First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis

Roberts, Jason A.; Kirkpatrick, Carl M.; Roberts, Michael S.; Dalley, Andrew J.; Lipman, Jeffrey

doi:10.1016/j.ijantimicag.2009.10.008

Cited by 159 publications

(144 citation statements)

References 47 publications

(71 reference statements)

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“…However, individual estimates in our study group ranged from 2.8 to 14.2 liters/h, which is not dissimilar to the range of other published data for critically ill or hospitalized patients (3 to 40 liters/h) (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Regarding piperacillin volume of distribution, the V c in this study was similar to other published data for both healthy volunteers and critically ill patients (13,18,19,21).…”

Section: Discussionsupporting

confidence: 86%

“…We found that piperacillin pharmacokinetics in this population have high interindividual variability compared to those in healthy volunteers (12,13) but are similar to those in other critically ill or hospitalized patients (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Nonetheless, we have also found that renal function, i.e., CL CR , remains the most important determinant of piperacillin dosing requirements.…”

Section: Discussionsupporting

confidence: 69%

“…The VPC showed an even distribution of the observed data across the percentiles of the simulated data. Table 3 compares the pharmacokinetic parameter estimates observed in our study with other published data from various patient populations (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). The parameter estimates from the present study generally show a lower mean piperacillin CL than data on healthy volunteers and critically patients when CL CR was taken into consideration.…”

Section: Resultssupporting

confidence: 62%

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Pharmacokinetics of Piperacillin in Critically Ill Australian Indigenous Patients with Severe Sepsis

Tsai

Stewart

Goud

et al. 2016

Antimicrob Agents Chemother

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iThere are no available pharmacokinetic data to guide piperacillin dosing in critically ill Australian Indigenous patients despite numerous reported physiological differences. This study aimed to describe the population pharmacokinetics of piperacillin in critically ill Australian Indigenous patients with severe sepsis. A population pharmacokinetic study of Indigenous patients with severe sepsis was conducted in a remote hospital intensive care unit. Plasma samples were collected over two dosing intervals and assayed by validated chromatography. Population pharmacokinetic modeling was conducted using Pmetrics. Nine patients were recruited, and a two-compartment model adequately described the data. The piperacillin clearance (CL), volume of distribution of the central compartment (V c ), and distribution rate constants from the central to the peripheral compartment and from the peripheral to the central compartment were 5.6 ؎ 3.2 liters/h, 14.5 ؎ 6.6 liters, 1.5 ؎ 0.4 h ؊1 , and 1.8 ؎ 0.9 h ؊1 , respectively, where CL and V c were found to be described by creatinine clearance (CL CR ) and total body weight, respectively. In this patient population, piperacillin demonstrated high interindividual pharmacokinetic variability. CL CR was found to be the most important determinant of piperacillin pharmacokinetics.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 69%

Section: Resultssupporting

confidence: 62%

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Pharmacokinetics of Piperacillin in Critically Ill Australian Indigenous Patients with Severe Sepsis

Tsai

Stewart

Goud

et al. 2016

Antimicrob Agents Chemother

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“…Although our study was not powered for the evaluation of efficacy, we speculate that children admitted to the ICU with lower disease severity and organ failure scores are most at risk for ARC and subsequent subtherapeutic antibiotic concentrations, as previously observed in adults. 41 Notably, children Also here, it is unclear whether these differences in volume of distribution are due to differences in body composition of the study population (e.g. larger total and extracellular body water content in neonates compared to infants and children), differences in disease severity (e.g.…”

Section: Discussionmentioning

confidence: 87%

Dose optimization of piperacillin/tazobactam in critically ill children

Cock¹,

Dijkman

Jaeger

et al. 2017

Journal of Antimicrobial Chemotherapy

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Running title: Paediatric piperacillin/tazobactam dose rationale SynopsisObjectives. The aim of this study was to characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen.Patients and Methods. This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg q6h based on piperacillin). Piperacillin/tazobactam concentrations were measured by a liquid chromatography-tandem mass spectrometry method. Pharmacokinetic data was analysed using nonlinear mixed effects modelling.Results. Piperacillin and tazobactam blood samples were collected from 47 patients (median age: 2.83 years; range: 2 months -15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model which included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 L/h and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) q4h over 2 hours, 100 mg/kg q4h given over 1 hour or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24h were minimally required to achieve the therapeutic targets for piperacillin (60 % fT>MIC>16 mg/L). Conclusion. Standard intermittent dosing regimens do not ensure optimalpiperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age.

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“…The pharmacokinetics of -lactam antibiotics is difficult to predict in the critically ill patient population due to the unpredictable effects of pathophysiologic processes particularly during sever sepsis and malignancy [13,14]. The drug's apparent volume of distribution and clearance may be elevated leading to sub-therapeutic plasma concentrations [4,[15][16][17][18][19][20][21][22][23][24]. On the other hand clearance may be unchanged [17] or decreased [4,18] and in the presence of organ dysfunction such acute kidney injury, diminished clearance may lead to massive accumulation and toxicity [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies

Sime

Roberts

et al. 2014

Journal of Chromatography B

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThere is strong evidence in literature supporting the benefit of monitoring plasma concentrations of -lactam antibiotics in the critically ill to ensure appropriateness of dosing.The objective of this work was to develop a method for the simultaneous determination of total concentrations piperacillin, benzylpenicillin, flucloxacillin, meropenem, ertapenem, cephazolin and ceftazidime in human plasma. Sample preparation involved protein precipitation with acetonitrile containing 0.1% formic acid and subsequent dilution of supernatant with 0.1% formic acid in water. Chromatographic separation was achieved on a reversed phase column (C18, 2.6µm, 2.1* 50 mm) via gradient elution using water and acetonitrile, each containing 0.1% formic acid, as mobile phase. Tandem mass spectrometry (MSMS) analysis was performed, after electrospray ionization in the positive mode, with multiple reaction monitoring (MRM). The method is accurate with the inter-day and intra-day accuracies of quality control samples (QCs) ranging from 95%-107% and 95%-108%, respectively. It is also precise with intra-day and inter-day coefficient of variations ranging from 4 to 12 % and 5-14% respectively. The lower limit of quantification was 0.1g/mL for each antibiotic except flucloxacillin (0.25g/mL). Recovery was greater than 96% for all analytes except for ertapenem (78%). Coefficients of variation for the matrix effect were less than 10% over the six batches of plasma. Analytes were stable over three freeze-thaw cycles, and for reasonable hours on the bench top as well as post-preparation. This novel liquid chromatography tandem mass spectrometry method proved accurate, precise and applicable for therapeutic drug monitoring and pharmacokinetic studies of the selected -lactam antibiotics.Page 5 Highlights  We present a method for simultaneous determination of seven beta-lactams in plasma  The selected antibiotics are those commonly used in critically ill patients  The method is accurate, precise and meets validation requirements by guidelines  It proved applicable for therapeutic drug monitoring and pharmacokinetic studies

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First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis

Cited by 159 publications

References 47 publications

Pharmacokinetics of Piperacillin in Critically Ill Australian Indigenous Patients with Severe Sepsis

Pharmacokinetics of Piperacillin in Critically Ill Australian Indigenous Patients with Severe Sepsis

Dose optimization of piperacillin/tazobactam in critically ill children

Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies

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