Systemic Antifungals

Introduction

Most forms of systemic or disseminated fungal infections, including aspergillosis, candidiasis, cryptococcosis, and histoplasmosis, typically require systemic antifungal treatment.

Azole Antifungals

Triazole antifungal drugs have a role in the prevention and systemic treatment of fungal infections, but the coverage and indications vary widely.

• Of the azoles, fluconazole has the narrowest spectrum and posaconazole has the broadest. They all have similar activity against most Candida spp.
• Fluconazole and voriconazole penetrate the CNS adequately to treat fungal meningitis.
• Fluconazole is excreted largely unchanged in the urine and can be used to treat candiduria.
• Oral ketoconazole has been withdrawn from the market due to the risk of severe hepatotoxicity (incidence and severity appears to be higher compared to the other azoles). Itraconazole has been associated with liver damage and should be avoided or used with caution in patients with liver disease; fluconazole is less frequently associated with hepatotoxicity.
• Voriconazole is the treatment of choice for aspergillosis; amphotericin B is an alternative.
• Oral preparations of itraconazole and posaconazole are not bioequivalent.
• Azoles have many clinically significant drug interactions.

Polyene Antifungals

Nystatin is mainly active against Candida species.

• It is poorly absorbed orally and is not absorbed through skin or mucous membranes when applied topically.
• Nystatin is used for oral, oropharyngeal and perioral infections by local application in the mouth, and for Candida albicans infection of the skin when applied topically.

Amphotericin B is active against a wide range of yeasts (including Candida and Cryptococcus species) and other fungi (including most Aspergillus species, but not A. terreus or A. nidulans), some Fusarium species, zygomycetes and phaeohyphomycetes, and Leishmania species.

• Amphotericin B is associated with significant toxicity, including infusion-related adverse effects, nephrotoxicity, electrolyte abnormalities (especially hypokalemia and hypomagnesemia) and anaemia; monitoring is essential.
• Lipid formulations of amphotericin B (Abelcet and AmBisome) are significantly less toxic and are recommended when the conventional formulation of amphotericin B is contraindicated because of toxicity, especially nephrotoxicity or when response to conventional amphotericin B is inadequate.

Echinocandins

The echinocandins anidulafungin, caspofungin and micafungin are active against most Candida species (including strains resistant to azoles and amphotericin B), and are used for treatment of severe candidal infection.

• Also active against Aspergillus spp. although only caspofungin is marketed to treat aspergillus infections (second line).
• Echinocandins are generally well tolerated and have similar safety and efficacy profiles.
• Anidulafungin is not hepatically metabolised and may be preferred in patients with severe hepatic impairment.

Other Antifungals

Flucytosine is used with amphotericin B in a synergistic combination for treatment of systemic candidiasis and cryptococcal meningitis.

• Due to the development of resistance, flucytosine should not be used alone.
• Dose-related bone marrow myelosuppression can occur which limits its use, particularly in HIV-positive patients; weekly blood counts are necessary during prolonged therapy.

Griseofulvin has a narrow antifungal spectrum (largely confined to dermatophyte infections, such as tinea corporis, tinea capitis, tinea unguium, tinea pedis, tinea cruris), is less effective than other systemic drugs (e.g. itraconazole, terbinafine) and requires prolonged courses.

• The use has been superseded by newer antifungals (e.g. itraconazole, terbinafine), particularly for nail infections.
• Administer with fatty food to increase absorption.

Terbinafine is the drug of choice for fungal nail infections and is also used for ringworm infections where oral treatment is considered appropriate.

• With oral use, discontinue treatment if liver toxicity develops (including jaundice, cholestasis and hepatitis) or in progressive skin rash (including Stevens-Johnson syndrome and toxic epidermal necrolysis.