Population pharmacokinetics of continuous infusion of piperacillin in critically ill patients.

Dosing recommendations for continuous infusion of piperacillin, a broad-spectrum beta-lactam antibiotic, are mainly guided by outputs from population pharmacokinetic models constructed with intermittent infusion data. However, the probability of target attainment in patients receiving piperacillin by continuous infusion may be overestimated when drug clearance estimates from population pharmacokinetic models based on intermittent infusion data are used, especially when higher doses (e.g. 16 g/24 h or more) are simulated. Therefore, the purpose of this study was to describe the population pharmacokinetics of piperacillin when infused continuously in critically ill patients. For this analysis, 270 plasma samples from 110 critically ill patients receiving piperacillin were available for population pharmacokinetic model building. A one-compartment model with linear clearance best described the concentration-time data. The mean ± standard deviation parameter estimates were 8.38 ± 9.91 L/h for drug clearance and 25.54 ± 3.65 L for volume of distribution. Creatinine clearance improved the model fit and was supported for inclusion as a covariate. In critically ill patients with renal clearance higher than 90 mL/min/1.73 m2, a high-dose continuous infusion of 24 g/24 h is insufficient to achieve adequate exposure (pharmacokinetic/pharmacodynamic target of 100% fT>4 x MIC) against susceptible Pseudomonas aerginosa isolates (MIC ≤16 mg/L). These findings suggest that merely increasing the dose of piperacillin, even with continuous infusion, may not always result in adequate piperacillin exposure. This should be confirmed by evaluating piperacillin target attainment rates in critically ill patients exhibiting high renal clearance.

A Simulation Study Reveals Lack of Pharmacokinetic/Pharmacodynamic Target Attainment in De-escalated Antibiotic Therapy in Critically Ill Patients.

De-escalation of empirical antibiotic therapy is often included in antimicrobial stewardship programs in critically ill patients, but differences in target attainment when antibiotics are switched are rarely considered. The primary objective of this study was to compare the fractional target attainments of contemporary dosing of empirical broad-spectrum ß-lactam antibiotics and narrower-spectrum antibiotics for a number pathogens for which de-escalation may be considered. The secondary objective was to determine whether alternative dosing strategies improve target attainment. We performed a simulation study using published population pharmacokinetic (PK) studies in critically ill patients for a number of broad-spectrum ß-lactam antibiotics and narrower-spectrum antibiotics. Simulations were undertaken using a data set obtained from critically ill patients with sepsis without absolute renal failure (n = 49). The probability of target attainment of antibiotic therapy for different microorganisms for which de-escalation was applied was analyzed. EUCAST MIC distribution data were used to calculate fractional target attainment. The probability that therapeutic exposure will be achieved was lower for the narrower-spectrum antibiotics with conventional dosing than for the broad-spectrum alternatives and could drastically be improved with higher dosages and different modes of administrations. For a selection of microorganisms, the probability that therapeutic exposure will be achieved was overall lower for the narrower-spectrum antibiotics using conventional dosing than for the broad-spectrum antibiotics.

Does consistent piperacillin dosing result in consistent therapeutic concentrations in critically ill patients? A longitudinal study over an entire antibiotic course.

Piperacillin plasma concentrations are known to vary between critically ill patients. However, there are no comprehensive data on the variability of antibiotic concentrations within the same patient. The purpose of this study was to investigate the adequacy of dosing during an entire 7-day antibiotic course and to investigate the variability in antibiotic trough concentrations both between patients and within the same patient. Piperacillin trough concentrations were measured daily in critically ill patients with normal renal function. The drug assay was performed using UPLC-MS/MS. The pharmacokinetic/pharmacodynamic target was 100% fT>MIC of the Pseudomonas aeruginosa EUCAST breakpoint. Within- and between-patient variability were calculated as percent coefficient of variation (CV). Eleven patients treated for pneumonia were included in this nested prospective observational cohort study. The median (range) age was 67 (18-79) years, weight was 75 (57-90)kg and BMI was 23.5 (22.3-26.4). The median (range) creatinine clearance on Day 1 of antibiotic treatment was 102 (62-154)mL/min. Trough concentrations were variable, ranging from 4.9 mg/L to 98.0 mg/L. A median CV of 40% for within-patient variability and 57% for between-patient variability was found. Within-patient variability was inversely correlated with SOFA score (R = 0.65, P = 0.027) and APACHE II score on admission (R = 0.73, P = 0.009). In conclusion, piperacillin concentrations varied widely both between patients and within the same patient. Within-patient variability was inversely correlated with disease severity. Consistent dosing of piperacillin/tazobactam does not result in consistent piperacillin concentrations throughout the entire treatment period.