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. 2021 Mar 25;10(4):348.
doi: 10.3390/antibiotics10040348.

Population Pharmacokinetics of Piperacillin in Non-Critically Ill Patients with Bacteremia Caused by Enterobacteriaceae

Vicente Merino-Bohórquez  1   2 , Fernando Docobo-Pérez  3   4   5 , Adoración Valiente-Méndez  4   5   6 , Mercedes Delgado-Valverde  4   5   6 , Manuel Cameán  1 , William W Hope  7   8 , Álvaro Pascual  3   4   5   6 , Jesús Rodríguez-Baño  4   5   6   9
Affiliations

Population Pharmacokinetics of Piperacillin in Non-Critically Ill Patients with Bacteremia Caused by Enterobacteriaceae

Vicente Merino-Bohórquez et al. Antibiotics (Basel). .

Abstract

This study analyzes the pharmacokinetic variability of piperacillin in non-critically ill patients with Enterobacteriaceae bloodstream infections (EBSI) and explores predicted clinical outcomes and piperacillin-related neurotoxicity under different renal conditions. Hospitalized, non-critically ill patients treated with piperacillin-tazobactam for EBSI were included. Four serum samples per patient were collected and analyzed. A population pharmacokinetic model was developed using the Pmetrics package for R. Monte Carlo simulations of various dosage regimens of 4 g piperacillin, administered q8 h or q12 h by short (0.5 h) or long (4 h) infusion, following the different glomerular filtration rate (GFR) categories used to classify chronic kidney disease (Kidney Disease: Improving Global Outcomes, KDIGO) to determine the probability of target attainment (PTA) using a free drug concentrations above the minimal inhibitory concentration (fT > MIC) of 50% for efficacy and targets for piperacillin-associated neurotoxicity. Twenty-seven patients (102 samples) were included. Extended piperacillin infusions reached a PTA > 90% (50%fT > MIC) within the susceptibility range, although a loading dose did not greatly improve the expected outcome. Long infusions reduced the expected toxicity in patients with severe renal impairment. The study supports the use of extended infusions of piperacillin in non-critically ill patients with EBSI. No benefits of a loading dose were expected in our population. Finally, extended infusions may reduce the risk of toxicity in patients with severe renal impairment.

Keywords: Enterobacteriaceae; bloodstream infection; nephrotoxicity; neurotoxicity; pharmacokinetics; piperacillin–tazobactam; renal function.

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Conflict of interest statement

J.R.-B. has been scientific coordinator of a research project unrelated to the project funded by AstraZeneca and a speaker at accredited educational activities funded by Merck through unrestricted grants. J.R.-B. and A.P. received funding for research from COMBACTE-NET (grant agreement 115523), COMBACTE-CARE (grant agreement 115620), and COMBACTE-MAGNET (grant agreement 115737) projects under the Innovative Medicines Initiative (IMI), the European Union and EFPIA companies in kind. W.W.H. has received research funding from Pfizer, Gilead, Astellas, AiCuris, Amplyx, Spero Therapeutics, and F2G and has acted as a consultant and/or has given talks for Pfizer, Basilea, Astellas, F2G, Nordic Pharma, Medicines Company, Amplyx, Mayne Pharma, Spero Therapeutics, Auspherix, Cardeas, and Pulmocide. All other authors have no conflicts to declare.

Figures

Figure 1
Figure 1
Diagnostic plots of the final population pharmacokinetic covariate model. (a) Observed piperacillin concentrations versus population predicted concentration (R2 = 0.39); (b) observed piperacillin concentrations versus individual predicted concentrations (R2 = 0.908). The continuous line represents the regression line, and the dashed line is the line of identity.
Figure 2
Figure 2
Normalized distribution predicted error (NPDE) versus predicted piperacillin concentration (a) and time (b). The NPDE should be a standard normal distribution with a mean of 0 and a standard deviation of 1, i.e., ~N (0,1). The approximately normal distribution of NPDE points, as indicated by the quantile–quantile (Q-Q) plot (c) and the NPDE histogram (d), centered at 0, indicates that the population model predictions are minimally systematically biased. The horizontal dashed lines in the top left and top right panels are at −2, 0 (the mean), and +2 standard deviations for the ideal normal distribution, and the surrounding error of 95% is shown with gray boxes. The solid horizontal lines are the actual distributions of the NPDE. The histogram columns in the bottom right panel compare the actual frequencies of NPDE with the ideal normal distribution (dashed line).
Figure 3
Figure 3
Weighted residual error plot (population predicted versus observed concentrations, mg/L) versus population predictions (a) and time of observation (b) and frequency distribution of weighted residual errors (c).
See this image and copyright information in PMC

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