title: Effect of different renal function on antibacterial effects of piperacillin against Pseudomonas aeruginosa evaluated via the hollow-fibre infection model and mechanism-based modelling.
abstract: Pathophysiological changes in critically ill patients can cause severely altered pharmacokinetics and widely varying antibiotic exposures. The impact of altered pharmacokinetics on bacterial killing and resistance has not been characterized in the dynamic hollow-fibre in vitro infection model (HFIM).
  
  
  
  A clinical Pseudomonas aeruginosa isolate (piperacillin MIC 4 mg/L) was studied in the HFIM (inoculum ∼10(7) cfu/mL). Pharmacokinetic profiles of three piperacillin dosing regimens (4 g 8-, 6- and 4-hourly, 30 min intravenous infusion) as observed in critically ill patients with augmented renal clearance (ARC), normal renal function or impaired renal function (creatinine clearances of 250, 110 or 30 mL/min, respectively) were simulated over 7 days. The time courses of total and less-susceptible populations and MICs were determined. Mechanism-based modelling was performed in S-ADAPT.
  
  
  
  For all regimens with ARC and regimens with 8- or 6-hourly dosing with normal renal function, initial killing of ≤∼2 log10 was followed by regrowth to 10(8)-10(9) cfu/mL at 48 h. For 8- and 6-hourly dosing at normal renal function, the proportion of less-susceptible colonies increased ∼10-100-fold above those in ARC and control arms. Regimens achieving an fCmin of ≥5× MIC resulted in bacterial killing of 3-4 log10 without regrowth and suppressed less-susceptible populations to ≤∼2 log10. The mechanism-based model successfully quantified the time course of bacterial growth, killing and regrowth.
  
  
  
  Only high piperacillin concentrations prevented regrowth of P. aeruginosa. Individualized dosing regimens that account for altered pharmacokinetics and aim for higher-than-standard antibiotic exposures to achieve an fCmin of ≥5× MIC were required to maximize bacterial killing and suppress emergence of resistance.
authors.affiliation: Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Bergen
authors.affiliation: Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
authors.forename: Jürgen B
authors.initials: JB
authors.lastname: Bulitta
authors.affiliation: Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Carl M J
authors.initials: CM
authors.lastname: Kirkpatrick
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Rogers
authors.affiliation: Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: McGregor
authors.affiliation: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wallis
authors.affiliation: The University of Queensland Center for Clinical Research, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Paterson
authors.affiliation: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia 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
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA cornelia.landersdorfer@monash.edu.
authors.forename: Cornelia B
authors.initials: CB
authors.lastname: Landersdorfer
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016638:Critical Illness; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D010878:Piperacillin