title: Association between augmented renal clearance and clinical outcomes in patients receiving β-lactam antibiotic therapy by continuous or intermittent infusion: a nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial.
abstract: Augmented renal clearance (ARC) is known to influence β-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive β-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CLCr) measured on Day 1 was used to identify ARC, defined as CLCr≥ 130 mL/min. Patients receiving any form of renal replacement therapy were excluded. Primary outcome was alive ICU-free days at Day 28. Secondary outcomes included 90-day mortality and clinical cure at 14 days following antibiotic cessation. A total of 254 patients were included, among which 45 (17.7%) manifested ARC [median (IQR) CLCr165 (144-198) mL/min]. ARC patients were younger (P <0.001), more commonly male (P = 0.04) and had less organ dysfunction (P <0.001). There was no difference in ICU-free days at Day 28 [ARC, 21 (12-24) days; no ARC, 21 (11-25) days; P = 0.89], although clinical cure was significantly greater in the unadjusted analysis in those manifesting ARC [33/45 (73.3%) vs. 115/209 (55.0%) P = 0.02]. This was attenuated in the multivariable analysis. No difference was noted in 90-day mortality. There were no statistically significant differences in clinical outcomes in ARC patients according to the dosing strategy employed. In this substudy of a large clinical trial of β-lactam antibiotics in severe sepsis, ARC was not associated with any differences in outcomes, regardless of dosing strategy.
authors.affiliation: Department of Intensive Care and Hyperbaric Medicine, The Alfred Hospital, Melbourne, VIC, Australia; Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia. Electronic address: a.udy@alfred.org.au.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Udy
authors.affiliation: Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Dulhunty
authors.affiliation: Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia; Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
authors.affiliation: Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia; Department of Infectious Diseases, John Hunter Hospital, Newcastle, NSW, Australia.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Davis
authors.affiliation: Department of Intensive Care, Royal Perth Hospital, Perth, WA, Australia; School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.
authors.forename: Steven A R
authors.initials: SAR
authors.lastname: Webb
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; Department of Intensive Care, Austin Hospital, Melbourne, VIC, Australia.
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Bellomo
authors.affiliation: Prince of Wales Hospital, Hong Kong SAR; Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Charles
authors.initials: C
authors.lastname: Gomersall
authors.affiliation: Department of Intensive Care, Blacktown Hospital, Blacktown, NSW, Australia.
authors.forename: Charudatt
authors.initials: C
authors.lastname: Shirwadkar
authors.affiliation: Department of Intensive Care, Austin Hospital, Melbourne, VIC, Australia.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Eastwood
authors.affiliation: Critical Care and Trauma Division, The George Institute for Global Health, Sydney, NSW, Australia; St George Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Myburgh
authors.affiliation: Infectious Diseases Unit, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; The University of Queensland Centre for Clinical Research, Brisbane, QLD, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Paterson
authors.affiliation: Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Therese
authors.initials: T
authors.lastname: Starr
authors.affiliation: Clinical Trials and Biostatistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Sanjoy K
authors.initials: SK
authors.lastname: Paul
authors.affiliation: Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D015331:Cohort Studies; D003404:Creatinine / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology*; D008875:Middle Aged; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology; D016896:Treatment Outcome; D047090:beta-Lactams / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D003404:Creatinine
keywords: Augmented renal clearance; Critical illness; Sepsis; β-Lactams