title: A pilot study on pharmacokinetic/pharmacodynamic target attainment in critically ill patients receiving piperacillin/tazobactam.
abstract: BACKGROUND
  In critically ill patients, multi-trauma and intensive therapy can influence the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics with time-dependent bacterial killing. Consequently, PK/PD targets (%fT>MIC) - crucial for antimicrobial effects -may not be attained.
  
  
  METHODS
  Two patients admitted to the surgical ICU of the University Hospital in Hradec Králove for multiple-trauma were given piperacillin/tazobactam by 1-hour IV infusion 4/0.5 g every 8h. PK variables: total and renal clearance (CLtot, CLR), volume of distribution (Vd), and elimination half-life (T1/2) were calculated, followed by glomerular filtration rate (MDRD) and cumulative fluid balance (CFB-total fluid volume based on 24-h registered fluid intake minus output). The PK/PD target attainment (100%fT>MIC) was defined as free (f) piperacillin plasma concentrations that remain, during the entire dosing interval (T), above the minimum inhibitory concentration (100%fT>MIC) within days 4-8 (when CFB culminates and disappears). Piperacillin concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and corrected for unbound fraction (22%).
  
  
  RESULTS
  CFB culminated over days 2-5 reaching 15-30 L and was associated with a large Vd (29-42 L). While MDRD in patient 1 was low (0.3-0.4 mL s⁻¹ 1.7 m⁻²), that of patient 2 was increasing (> 3.1 mL s⁻¹ 1.7 m⁻²), which was associated with augmented CLR. In patient 2, the fT reached only 62, 52, and 44% on days 4, 6, and 8, respectively. In patient 1, the %fT was much higher, attaining values four to fivefold greater than that targeted.
  
  
  CONCLUSIONS
  Critically ill patients are at risk of drug under- or overdosing without dose up-titration with regard to covariate effects and individual drug pharmacokinetics.
authors.forename: Jiřina
authors.initials: J
authors.lastname: Martínková
authors.forename: Manu L N G
authors.initials: ML
authors.lastname: Malbrain
authors.forename: Eduard
authors.initials: E
authors.lastname: Havel
authors.forename: Petr
authors.initials: P
authors.lastname: Šafránek
authors.forename: Jan
authors.initials: J
authors.lastname: Bezouška
authors.affiliation: Surgical Department, University Hospital, Hradec Králové, Czech Republic. kaskam@lfhk.cuni.cz.
authors.forename: Milan
authors.initials: M
authors.lastname: Kaška
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D016638:Critical Illness; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010865:Pilot Projects; D010878:Piperacillin / Q000493:pharmacokinetics / Q000494:pharmacology; D000077725:Piperacillin, Tazobactam Drug Combination; D011446:Prospective Studies; D065093:beta-Lactamase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D065093:beta-Lactamase Inhibitors; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin
keywords: PK/PD target attainment; body fluid retention; critically ill patients; personalised therapy; pharmacodynamics; pharmacokinetics; piperacillin