title: Population pharmacokinetics and probability of target attainment of meropenem in critically ill patients.
abstract: OBJECTIVE
  Patients admitted to intensive care unit (ICU) with Klebsiella pneumoniae infections are characterized by high mortality. The aims of the present study were to investigate the population pharmacokinetics parameters and to assess the probability of target attainment of meropenem in critically ill patients to provide information for more effective regimens.
  
  
  METHODS
  Twenty-seven consecutive patients were included in the study. Meropenem was administered as 3-h intravenous (i.v.) infusions at doses of 1-2 g every 8 or 12 h. Meropenem plasma concentrations were measured by a high-performance liquid chromatography (HPLC) method, and a population pharmacokinetics analysis was performed using NONMEM software. Meropenem plasma disposition was simulated for extended (3 h; 5 h) or continuous i.v. infusions, and the following parameters were calculated: time during which free drug concentrations were above minimum inhibitory concentration (MIC) (fT > MIC), free minimum plasma concentrations above 4× MIC (fCmin > 4× MIC), probability of target attainment (PTA), and cumulative fraction of response (CFR).
  
  
  RESULTS
  Gender and severity of sepsis affected meropenem clearance, whose typical population values ranged from 6.22 up to 12.04 L/h (mean ± standard deviation (SD) value, 9.38 ± 4.47 L/h). Mean C min value was 7.90 ± 7.91 mg/L, suggesting a high interindividual variability. The simulation confirmed that 88 and 97.5 % of patients achieved effective C min > 4× MIC values after 3- and 5-h i.v. infusions of meropenem 2 g × 3/day, respectively. On the contrary, the same total daily doses reached the target C min > 4× MIC values in 100 % of patients when administered as continuous i.v. infusions.
  
  
  CONCLUSIONS
  Several factors may influence meropenem pharmacokinetics in ICU patients. Continuous i.v. infusions of meropenem seem to be more effective than standard regimens to achieve optimal therapeutic targets.
authors.affiliation: Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Viale Benedetto XV, n. 2, 16132, Genoa, Italy. francesca.mattioli@unige.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mattioli
authors.affiliation: Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Viale Benedetto XV, n. 2, 16132, Genoa, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Fucile
authors.affiliation: Infectious Diseases Clinics, IRCCS A.O.U San Martino-IST, University of Genoa, Largo R. Benzi, n. 10, 16132, Genoa, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Del Bono
authors.affiliation: Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Viale Benedetto XV, n. 2, 16132, Genoa, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Marini
authors.affiliation: Infectious Diseases Clinics, IRCCS A.O.U San Martino-IST, University of Genoa, Largo R. Benzi, n. 10, 16132, Genoa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Parisini
authors.affiliation: Anesthesia and Intensive Care, Department Surgical Sciences and Integrated Diagnostics, IRCCS A.O.U San Martino-IST, University of Genoa, Largo R. Benzi, n. 10, 16132, Genoa, Italy.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Molin
authors.affiliation: Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Viale Benedetto XV, n. 2, 16132, Genoa, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Zuccoli
authors.affiliation: Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Viale Benedetto XV, n. 2, 16132, Genoa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Milano
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, n.10, 56126, Pisa, Italy.
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.affiliation: Section of Microbiology-DISC, University of Genoa, Largo R. Benzi, n. 10, 16132, Genoa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Marchese
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, n.10, 56126, Pisa, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Polillo
authors.affiliation: Infectious Diseases Clinics, IRCCS A.O.U San Martino-IST, University of Genoa, Largo R. Benzi, n. 10, 16132, Genoa, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Viscoli
authors.affiliation: Anesthesia and Intensive Care, Department Surgical Sciences and Integrated Diagnostics, IRCCS A.O.U San Martino-IST, University of Genoa, Largo R. Benzi, n. 10, 16132, Genoa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pelosi
authors.affiliation: Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Viale Benedetto XV, n. 2, 16132, Genoa, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Martelli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, n.10, 56126, Pisa, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Di Paolo
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016638:Critical Illness; D003428:Cross Infection / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007710:Klebsiella Infections / Q000188:drug therapy / Q000378:metabolism*; D007711:Klebsiella pneumoniae; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D008954:Models, Biological; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism*; D013845:Thienamycins / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem
keywords: Critically ill patients; Meropenem; Population pharmacokinetic; Therapeutic drug monitoring