Clinical Pharmacokinetics of Vancomycin in Critically Ill Children

Abstract

Background and objective: Critically ill children exhibit altered pharmacokinetic parameters of vancomycin, mainly due to altered renal excretion and volume of distribution (as a result of altered plasma protein concentrations). We assessed the pharmacokinetic parameters of vancomycin in this subpopulation.

Methods: Vancomycin trough concentrations in critically ill children were obtained following first dose and at steady state. Using a one-compartment model, clearance (CL), volume of distribution (Vd), elimination half-life (t_1/2), and area under the time-concentration curve for 24 h (AUC_0-24) were estimated. Subgroup analyses were carried out, with patients differentiated based on age, renal clearance, outcome, and renal dysfunction. Protein-free vancomycin concentrations were calculated using a previously reported formula.

Results: Twenty-two samples were evaluated for first-dose and 182 for steady-state pharmacokinetics, and similar pharmacokinetic parameter values were observed at first dose and at steady state. Only 36.4% and 47.3% of the samples attained the recommended AUC_0-24 (mg·hr/L) of > 400 at first dose and at steady state, while 62.5% of the patients with renal dysfunction achieved this target. Nearly 40% of the patients had augmented renal clearance (ARC), which was associated with higher CL, shorter t_1/2, and lower AUC values. Amongst the patients with ARC, none had AUC_0-24 (mg·hr/L) > 400 at first dose, while 16% achieved this target at steady state. Volume of distribution was significantly higher in infants and a decreasing trend was observed in toddlers, children, and older children at steady state. Children with renal dysfunction had lower CL, prolonged t_1/2, and higher AUC values than patients with normal renal clearance at first dose. A good correlation was observed between trough concentration and AUC_0-24, as corroborated by the area under the receiver operating characteristic curve. The median fraction of protein-free vancomycin was around 77%.

Conclusion: Vancomycin dosing strategies in younger children should be revisited, and increased doses should be considered for critically ill children with ARC in order to achieve therapeutic concentrations of AUC_0-24.