Antifungal Drugs

Antifungal drugs treat fungal infections, which range from superficial dermatophytosis and candidiasis to life-threatening invasive disease such as cryptococcal meningitis, invasive aspergillosis and candidaemia. Few classes exist because fungal cells are eukaryotic, so targets are restricted to ergosterol, the cell wall and a small number of fungal-specific enzymes.

Mechanism by class.

• Polyenes (amphotericin B, nystatin): bind ergosterol and form membrane pores. Fungicidal.
• Azoles (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole): inhibit lanosterol 14-alpha-demethylase, blocking ergosterol synthesis. Fungistatic against yeasts, fungicidal against Aspergillus for the mould-active agents.
• Echinocandins (caspofungin, micafungin, anidulafungin): inhibit beta-1,3-D-glucan synthase in the cell wall. Fungicidal against Candida.
• Allylamines (terbinafine): inhibit squalene epoxidase. Fungicidal against dermatophytes.
• Flucytosine: converted to 5-fluorouracil in fungal cells, inhibiting DNA and RNA synthesis.
• Griseofulvin: disrupts microtubules in dermatophytes.

• Yeast infections (Candida, Cryptococcus): fluconazole is first-line for most mucosal disease; amphotericin B with flucytosine for cryptococcal meningitis; echinocandins for invasive candidiasis.
• Mould infections (Aspergillus): voriconazole or isavuconazole first-line; liposomal amphotericin B alternative; mucormycosis needs liposomal amphotericin B or isavuconazole or posaconazole, since voriconazole and echinocandins are inactive.
• Endemic mycoses (histoplasmosis): liposomal amphotericin B then itraconazole.
• Dermatophytes: topical azoles or terbinafine; oral terbinafine, itraconazole or griseofulvin for scalp, nail and extensive disease.
• Flucytosine: 25 mg/kg every 6 hours, never alone, with dose reduction in kidney impairment; marrow toxicity.

Spectrum gaps. Fluconazole is inactive against Aspergillus and Candida krusei. Echinocandins are inactive against Cryptococcus and have poor penetration into the brain, urine and vitreous. Terbinafine and griseofulvin act against dermatophytes only.

Invasive candidiasis. An echinocandin first (caspofungin 70 mg loading then 50 mg daily, or micafungin 100 mg daily). Step down to fluconazole 400 mg daily (800 mg loading) when the isolate is susceptible and the patient is stable. Continue for 14 days after the first negative blood culture.

Cryptococcal meningitis. Induction with single-dose liposomal amphotericin B 10 mg/kg plus flucytosine 100 mg/kg daily and fluconazole 1200 mg daily for 14 days, or a 7-day regimen of amphotericin B with flucytosine. Then fluconazole 800 mg daily for 8 weeks and 200 mg daily maintenance until immune recovery. Repeated lumbar puncture manages raised pressure.

Invasive aspergillosis. Voriconazole 6 mg/kg every 12 hours for 2 doses, then 4 mg/kg every 12 hours (or oral equivalent), adjusted to trough levels, for at least 6 to 12 weeks.

Superficial disease. Topical clotrimazole or terbinafine for localised skin disease; oral terbinafine 250 mg daily for 2 to 4 weeks for tinea corporis and 6 to 12 weeks for nails; griseofulvin 20 to 25 mg/kg daily for 6 to 8 weeks in tinea capitis.

Region. In East Africa, cryptococcal meningitis with advanced HIV disease, histoplasmosis, tinea capitis in children, sporotrichosis, chromoblastomycosis and eumycetoma are common. Flucytosine and liposomal amphotericin B supply is limited and affects regimen choice.

Class safety.

• Amphotericin B: nephrotoxicity, hypokalaemia, hypomagnesaemia, infusion reactions.
• Azoles: hepatotoxicity, QT prolongation, many CYP interactions, teratogenicity.
• Echinocandins: generally well tolerated; infusion reactions, mild liver enzyme rise.
• Flucytosine: marrow suppression, hepatitis, enterocolitis.
• Terbinafine: taste disturbance, rare hepatotoxicity.

Monitoring. Liver enzymes baseline and during azole or terbinafine therapy; ECG and electrolytes with QT-prolonging azoles; creatinine, potassium and magnesium daily or at least twice weekly on amphotericin B; full blood count and flucytosine levels (2 hours after dose, target 30 to 80 mg/L); voriconazole trough 1 to 5.5 mg/L.

Special groups.

• Pregnancy: avoid azoles (especially high-dose fluconazole in the first trimester, associated with craniofacial and skeletal malformations); use amphotericin B for invasive disease and topical clotrimazole for superficial disease.
• Breastfeeding: fluconazole is acceptable; amphotericin B and echinocandins are poorly absorbed orally; avoid voriconazole.
• Kidney impairment: halve fluconazole after the loading dose when creatinine clearance is under 50 mL/min; reduce flucytosine; avoid intravenous voriconazole and itraconazole in severe impairment because of the solvent.
• Liver disease: halve voriconazole maintenance in mild to moderate cirrhosis; avoid terbinafine.

Referral and escalation. Refer invasive fungal disease, treatment failure and azole-resistant isolates to infectious diseases or microbiology.