Precision dosing of systemic antifungals in adults: therapeutic drug monitoring, empiric dose optimization and barriers to implementation

Therapeutic drug monitoring (TDM) is essential for optimizing systemic antifungal therapy, particularly for agents with narrow therapeutic windows, variable pharmacokinetics (PK) or established exposure-response relationships. By enabling individualized dosing, TDM improves efficacy, reduces toxicity and helps prevent resistance. This review synthesizes current evidence and recommendations for antifungal TDM across available and emerging agents, including triazoles, flucytosine, echinocandins, amphotericin B, and novel therapies such as ibrexafungerp, olorofim and fosmanogepix. Voriconazole, posaconazole and itraconazole exhibit substantial interpatient variability and concentration-dependent toxicity, supporting routine TDM. Fluconazole is generally predictable but may warrant monitoring in critically ill patients, those on renal replacement therapy, or with central nervous system infections, though empiric dose escalation is often more practical. Isavuconazole has more stable PK, limiting TDM to select high-risk scenarios. Flucytosine requires TDM due to its narrow therapeutic index and resistance risk, particularly in renal impairment. Echinocandins are safe, but critically ill or obese patients may be underexposed, warranting empiric dose adjustments over routine TDM. Liposomal amphotericin B exhibits complex PK with plasma concentrations poorly reflecting active drug, precluding reliable TDM. Emerging antifungals lack sufficient data to support routine TDM. Despite strong justification, real-world utilization remains inconsistent, constrained by access, logistics and interpretive challenges. Expanding timely access, standardizing protocols and developing consensus-driven guidance, while using empiric dosing strategies where appropriate, are essential to ensure safe, effective and individualized antifungal therapy.