Table of contents · 10 sections
In a nutshell. Antifungals are classified by their target: polyenes (amphotericin B) bind membrane ergosterol; azoles (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole) block ergosterol synthesis (14α-demethylase); echinocandins (caspofungin, micafungin, anidulafungin) inhibit cell wall 1,3-β-D-glucan synthase; allylamines (terbinafine) inhibit squalene epoxidase. Candidiasis: echinocandins for severe cases; fluconazole for uncomplicated. Cryptococcosis: amphotericin B + flucytosine → fluconazole. Aspergillosis: voriconazole is the first-line choice, isavuconazole is an alternative.
1. Classification by structure and target
| Class | Target | Drugs |
|---|---|---|
| Polyenes | Ergosterol → membrane pores | Amphotericin B (deoxycholate, liposomal), nystatin |
| Azoles (triazoles/imidazoles) | 14α-demethylase (CYP51) — ergosterol synthesis | Fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole, ketoconazole |
| Echinocandins | Cell wall 1,3-β-D-glucan synthase | Caspofungin, micafungin, anidulafungin, rezafungin |
| Allylamines | Squalene epoxidase | Terbinafine, naftifine |
| Pyrimidine analogues | Fungal RNA/DNA | Flucytosine (5-FC) |
| Novel | Miscellaneous | Ibrexafungerp, rezafungin, olorofim, fosmanogepix |
2. Amphotericin B
- Polyene, binds ergosterol → membrane pores → lysis.
- Broad spectrum: Candida, Cryptococcus, Aspergillus, Mucor, endemic mycoses (Histoplasma, Coccidioides, Blastomyces).
- Formulations: deoxycholate (inexpensive, nephrotoxic), lipid-based (liposomal AmBisome, lipid complex Abelcet) — ↓ nephrotoxicity.
- Side effects: nephrotoxicity, hypokalemia, hypomagnesemia, infusion-related reactions (fever, chills), anemia.
- Premedication: paracetamol, diphenhydramine, hydrocortisone; saline loading 500 ml before and after.
- Indications: cryptococcal meningitis, invasive candidiasis in pregnancy, mucormycosis.
3. Azoles
Fluconazole
- Spectrum: Candida (excluding C. krusei, C. glabrata with resistance), Cryptococcus.
- Inactive against Aspergillus, Mucor.
- Good bioavailability (90%), penetration into the CNS and eye.
- Doses: 400–800 mg/day for systemic mycoses; 150 mg single dose for vulvovaginal candidiasis.
- Side effects: hepatotoxicity, QT prolongation, teratogenicity.
Itraconazole
- Spectrum: Aspergillus, Histoplasma, Blastomyces, dermatophytes.
- Bioavailability depends on pH (capsules require an acidic stomach), oral solution is preferred.
- Therapeutic drug monitoring (TDM) — target > 1 mg/L.
- Contraindicated in heart failure (negative inotropic effect).
Voriconazole
- First-line agent for invasive aspergillosis.
- Spectrum: Aspergillus, Candida (including C. krusei), Scedosporium, Fusarium.
- Non-linear pharmacokinetics; TDM is mandatory (target 2–5 mg/L).
- Side effects: visual disturbances (photopsia), hepatotoxicity, phototoxicity with ↑ risk of squamous cell carcinoma, periostitis, hallucinations.
- CYP2C19 polymorphism: rapid metabolizers require an ↑ dose.
Posaconazole
- Broadest spectrum: + Mucor.
- Indications: prophylaxis in profound neutropenia (AML, HSCT), treatment of mucormycosis.
- Formulations: suspension, delayed-release tablets, IV.
- TDM: target > 0.7 mg/L for prophylaxis, > 1 mg/L for treatment.
Isavuconazole
- Prodrug (isavuconazonium sulfate).
- Spectrum: Aspergillus, Mucor, Candida.
- Linear PK, convenient dosing, does not prolong QT (shortens it).
- Alternative to voriconazole and amphotericin in mucormycosis.
General features of azoles
- CYP metabolism; potent CYP3A4 inhibitors → drug interactions (warfarin, statins, tacrolimus, voriconazole ↑ levels).
- Hepatotoxicity — enzyme monitoring.
- QT prolongation (except isavuconazole).
4. Echinocandins
- Caspofungin, micafungin, anidulafungin, rezafungin.
- Inhibit 1,3-β-D-glucan synthase → cell wall disruption.
- Spectrum: Candida (including azole-resistant), Aspergillus (salvage therapy only); inactive against Cryptococcus, Mucor.
- IV administration only, poor penetration into the CNS and eye.
- Excellent safety profile — drug of choice for severe candidiasis in the ICU.
- Rezafungin — once-weekly dosing.
5. Allylamines and others
Terbinafine
- Inhibits squalene epoxidase → accumulation of toxic squalene.
- Main indications: dermatophytosis, onychomycosis.
- Treatment course for onychomycosis: fingernails 6 weeks, toenails 12 weeks.
- Hepatotoxicity, taste disturbances.
Flucytosine (5-FC)
- Cytosine analogue, converted to 5-FU within the fungal cell.
- Always used in combination (resistance develops rapidly).
- Classic regimen for cryptococcal meningitis: amphotericin B + flucytosine → fluconazole.
- Hematotoxicity — CBC monitoring.
Topical agents
- Clotrimazole, miconazole, econazole, sertaconazole — vaginal candidiasis, skin mycoses.
- Nystatin — mucous membranes (not absorbed per os).
- Ciclopirox, amorolfine — onychomycosis.
6. Treatment of key mycoses
Invasive candidiasis/candidemia
- First-line — echinocandin.
- De-escalation to fluconazole if stable, susceptible, and no prior azole exposure.
- CVC removal, ophthalmological examination, echocardiography.
- Duration: 14 days from the first negative blood culture.
Aspergillosis
- First-line — voriconazole or isavuconazole.
- Alternative — liposomal amphotericin B.
- Combination of voriconazole + echinocandin — in severe cases.
- Duration: minimum 6–12 weeks, until resolution.
Cryptococcosis
- Induction: liposomal amphotericin B + flucytosine for 2 weeks.
- Consolidation: fluconazole 400–800 mg for 8 weeks.
- Maintenance: fluconazole 200 mg ≥ 1 year (in HIV — until CD4 > 100 recovery and viral suppression).
- Intracranial pressure monitoring — repeated LPs.
Mucormycosis
- Aggressive surgery + liposomal amphotericin B (high doses 5–10 mg/kg).
- Alternatives/step-down: posaconazole, isavuconazole.
- Correction of predisposing factors: DKA, immunosuppression.
Pneumocystosis (P. jirovecii)
- Co-trimoxazole (not an antifungal by class, but used for mycosis) 15–20 mg/kg/day based on TMP, 21 days.
- Alternatives: pentamidine, clindamycin + primaquine, atovaquone.
- Corticosteroids if PaO₂ < 70 mm Hg.
7. Prophylaxis
- Posaconazole — in profound neutropenia (AML, MDS, allo-HSCT).
- Fluconazole — early period of allo-HSCT, liver transplantation.
- Co-trimoxazole — pneumocystis prophylaxis at CD4 < 200, immunosuppression.
8. Pharmacogenetics and monitoring
- Voriconazole — TDM mandatory (CYP2C19 polymorphism).
- Posaconazole suspension — low bioavailability, TDM.
- Itraconazole — variable PK, TDM.
- Liver function — all azoles, terbinafine.
- Renal function, K⁺, Mg²⁺ — amphotericin B.
- FBC — flucytosine.
9. Drug Interactions
- Azoles ↑ levels of: warfarin, statins (rhabdomyolysis!), tacrolimus, cyclosporine, sirolimus, benzodiazepines, methadone, vincristine.
- Rifampicin ↓ azole levels.
- Combination of voriconazole + rifampicin, carbamazepine, phenobarbital — contraindicated.
10. FAQ
Why doesn't fluconazole work against Aspergillus?
Moulds have structural differences in CYP51 and efflux pumps that fluconazole cannot bypass. For Aspergillus — voriconazole/isavuconazole/posaconazole.
When is TDM required?
Voriconazole (always), posaconazole suspension, itraconazole, flucytosine. The goal is efficacy and toxicity prevention.
What is the difference between caspofungin and micafungin?
Minor differences in dosing and associated safety profiles; both are effective in invasive candidiasis. Anidulafungin does not require dose adjustment in hepatic impairment.
Why doesn't voriconazole work in mucormycosis?
Mucorales have a 14α-demethylase resistant to voriconazole, but are susceptible to posaconazole and isavuconazole.
Can azoles be given during pregnancy?
High-dose fluconazole is teratogenic (Category D); a single 150 mg dose is considered safe. Itraconazole, voriconazole, posaconazole — contraindicated. Amphotericin B and echinocandins — permitted.
See also: Antibiotics · Antivirals · Sepsis · HIV · Pharmacology Catalog