title: Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration.
abstract: Fluconazole is a widely used antifungal agent in critically ill patients. It is predominantly (60-80%) excreted unchanged in urine. Sustained low-efficiency diafiltration (SLED-f) is increasingly being utilised in critically ill patients because of its practical advantages over continuous renal replacement therapy. To date, the effect of SLED-f on fluconazole pharmacokinetics and dosing has not been studied. The objective of this study was to describe the pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving SLED-f and to compare this with other forms of renal replacement therapy. Serial blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from an arterial catheter before and after SLED-f from three patients during one session. Fluconazole concentrations were measured using a validated chromatography method. Median clearance (CL) and 24-h area under the concentration-time curve (AUC0-24) were 2.1L/h and 152 mg·h/L, respectively, whilst receiving SLED-f. Moreover, 72% of fluconazole was cleared by a single SLED-f session (6h) compared with previous reports of 33-38% clearance by a 4-h intermittent haemodialysis session. CL and AUC0-24 were comparable with previous observations in a pre-dilution mode of continuous venovenous haemodiafiltration. The observed rebound concentration of fluconazole post SLED-f was <2%. Although a definitive dosing recommendation is not possible due to the small patient number, it is clear that doses >200mg daily are likely to be required to achieve the PK/PD target for common pathogens because of significant fluconazole clearance by SLED-f.
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia; Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia. Electronic address: mahi716@yahoo.com.
authors.forename: Mahipal G
authors.initials: MG
authors.lastname: Sinnollareddy
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia; Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Roberts
authors.affiliation: Burns, Trauma and Critical Care Research Centre, 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: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia; Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Robertson
authors.affiliation: Department of Intensive Care Medicine, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Peake
authors.affiliation: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia; Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000628:therapy*; D000368:Aged; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D015725:Fluconazole / Q000493:pharmacokinetics*; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies; D017582:Renal Replacement Therapy
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole
keywords: Critically ill patients; Extended daily diafiltration; Fluconazole; Pharmacokinetics; Renal replacement therapy; Sustained low-efficiency diafiltration