title: Total and unbound ceftriaxone pharmacokinetics in critically ill Australian Indigenous patients with severe sepsis.
abstract: In the absence of specific data to guide optimal dosing, this study aimed to describe the pharmacokinetics of ceftriaxone in severely septic Australian Indigenous patients and to assess achievement of the pharmacodynamic target of the regimens prescribed. A pharmacokinetic study was conducted in a remote hospital intensive care unit in patients receiving ceftriaxone dosing of 1 g every 12 h (q12h). Serial blood and urine samples were collected over one dosing interval on two consecutive days. Samples were assayed using a validated chromatography method for total and unbound concentrations. Concentration-time data collected were analysed with a non-compartmental approach. A total of 100 plasma samples were collected from five subjects. Ceftriaxone clearance, volume of distribution at steady-state, elimination half-life and elimination rate constant estimates were 0.9 (0.6-1.5) L/h, 11.2 (7.6-13.4) L, 9.5 (3.2-10.2) h and 0.07 (0.07-0.21) h-1, respectively. The unbound fraction of ceftriaxone ranged between 14% and 43%, with a higher unbound fraction present at higher total concentrations. The unbound concentrations at 720 min from the initiation of infusion for the first and second dosing intervals were 7.2 (4.8-10.7) mg/L and 7.8 (4.7-12.1) mg/L respectively, which exceeds the minimum inhibitory concentration of all typical target pathogens. In conclusion, the regimen of ceftriaxone 1 g q12h is adequate for critically ill Australian Indigenous patients with severe sepsis caused by non-resistant pathogens.
authors.affiliation: Burns, Trauma & 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.forename: Danny
authors.initials: D
authors.lastname: Tsai
authors.affiliation: Department of Intensive Care Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia.
authors.forename: Penelope
authors.initials: P
authors.lastname: Stewart
authors.affiliation: Department of Intensive Care Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Goud
authors.affiliation: Emergency Department, Alice Springs Hospital, Alice Springs, Northern Territory, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gourley
authors.affiliation: Department of Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia; Department of Infectious Diseases, The Northern Hospital, Epping, Melbourne, Victoria, Australia.
authors.forename: Saliya
authors.initials: S
authors.lastname: Hewagama
authors.affiliation: Department of Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia; Monash Infectious Diseases, Monash Health, Clayton, Melbourne, Victoria, Australia.
authors.forename: Sushena
authors.initials: S
authors.lastname: Krishnaswamy
authors.affiliation: Burns, Trauma & Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wallis
authors.affiliation: Burns, Trauma & Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Burns, Trauma & Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001315:Australia; D002443:Ceftriaxone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002845:Chromatography; D016638:Critical Illness; D006207:Half-Life; D006801:Humans; D007362:Intensive Care Units; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D044382:Population Groups; D011446:Prospective Studies; D011485:Protein Binding; D018805:Sepsis; D013997:Time Factors; D014556:Urine / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D002443:Ceftriaxone
keywords: Critically ill; Indigenous; Pharmacokinetics; Severe sepsis; β-Lactam