title: Piperacillin concentration in relation to therapeutic range in critically ill patients--a prospective observational study.
abstract: BACKGROUND
  Piperacillin levels after standard dosing have been shown frequently to be subtherapeutic, especially when renal clearance was augmented. Here, we aimed to determine if piperacillin was in its therapeutic range in a typically heterogeneous intensive care unit patient group, and also to describe target attainment dependent on daily dosage, creatinine clearance, and renal replacement therapy (RRT).
  
  
  METHODS
  Sixty patients with severe infections were included in this monocentric prospective observational study. Patients received 4.5 g of piperacillin-tazobactam two to three times daily by intermittent infusion depending on renal function according to clinical guidelines. Over 4 days, multiple serum samples (median per patient, 29; in total, 1627) were obtained to determine total piperacillin concentrations using ultra-high-performance liquid chromatography/tandem mass spectrometry.
  
  
  RESULTS
  A high heterogeneity of patient characteristics was observed (e.g., on day 1: creatinine clearance 2-233 mL/min and ten patients on RRT). Piperacillin trough levels showed inter-individual variation from 123 to >1785-fold on different study days. Each day, approximately 50% and 60% of the patients had piperacillin levels below the target ranges 1 and 2, respectively [defined for the calculated unbound piperacillin fraction according to the literature as 100% time above MIC (100%fT > MIC) (target range 1) and ≥ 50%fT > 4 × MIC (target range 2); MIC = 16 mg/L]. Whereas only the minority of patients who received piperacillin-tazobactam three times daily (TID) reached target 1 (38% on day 1), most patients who received piperacillin-tazobactam only twice daily (BID) because of severely impaired renal function reached this target (100% on day 1). Patients with RRT had significant higher percentages of fT > MIC. Zero percent, 55% and 100% of patients without RRT who received antibiotics TID reached target 1 when creatinine clearance was > 65 mL/min, 30-65 mL/min and < 30 mL/min, respectively. In patients with causative strains only sensitive to piperacillin-tazobactam of all antibiotics given to the patient, piperacillin levels negatively correlated with CRP concentrations of day 4 (p < 0.05).
  
  
  CONCLUSIONS
  A dosage of 4.5 g piperacillin-tazobactam TID seems to be frequently insufficient in critically ill patients, and also in patients where renal function is mildly to moderately impaired. For these patients, prescription of 4.5 g piperacillin-tazobactam four times daily could be considered.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01793012. Registered 24 January 2013.
authors.affiliation: Institute of Laboratory Medicine, Hospital of the Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zander
authors.affiliation: Department of Anaesthesiology, Hospital of the Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
authors.forename: Gundula
authors.initials: G
authors.lastname: Döbbeler
authors.affiliation: Institute of Laboratory Medicine, Hospital of the Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Nagel
authors.affiliation: Institute of Laboratory Medicine, Hospital of the Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Maier
authors.affiliation: Department of Anaesthesiology, Hospital of the Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Scharf
authors.affiliation: Institute of Laboratory Medicine, Hospital of the Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
authors.forename: Mikayil
authors.initials: M
authors.lastname: Huseyn-Zada
authors.affiliation: Max von Pettenkofer-Institute, Ludwig-Maximilians-University of Munich, Marchioninistrasse 17, 81377, Munich, Germany.
authors.forename: Jette
authors.initials: J
authors.lastname: Jung
authors.affiliation: Department of Anaesthesiology, Hospital of the Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Frey
authors.affiliation: Institute of Laboratory Medicine, Hospital of the Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Vogeser
authors.affiliation: Department of Anaesthesiology, Hospital of the Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, 81377, Munich, Germany. Michael.Zoller@med.uni-muenchen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Zoller
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D003422:Critical Care / Q000379:methods; D016638:Critical Illness / Q000401:mortality / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005858:Germany; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D010878:Piperacillin / Q000008:administration & dosage* / Q000032:analysis / Q000494:pharmacology*; D011446:Prospective Studies; D017582:Renal Replacement Therapy
chemical_list: D000900:Anti-Bacterial Agents; D010878:Piperacillin
keywords: Antibiotics; C-reactive protein; Creatinine clearance; Dosage; Intensive care unit; Renal replacement therapy; Target range; Variability