Effect of Cystatin C on Vancomycin Clearance Estimation in Critically Ill Children Using a Population Pharmacokinetic
Kevin J Downes1,2,3,4, Nicole R Zane1, Athena F Zuppa1,5,6
1The Center for Clinical Pharmacology, Children's Hospital of Philadelphia.
Insights
Cystatin C (CysC)-based equations provide a more accurate estimation of vancomycin clearance in critically ill children compared to the standard bedside Schwartz equation, improving drug dosing and patient care.
Area of Science:
- Pediatric Critical Care Medicine
- Pharmacokinetics and Drug Metabolism
- Renal Function Assessment
Background:
- Vancomycin elimination relies on glomerular filtration, but current methods for estimating kidney function in children are often unreliable.
- Accurate estimation of glomerular filtration rate (GFR) is crucial for optimizing vancomycin dosing in pediatric patients.
- The study addresses the limitations of traditional creatinine-based GFR estimations in critically ill children.
Purpose of the Study:
- To compare the performance of cystatin C (CysC)-based glomerular filtration rate (GFR) equations against the bedside Schwartz creatinine-based equation.
- To determine the most suitable method for estimating vancomycin clearance (CL) in critically ill pediatric patients.
- To enhance the accuracy of vancomycin dosing through improved GFR estimation.
Main Methods:
- A prospective observational study involving critically ill children (2-18 years) receiving intravenous vancomycin.
- Collection of vancomycin levels and plasma cystatin C (CysC) measurements.
- Nonlinear mixed-effects modeling (NONMEM) to evaluate the impact of estimated GFR (eGFR) on vancomycin CL, comparing CysC-based equations with the bedside Schwartz equation.
Main Results:
- A 1-compartment model with allometric scaling best described vancomycin pharmacokinetics.
- Inclusion of eGFR derived from CysC-based equations significantly improved the pharmacokinetic model fit compared to the bedside Schwartz equation.
- An eGFR equation incorporating both creatinine and CysC yielded the greatest improvement in model fit, indicating superior accuracy.
Conclusions:
- Cystatin C (CysC)-based equations offer a more precise estimation of vancomycin clearance (CL) in critically ill children than the bedside Schwartz equation.
- These findings support the use of CysC-based GFR estimations for optimizing vancomycin therapy in pediatric intensive care settings.
- Improved GFR estimation using CysC can lead to more accurate vancomycin dosing and potentially better patient outcomes.
Background:
Vancomycin is eliminated by glomerular filtration, but current approaches to estimate kidney function in children are unreliable. The authors sought to compare the suitability of cystatin C (CysC)-based glomerular filtration rate equations with the most commonly used creatinine-based equation, bedside Schwartz, to estimate vancomycin clearance (CL).
Methods:
This prospective observational study enrolled critically ill patients (2-18 years) receiving intravenous vancomycin at the Children's Hospital of Philadelphia during December 2015-November 2017. Vancomycin levels were collected during clinical care and at 3 times during a single dosing interval. Plasma CysC was measured within 24 hours before intravenous vancomycin (baseline) initiation or immediately after enrollment and along with the third pharmacokinetic sample. Nonlinear mixed effects modeling was performed using NONMEM software. Covariate selection was used to test model fit with inclusion of the estimated glomerular filtration rate (eGFR) on CL using bedside Schwartz versus various published CysC-based equations.
Results:
In total, 83 vancomycin levels were obtained from 20 children. The median age was 12.7 years; 6 patients were women. A 1-compartment model best described the data; CL was allometrically scaled to 0.75. During covariate selection, inclusion of the eGFR calculated using a CysC-based equation significantly improved model fit [reduction in objective function value (OFV) range: -17.191 to -18.704] than bedside Schwartz ([INCREMENT]OFV -12.820). Including the full age spectrum equation, an eGFR equation based on both creatinine and CysC, led to the largest OFV reduction (-22.913); female sex was also a significant covariate of CL in the model. Final model pharmacokinetic indices were CL = 0.29 L/h/kg and volume of distribution = 0.48 L/kg.
Conclusions:
CysC-based equations help better estimate vancomycin CL than bedside Schwartz in critically ill children.
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