title: Population pharmacokinetics of piperacillin and tazobactam in critically ill patients undergoing continuous renal replacement therapy: application to pharmacokinetic/pharmacodynamic analysis.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics of piperacillin/tazobactam in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to assess the success of the therapy against susceptible bacteria.
  
  
  METHODS
  Sixteen patients undergoing CRRT with different degrees of renal function were included in the study. Blood and ultrafiltrate samples were drawn after administration of piperacillin/tazobactam (4/0.5 g) every 4, 6 or 8 h. The data were analysed by a population approach using NONMEM 7.2. The probability of target attainment (PTA) of maintaining free piperacillin levels above the MIC during the entire dosing interval was estimated by simulation of intermittent and continuous infusions.
  
  
  RESULTS
  The pharmacokinetics of piperacillin and tazobactam were best described by two-compartment models where the elimination of both drugs was conditioned by renal [dependent on creatinine clearance (CLCR)], non-renal and extracorporeal clearances. A 20 min infusion of piperacillin/tazobactam administered every 6 h provided high PTAs against MICs ≤ 32 mg/L in patients with severe renal failure. In patients with normal or moderate renal function PTAs ≥ 90% were only obtained up to MICs ≤ 8 mg/L with short infusions. However, simulating continuous infusion, higher probabilities of success were obtained against MICs of 32 and 16 mg/L when CLCR was 50 and 100 mL/min, respectively.
  
  
  CONCLUSIONS
  Population pharmacokinetic models have been developed and validated for piperacillin and tazobactam. Based on the pharmacokinetic/pharmacodynamic analysis, dosing recommendations are given considering the residual renal function of the patient and the MIC for the isolated bacteria.
authors.affiliation: Pharmacokinetics, Nanotechnology and Gene Therapy Group, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Asín-Prieto
authors.forename: Alicia
authors.initials: A
authors.lastname: Rodríguez-Gascón
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
authors.forename: Amaia
authors.initials: A
authors.lastname: Soraluce
authors.forename: Javier
authors.initials: J
authors.lastname: Maynar
authors.forename: José Ángel
authors.initials: JÁ
authors.lastname: Sánchez-Izquierdo
authors.forename: Arantxazu
authors.initials: A
authors.lastname: Isla
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016638:Critical Illness; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000077725:Piperacillin, Tazobactam Drug Combination; D011446:Prospective Studies; D017582:Renal Replacement Therapy; D044967:Serum / Q000737:chemistry; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin
keywords: PD; PK; antimicrobial therapy; intensive care; population pharmacokinetics; renal replacement therapy; β-lactams