title: Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance?
abstract: BACKGROUND
  The aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on piperacillin pharmacokinetic/pharmacodynamic (PK/PD) target attainment (time above MIC (fT>MIC)) in critically ill patients with sepsis receiving intermittent dosing.
  
  
  METHODS
  To be eligible for enrolment, critically ill patients with sepsis had to be receiving piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood samples were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CLCR). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT>MIC was calculated for varying MIC and CLCR values.
  
  
  RESULTS
  In total, 48 patients provided data. Increasing CLCR values were associated with lower trough plasma piperacillin concentrations (P < 0.01), such that with an MIC of 16 mg/L, 100% fT>MIC would be achieved in only one-third (n = 16) of patients. Mean piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CLCR (r = 0.58, P < 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% fT>MIC, was noted with increasing CLCR measures.
  
  
  CONCLUSIONS
  Standard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CLCR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.
authors: Department of Intensive Care and Hyperbaric Medicine, The Alfred Hospital, Commercial Road, Melbourne, Victoria, 3181, Australia. a.udy@alfred.org.au.
authors: Andrew A
authors: AA
authors: Udy
authors: Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Butterfield Street, Brisbane, Queensland, 4029, Australia. j.lipman@uq.edu.au.|Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Butterfield Street, Brisbane, Queensland, 4029, Australia. j.lipman@uq.edu.au.
authors: Jeffrey
authors: J
authors: Lipman
authors: Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Butterfield Street, Brisbane, Queensland, 4029, Australia. paul.jarrett@health.qld.gov.au.
authors: Paul
authors: P
authors: Jarrett
authors: Statistics Unit, QIMR Berghofer Medical Research Institute, Herston Road, Brisbane, Queensland, 4029, Australia. Kerenaftali.Klein@qimrberghofer.edu.au.
authors: Kerenaftali
authors: K
authors: Klein
authors: Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Butterfield Street, Brisbane, Queensland, 4029, Australia. s.wallis@uq.edu.au.
authors: Steven C
authors: SC
authors: Wallis
authors: Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Royal Parade, Melbourne, Victoria, 3052, Australia. Kashyap.Patel@monash.edu.
authors: Kashyap
authors: K
authors: Patel
authors: Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Royal Parade, Melbourne, Victoria, 3052, Australia. Carl.Kirkpatrick@monash.edu.
authors: Carl M J
authors: CM
authors: Kirkpatrick
authors: Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Butterfield Street, Brisbane, Queensland, 4029, Australia. peter.kruger@health.qld.gov.au.|Department of Intensive Care Medicine, Princess Alexandra Hospital, Ipswich Road, Brisbane, Queensland, 4102, Australia. peter.kruger@health.qld.gov.au.
authors: Peter S
authors: PS
authors: Kruger
authors: Department of Infectious Diseases, Royal Brisbane and Women's Hospital, Butterfield Street, Brisbane, Queensland, Australia. david.antibiotics@gmail.com.|Centre for Clinical Research, The University of Queensland, Butterfield Street, Brisbane, Queensland, 4029, Australia. david.antibiotics@gmail.com.
authors: David L
authors: DL
authors: Paterson
authors: School of Pharmacy and Medical Sciences, University of South Australia, North Terrace, Adelaide, South Australia, 5000, Australia. m.roberts@uq.edu.au.
authors: Michael S
authors: MS
authors: Roberts
authors: Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Butterfield Street, Brisbane, Queensland, 4029, Australia. j.roberts2@uq.edu.au.|Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Butterfield Street, Brisbane, Queensland, 4029, Australia. j.roberts2@uq.edu.au.
authors: Jason A
authors: JA
authors: Roberts
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D003404:Creatinine / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D016638:Critical Illness / Q000628:therapy*; D005260:Female; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D010878:Piperacillin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D017582:Renal Replacement Therapy / Q000706:statistics & numerical data*
chemical_list: D000900:Anti-Bacterial Agents; D003404:Creatinine; D010878:Piperacillin
references: Clin Pharmacokinet. 2010;49(1):1-16
references: 20000886
references: Anesth Analg. 2010 Dec;111(6):1505-10
references: 21048095
references: J Antimicrob Chemother. 2005 May;55(5):601-7
references: 15772142
references: Anaesth Intensive Care. 2011 Nov;39(6):999-1000
references: 22165348
references: Int J Antimicrob Agents. 2012 Apr;39(4):311-6
references: 22386743
references: Clin Infect Dis. 2014 Apr;58(8):1072-83
references: 24429437
references: Curr Pharm Biotechnol. 2011 Dec;12(12):1991-5
references: 21554219
references: Crit Care. 2013;17(3):R84
references: 23642005
references: Int J Antimicrob Agents. 2010 Feb;35(2):156-63
references: 20018492
references: Crit Care Med. 2014 Mar;42(3):520-7
references: 24201175
references: Intensive Care Med. 2013 Feb;39(2):165-228
references: 23361625
references: Int J Antimicrob Agents. 2008 Apr;31(4):345-51
references: 18313273
references: Antimicrob Agents Chemother. 2007 May;51(5):1725-30
references: 17307978
references: Nat Rev Nephrol. 2011 Sep;7(9):539-43
references: 21769107
references: Chest. 2012 Jul;142(1):30-9
references: 22194591
references: Clin Infect Dis. 1998 Jan;26(1):1-10; quiz 11-2
references: 9455502
references: J Crit Care. 2013 Oct;28(5):695-700
references: 23683557
references: Int J Antimicrob Agents. 2012 May;39(5):420-3
references: 22386742
references: Diagn Microbiol Infect Dis. 2011 Mar;69(3):291-306
references: 21353957
references: Crit Care. 2011;15(1):R49
references: 21291554
references: Int J Antimicrob Agents. 2009 Dec;34(6):523-8
references: 19748767
references: Chest. 1992 Jun;101(6):1644-55
references: 1303622
references: Intensive Care Med. 2013 Dec;39(12):2070-82
references: 24045886
references: BMC Nephrol. 2013;14:250
references: 24225349
references: BMC Anesthesiol. 2011 Feb 20;11:3
references: 21333028
references: Crit Care Med. 2013 Feb;41(2):489-95
references: 23263583
references: Antimicrob Agents Chemother. 2010 Jan;54(1):460-5
references: 19858253
references: J Antimicrob Chemother. 2001 Apr;47(4):421-9
references: 11266414
references: Nutr Diabetes. 2014 Jun 23;4:e119
references: 24956136
references: Intensive Care Med. 2013 Jul;39(7):1247-52
references: 23604132
references: Ann Pharmacother. 2012 Jul-Aug;46(7-8):952-9
references: 22693271
references: Antimicrob Agents Chemother. 2012 Dec;56(12):6343-8
references: 23045356
references: BMC Nephrol. 2012;13:124
references: 23013403
references: Clin Pharmacol Ther. 1979 Jul;26(1):41-53
references: 445961
references: Crit Care Med. 2012 Apr;40(4):1329-32
references: 22425824
references: Crit Care. 2011;15(3):R139
references: 21651804
references: Crit Care. 2013;17(1):R35
references: 23448570
references: Comput Methods Programs Biomed. 1999 Apr;59(1):19-29
references: 10215174
references: Anaesth Intensive Care. 2011 Nov;39(6):1022-9
references: 22165353
references: Crit Care Med. 2006 Jun;34(6):1589-96
references: 16625125
references: Nat Rev Microbiol. 2004 Apr;2(4):289-300
references: 15031728
references: Int J Antimicrob Agents. 2013 Jul;42(1):90-3
references: 23590897
references: Br J Clin Pharmacol. 2007 May;63(5):583-94
references: 17166188