Pharmacokinetics and pharmacodynamics of antifungals in children and their clinical implications

Abstract

Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of the causative pathogen, appropriate antifungal selection, and optimisation of its pharmacokinetic and pharmacodynamic properties to maximise its antifungal activity and minimise toxicity and the emergence of resistance. This review highlights salient scientific advancements in paediatric antifungal pharmacotherapies and focuses on pharmacokinetic and pharmacodynamic studies that underpin current clinical decision making. Four classes of drugs are widely used in the treatment of invasive fungal infections in children, including the polyenes, triazoles, pyrimidine analogues and echinocandins. Several lipidic formulations of the polyene amphotericin B have substantially reduced the toxicity associated with the traditional amphotericin B formulation. Monotherapy with the pyrimidine analogue flucytosine rapidly promotes the emergence of resistance and cannot be recommended. However, when used in combination with other antifungal agents, therapeutic drug monitoring of flucytosine has been shown to reduce high peak flucytosine concentrations, which are strongly associated with toxicity. The triazoles feature large inter-individual pharmacokinetic variability, although this pattern is less pronounced with fluconazole. In clinical trials, posaconazole was associated with fewer adverse effects than other members of the triazole family, though both posaconazole and itraconazole display erratic absorption that is influenced by gastric pH and the gastric emptying rate. Limited data suggest that the clinical response to therapy may be improved with higher plasma posaconazole and itraconazole concentrations. For voriconazole, pharmacokinetic studies among children have revealed that children require twice the recommended adult dose to achieve comparable blood concentrations. Voriconazole clearance is also affected by the cytochrome P450 (CYP) 2C19 genotype and hepatic impairment. Therapeutic drug monitoring is recommended as voriconazole pharmacokinetics are highly variable and small dose increases can result in marked changes in plasma concentrations. For the echinocandins, the primary source of pharmacokinetic variability stems from an age-dependent decrease in clearance with increasing age. Consequently, young children require larger doses per kilogram of body weight than older children and adults. Routine therapeutic drug monitoring for the echinocandins is not recommended. The effectiveness of many systemic antifungal agents has been correlated with pharmacodynamic targets in in vitro and in murine models of invasive candidiasis and aspergillosis. Further study is needed to translate these findings into optimal dosing regimens for children and to understand how these agents interact when multiple antifungal agents are used in combination.

Fig. 1

The four most common classes of systemic antifungal agents used in the treatment of invasive fungal infections and their mechanisms of action

Fig. 2

Antifungal pharmacodynamics in murine models of invasive candidiasis. a Amphotericin B dose fractionation studies for three dosing intervals and the log₁₀ colony-forming units per gram of kidney in a neutropenic mouse model of disseminated candidiasis (data from Andes et al. [15]). b Flucytosine dose fractionation studies for four dosing intervals and the mean Candida density in the kidneys of neutropenic mice (data from Andes and van Ogtrop [12]). c Fluconazole dose fractionation studies for three dosing intervals and mean fungal density in the kidneys of mice with invasive candidiasis (data from Louie et al. [13]). d Anidulafungin dose fractionation studies for four dosing intervals and the mean change in Candida density in the kidneys of neutropenic mice with invasive candidiasis (data from Andes [24]). CFU colony-forming units, qx hrs every x hours