Dosing regimen of meropenem for adults with severe burns: A population pharmacokinetic study with Monte Carlo simulations

Abstract

Objectives: 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. Patients and 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 PKwas 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 parameterswere 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.