Pharmacokinetics of Piperacillin/Tazobactam in Children
Introduction: Piperacillin/tazobactam is a frequently prescribed antibiotic in pediatric intensive care units, but pharmacokinetic data to justify the optimal piperacillin/tazobactam dosing regimen are sparse in critically ill children.
Methods: Blood samples (2–4 per child) were collected from 13 children ages 9 months to 6 years admitted to the pediatric intensive care unit who were receiving standard piperacillin/tazobactam dosing regimens to treat infections. Piperacillin concentrations were measured by a bioassay, and the population pharmacokinetics of the piperacillin component was conducted using nonparametric adaptive grid (BigNPAG) with adaptive γ. Multiple models were tested to determine the best fit of the data. A 5000 patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for piperacillin/tazobactam 50 mg/kg (of the piperacillin component) every 4 hours, 80 mg/kg every 8 hours and 100 mg/kg every 6 hours as 0.5-, 3- or 4-hour infusions in a population of 1- to 6-year-old male children. Centers for Disease Control and Prevention weight for age charts were used as weight distributions. The percent of the dosing interval of the free drug is above the minimum inhibitory concentration (MIC) (fT>MIC) was calculated over a range of MICs from 0.03 to 128 μg/mL. The bactericidal target attainment was defined as ≥50% fT>MIC for piperacillin/tazobactam. PTA ≥90% at each MIC was defined as optimal.
Results: A 2 compartment model fitted piperacillin concentration data the best. Mean (standard deviation) population estimates for clearance, volume of the central compartment (Vc) and intercompartment transfer constants were 0.299 (0.128) L/hr/kg, 0.249 (0.211) L/kg, 6.663 (6.871) hours and 8.48 (7.74) hours, respectively. This resulted in a mean (standard deviation) elimination half-life of 1.39 (0.62) hours. The bias, precision and r for the individual predicted versus observed concentrations were -0.055, 0.96 μg/mL and 0.999, respectively. The only dosing regimens that achieved optimal PTA at the Clinical Laboratory Standards Institute susceptibility breakpoint of 16 μg/mL against Psuedomonas aeruginosa were 100 mg/kg every 6 hours administered as a 3-hour prolonged infusion and 400 mg/kg administered as a 24-hour continuous infusion. These dosing regimens also achieved 77.7% and 74.8% PTA, respectively, at a MIC of 32 μg/mL.
Conclusion: These are the first pharmacokinetic data of piperacillin/tazobactam (piperacillin component) in critically ill pediatric patients (1–6 years of age). Based on these data, 100 mg/kg q6h as a 3-hour infusion and 400 mg/kg continuous infusion were the only regimens to provide optimal PTA at the Clinical Laboratory Standards Institute breakpoint of 16 μg/mL.
Treatment of infections associated with critical illness remains a significant challenge in the intensive care unit (ICU), and the need for improvements in current treatment strategies is paramount. Current evidence suggests that with source control of the pathogen, early and appropriate antimicrobial therapy remains the most important intervention. Given the increasing incidence of resistant bacterial infections, further research toward optimizing antimicrobial therapy is a priority.
Piperacillin/tazobactam, a broad-spectrum β-lactam/β-lactamase inhibitor antibiotic combination, is commonly prescribed in the pediatric population for empiric therapy in hospitals, including the ICU. Pharmacokinetic data to guide dosing in children, however, are limited to healthy volunteers or non-ICU patients. To our knowledge, no pharmacokinetic data in critically ill children are available for piperacillin/tazobactam. Compared with adults, children have a greater number of functioning nephrons and, therefore, have greater clearance (CL) via glomerular filtration. As a result, children between the ages of 6 months to 6 years usually have a renal elimination of drugs that is at least 2 times faster than adults 18 years of age and older. In addition to age-related differences in pharmacokinetics, a wide array of pathophysiologic changes occur in critical illness, which can further complicate dosing selection. Critically ill patients can have increases in their volume of distribution (Vd) due to fluid balance strategies and intravascular perfusion changes; such changes might reduce the peak concentrations achieved after an infusion. Furthermore, critically ill patients can often have sepsis-induced decreases or increases in cardiac output, which can result in hypo- or hyperperfusion of the kidneys and thus alterations in drug CL.
For β-lactam antibiotics like piperacillin/tazobactam, there is a direct relationship between the time that free drug concentrations remain above the minimum inhibitory concentration (MIC), referred to as fT>MIC, and the killing of bacteria. Therefore, significant alterations in CL can affect the drug exposure necessary for an antimicrobial effect. An understanding of pharmacokinetic and pharmacodynamic changes in critically ill children is crucial to determining the most appropriate dose and interval selection in the pediatric ICU (PICU) setting of piperacillin/tazobactam.
Abstract and Introduction
Abstract
Introduction: Piperacillin/tazobactam is a frequently prescribed antibiotic in pediatric intensive care units, but pharmacokinetic data to justify the optimal piperacillin/tazobactam dosing regimen are sparse in critically ill children.
Methods: Blood samples (2–4 per child) were collected from 13 children ages 9 months to 6 years admitted to the pediatric intensive care unit who were receiving standard piperacillin/tazobactam dosing regimens to treat infections. Piperacillin concentrations were measured by a bioassay, and the population pharmacokinetics of the piperacillin component was conducted using nonparametric adaptive grid (BigNPAG) with adaptive γ. Multiple models were tested to determine the best fit of the data. A 5000 patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for piperacillin/tazobactam 50 mg/kg (of the piperacillin component) every 4 hours, 80 mg/kg every 8 hours and 100 mg/kg every 6 hours as 0.5-, 3- or 4-hour infusions in a population of 1- to 6-year-old male children. Centers for Disease Control and Prevention weight for age charts were used as weight distributions. The percent of the dosing interval of the free drug is above the minimum inhibitory concentration (MIC) (fT>MIC) was calculated over a range of MICs from 0.03 to 128 μg/mL. The bactericidal target attainment was defined as ≥50% fT>MIC for piperacillin/tazobactam. PTA ≥90% at each MIC was defined as optimal.
Results: A 2 compartment model fitted piperacillin concentration data the best. Mean (standard deviation) population estimates for clearance, volume of the central compartment (Vc) and intercompartment transfer constants were 0.299 (0.128) L/hr/kg, 0.249 (0.211) L/kg, 6.663 (6.871) hours and 8.48 (7.74) hours, respectively. This resulted in a mean (standard deviation) elimination half-life of 1.39 (0.62) hours. The bias, precision and r for the individual predicted versus observed concentrations were -0.055, 0.96 μg/mL and 0.999, respectively. The only dosing regimens that achieved optimal PTA at the Clinical Laboratory Standards Institute susceptibility breakpoint of 16 μg/mL against Psuedomonas aeruginosa were 100 mg/kg every 6 hours administered as a 3-hour prolonged infusion and 400 mg/kg administered as a 24-hour continuous infusion. These dosing regimens also achieved 77.7% and 74.8% PTA, respectively, at a MIC of 32 μg/mL.
Conclusion: These are the first pharmacokinetic data of piperacillin/tazobactam (piperacillin component) in critically ill pediatric patients (1–6 years of age). Based on these data, 100 mg/kg q6h as a 3-hour infusion and 400 mg/kg continuous infusion were the only regimens to provide optimal PTA at the Clinical Laboratory Standards Institute breakpoint of 16 μg/mL.
Introduction
Treatment of infections associated with critical illness remains a significant challenge in the intensive care unit (ICU), and the need for improvements in current treatment strategies is paramount. Current evidence suggests that with source control of the pathogen, early and appropriate antimicrobial therapy remains the most important intervention. Given the increasing incidence of resistant bacterial infections, further research toward optimizing antimicrobial therapy is a priority.
Piperacillin/tazobactam, a broad-spectrum β-lactam/β-lactamase inhibitor antibiotic combination, is commonly prescribed in the pediatric population for empiric therapy in hospitals, including the ICU. Pharmacokinetic data to guide dosing in children, however, are limited to healthy volunteers or non-ICU patients. To our knowledge, no pharmacokinetic data in critically ill children are available for piperacillin/tazobactam. Compared with adults, children have a greater number of functioning nephrons and, therefore, have greater clearance (CL) via glomerular filtration. As a result, children between the ages of 6 months to 6 years usually have a renal elimination of drugs that is at least 2 times faster than adults 18 years of age and older. In addition to age-related differences in pharmacokinetics, a wide array of pathophysiologic changes occur in critical illness, which can further complicate dosing selection. Critically ill patients can have increases in their volume of distribution (Vd) due to fluid balance strategies and intravascular perfusion changes; such changes might reduce the peak concentrations achieved after an infusion. Furthermore, critically ill patients can often have sepsis-induced decreases or increases in cardiac output, which can result in hypo- or hyperperfusion of the kidneys and thus alterations in drug CL.
For β-lactam antibiotics like piperacillin/tazobactam, there is a direct relationship between the time that free drug concentrations remain above the minimum inhibitory concentration (MIC), referred to as fT>MIC, and the killing of bacteria. Therefore, significant alterations in CL can affect the drug exposure necessary for an antimicrobial effect. An understanding of pharmacokinetic and pharmacodynamic changes in critically ill children is crucial to determining the most appropriate dose and interval selection in the pediatric ICU (PICU) setting of piperacillin/tazobactam.