Hepatotoxicity of Antifungal Agents in Invasive Mycoses

The management of invasive mycoses relies heavily on systemic antifungal agents, yet their use is frequently complicated by liver injury. Hepatotoxicity manifests through elevations in transaminases, cholestatic patterns or fulminant liver failure, with severity influenced by drug class, dosage, treatment duration and host factors such as pre-existing liver disease or concomitant medications. Azoles, notably voriconazole and itraconazole, carry the highest risk, owing to extensive hepatic metabolism via the cytochrome P450 system and generation of reactive metabolites. Echinocandins and amphotericin formulations exhibit comparatively lower hepatotoxic potential but remain not entirely devoid of risk, especially in high-dose or prolonged regimens. Pharmacokinetic variability, drug–drug interactions and genetic polymorphisms further modulate exposure and toxicity. In response, therapeutic drug monitoring and adaptive dosing strategies have gained prominence, alongside in vitro cytotoxicity profiling and real-world pharmacovigilance, to optimise efficacy while mitigating liver injury. Understanding the mechanistic basis of antifungal hepatotoxicity and refining clinical management remain global priorities, particularly in immunocompromised and critically ill populations.

Research from Nature Portfolio

Recent studies using large pharmacovigilance databases have delineated specific safety signals for triazole antifungals. Disproportionality analysis of spontaneous adverse-event reports identified a strong association between long-term voriconazole use and periostitis, implicating fluoride accumulation and skeletal toxicity, while no comparable signals emerged for other triazoles. This work underscores the value of real-world data mining to uncover uncommon but clinically significant hepatic or skeletal adverse effects, informing vigilant monitoring and alternative antifungal selection when warranted.

Hepatotoxicity of Antifungal Agents in Invasive Mycoses publication trend

The graph below shows the total number of articles in hepatotoxicity of antifungal agents in invasive mycoses across all publications each year (not limited to Nature Index journals).

Technical terms

Hepatotoxicity: Liver injury caused by chemical agents, characterised by altered liver enzymes, cholestasis or hepatic failure.

Azoles: Antifungal class that inhibits ergosterol synthesis via fungal cytochrome P450, prone to drug interactions and metabolic liabilities.

Echinocandins: Lipopeptide antifungals that block β-1,3-D-glucan synthesis in fungal cell walls, with lower hepatic metabolism.

Drug-induced liver injury (DILI): Adverse hepatic reaction to medications, ranging from mild enzyme elevation to fulminant failure.

Therapeutic drug monitoring: Measurement of drug concentrations to optimise dosage and reduce toxicity, especially for agents with narrow therapeutic windows.

References

1. Using disproportionality analysis to explore the association between periostitis and triazole antifungals in the FDA Adverse Event Reporting System Database. Scientific Reports (2023).
2. Pre-Existing Liver Disease and Toxicity of Antifungals. Journal of Fungi (2018).
3. Antifungal Drugs and Drug-Induced Liver Injury: A Real-World Study Leveraging the FDA Adverse Event Reporting System Database. Frontiers in Pharmacology (2022).
4. Hepatotoxicity of Antimycotics Used for Invasive Fungal Infections: In Vitro Results. BioMed Research International (2017).