Population Pharmacokinetics of Piperacillin in the Early Phase of Septic Shock: Does Standard Dosing Result in Therapeutic Plasma Concentrations?

Abstract

e 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.) A ppropriate early antimicrobial therapy is of utmost importance for reducing mortality in critically ill patients with sepsis and septic shock (1-3). Pathophysiological changes associated with the septic process, such as changes in volume of distribution (V), drug clearance (CL), decrease in plasma protein concentration, and organ dysfunction, lead to pharmacokinetic (PK) changes that may alter the efficacy of the antimicrobial given (4). As a consequence, antibiotic plasma concentrations are variable and hard to predict in these patients, which makes optimal antibiotic exposure a challenge, especially in the early phase of treatment (5, 6). In septic shock patients, appropriate dosing is of greater importance, as effective antimicrobial therapy within the first hour of documented hypotension is associated with increased survival to hospital discharge (7).Piperacillin-tazobactam is a ␤-lactam-␤-lactamase inhibitor combination with a broad spectrum of antibacterial activity (8), frequently used for empirical treatment in critically ill patients. It is an antibiotic with time-dependent antibacterial activit...

Scaling beta‐lactam antimicrobial pharmacokinetics from early life to old age

“…A flowchart of study selection for each drug is provided in Figure . A total of 2082 articles were identified and screened, with 130 studies included in the final analysis . Some studies provided PK parameters for two drugs (e.g.…”

Using Population Pharmacokinetic Modeling and Monte Carlo Simulations To Determine whether Standard Doses of Piperacillin in Piperacillin-Tazobactam Regimens Are Adequate for the Management of Febrile Neutropenia

“…Indeed, clearance of piperacillin is highly dependent on the renal function of the study cohort, and this in many ways explains the different reported mean piperacillin clearances in different patient populations. In the critically ill, for instance, clearance could be elevated (e.g., 17.1 liters [18]) or similar/slightly higher (e.g., 13.8 liters/h [15,16] and 14.0 Ϯ 7.1 liters [17]) or may even be reduced (e.g., 3.6 liters/h [19] and 5.6 Ϯ 3.2 liters/h [12]) compared to healthy volunteers (13). It could be particularly high in those patients with burns and trauma (20).…”

Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?

“…Serial blood samples were collected over one dosing interval for up to three consecutive days if piperacillin-tazobactam treatment was maintained. The sampling times were optimized in the PopED (version 2.13) optimal design tool (42), given a prior piperacillin PK model for septic shock patients (4), and were focused on providing information on the population PK and the individual fT MIC (for further details, see A. N. Kristoffersson's unpublished presentation at the Population Optimum Design of Experiments [PODE] workshop, Uppsala, Sweden, 20 June 2016 [http:// www.maths.qmul.ac.uk/~bb/PODE/PODE2016_AKristoffersson.pdf ]). At the first day after study inclusion, each patient had three blood samples drawn.…”

“…It has previously been shown that standard treatment with piperacillin-tazobactam (4 g/0.5 g) every 8 h (q8h) may result in subtherapeutic concentrations in septic shock patients admitted to an intensive care unit (ICU) (4). In the present study, we wanted to assess if there is a similar risk of subtherapeutic concentrations among less critically ill septic patients admitted to a general ward.…”

“…Most hospitals worldwide use a standard fixed-dose regimen for treatment, but with numerous pharmacokinetic (PK) alterations being seen in this patient population (2), how do we know that this dose is right? Due to the pathophysiological changes associated with the septic process, antibiotic plasma concentrations are variable and hard to predict (3,4). Optimal dosing and exposure can therefore be a challenge in septic patients, and standard antibiotic dosing regimens may result in subtherapeutic concentrations and therapeutic failure (5,6).…”