Antifungals
Drugs used to treat fungal infections ranging from superficial dermatophyte and candidal infections to life-threatening invasive mycoses. Key classes include azoles (fluconazole, itraconazole, voriconazole), polyenes (amphotericin B), echinocandins (caspofungin), and allylamines (terbinafine). Drug interactions (CYP450), hepatotoxicity, and nephrotoxicity are major prescribing considerations.
Key Facts
- Azoles: inhibit lanosterol 14-alpha demethylase (CYP51) → impair ergosterol synthesis → fungistatic (mostly)
- Fluconazole 50–400 mg OD: first-line for mucosal/systemic Candida; good CSF penetration; renal excretion; fewer interactions than others
- Itraconazole 100–200 mg OD: broad spectrum (dermatophytes, Aspergillus, Candida); CYP3A4 inhibitor; check LFTs; negative inotrope
- Voriconazole: first-line for invasive aspergillosis; TDM required; visual disturbances, hepatotoxicity, photosensitivity (SCC risk)
- Amphotericin B: polyene; binds ergosterol → pore formation → fungicidal; nephrotoxic - use liposomal formulation to reduce toxicity
- Terbinafine 250 mg OD: allylamine; best for dermatophytes; first-line for onychomycosis and tinea capitis; hepatotoxicity risk; check LFTs
- Echinocandins (caspofungin, anidulafungin): inhibit beta-1,3-glucan synthesis; fungicidal for Candida; first-line for invasive candidiasis in unwell patients
- CYP450 interactions: azoles are potent CYP inhibitors - check BNF interactions before prescribing
Overview
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
Clinical Presentation
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
Differential Diagnosis
| Infection Type | First-Line | Second-Line |
|---|---|---|
| Oropharyngeal candidiasis | Nystatin or fluconazole 50 mg OD | Itraconazole |
| Vulvovaginal candidiasis | Fluconazole 150 mg single dose | Topical clotrimazole |
| Invasive candidiasis | Echinocandin (caspofungin) | Fluconazole (if stable) |
| Invasive aspergillosis | Voriconazole | Liposomal amphotericin B |
| Cryptococcal meningitis | Amphotericin B + flucytosine (induction) | Fluconazole (maintenance) |
| Dermatophytes | Terbinafine (systemic) or topical azole | Itraconazole |
| Mucormycosis | Liposomal amphotericin B | Posaconazole |
Diagnosis / Investigation
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
Management
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
Prognosis
- 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
Other Relevant Information
Antifungal Drug Comparison
| Drug | Class | Route | Spectrum | Key Toxicity |
|---|---|---|---|---|
| Fluconazole | Azole | PO/IV | Candida, Crypto | Hepatotoxicity, interactions |
| Itraconazole | Azole | PO | Broad | Hepatotoxicity, negative inotrope |
| Voriconazole | Azole | PO/IV | Aspergillus, broad | Visual, hepatotoxicity, photosensitivity |
| Amphotericin B | Polyene | IV | Broadest | Nephrotoxicity |
| Caspofungin | Echinocandin | IV | Candida, Aspergillus | Well-tolerated |
| Terbinafine | Allylamine | PO | Dermatophytes | Hepatotoxicity, taste |
Azole CYP450 Interactions
| Azole | CYP Inhibited | High-Risk Interactions |
|---|---|---|
| Fluconazole | 2C9, 3A4 (mild) | Warfarin, phenytoin |
| Itraconazole | 3A4 (potent) | Simvastatin, ciclosporin, digoxin |
| Voriconazole | 2C19, 3A4, 2C9 | Sirolimus, ciclosporin, warfarin |