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Fluconazole is primarily used to treat systemic fungal infections due to its effectiveness against a variety of fungi, particularly Candida and Cryptococcus species. Its oral bioavailability and central nervous system penetration make it particularly useful for treating conditions like cryptococcal meningitis and candidemia. The drug works by inhibiting the synthesis of ergosterol, an essential component of fungal cell membranes, leading to cell death.

Other antifungal agents, such as nystatin, are typically used for superficial infections and are not effective for systemic treatment. Ketoconazole, while also used for systemic infections, has been largely replaced by fluconazole due to side effects and drug interactions. Voriconazole is another potent antifungal agent, primarily used for invasive aspergillosis and other serious fungal infections; however, fluconazole is more commonly the first-line treatment for systemic infections in a broader range of contexts. Thus, fluconazole stands out as the primary choice for treating systemic fungal infections.