Tsai, Danny

Zam B B

Tongs C

Chiong F

Sajiv, Cherian

Pawar B

Ashok A

Cooper, Brynley

Tong S Y C

Janson, Sonja

Wallis S C

Roberts J A

Parker S L

2023-08-02

OBJECTIVES: To describe the total and unbound population pharmacokinetics of a 2 g three-times-weekly post-dialysis ceftriaxone regimen in Indigenous Australian patients requiring hemodialysis. METHODS: A pharmacokinetic study was carried out in the dialysis unit of a remote Australian hospital. Adult Indigenous patients on intermittent hemodialysis (using a high-flux dialyzer) and treated with a 2 g three-times-weekly ceftriaxone regimen were recruited. Plasma samples were serially collected over two dosing intervals and assayed using validated methodology. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics in R. The probability of pharmacokinetic/pharmacodynamic target attainment (unbound trough concentrations ≥1 mg/L) and toxicity [trough concentrations (total)  ≥100 mg/L] were simulated for various dosing strategies. RESULTS: Total and unbound concentrations were measured in 122 plasma samples collected from 16 patients (13 female) with median age 57 years. A two-compartment model including protein-binding adequately described the data, with serum bilirubin concentrations associated (inversely) with ceftriaxone clearance. The 2 g three-times-weekly regimen achieved 98% probability to maintain unbound ceftriaxone concentrations ≥1 mg/L for a serum bilirubin of 5 µmol/L. Incremental accumulation of ceftriaxone was observed in those with bilirubin concentrations >5 µmol/L. Three-times-weekly regimens were less probable to achieve toxic exposures compared with once-daily regimens. Ceftriaxone clearance was increased by >10-fold during dialysis. CONCLUSIONS: A novel 2 g three-times-weekly post-dialysis ceftriaxone regimen can be recommended for a bacterial infection with an MIC ≤1 mg/L. A 1 g three-times-weekly post-dialysis regimen is recommended for those with serum bilirubin ≥10 µmol/L. Administration of ceftriaxone during dialysis is not recommended.

Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.

UQ Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia.

Pharmacy Department, Alice Springs Hospital, Alice Springs, NT, Australia.

Pharmacy Department, Alfred Health, Melbourne, VIC, Australia.

Northern Territory Medical Program, College of Medicine and Public Health, Flinders University, Darwin, NT, Australia.

Department of Medicine, Alice Springs Hospital, Alice Springs, NT, Australia.

Department of Nephrology, Alice Springs Hospital, Alice Springs, NT, Australia.

Department of Infectious Diseases, Alfred Health, Melbourne, VIC, Australia.

Victorian Infectious Diseases Service, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.

Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.

Department of Infectious Diseases, Royal Darwin Hospital, Darwin, NT, Australia.

Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.

Department of Pharmacy, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.

Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, QLD, Australia.

Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France.

J Antimicrob Chemother . 2023 Aug 2;78(8):1963-1973. doi: 10.1093/jac/dkad190.

0000-0002-7059-8808

0000-0002-1368-8356

0000-0002-2392-9854

0000-0001-6218-435X

0000-0002-6124-7475

https://pubmed.ncbi.nlm.nih.gov/37367723/?otool=iaurydwlib

https://hdl.handle.net/10137/12509

78

Adult

Humans

Female

Middle Aged

*Ceftriaxone/pharmacokinetics

*Anti-Bacterial Agents

Australian Aboriginal and Torres Strait Islander Peoples

Australia

Renal Dialysis

Bilirubin

Monte Carlo Method

Critical Illness

Microbial Sensitivity Tests

Validating a novel three-times-weekly post-hemodialysis ceftriaxone regimen in infected Indigenous Australian patients-a population pharmacokinetic study.

Journal Article

Publication