Fluconazole

The introduction of fluconazole in 1990 was a breakthrough in antifungal pharmacotherapy. Fluconazole is highly bioavailable, available in both oral and IV formulations, and active against many species of Candida and other yeasts. Prior to fluconazole’s approval, clinicians were faced with the toxicity and inconvenience of amphotericin B for serious forms of candidiasis. Fluconazole has a low incidence of serious adverse reactions, converting from IV to oral therapy is simple, and there are no limitations with regards to food or antacid therapy (Table 31-1). Though a shift toward non-albicans species of Candida has affected the utility of fluconazole, it remains an important, frequently utilized agent. The primary limitation to fluconazole’s use is its lack of activity against molds such as Aspergillus.

Important Facts

• Fluconazole has no activity against C krusei, rare activity against C auris, and variable activity against C glabrata. Use against C glabrata should generally be only when fluconazole susceptibility has been documented, and can require doses of 800 mg/day of fluconazole after a loading dose. If your lab does not do susceptibility testing of fungi, consider an alternative agent such as an echinocandin.
• Fluconazole is often given as prophylaxis against Candida infections in susceptible populations like intensive care unit patients or patients with some cancers. Are you treating a patient who was receiving fluconazole prophylaxis and now has yeast in the blood? Try an echinocandin instead (since they may have fluconazole-resistant Candida). Even species of Candida that are normally susceptible to fluconazole (e.g., C albicans) can be resistant if the patient has recently received extended fluconazole prophylaxis.
• The high bioavailability of fluconazole (1:1 IV:po dosing) makes it an excellent therapy to transition to as patients tolerate oral medications.

What It’s Good For

Fluconazole remains a drug of choice for many susceptible fungal infections, including invasive and noninvasive candidiasis and cryptococcal disease. It is also used for some dimorphic fungal infections, such as coccidioidomycosis.

Don’t Forget!

Not all species of Candida are fluconazole-susceptible. Ensure that you check your patient’s isolate before committing to a definitive course of therapy with it.

All azoles inhibit fungal cytochrome P450 14-alpha demethylase, inhibiting the conversion of lanosterol into ergosterol, which is a component of the fungal cell membrane.

• Good: Candida albicans, Candida tropicalis, Candida parapsilosis, Candida lusitaniae, Cryptococcus neoformans, Coccidioides immitis
• Moderate: Candida glabrata (can be susceptible dose-dependent, or resistant)
• Poor: Molds, many dimorphic fungi, Candida krusei, Candida auris

Though fluconazole is generally well tolerated, hepatotoxicity is a concern and should be monitored for courses longer than a few days. As with all azoles, interactions with many drugs metabolized by the cytochrome P450 system are possible. Prolongation of the corrected QT interval (QTc) can be seen, and patients with risk factors for cardiac arrhythmias may require ECG monitoring.

Fluconazole doses for systemic fungal infections may be escalated, particularly for the treatment of C glabrata or Coccidioides infections. Be sure to adjust dosing with regard to renal function, because the drug has a significant component of renal elimination (unlike other azoles). Vulvovaginal candidiasis requires only a one-time dose of 150 mg of fluconazole.