All azole drugs are prone to drug interactions because they affect the mammalian cytochrome P450 enzyme system to some extent. The most significant reactions are indicated below.
Ketoconazole was the first oral azole introduced into clinical use. It is distinguished from triazoles by its greater propensity to inhibit mammalian cytochrome P450 enzymes; that is, it is less selective for fungal P450 than are the newer azoles. As a result, systemic ketoconazole has fallen out of clinical use in the USA and is not discussed in any detail here. It is no longer recommended for the treatment of fungal nail or skin infections.
Itraconazole is available in oral and intravenous formulations and is used at a dosage of 100–400 mg/d. Drug absorption from capsules is increased by food and by low gastric pH. Like other lipid-soluble azoles, it interacts with hepatic microsomal enzymes, though to a lesser degree than ketoconazole. An important drug interaction is reduced bioavailability of itraconazole when taken with rifamycins (rifampin, rifabutin, rifapentine). It does not affect mammalian steroid synthesis, and its effects on the metabolism of other hepatically cleared medications are much less than those of ketoconazole. While itraconazole displays potent antifungal activity, effectiveness can be limited by reduced bioavailability. Newer formulations, including an oral liquid and an intravenous preparation, have utilized cyclodextrin as a carrier molecule to enhance solubility and bioavailability. Like ketoconazole, itraconazole penetrates poorly into the cerebrospinal fluid. Itraconazole is the azole of choice for treatment of disease due to the dimorphic fungi Histoplasma, Blastomyces, and Sporothrix. Itraconazole has activity against Aspergillus sp, but it has been replaced by voriconazole as the azole of choice for aspergillosis. Itraconazole is used extensively in the treatment of dermatophytoses and onychomycosis.
Fluconazole displays a high degree of water solubility and good cerebrospinal fluid penetration. Unlike ketoconazole and itraconazole, its oral bioavailability is high. Drug interactions are also less common because fluconazole has the least effect of all the azoles on hepatic microsomal enzymes. Because of fewer hepatic enzyme interactions and better gastrointestinal tolerance, fluconazole has the widest therapeutic index of the azoles, permitting more aggressive dosing in a variety of fungal infections. The drug is available in oral and intravenous formulations and is used at a dosage of 100–800 mg/d.
Fluconazole is the azole of choice in the treatment and secondary prophylaxis of cryptococcal meningitis. Intravenous fluconazole has been shown to be equivalent to amphotericin B in treatment of candidemia in ICU patients with normal white blood cell counts, although echinocandins may have superior activity for this indication. Fluconazole is the agent most commonly used for the treatment of mucocutaneous candidiasis. Activity against the dimorphic fungi is mainly limited to coccidioidal disease, and in particular for meningitis, where high doses of fluconazole often obviate the need for intrathecal amphotericin B. Fluconazole displays no activity against Aspergillus or other filamentous fungi.
Prophylactic use of fluconazole has been demonstrated to reduce fungal disease in bone marrow transplant recipients and AIDS patients, but the emergence of fluconazole-resistant fungi has raised concerns about this indication.