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Optimised dosing of vancomycin in critically ill Indigenous Australian patients with severe sepsis
D Tsai1, P C Stewart, S Hewagama2
1Burns, Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland; Centre for Remote Health, Flinders University, Adelaide, South Australia; Pharmacy Department, Alice Springs Hospital, Alice Springs, Northern Territory.
Abstract:
Vancomycin is a commonly used antibiotic due to the high burden of methicillin-resistant Staphylococcus aureus infections. This study aimed to describe the pharmacokinetics (PK) of vancomycin in Australian Indigenous patients with severe sepsis, and advise an optimal dosing strategy. A population PK study was conducted in a remote Australian intensive care unit (ICU). Serial plasma samples were collected over one to two dosing intervals and assayed by validated chromatography. Concentration-time data collected were analysed using Pmetrics® software. The final population PK model was then used for Monte Carlo dosing simulations to determine optimal loading and intermittent maintenance doses. Fifteen Indigenous subjects were included for analysis with a median (interquartile range, IQR) age, weight and creatinine clearance (CrCL) of 43 (34-46) years, 73 (66-104) kg and 99 (56-139) ml/minute respectively. A two-compartment model described the data adequately. Vancomycin clearance (CL) and volume of distribution of the central compartment (Vc) were described by CrCL and patient weight respectively. Median (IQR) CL, Vc, distribution rate constants from central to peripheral, and from peripheral to central compartments were 4.6 (3.8-5.6) litres per hour, 25.4 (16.1-31.3) litres, 0.46 (0.28-0.52)/hour and 0.25 (0.12-0.37)/hour respectively. No significant interethnic PK differences were observed in comparison to published data. Therapeutic loading doses were significantly dependent on both weight and CrCL, whereas maintenance doses were dependent on CrCL. In the absence of severe renal impairment, initiation of maintenance dose eight hours post-loading dose achieved higher probability of target attainment at 24 hours. This is the first report of vancomycin PK in this patient group.
Insights
This study details vancomycin pharmacokinetics in Australian Indigenous patients with severe sepsis. Optimal dosing strategies were identified, showing no significant interethnic differences and guiding weight and kidney function-based adjustments for better treatment outcomes.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Infectious Diseases
- Critical Care Medicine
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a significant health burden, necessitating effective antibiotic use.
- Vancomycin is a critical antibiotic for treating MRSA infections, but optimal dosing requires understanding patient-specific factors.
- Limited pharmacokinetic data exists for vancomycin in specific populations, such as Australian Indigenous patients with severe sepsis.
Purpose of the Study:
- To characterize the population pharmacokinetics (PK) of vancomycin in Australian Indigenous patients experiencing severe sepsis.
- To develop and propose an optimized vancomycin dosing strategy for this patient group.
- To compare PK parameters with existing data, investigating potential interethnic differences.
Main Methods:
- A prospective population PK study was conducted in a remote Australian intensive care unit (ICU).
- Serial plasma vancomycin concentrations were measured using validated chromatography.
- Data were analyzed using Pmetrics® software, followed by Monte Carlo simulations for dosing optimization.
Main Results:
- Fifteen Indigenous subjects were analyzed, with median age, weight, and creatinine clearance (CrCL) of 43 years, 73 kg, and 99 ml/minute, respectively.
- A two-compartment model adequately described vancomycin PK, with clearance (CL) and central volume of distribution (Vc) influenced by CrCL and weight.
- No significant interethnic PK differences were observed compared to published data; loading and maintenance doses were dependent on weight and CrCL.
Conclusions:
- This study provides the first report on vancomycin PK in Australian Indigenous patients with severe sepsis.
- Optimal vancomycin dosing is significantly influenced by patient weight and renal function (CrCL).
- Initiating maintenance doses 8 hours post-loading dose improves the probability of achieving therapeutic targets within 24 hours, especially in patients without severe renal impairment.
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