The population of immunocompromised children at risk for invasive fungal disease continues to grow. This population includes children with primary and acquired immune deficiencies, recipients of solid-organ and stem cell transplants, children with malignancy receiving chemotherapy agents, and those with autoinflammatory or autoimmune conditions receiving immune-modulating therapies. Fortunately, in conjunction with this growth, there has been a steady growth in the armamentarium of antifungal agents, including development of new classes of antifungal agents (e.g., echinocandins), as well as newer generations of an older antifungal class, the azoles. Despite the increase in number of antifungal agents, the fungal pathogens encountered in children are variable and often responsive to only a select number of antifungal agents. Coupled with the risk of significant drug–drug interactions, therapeutic options available to a clinician for a given clinical scenario are limited.
This chapter provides an overview of the pharmacokinetics for and empiric coverage provided by each of the antifungal agents with a focus on treatment of invasive fungal disease in immunocompromised hosts. Guidance for cutaneous infections commonly seen in otherwise healthy children is also provided. There are limited in vitro sensitivity data for many fungal pathogens, and so the recommendations in this chapter should be considered only as a guide for clinical care. The clinical management of children with invasive fungal disease should be done with the support of an experienced infectious diseases clinician and clinical pharmacist.
PRINCIPLES OF ANTIFUNGAL THERAPY
PHARMACOKINETICS AND PHARMACODYNAMICS
It has been close to seven decades since the first antifungal agents became available for clinical use, with a marked increase in the number of available systemic antifungal agents during the last 30 years. Although the development of these agents has greatly enhanced the armamentarium of clinicians treating invasive fungal disease, the optimal pediatric dose for many of these agents remains elusive. The dearth of pediatric-specific pharmacokinetic and pharmacodynamic (PK/PD) data is at least in part related to the variation in PK/PD parameters across different pediatric subgroups, including premature infants, neonates, children, and adolescents.
Often pediatric-specific PK studies are performed to match drug exposures that would be consistent with those of adults.1 This approach is often ignorant of complexities relevant to drug dosing with specific pediatric subgroups. Mandates from the FDA for pharmaceutical drug companies to pursue pediatric specific PK/PD data at the time of drug approval have helped accelerate availability of pediatric data for novel antifungal agents, however, even with these novel agents the available data are limited. Ultimately, therapeutic drug monitoring is a key component of the utilization of many of the available antifungal agents. In particular, drug monitoring for flucytosine, itraconazole, posaconazole, and voriconazole is beneficial to both optimize effectiveness and reduce toxicity.2
In addition to being knowledgeable about pediatric-specific dosing regimens, clinicians prescribing antifungal agents to children also need to be keenly aware of potential drug–drug interactions and to understand ...