Antifungal Therapeutic Drug Monitoring: Established and Emerging Indications

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Abstract
The successful management of invasive fungal infections continues to pose a difficult challenge to clinicians. As the population of at-risk immunocompromised patients increases, the incidence of invasive mycosis has risen in parallel (57). Despite recent advances in antifungal pharmacology, the mor- bidity and mortality due to invasive fungal infections remain unacceptably high. Numerous factors determine the outcome of these infec- tions, including the host immune state, pathogen variables including drug susceptibility, location of the infection, timing of diagnosis relative to initiation of antifungal therapy, man- agement of the infection source (e.g., surgery or vascular cath- eter removal), and effective administration of the appropriate dose of the most potent and safe antifungal drug (Fig. 1). Few of these variables are under the control of the clinician. The choices of antifungal drug and dosing regimen are among the factors which the clinician can dictate. However, even if the appropriate drug and regimen are initiated, drug exposure at the site of infection may be inadequate due to pharmacokinetic variability and may contribute to treatment failure. Conversely, antifungal exposures may exceed those anticipated and may result in toxicity. Many antifungal drugs exhibit marked vari- ability in drug blood concentrations due to inconsistent absorp- tion, metabolism, elimination, or interaction with concomitant medications. An understanding of the pharmacokinetics and pharmacodynamics of these drugs has been demonstrated to be important to optimize drug choice and dosing regimen design. One tool to detect drug exposures outside of the ther- apeutic window is monitoring of drug concentration in blood. The utility of this tool to inform drug choice and dosing deci- sions is being increasingly explored. Several factors must be considered in determining the role of therapeutic drug monitoring in patient management (32, 86, 88). An accurate, rapid, and cost-effective drug assay must be readily available to the clinician. Two pharmacological features then determine the relevance of monitoring of concentrations of drug in blood. The foremost variable is an unpredictable drug dose-exposure relationship. Next, there must be a clear relationship between concentrations of drug in blood and ei- ther toxicity or treatment efficacy. Consideration of these phar- macological variables for available antifungal compounds is the focus of this review.