title: Optimising meropenem dosing in critically ill Australian Indigenous patients with severe sepsis.
abstract: Currently there are no pharmacokinetic (PK) data to guide antibiotic dosing in critically ill Australian Indigenous patients with severe sepsis. This study aimed to determine whether the population pharmacokinetics of meropenem were different between critically ill Australian Indigenous and critically ill Caucasian patients. Serial plasma and urine samples as well as clinical and demographic data were collected over two dosing intervals from critically ill Australian Indigenous patients. Plasma meropenem concentrations were assayed by validated chromatography. Concentration-time data were analysed with data from a previous PK study in critically ill Caucasian patients using Pmetrics. The population PK model was subsequently used for Monte Carlo dosing simulations to describe optimal doses for these patients. Six Indigenous and five Caucasian subjects were included. A two-compartment model described the data adequately, with meropenem clearance and volume of distribution of the central compartment described by creatinine clearance (CLCr) and patient weight, respectively. Patient ethnicity was not supported as a covariate in the final model. Significant differences were observed for meropenem clearance between the Indigenous and Caucasian groups [median 11.0 (range 3.0-14.1) L/h vs. 17.4 (4.3-30.3) L/h, respectively; P <0.01]. Standard dosing regimens (1 g intravenous every 8 h as a 30-min infusion) consistently achieved target exposures at the minimum inhibitory concentration breakpoint in the absence of augmented renal clearance. No significant interethnic differences in meropenem pharmacokinetics between the Indigenous and Caucasian groups were detected and CLCrwas found to be the strongest determinant of appropriate dosing regimens.
authors: Burns, Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Department of Intensive Care Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia; Pharmacy Department, Alice Springs Hospital, Alice Springs, Northern Territory, Australia. Electronic address: d.tsai@uq.edu.au.
authors: Danny
authors: D
authors: Tsai
authors: Department of Intensive Care Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia.
authors: Penelope
authors: P
authors: Stewart
authors: Department of Intensive Care Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia.
authors: Rajendra
authors: R
authors: Goud
authors: Emergency Department, Alice Springs Hospital, Alice Springs, Northern Territory, Australia.
authors: Stephen
authors: S
authors: Gourley
authors: Department of Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia; Department of Infectious Diseases, The Northern Hospital, Epping, Melbourne, Victoria, Australia.
authors: Saliya
authors: S
authors: Hewagama
authors: Department of Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia; Monash Infectious Diseases, Monash Health, Clayton, Melbourne, Victoria, Australia.
authors: Sushena
authors: S
authors: Krishnaswamy
authors: Burns, Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors: Steven C
authors: SC
authors: Wallis
authors: Burns, Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Department of Intensive Care Medicine, The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors: Jeffrey
authors: J
authors: Lipman
authors: Burns, Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Department of Intensive Care Medicine, The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors: Jason A
authors: JA
authors: Roberts
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001315:Australia; D016638:Critical Illness; D005260:Female; D006801:Humans; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D010949:Plasma / Q000737:chemistry; D044382:Population Groups; D011446:Prospective Studies; D018805:Sepsis / Q000188:drug therapy*; D013845:Thienamycins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013997:Time Factors; D014556:Urine / Q000737:chemistry; D044465:White People; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem
keywords: Critically ill; Pharmacokinetics; Severe sepsis; β-Lactam