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Tuesday, August 19, 2025

Antifungals


Introduction

Fungal infections (mycoses) range from superficial (dermatophytoses, candidiasis) to invasive and systemic (aspergillosis, cryptococcosis, mucormycosis). The increasing prevalence of immunocompromised states (HIV/AIDS, chemotherapy, organ transplantation, immunosuppressive therapy) has heightened the need for effective antifungal agents.

Antifungals are classified by their mechanism of action and site of activity. They may act on the fungal cell membrane (ergosterol synthesis or binding), the cell wall, or nucleic acid synthesis. Modern therapy includes systemic and topical agents, with azoles and echinocandins being the mainstay for invasive mycoses, and polyenes reserved for severe cases.

Classification of Antifungals

1. Polyenes

  • Mechanism: Bind to ergosterol in fungal cell membranes, creating pores → leakage of intracellular contents → cell death.

  • Generic Names: amphotericin B (systemic), nystatin (topical/oral suspension), natamycin.

  • Uses:

    • Amphotericin B: systemic mycoses (cryptococcosis, aspergillosis, mucormycosis, histoplasmosis).

    • Nystatin: oropharyngeal, cutaneous, and vaginal candidiasis.

    • Natamycin: ocular fungal infections.

  • Adverse Effects: Nephrotoxicity (amphotericin B), infusion reactions (fever, chills, hypotension), electrolyte disturbances (hypokalemia, hypomagnesemia).

2. Azoles

  • Mechanism: Inhibit lanosterol 14α-demethylase (a cytochrome P450 enzyme), blocking ergosterol synthesis.

  • Classes:

    • Imidazoles: ketoconazole, clotrimazole, miconazole.

    • Triazoles: fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole.

  • Uses:

    • Fluconazole: candidiasis, cryptococcal meningitis.

    • Itraconazole: histoplasmosis, blastomycosis, onychomycosis.

    • Voriconazole: invasive aspergillosis.

    • Posaconazole, isavuconazole: mucormycosis, refractory mycoses.

    • Topical azoles (clotrimazole, miconazole): dermatophytoses, vulvovaginal candidiasis.

  • Adverse Effects: Hepatotoxicity, GI upset, QT prolongation (except isavuconazole, which shortens QT), drug interactions via CYP450 inhibition.

  • Contraindications: Co-administration with drugs highly dependent on CYP3A4 metabolism (e.g., certain statins, benzodiazepines).

3. Echinocandins

  • Mechanism: Inhibit β-(1,3)-D-glucan synthase, preventing fungal cell wall synthesis.

  • Generic Names: caspofungin, micafungin, anidulafungin.

  • Uses:

    • Invasive candidiasis (candidemia).

    • Aspergillosis (salvage therapy).

  • Adverse Effects: Infusion reactions, hepatotoxicity, histamine release (flushing).

  • Advantages: Minimal drug interactions, fungicidal against Candida.

4. Allylamines

  • Mechanism: Inhibit squalene epoxidase, blocking ergosterol synthesis.

  • Generic Names: terbinafine, naftifine, butenafine.

  • Uses:

    • Terbinafine: oral therapy for onychomycosis, tinea infections.

    • Naftifine, butenafine: topical dermatophytoses.

  • Adverse Effects: Hepatotoxicity (oral terbinafine), GI upset, rash, taste disturbances.

5. Antimetabolite (Pyrimidine Analog)

  • Mechanism: Flucytosine is converted inside fungal cells to 5-fluorouracil → inhibits DNA and RNA synthesis.

  • Generic Name: flucytosine.

  • Uses:

    • In combination with amphotericin B for cryptococcal meningitis.

    • Candida infections (systemic).

  • Adverse Effects: Bone marrow suppression, hepatotoxicity, GI disturbances.

  • Note: Rarely used alone due to rapid resistance.

6. Griseofulvin

  • Mechanism: Binds fungal microtubules, disrupting mitosis.

  • Uses: Dermatophytoses (tinea capitis, corporis, pedis, unguium).

  • Adverse Effects: Headache, hepatotoxicity, photosensitivity, CYP450 induction (reduces effectiveness of warfarin and oral contraceptives).

  • Note: Replaced largely by terbinafine and itraconazole for onychomycosis.

7. Other Agents

  • Ciclopirox: Topical agent for superficial mycoses, onychomycosis.

  • Tolnaftate: Topical dermatophyte infections.

  • Tavaborole: Boron-based topical antifungal for onychomycosis (nail penetration).

Therapeutic Uses of Antifungals

  1. Superficial Mycoses:

    • Dermatophytoses: terbinafine, itraconazole, griseofulvin.

    • Candidiasis (oral, vaginal, cutaneous): clotrimazole, miconazole, fluconazole, nystatin.

  2. Subcutaneous Mycoses:

    • Sporotrichosis: itraconazole, potassium iodide (historical).

  3. Systemic Mycoses:

    • Histoplasmosis, blastomycosis, coccidioidomycosis: itraconazole, amphotericin B (severe cases).

    • Aspergillosis: voriconazole, amphotericin B, echinocandins.

    • Cryptococcosis: amphotericin B + flucytosine, followed by fluconazole.

    • Mucormycosis: amphotericin B, posaconazole, isavuconazole.

  4. Prophylaxis in Immunocompromised Patients:

    • Fluconazole for Candida prophylaxis.

    • Posaconazole for invasive mold prophylaxis in hematopoietic stem cell transplant recipients.

Contraindications

  • Amphotericin B: Hypersensitivity, caution in renal impairment.

  • Azoles: Avoid in severe hepatic impairment; drug-drug interactions via CYP450.

  • Echinocandins: Hypersensitivity reactions (rare).

  • Terbinafine: Active liver disease.

  • Griseofulvin: Porphyria, pregnancy (teratogenic).

  • Flucytosine: Bone marrow suppression, renal impairment.

Adverse Effects Summary

  • Polyenes: Nephrotoxicity, electrolyte disturbances, infusion reactions.

  • Azoles: Hepatotoxicity, QT prolongation, CYP interactions.

  • Echinocandins: Hepatotoxicity, infusion reactions.

  • Allylamines: Hepatotoxicity, taste disturbance.

  • Flucytosine: Myelosuppression, hepatotoxicity.

  • Griseofulvin: Headache, photosensitivity, teratogenicity.

  • Topicals (clotrimazole, miconazole, ciclopirox): Local irritation, dermatitis.

Drug Interactions

  • Azoles: Inhibit CYP3A4 → increase levels of warfarin, statins, cyclosporine, benzodiazepines.

  • Amphotericin B: Nephrotoxicity additive with aminoglycosides, cyclosporine.

  • Griseofulvin: Induces CYP450 → reduces effectiveness of oral contraceptives, warfarin.

  • Flucytosine: Increased bone marrow toxicity with other myelotoxic agents.

  • Terbinafine: Inhibits CYP2D6, interacts with tricyclic antidepressants, SSRIs, beta-blockers.

Clinical Considerations

  • Drug choice depends on infection site and severity:

    • Superficial → topical agents.

    • Systemic/invasive → systemic azoles, echinocandins, amphotericin B.

  • Resistance: Increasing concern with Candida glabrata (azole/echinocandin resistance) and Candida auris (multidrug resistance).

  • Monitoring:

    • Liver function (azoles, terbinafine, griseofulvin).

    • Renal function (amphotericin B, flucytosine).

    • Hematologic function (flucytosine).

  • Formulations: Liposomal amphotericin B reduces nephrotoxicity compared to conventional formulations.




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