Population Pharmacokinetic Analysis of Piperacillin/ Tazobactam in Korean Patients with Acute Infections

다국어 초록 (Multilingual Abstract)

Background: For more effective and safer usage of antibiotics, the dosing strategy should be individualized based on the patients’ characteristics, including race. The aim of this study was to investigate the population pharmacokinetic (PK) profiles of piperacillin and tazobactam in Korean patients with acute infections.
Materials and Methods: At least four consecutive 2/0.25 g or 4/0.5 g doses of piperacillin/tazobactam (TZP) were intravenously infused over 1 h every 8 h for patients with creatinine clearance (CLcr) ≤50 mL/min or CLcr >50 mL/min, respectively. Blood samples from 33 patients at a steady-state were taken pre-dose and at 0 min, 30 min, and 4-6 h after the fourth infusion. The population PK analysis was conducted using a non-linear mixed-effects method. A likelihood ratio test was used to select significant covariates, with significance levels of P <0.05 for selection and P <0.01 for elimination.
Results: Both piperacillin PK and tazobactam PK were well described by a two-compartment model with first-order elimination. Creatinine clearance and body weight, as covariates on clearance (CL) and volume of central compartment (V1), were selected among the covariates possibly affecting PK parameters of both drugs. CL was defined as CL = 2.9 + 4.03 × CLcr /47 for piperacillin and CL = 1.76 + 4.81 × CLcr /47 for tazobactam. V1 was defined as V1 = 19.5 × weight/60 for piperacillin and V1 = 22.6 × weight/60 for tazobactam.
Conclusion: The PK profiles of TZP at a steady-state in Korean patients with acute infections were well described by a two-compartment model with first-order elimination. Both piperacillin and tazobactam clearances were significantly influenced by creatinine clearance.

참고문헌 (Reference)

1 Roberts JA, "Therapeutic drug monitoring of β-lactams in critically ill patients: proof of concept" 36 : 332-339, 2010

2 Turnidge JD, "The pharmacodynamics of β-lactams" 27 : 10-22, 1998

3 Cheatham SC, "Steady-state pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese patients" 41 : 52-56, 2013

4 Tumbarello M, "Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment" 51 : 1987-1994, 2007

5 Kiem S, "Population pharmacokinetics of levofloxacin in Korean patients" 28 : 308-313, 2016

6 Li C, "Population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam in patients with complicated intra-abdominal infection" 56 : 388-395, 2005

7 Chung EK, "Population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese and nonobese patients" 55 : 899-908, 2015

8 Jeon S, "Population pharmacokinetic analysis of piperacillin in burn patients" 58 : 3744-3751, 2014

9 Maltezou HC, "Piperacillin/tazobactam versus cefotaxime plus metronidazole for treatment of children with intra-abdominal infections requiring surgery" 20 : 643-646, 2001

10 Gin A, "Piperacilin-tazobactam: a beta-lactam/beta-lactamase inhibitor combination" 5 : 365-383, 2007

11 Oh KH, "Pharmacokinetics of intravenous piperacillin administration in patients undergoing on-line hemodiafiltration" 53 : 3266-3268, 2009

12 Hayashi Y, "Pharmacokinetic evaluation of piperacillin-tazobactam" 6 : 1017-1031, 2010

13 Huang WT, "Neurotoxicity associated with standard doses of piperacillin in an elderly patient with renal failure" 37 : 374-376, 2009

14 Karino F, "Nephrotoxicity induced by piperacillin-tazobactam in late elderly Japanese patients with nursing and healthcare associated pneumonia" 37 : 1971-1976, 2014

15 Morgan DJ, "Lean body mass as a predictor of drug dosage. Implications for drug therapy" 26 : 292-307, 1994

16 Johnson JA, "Influence of race or ethnicity on pharmacokinetics of drugs" 86 : 1328-1333, 1997

17 Felton TW, "Indivisualization of piperacillin dosing for critically ill patients: dosing software to optimize antimicrobial therapy" 58 : 4094-4102, 2014

18 Peralta G, "Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp bacteremia. A multicentric cohort study" 12 : 245-, 2012

19 Patel N, "Identification of optimal renal dosage adjustments for traditional and extended-infusion piperacillin-tazobactam dosing refimens in hospitalized patients" 54 : 460-465, 2010

20 Mckinnon PS, "Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections" 31 : 345-351, 2008

21 Chen ML, "Ethnic or racial differences revisited: impact of dosage regimen form on pharmacokinetics and pharmacodynamics" 45 : 957-964, 2006

22 Cheymol G, "Effects of obesity on pharmacokinetics implications for drug therapy" 39 : 215-231, 2000

23 Tamma PD, "Does the piperacillin minimum inhibitory concentration for Pseudomonas aeruginosa influence clinical outcomes of children with pseudomonal bacteremia?" 55 : 799-806, 2012

24 Dulhunty JM, "Continous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial" 56 : 236-244, 2013

25 Lodise TP, "Application of antimicrobial pharmacodynamics concepts into clinical practice: focus on β-lactam antibiotics: insights form the Society of Infectious Diseases Pharmacists" 26 : 1320-1332, 2006