Dose optimisation of antibiotics in children: application of pharmacokinetics/pharmacodynamics in paediatrics

Abstract

The judicious use of antibiotics to combat infections in children relies upon appropriate selection of an agent, dose and duration to maximise efficacy and to minimise toxicity. Critical to dose optimisation is an understanding of the pharmacokinetics and pharmacodynamics of available drugs. Optimal dosing strategies may take advantage of pharmacokinetic/pharmacodynamic (PK/PD) principles so that antibiotic dosing can be individualised to assure effective bacterial killing in patients who have altered pharmacokinetics or who have infections with less susceptible or resistant organisms. This review will outline the fundamentals of antimicrobial pharmacokinetics/pharmacodynamics through discussion of antibacterial agents most often used in children. We aim to highlight the importance of dose optimisation in paediatrics and describe non-conventional dosing strategies that can take advantage of PK/PD principles at the bedside.

Keywords: Antibiotics; Dose optimisation; PK/PD; Pharmacodynamics; Pharmacokinetics.

Fig. 1

Pharmacokinetic/pharmacodynamic (PK/PD) relationships between antibiotic concentrations relative to the minimum inhibitory concentration (MIC) over time. Three principle PK/PD parameters most often correlate with the clinical efficacy of different antibiotic classes: (1) maximum concentration (C_max)/MIC ratio for concentration-dependent drugs; (2) percentage of the dosing interval above the MIC (T_>MIC) for time-dependent drugs with minimal-to-no persistent effects; and (3) area under the concentration–time curve (AUC, shaded area)/MIC ratio for time-dependent drugs with moderate-to-prolonged persistent effects.

Fig. 2

Time above the minimum inhibitory concentration (MIC) for intermittent, extended and continuous infusion of time-dependent drugs. Extended or continuous infusion of time-dependent drugs can improve the percentage of the dosing interval above the MIC (T_>MIC), particularly when treating infections with elevated MICs. Intermittent infusion (solid line), extended infusion (dashed line) and continuous infusion (dotted line) are compared with the time that each dosing regimen is below the MIC, highlighted by the grey area. Curves were generated using the same total daily dose and consistent pharmacokinetic parameters for each regimen.