8.3 Antifungal Drugs
Antifungal agents target differences between fungal and mammalian cells, primarily focusing on ergosterol (fungal cell membrane sterol) and cell wall synthesis. Treatment depends on fungal species, infection site, and immune status.
Fungal Cell Targets
Ergosterol Synthesis
Azoles inhibit 14α-demethylase (CYP51), blocking conversion of lanosterol to ergosterol
Membrane Integrity
Polyenes (amphotericin B) bind ergosterol, forming pores and causing cell lysis
Cell Wall Synthesis
Echinocandins inhibit β-1,3-glucan synthase, weakening fungal cell wall
Azole Antifungals
Mechanism of Action
Azoles inhibit fungal cytochrome P450 enzyme 14α-demethylase, preventing conversion of lanosterol to ergosterol. This disrupts membrane integrity and function. Generally fungistatic.
Imidazoles (Topical)
Used for superficial fungal infections (dermatophytes, Candida)
- • Clotrimazole: Vaginal candidiasis, dermatophyte infections
- • Miconazole: Vulvovaginal candidiasis, tinea infections
- • Ketoconazole: Topical for seborrheic dermatitis (oral use limited due to hepatotoxicity)
Route: Topical creams, ointments, vaginal suppositories
Triazoles (Systemic)
Broader spectrum; better safety profile than imidazoles. Preferred for systemic fungal infections.
Fluconazole
Spectrum:
- • Candida (except C. krusei, some C. glabrata)
- • Cryptococcus neoformans (meningitis)
- • Coccidioides (valley fever)
- • NO activity against Aspergillus or mucormycosis
Clinical Uses:
- • Vaginal/oropharyngeal candidiasis
- • Cryptococcal meningitis (AIDS)
- • Candidemia (non-resistant species)
- • CNS penetration (lipophilic)
⚠️ Drug interactions (CYP3A4/2C9); QT prolongation; teratogenic
Itraconazole
Spectrum:
- • Aspergillus (but voriconazole preferred)
- • Histoplasma, Blastomyces, Sporothrix
- • Dermatophytes (onychomycosis)
Adverse Effects:
- • Negative inotrope (avoid in heart failure)
- • Hepatotoxicity
- • Drug interactions (potent CYP3A4 inhibitor)
Voriconazole
Spectrum:
- • Aspergillus (drug of choice for invasive aspergillosis)
- • Candida (including some fluconazole-resistant)
- • Fusarium, Scedosporium
- • NO activity against mucormycosis
Adverse Effects:
- • Visual disturbances (transient, common)
- • Hepatotoxicity (monitor LFTs)
- • Photosensitivity, skin cancer risk
- • CYP2C19 polymorphism affects levels
Posaconazole
- • Broad spectrum (Aspergillus, Candida, Mucorales)
- • Salvage therapy for refractory invasive fungal infections
- • Prophylaxis in high-risk neutropenic patients (leukemia, transplant)
- Delayed-release tablets or IV formulation preferred over suspension
Isavuconazole
- • Active against Aspergillus and Mucorales
- • Alternative to voriconazole/amphotericin B
- • Fewer drug interactions than other azoles
Polyene Antifungals
Amphotericin B
Mechanism of Action:
Binds to ergosterol in fungal cell membranes, forming pores that allow leakage of intracellular contents (K+, Mg2+), leading to cell death. Fungicidal. Also binds cholesterol in mammalian cells (toxicity).
Clinical Uses:
- • Broadest spectrum: Most systemic mycoses
- • Candida, Aspergillus, Cryptococcus
- • Mucormycosis (drug of choice)
- • Histoplasma, Blastomyces, Coccidioides
- • Severe/life-threatening infections
- IV only (not absorbed orally); does not cross BBB well
⚠️ Major Toxicities:
- • Nephrotoxicity: Dose-limiting; monitor CrCl (often reversible)
- • Infusion reactions: Fever, chills, rigors ("shake and bake")
- • Hypokalemia, hypomagnesemia (renal wasting)
- • Anemia (decreased erythropoietin)
- • Thrombophlebitis at infusion site
- Premedicate with acetaminophen, antihistamines; slow infusion
Lipid Formulations:
Liposomal and lipid complex formulations reduce toxicity (especially nephrotoxicity) but are expensive:
- • Liposomal amphotericin B (AmBisome): Lowest toxicity; preferred in renal impairment
- • Amphotericin B lipid complex (Abelcet): Intermediate toxicity
- • Amphotericin B colloidal dispersion (Amphotec): Less commonly used
Echinocandins
Mechanism of Action
Inhibit β-1,3-glucan synthase (encoded by FKS genes), preventing synthesis of β-glucan, a major component of fungal cell walls. Fungicidal against Candida; fungistatic against Aspergillus.
Agents:
- Caspofungin:
- • First echinocandin approved
- • Loading dose required
- Micafungin:
- • No loading dose needed
- • Prophylaxis in transplant
- Anidulafungin:
- • Longest half-life
- • No dose adjustment in renal/hepatic impairment
Clinical Use & Spectrum:
- • Candida: Including azole-resistant species (C. glabrata, C. krusei)
- • Aspergillus: Salvage therapy or combination with voriconazole
- • First-line for candidemia in non-neutropenic patients
- • IV only (not orally bioavailable)
- • No CNS penetration
- ✓ Excellent safety profile; minimal drug interactions
Limitations:
- • NO activity against Cryptococcus, Mucorales, or endemic mycoses (lack β-glucan)
- • Resistance emerging in Candida (FKS mutations)
Other Antifungals
Flucytosine (5-FC)
Nucleoside analog converted to 5-fluorouracil inside fungal cells, inhibiting DNA and RNA synthesis.
- • Use: Cryptococcal meningitis (with amphotericin B)
- • Synergy: Amphotericin B increases uptake into fungal cells
- • Resistance: Develops rapidly if used alone
- ⚠️ Bone marrow suppression, hepatotoxicity; monitor CBC, LFTs
Griseofulvin
Interferes with fungal microtubule function, disrupting mitosis. Deposited in keratin precursor cells.
- • Use: Dermatophyte infections (tinea capitis, onychomycosis)
- • Requires prolonged therapy (weeks to months)
- • CYP450 inducer; headache, GI upset
- Largely replaced by oral azoles (itraconazole, terbinafine)
Terbinafine
Inhibits squalene epoxidase, blocking ergosterol synthesis (different step than azoles).
- • Use: Onychomycosis (nail fungus), tinea infections
- • Oral and topical formulations
- • Fungicidal against dermatophytes
- Better cure rates for onychomycosis than griseofulvin
Nystatin
Polyene similar to amphotericin B; binds ergosterol, forming membrane pores.
- • Use: Topical only (too toxic for systemic use)
- • Oropharyngeal candidiasis (oral suspension, "swish and swallow")
- • Cutaneous/vaginal Candida infections
Antifungal Therapy by Organism
| Organism | Clinical Presentation | First-Line Treatment |
|---|---|---|
| Candida albicans | Mucocutaneous, candidemia | Fluconazole (local); echinocandin (systemic) |
| Aspergillus | Invasive pulmonary aspergillosis | Voriconazole or isavuconazole |
| Cryptococcus | Meningitis (HIV/AIDS) | Amphotericin B + flucytosine → fluconazole maintenance |
| Mucorales | Rhinocerebral mucormycosis (DKA, immunosuppressed) | Amphotericin B (liposomal) + surgical debridement |
| Histoplasma | Pulmonary histoplasmosis (endemic to Ohio/Mississippi valleys) | Itraconazole (mild); amphotericin B (severe) |
| Dermatophytes | Tinea (ringworm), onychomycosis | Topical azoles; terbinafine (nails) |