Population Pharmacokinetic Analysis of Piperacillin in Burn Patients

Jeon, Sangil; Han, Seunghoon; Hong, Tae Kyung; Paek, Jeongki; Woo, Heungjeong

doi:10.1128/aac.02089-13

Cited by 25 publications

(28 citation statements)

References 30 publications

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“…Exposure to tazobactam is believed to prolong the susceptibility to piperacillin-induced bactericidal effects even when the concentration of the ␤-lactamase inhibitor is no longer detectable (37,38). Our recommendations regarding piperacillin-tazobactam dosing regimens are therefore based on piperacillin concentrations only, which is in line with several other studies (14,39,40).…”

Section: Discussionsupporting

confidence: 75%

“…The piperacillin CL and total V in the present patient population were also substantially lower than in other patient populations who received piperacillin as intermittent bolus dosing, such as patients with intra-abdominal infections (13.7 liters/h and 22.4 liters, respectively [41]) and patients with nosocomial infections (13.8 liters/h and 21.7 liters, respectively [42]). Jeon et al (39) measured piperacillin plasma concentrations in burn patients. Their data were also described with a two-compartment population PK model with creatinine clearance and sepsis as significant covariates.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Öbrink-Hansen

Juul

Storgaard

et al. 2015

Antimicrob Agents Chemother

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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...

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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

Öbrink-Hansen

Juul

Storgaard

et al. 2015

Antimicrob Agents Chemother

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“…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.…”

Section: Resultsmentioning

confidence: 99%

“… reported a piperacillin clearance of 6.8 l h –1 70 kg –1 , whereas Jeon et al . reported a figure of 17.2 l h –1 70 kg –1 in critically ill patients with burns.…”

Section: Introductionmentioning

confidence: 96%

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

Lonsdale

Baker

Kipper

et al. 2018

Brit J Clinical Pharma

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“…It could be particularly high in those patients with burns and trauma (20). For example, a pharmacokinetic model for burn patients predicts elevated clearance of 16 liters/h for patients when CL CR is 130 ml/min and 20 ml/min when CL CR is 160 ml/min (21). This is comparable to the elevated mean clearance observed in the current study (18.2 Ϯ 4.8 liters/h) and, consistent with other studies, contributes to suboptimal therapeutic exposure from traditional dosing regimens.…”

Section: Discussionmentioning

confidence: 99%

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

Sime

Hahn

Warner

et al. 2017

Antimicrob Agents Chemother

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Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in suboptimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for hematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Nonparametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with the Pmetrics package for R. A twocompartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 Ϯ 12 years [means Ϯ standard deviations] and weight of 77 Ϯ 16 kg). Parameter estimates were CL of 18.0 Ϯ 4.8 liters/h, volume of distribution of the central compartment of 14.3 Ϯ 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 Ϯ 1.35 h Ϫ1 , and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 Ϯ 7.81 h Ϫ1 . High creatinine clearance (CL CR ) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of Ͼ90% for an unbound concentration of piperacillin remaining above the MIC (fT ϾMIC ) of 50%. Only continuous regimens achieved Ͼ90% PTA for 100% fT ϾMIC when CL CR was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal (Ͻ85%) for conventional regimens for both empirical and directed therapy considering 50% and 100% fT ϾMIC . FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CL CR or with known/presumed infections from high-MIC bacteria.KEYWORDS febrile neutropenia, piperacillin, population pharmacokinetics

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Population Pharmacokinetic Analysis of Piperacillin in Burn Patients

Cited by 25 publications

References 30 publications

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

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

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

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

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