Key Facts

Antifungal prescribing ranges from topical agents for superficial infections to potent systemic drugs for life-threatening invasive mycoses. Understanding the spectrum, pharmacokinetics, and toxicity of each class is essential for safe and effective prescribing.

Classification and Mechanism

• Azoles: inhibit ergosterol synthesis (lanosterol 14α-demethylase/CYP51) → fungistatic
• Polyenes (amphotericin B, nystatin): bind ergosterol → pore formation → cell lysis → fungicidal
• Echinocandins (caspofungin, anidulafungin, micafungin): inhibit β-1,3-glucan synthase → cell wall disruption → fungicidal (Candida), fungistatic (Aspergillus)
• Allylamines (terbinafine): inhibit squalene epoxidase → block ergosterol synthesis → fungicidal
• Flucytosine (5-FC): pyrimidine analogue → inhibits DNA/RNA synthesis; always used in combination (resistance develops rapidly alone)

Pathophysiology

• Fungal cell membrane contains ergosterol (equivalent to cholesterol in human cells)
• Most antifungals target ergosterol synthesis or function → selective toxicity
• Amphotericin B: also binds human cholesterol → significant nephrotoxicity

Indications by Drug

• Fluconazole: vaginal/oropharyngeal/oesophageal candidiasis, invasive candidiasis, cryptococcal meningitis
• Itraconazole: dermatophytes, sporotrichosis, allergic bronchopulmonary aspergillosis (ABPA), onychomycosis
• Voriconazole: invasive aspergillosis (first-line), Scedosporium, Fusarium
• Posaconazole: prophylaxis in haem-onc patients; mucormycosis (with amphotericin B)
• Amphotericin B: invasive fungal infections unresponsive to azoles; mucormycosis; cryptococcal meningitis (induction)
• Caspofungin: invasive candidiasis (first-line in critically ill); empirical antifungal in febrile neutropenia
• Terbinafine: dermatophyte infections — tinea capitis, onychomycosis
• Nystatin: topical/oral Candida (oral suspension for thrush — 100,000 units QDS)

Major Side Effects

• Azoles: hepatotoxicity (monitor LFTs), GI upset, drug interactions (CYP inhibition)
• Voriconazole: visual disturbances (photopsia — ~30%), photosensitivity, hepatotoxicity, periostitis
• Amphotericin B: nephrotoxicity (dose-limiting), hypokalaemia, hypomagnesaemia, fever/rigors, anaemia
• Terbinafine: hepatotoxicity, taste disturbance, rash
• Echinocandins: generally well-tolerated; histamine-related reactions, hepatotoxicity (rare)

Red Flags

• Rising creatinine on amphotericin B → switch to liposomal formulation or alternative
• Deranged LFTs on azoles/terbinafine → stop and investigate
• Visual symptoms on voriconazole → common but reversible; monitor
• Drug interaction alert → check CYP450 interactions before starting any azole

Before Starting

• LFTs: baseline before azoles and terbinafine; monitor regularly
• U&Es: renal function before amphotericin B; monitor closely during treatment
• Drug interaction check: essential for all azoles (BNF interactions)
• Fungal culture/sensitivity: guide therapy where possible

During Treatment

• TDM: voriconazole (trough 1–5.5 mg/L), itraconazole (trough >1 mg/L), flucytosine
• LFTs: weekly–fortnightly for first 2 months of azole/terbinafine
• U&Es, Mg2+, K+: twice-weekly during amphotericin B
• FBC: monitor for anaemia (amphotericin B)

Special Tests

• Galactomannan antigen: Aspergillus biomarker — monitor response to treatment
• Beta-D-glucan: pan-fungal biomarker
• Fungal PCR: species identification

Topical Antifungals

• Clotrimazole 1% cream BD: first-line for localised superficial dermatophyte/candidal infection
• Nystatin 100,000 units/mL oral suspension QDS: oral candidiasis
• Ketoconazole 2% shampoo: pityriasis versicolor, seborrhoeic dermatitis

Systemic Antifungals

• Terbinafine 250 mg OD: dermatophytes — onychomycosis (6–12 weeks), tinea capitis (4–6 weeks)
• Fluconazole 50–200 mg OD: mucosal candidiasis; 400 mg/day for invasive candidaemia; 200 mg/day maintenance for cryptococcal meningitis
• Itraconazole 200 mg OD-BD: ABPA, sporotrichosis, histoplasmosis; pulse dosing for onychomycosis
• Voriconazole 200–300 mg BD: invasive aspergillosis — loading dose 6 mg/kg BD day 1, then 4 mg/kg BD
• Caspofungin 70 mg IV day 1, then 50 mg OD: invasive candidiasis, empirical neutropenic fever
• Liposomal amphotericin B 3–5 mg/kg/day IV: mucormycosis, severe invasive fungal infection
• Flucytosine 25 mg/kg QDS: always in combination (with amphotericin B for cryptococcal meningitis)

Referral Criteria

• Microbiology/infectious diseases: invasive fungal infections, treatment failure
• Haematology: fungal prophylaxis in neutropenic patients
• Dermatology: resistant superficial fungal infections

• Superficial infections: excellent prognosis with appropriate treatment
• Invasive candidiasis: mortality ~30–40% (higher in critically ill); echinocandins improve outcomes
• Invasive aspergillosis: mortality ~30–50%; improved with early voriconazole
• Mucormycosis: mortality ~40–80%; requires surgical debridement + amphotericin B
• Cryptococcal meningitis: mortality ~10–20% in HIV with appropriate treatment (higher without ART)
• Drug toxicity (amphotericin B nephrotoxicity): usually reversible if recognised early

Antifungal Drug Comparison

Azole CYP450 Interactions