Which systemic antifungal is least likely to cause hepatotoxicity?

The reason why echinocandins are considered the systemic antifungal agents least likely to cause hepatotoxicity is due to their distinct mechanism of action and metabolic pathways. Echinocandins target the fungal cell wall by inhibiting the synthesis of beta-(1,3)-D-glucan, an essential component in many pathogenic fungi. This mode of action is different from azoles, polyenes, and allylamines, which primarily affect fungal cell membranes or cellular processes that are more likely to interact with liver enzymes.

Echinocandins are predominantly cleared by non-hepatic routes, such as being metabolized by nonspecific proteolytic enzymes and excreted mainly by the kidneys. This reduces the burden on the liver and minimizes the risk of liver enzyme elevation or hepatotoxicity, which is a concern with other antifungal classes. In contrast, azoles, polyenes, and allylamines can have varying degrees of hepatic involvement in their metabolism or clearance, making them more prone to causing liver-related side effects in certain patients, especially those with preexisting liver conditions or when used with other hepatotoxic medications.