Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain Critical Care Department, Joan XXIII University Hospital, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Tarragona, Spain.
authors.forename: Alejandro H
authors.initials: AH
authors.lastname: Rodríguez
authors.affiliation: Department of Clinical Pharmacology, Sabadell Hospital, Institut Universitari Parc Taulí-Universitat Autònoma de Barcelona (UAB), Sabadell, Spain Pharmacology, Therapeutics and Toxicology Department, Universitat Autònoma de Barcelona (UAB), Sabadell, Spain.
authors.forename: Caridad
authors.initials: C
authors.lastname: Pontes
authors.affiliation: Universitat de Barcelona (UB), Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Department of Clinical Pharmacology, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Calvo
authors.affiliation: Fundació Privada Clínic per la Recerca Biomèdica, Barcelona, Spain Universitat de Barcelona (UB), Barcelona, Spain Centro de Investigación Biomédica En Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Respiratory Critical Care Unit, Pneumology Department, Institut Clínic del Tòrax, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Torres
authors.affiliation: Critical Care Department, Sabadell Hospital, University Institute Parc Taulí-Universitat Autònoma de Barcelona (UAB), Sabadell, Spain Centro de Investigación Biomédica En Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain Multidisciplinary Intensive Care Research Organization (MICRO), Critical Care Department, St. James University Hospital, Trinity Centre for Health Sciences, Dublin, Ireland.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Martín-Loeches
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016638:Critical Illness; D005260:Female; D006801:Humans; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011446:Prospective Studies; D017582:Renal Replacement Therapy; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism* / Q000628:therapy; D013845:Thienamycins / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem