Therapeutic Drug Monitoring of the Echinocandin Antifungal Agents: Is There a Role in Clinical Practice? A Position Statement of the Anti-Infective Drugs Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

PURPOSE: Reduced exposure to echinocandins has been reported in specific patient populations, such as critically ill patients; however, fixed dosing strategies are still used. The present review examines the accumulated evidence supporting echinocandin therapeutic drug monitoring (TDM) and summarizes available assays and sampling strategies. METHODS: A literature search was conducted using PubMed in December 2020, with search terms such as echinocandins, anidulafungin, caspofungin, micafungin, or rezafungin with pharmacology, pharmacokinetics (PKs), pharmacodynamics (PDs), drug-drug interactions, TDM, resistance, drug susceptibility testing, toxicity, adverse drug reactions, bioanalysis, chromatography, and mass spectrometry. Data on PD/PD (PK/PD) outcome markers, drug resistance, PK variability, drug-drug interactions, assays, and TDM sampling strategies were summarized. RESULTS: Echinocandins demonstrate drug exposure-efficacy relationships, and maximum concentration/minimal inhibitory concentration ratio (Cmax/MIC) and area under the concentration-time curve/MIC ratio (AUC/MIC) are proposed PK/PD markers for clinical response. The relationship between drug exposure and toxicity remains poorly clarified. TDM could be valuable in patients at risk of low drug exposure, such as those with critical illness and/or obesity. TDM of echinocandins may also be useful in patients with moderate liver impairment, drug-drug interactions, hypoalbuminemia, and those undergoing extracorporeal membrane oxygenation, as these conditions are associated with altered exposure to caspofungin and/or micafungin. Assays are available to measure anidulafungin, micafungin, and caspofungin concentrations. A limited-sampling strategy for anidulafungin has been reported. CONCLUSIONS: Echinocandin TDM should be considered in patients at known risk of suboptimal drug exposure. However, for implementing TDM, clinical validation of PK/PD targets is needed.

From Therapeutic Drug Monitoring to Model-Informed Precision Dosing for Antibiotics.

Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have evolved as important tools to inform rational dosing of antibiotics in individual patients with infections. In particular, critically ill patients display altered, highly variable pharmacokinetics and often suffer from infections caused by less susceptible bacteria. Consequently, TDM has been used to individualize dosing in this patient group for many years. More recently, there has been increasing research on the use of MIPD software to streamline the TDM process, which can increase the flexibility and precision of dose individualization but also requires adequate model validation and re-evaluation of existing workflows. In parallel, new minimally invasive and noninvasive technologies such as microneedle-based sensors are being developed, which-together with MIPD software-have the potential to revolutionize how patients are dosed with antibiotics. Nonetheless, carefully designed clinical trials to evaluate the benefit of TDM and MIPD approaches are still sparse, but are critically needed to justify the implementation of TDM and MIPD in clinical practice. The present review summarizes the clinical pharmacology of antibiotics, conventional TDM and MIPD approaches, and evidence of the value of TDM/MIPD for aminoglycosides, beta-lactams, glycopeptides, and linezolid, for which precision dosing approaches have been recommended.