Population pharmacokinetics of piperacillin in the early phase of septic shock: does standard dosing result in therapeutic plasma concentrations?
Antibiotic dosing in septic shock patients poses a challenge for clinicians due to the pharmacokinetic (PK) variability seen in this patient population. Piperacillin-tazobactam is often used for empirical treatment, and initial appropriate dosing is crucial for reducing mortality. Accordingly, we determined the pharmacokinetic profile of piperacillin (4 g) every 8 h, during the third consecutive dosing interval, in 15 patients treated empirically for septic shock. We developed a population pharmacokinetic model to assess empirical dosing and to simulate alternative dosing regimens and modes of administration. Time above the MIC (T>MIC) predicted for each patient was evaluated against clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter). Pharmacokinetic-pharmacodynamic (PK/PD) targets evaluated were 50% fT>4×MIC and 100% fT>MIC. A population PK model was developed using NONMEM, and data were best described by a two-compartment model. Central and intercompartmental clearances were 3.6 liters/h (relative standard error [RSE], 15.7%) and 6.58 liters/h (RSE, 16.4%), respectively, and central and peripheral volumes were 7.3 liters (RSE, 11.8%) and 3.9 liters (RSE, 9.7%), respectively. Piperacillin plasma concentrations varied considerably between patients and were associated with levels of plasma creatinine. Patients with impaired renal function were more likely to achieve predefined PK/PD targets than were patients with preserved or augmented renal function. Simulations of alternative dosing regimens showed that frequent intermittent bolus dosing as well as dosing by extended and continuous infusion increases the probability of attaining therapeutic plasma concentrations. For septic shock patients with preserved or augmented renal function, dose increment or prolonged infusion of the drug needs to be considered. (This study has been registered at ClinicalTrials.gov under registration no. NCT02306928.).
Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark krisoebr@rm.dk.
Kristina
K
Öbrink-Hansen
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Rasmus Vestergaard
RV
Juul
Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark.
Merete
M
Storgaard
Department of Clinical Microbiology, Aarhus University Hospital, Skejby, Denmark.
Marianne Kragh
MK
Thomsen
Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, Denmark.
Tore Forsingdal
TF
Hardlei
Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, Denmark.
Birgitte
B
Brock
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Mads
M
Kreilgaard
Department of Anesthesia and Intensive Care Medicine, Aarhus University Hospital, Skejby, Denmark.
Jakob
J
Gjedsted
D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood* / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010878:Piperacillin / Q000097:blood* / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D011446:Prospective Studies; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012772:Shock, Septic / Q000097:blood* / Q000188:drug therapy*; D000078142:Tazobactam
D000900:Anti-Bacterial Agents; D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin