title: Dosing regimen of meropenem for adults with severe burns: a population pharmacokinetic study with Monte Carlo simulations.
abstract: OBJECTIVE
  To develop a population model to describe the pharmacokinetics (PK) of intravenous meropenem in adult patients with severe burns and investigate potential relationships between dosage regimens and antimicrobial efficacy.
  
  
  METHODS
  A dose of 1 g every 8 h was administered to adult patients with total body surface area burns of ≥15%. Doses for subsequent courses were determined using results from the initial course and the patient's clinical condition. Five plasma meropenem concentrations were typically measured over the dosage interval on one to four occasions. An open, two-compartment PK model was fitted to the meropenem concentrations using NONMEM and the effect of covariates on meropenem PK was investigated. Monte Carlo simulations investigated dosage regimens to achieve a target T>MIC for ≥40%, ≥60% or ≥80% of the dose interval.
  
  
  RESULTS
  Data comprised 113 meropenem concentration measurements from 20 dosage intervals in 12 patients. The parameters were CL (L/h) = 0.196 L/h/kg × [1 - 0.023 × (age - 46)] × [1 - 0.049 × (albumin - 15)], V1 = 0.273 L/kg × [1 - 0.049 × (albumin - 15)], Q = 0.199 L/h/kg and V2 = 0.309 L/kg × [1 - 0.049 × (albumin - 15)]. For a target of ≥80% T>MIC, the breakpoint was 8 mg/L for doses of 1 g every 4 h and 2 g every 8 h given over 3 h, but only 4 mg/L if given over 5 min.
  
  
  CONCLUSIONS
  Although 1 g 8 hourly should be effective against Escherichia coli and CoNS, higher doses, ideally with a longer infusion time, would be more appropriate for empirical therapy, mixed infections and bacteria with MIC values ≥4 mg/L.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK Division of Pharmacy and Pharmaceutics, Department of Engineering, Miguel Hernandez University, Alicante, Spain.
authors.forename: Amelia
authors.initials: A
authors.lastname: Ramon-Lopez
authors.affiliation: Pharmacy Department, Queen Victoria Hospital NHS Foundation Trust, East Grinstead, UK jane.allen4@nhs.net.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Allen
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK Pharmacy Department, Western Infirmary, Glasgow, UK.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Thomson
authors.affiliation: Burns Centre, Queen Victoria Hospital NHS Foundation Trust, East Grinstead, UK.
authors.forename: Bajlit S
authors.initials: BS
authors.lastname: Dheansa
authors.affiliation: School of Pharmacy & Biomolecular Sciences, University of Brighton, Brighton, UK.
authors.forename: S Elizabeth
authors.initials: SE
authors.lastname: James
authors.affiliation: School of Pharmacy & Biomolecular Sciences, University of Brighton, Brighton, UK.
authors.forename: Geoff W
authors.initials: GW
authors.lastname: Hanlon
authors.affiliation: Department of Microbiology, Surrey and Sussex Healthcare NHS Trust, Redhill, UK.
authors.forename: Bruce
authors.initials: B
authors.lastname: Stewart
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: J Graham
authors.initials: JG
authors.lastname: Davies
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001424:Bacterial Infections / Q000188:drug therapy*; D002056:Burns / Q000150:complications*; D005260:Female; D006801:Humans; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D009010:Monte Carlo Method; D010949:Plasma / Q000737:chemistry; D013845:Thienamycins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem
keywords: PK; antibiotics; carbapenems; intensive care; pharmacodynamics