title: Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model.
abstract: Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. APseudomonas aeruginosaisolate (MICmeropenem0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum ∼107.5CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ∼10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (≤∼2.5 log10). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5- and 1-g regimens with normal renal function (fT>5×MIC= 56 and 69%,fCmin/MIC < 2); the emergence of less-susceptible populations (≥32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (fT>5×MIC≥ 82%,fCmin/MIC ≥ 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.
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, Gainesville, Florida, 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: CMJ
authors.lastname: Kirkpatrick
authors.affiliation: Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.|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: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
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.|Centre for Translational Anti-infective Pharmacodynamics, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
authors.affiliation: Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia cornelia.landersdorfer@monash.edu.|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, New York, USA.
authors.forename: Cornelia B
authors.initials: CB
authors.lastname: Landersdorfer
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003404:Creatinine / Q000378:metabolism; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D000077731:Meropenem; D008657:Metabolic Clearance Rate / Q000502:physiology*; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000302:isolation & purification; D013845:Thienamycins / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D003404:Creatinine; D000077731:Meropenem
keywords: augmented renal clearance; critically ill; pharmacodynamic modeling; pharmacokinetics