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Dose optimization of piperacillin/tazobactam in critically ill children

Pieter De Cock (UGent) , Sven C van Dijkman, Annik de Jaeger (UGent) , Jef Willems (UGent) , Mieke Carlier (UGent) , Alain Verstraete (UGent) , Joris Delanghe (UGent) , Hugo Robays (UGent) , Johan Vande Walle (UGent) , Oscar E Della Pasqua, et al.
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Abstract
Objectives: 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 every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling. Results: Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that 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 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) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60% fT(> MIC) > 16 mg/L). Conclusions: Standard intermittent dosing regimens do not ensure optimal piperacillin/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.
Keywords
EXTENDED-INFUSION PIPERACILLIN, AUGMENTED RENAL CLEARANCE, BETA-LACTAM ANTIBIOTICS, INTENSIVE-CARE-UNIT, POPULATION PHARMACOKINETICS, CYSTATIN-C, CREATININE MEASUREMENTS, HEALTHY-VOLUNTEERS, CYSTIC-FIBROSIS, TAZOBACTAM

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Chicago
De Cock, Pieter, Sven C van Dijkman, Annik de Jaeger, Jef Willems, Mieke Carlier, Alain Verstraete, Joris Delanghe, et al. 2017. “Dose Optimization of Piperacillin/tazobactam in Critically Ill Children.” Journal of Antimicrobial Chemotherapy 72 (7): 2002–2011.
APA
De Cock, P., van Dijkman, S. C., de Jaeger, A., Willems, J., Carlier, M., Verstraete, A., Delanghe, J., et al. (2017). Dose optimization of piperacillin/tazobactam in critically ill children. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 72(7), 2002–2011.
Vancouver
1.
De Cock P, van Dijkman SC, de Jaeger A, Willems J, Carlier M, Verstraete A, et al. Dose optimization of piperacillin/tazobactam in critically ill children. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY. 2017;72(7):2002–11.
MLA
De Cock, Pieter, Sven C van Dijkman, Annik de Jaeger, et al. “Dose Optimization of Piperacillin/tazobactam in Critically Ill Children.” JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY 72.7 (2017): 2002–2011. Print.
@article{8545237,
  abstract     = {Objectives: 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 every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling. 
Results: Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that 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 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) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60\% fT({\textrangle} MIC) {\textrangle} 16 mg/L). 
Conclusions: Standard intermittent dosing regimens do not ensure optimal piperacillin/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 {\textrangle} 2 months of age.},
  author       = {De Cock, Pieter and van Dijkman, Sven C and de Jaeger, Annik and Willems, Jef and Carlier, Mieke and Verstraete, Alain and Delanghe, Joris and Robays, Hugo and Vande Walle, Johan and Della Pasqua, Oscar E and De Paepe, Peter},
  issn         = {0305-7453},
  journal      = {JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY},
  language     = {eng},
  number       = {7},
  pages        = {2002--2011},
  title        = {Dose optimization of piperacillin/tazobactam in critically ill children},
  url          = {http://dx.doi.org/10.1093/jac/dkx093},
  volume       = {72},
  year         = {2017},
}

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