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Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass to optimize dosing regimens for children undergoing cardiac surgery

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Abstract
Objectives: The objective of this study was to characterize cefazolin serum pharmacokinetics in children before, during and after cardiopulmonary bypass (CPB), in order to derive an evidence-based dosing regimen. Patients and methods: This study included children who received cefazolin before surgical incision, before cessation of CPB and after surgery. Blood samples of total and unbound cefazolin concentrations were collected before, during and after CPB. The cefazolin concentration-time profiles were analysed using population pharma-cokinetic modelling and predictors for interindividual variability in pharmacokinetic parameters were investigated. Subsequently, optimized dosing regimens were developed using stochastic simulations. Clinicaltrials. gov: NCT02749981. Results: A total of 494 total and unbound cefazolin concentrations obtained from 56 children (aged 6 days to 15 years) were included. A two-compartment model with first-order elimination plus an additional compartment for the effect of CPB best described the data. Clearance (1.56 L/h), central volume (1.93 L) and peripheral volume (2.39 L) were allometrically scaled by body weight. The estimated glomerular filtration rate(eGFR) was identified as a covariate on clearance and the serum albumin concentration was associated with maximum protein binding capacity. Our simulations showed that an additional bolus dose at the start of CPB improves the PTA in typical patients from 59% to >94%. Prolonged surgery and preserved renal function (i.e. drop in eGFR < 25%) had a negative impact on PTA. Conclusions: We propose an optimized dosing regimen for cefazolin during cardiac surgery in paediatric patients to avoid treatment failure due to inadequate antibiotic prophylaxis.
Keywords
SURGICAL SITE INFECTIONS, CRITICALLY-ILL CHILDREN, RISK-FACTORS, ANTIBIOTIC-PROPHYLAXIS, CARDIOVASCULAR-SURGERY, TISSUE PHARMACOKINETICS, PLASMA-CONCENTRATIONS, PEDIATRIC POPULATION, PROTEIN-BINDING, RENAL-FUNCTION

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Citation

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Chicago
De Cock, Pieter, Hussain Mulla, Sarah Desmet, Filip De Somer, Brett C McWhinney, Jacobus PJ Ungerer, Anneliese Moerman, et al. 2017. “Population Pharmacokinetics of Cefazolin Before, During and After Cardiopulmonary Bypass to Optimize Dosing Regimens for Children Undergoing Cardiac Surgery.” Journal of Antimicrobial Chemotherapy 72 (3): 791–800.
APA
De Cock, P., Mulla, H., Desmet, S., De Somer, F., McWhinney, B. C., Ungerer, J. P., Moerman, A., et al. (2017). Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass to optimize dosing regimens for children undergoing cardiac surgery. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 72(3), 791–800.
Vancouver
1.
De Cock P, Mulla H, Desmet S, De Somer F, McWhinney BC, Ungerer JP, et al. Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass to optimize dosing regimens for children undergoing cardiac surgery. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY. 2017;72(3):791–800.
MLA
De Cock, Pieter, Hussain Mulla, Sarah Desmet, et al. “Population Pharmacokinetics of Cefazolin Before, During and After Cardiopulmonary Bypass to Optimize Dosing Regimens for Children Undergoing Cardiac Surgery.” JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY 72.3 (2017): 791–800. Print.
@article{8500229,
  abstract     = {Objectives: The objective of this study was to characterize cefazolin serum pharmacokinetics in children before, during and after cardiopulmonary bypass (CPB), in order to derive an evidence-based dosing regimen. 
Patients and methods: This study included children who received cefazolin before surgical incision, before cessation of CPB and after surgery. Blood samples of total and unbound cefazolin concentrations were collected before, during and after CPB. The cefazolin concentration-time profiles were analysed using population pharma-cokinetic modelling and predictors for interindividual variability in pharmacokinetic parameters were investigated. Subsequently, optimized dosing regimens were developed using stochastic simulations. Clinicaltrials. gov: NCT02749981. 
Results: A total of 494 total and unbound cefazolin concentrations obtained from 56 children (aged 6 days to 15 years) were included. A two-compartment model with first-order elimination plus an additional compartment for the effect of CPB best described the data. Clearance (1.56 L/h), central volume (1.93 L) and peripheral volume (2.39 L) were allometrically scaled by body weight. The estimated glomerular filtration rate(eGFR) was identified as a covariate on clearance and the serum albumin concentration was associated with maximum protein binding capacity. Our simulations showed that an additional bolus dose at the start of CPB improves the PTA in typical patients from 59\% to {\textrangle}94\%. Prolonged surgery and preserved renal function (i.e. drop in eGFR {\textlangle} 25\%) had a negative impact on PTA. 
Conclusions: We propose an optimized dosing regimen for cefazolin during cardiac surgery in paediatric patients to avoid treatment failure due to inadequate antibiotic prophylaxis.},
  author       = {De Cock, Pieter and Mulla, Hussain and Desmet, Sarah and De Somer, Filip and McWhinney, Brett C and Ungerer, Jacobus PJ and Moerman, Anneliese and Commeyne, Sabrina and Vande Walle, Johan and Francois, Katrien and Van Hasselt, Johan GC and De Paepe, Peter},
  issn         = {0305-7453},
  journal      = {JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY},
  keyword      = {SURGICAL SITE INFECTIONS,CRITICALLY-ILL CHILDREN,RISK-FACTORS,ANTIBIOTIC-PROPHYLAXIS,CARDIOVASCULAR-SURGERY,TISSUE PHARMACOKINETICS,PLASMA-CONCENTRATIONS,PEDIATRIC POPULATION,PROTEIN-BINDING,RENAL-FUNCTION},
  language     = {eng},
  number       = {3},
  pages        = {791--800},
  title        = {Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass to optimize dosing regimens for children undergoing cardiac surgery},
  url          = {http://dx.doi.org/10.1093/jac/dkw496},
  volume       = {72},
  year         = {2017},
}

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