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PH8.8 | PH8.8 | Antifungal Drugs — SDL Guide — SDL Guide

Learning Objectives

• Explain the types, kinetics, dynamics, and adverse effects of drugs used for fungal infections
• Classify antifungal drugs by their mechanism of action and target site
• Select appropriate antifungal therapy for common clinical scenarios including oral/vaginal candidiasis, invasive candidiasis, Aspergillus infection, cryptococcal meningitis, and dermatophytosis

INSTRUCTIONS

Fungal infections have increased dramatically over the past three decades, driven by growing populations of immunocompromised patients (HIV/AIDS, haematological malignancies, solid organ transplant recipients, critically ill patients on broad-spectrum antibiotics). As a clinician, you will encounter both superficial fungal infections (extremely common — oral thrush in HIV patients, vulvovaginal candidiasis, dermatophytosis) and life-threatening invasive infections (invasive aspergillosis, candidaemia, cryptococcal meningitis). The pharmacological challenge is unique: fungi are eukaryotes sharing many metabolic processes with human cells, making selective toxicity more difficult than for bacteria.

References

• Tripathi KD. Essentials of Medical Pharmacology, 8th ed., Ch 59 (textbook)
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th ed., Ch 60 (textbook)
• IDSA Guidelines: Aspergillosis 2016; Candidiasis 2016; Cryptococcal Meningitis 2010 (guideline)

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Version 2.0 | NMC CBUC 2024

Fungal Infection Pathophysiology: Why Antifungals Are Harder Than Antibacterials

The fundamental pharmacological challenge of treating fungal infections is that fungi are eukaryotes — like human cells, they have a nucleus, mitochondria, ribosomes identical in structure to the human 80S ribosome, and similar signalling pathways. This eukaryotic nature eliminates the most productive antibacterial targets: bacteria-specific 70S ribosomes, cell-wall peptidoglycan, and prokaryotic DNA gyrase.

The exploitable differences between fungal and human cells are fewer but clinically leverageable:
1. Ergosterol — the principal sterol of fungal cell membranes (humans use cholesterol). Structural differences between ergosterol and cholesterol allow certain drugs (polyenes, azoles, allylamines) to selectively target fungal membranes or their ergosterol biosynthesis pathway.
2. β-1,3-D-glucan — a polysaccharide component of the fungal cell wall, absent in mammalian cells. This is the target of echinocandins.
3. Cytosine deaminase — present in fungi (converts 5-FC to 5-FU, the active form); mammalian cells lack this enzyme in significant amounts, providing selectivity for flucytosine.

The clinical spectrum of fungal disease ranges from superficial (dermatophytosis, oral thrush, vaginal candidiasis — primarily in immunocompetent patients) to deep-seated/systemic (pneumocystosis, histoplasmosis, coccidioidomycosis — regional endemics) to life-threatening invasive (candidaemia, invasive aspergillosis, mucormycosis, cryptococcal meningitis — primarily in immunocompromised hosts). The severity of immunosuppression determines the likely fungal pathogen and the required intensity of antifungal therapy.

Key clinical contexts triggering antifungal need in India:
- HIV/AIDS — oral and oesophageal candidiasis; cryptococcal meningitis; Pneumocystis jirovecii pneumonia
- Neutropenia post-chemotherapy — invasive aspergillosis, invasive candidiasis
- Solid organ transplant recipients — Aspergillus, non-albicans Candida, Cryptococcus
- Broad-spectrum antibiotics → microbiome disruption → Candida overgrowth (vaginal candidiasis; C. difficile does not apply here but the ecological principle does)
- Corticosteroids + uncontrolled diabetes → mucormycosis (COVID-19 pandemic illustration)
- Prolonged ICU stay + central venous catheter → candidaemia

Therapeutic Goal: Exploit Ergosterol-Based Selective Toxicity

The central therapeutic strategy in antifungal pharmacology is exploiting the ergosterol pathway as the point of maximal selective toxicity. Three major drug classes attack this pathway at different points, and understanding their positions in the pathway prevents confusion about their mechanisms and spectra:

The ergosterol biosynthesis pathway (simplified):
Acetate → Squalene → [Squalene epoxidase: TERBINAFINE target] → Lanosterol → [14α-demethylase/CYP51: AZOLE target] → Ergosterol → [Ergosterol in membrane: POLYENE target]

• Polyenes (amphotericin B, nystatin): act at the END of the pathway — bind ergosterol already incorporated into the membrane, forming channels → ion leak → cell death. These are fungicidal because they physically disrupt the existing membrane, regardless of whether the organism is actively synthesising ergosterol.
• Azoles: act in the MIDDLE — inhibit 14α-demethylase (CYP51), blocking the conversion of lanosterol to ergosterol. This depletes ergosterol AND causes accumulation of toxic 14α-methylated sterols. Azoles are primarily fungistatic (they slow synthesis but cannot drain existing ergosterol from the membrane), requiring host immune clearance to kill the organism.
• Allylamines (terbinafine): act at the BEGINNING — inhibit squalene epoxidase, blocking squalene → squalene oxide conversion. This depletes ergosterol AND causes toxic squalene accumulation (directly membrane-disruptive). More fungicidal than azoles for dermatophytes.

The additional target — β-1,3-glucan synthase (echinocandins) — is orthogonal to the ergosterol pathway, targeting cell wall synthesis rather than membrane ergosterol. This is why echinocandins and azoles can be used synergistically: different targets, potentially additive mechanisms.

Antifungal Drug Target Sites in the Fungal Cell

Classification of Antifungal Drugs by Target

A systematic classification by pharmacological target organises all antifungal drugs logically:

Class 1 — Polyenes (ergosterol-binding):
- Amphotericin B (AmB): broad-spectrum fungicidal (Candida, Aspergillus, Cryptococcus, Mucor, dimorphic fungi); IV formulation; significant nephrotoxicity (conventional). Lipid formulations (liposomal AmB/L-AmB, amphotericin B lipid complex/ABLC, amphotericin B colloidal dispersion/ABCD) reduce nephrotoxicity by altering pharmacokinetics and RES uptake.
- Nystatin: too toxic for systemic use; topical only (oral thrush as oral suspension — 'swish and swallow'; vaginal candidiasis as pessary; skin candidiasis as cream).

Class 2 — Azoles (CYP51/14α-demethylase inhibitors):
- Imidazoles (2 nitrogen atoms in ring): clotrimazole, miconazole — topical only (less CYP-selective, more human CYP inhibition at systemic levels).
- Triazoles (3 nitrogen atoms — more CYP51-selective): fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole — systemic use.

Class 3 — Echinocandins (β-1,3-glucan synthase inhibitors):
- Caspofungin, micafungin, anidulafungin — IV only; fungicidal vs Candida; NOT active vs Cryptococcus (which has minimal β-glucan in its polysaccharide capsule).

Class 4 — Allylamines (squalene epoxidase inhibitors):
- Terbinafine — primarily for dermatophytes; oral (systemic) for onychomycosis; topical for tinea pedis/corporis.

Class 5 — Others:
- Flucytosine (5-FC): antimetabolite (DNA/RNA synthesis); ONLY in combination with AmB for cryptococcal meningitis; NOT used alone (rapid resistance).
- Griseofulvin: disrupts microtubule function → impairs mitotic spindle → antimitotic effect against dermatophytes; oral; long course required (months for nail infections); largely superseded by terbinafine.