Antifungal Agents — Mechanisms & Spectrum
Microbiology · Mycology · lean revision notes
Antifungal Agents — Mechanisms & Spectrum
Antifungals exploit the few structural differences between the fungal and human cell — chiefly ergosterol (the fungal membrane sterol, in place of human cholesterol) and the β-1,3-glucan cell wall. Knowing which enzyme/structure each class hits and the drug-of-choice (DOC) for each named infection is the single highest-yield axis for NEET PG.
Big-picture classification by target
Fungi differ from human cells at three exploitable points: the cell membrane (ergosterol), the cell wall (glucan/chitin), and nucleic acid synthesis. Every major antifungal maps onto one of these.
| Target | Class | Prototype drugs | Mechanism |
|---|---|---|---|
| Ergosterol (binds it) | Polyenes | Amphotericin B, Nystatin | Bind ergosterol → membrane pores → K⁺/Mg²⁺ leak → cell death (fungicidal) |
| Ergosterol synthesis (CYP51/14-α-demethylase) | Azoles | Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazole, Ketoconazole | Inhibit lanosterol 14-α-demethylase → ↓ergosterol, toxic sterol build-up (fungistatic, mostly) |
| Ergosterol synthesis (squalene epoxidase) | Allylamines | Terbinafine, Naftifine | Inhibit squalene epoxidase → squalene accumulates (toxic), ↓ergosterol |
| β-1,3-glucan synthase (cell wall) | Echinocandins | Caspofungin, Micafungin, Anidulafungin | Inhibit 1,3-β-D-glucan synthase → defective wall (fungicidal vs Candida, static vs Aspergillus) |
| Microtubules | Griseofulvin | Griseofulvin | Disrupts mitotic spindle/microtubules; deposits in keratin (fungistatic) |
| Nucleic acid | Pyrimidine analogue | Flucytosine (5-FC) | Converted to 5-FU → inhibits thymidylate synthase + RNA synthesis |
High-yield: Polyenes bind ergosterol; azoles and allylamines block its synthesis at different enzymes (azole = 14-α-demethylase/CYP51; terbinafine = squalene epoxidase). Echinocandins act on the cell wall (glucan), not the membrane.
Mnemonic for ergosterol-synthesis enzymes: "Azoles Act After (later step, demethylase); Terbinafine Takes the Top (earlier step, squalene epoxidase)."
Polyenes — Amphotericin B
Mechanism & spectrum
Amphotericin B (Amp B) binds ergosterol in the fungal membrane and forms ion channels → leakage of intracellular cations → fungicidal. It has the broadest spectrum of any antifungal and remains the gold-standard for severe, life-threatening systemic mycoses.
- Active against: Candida, Cryptococcus, Aspergillus, Histoplasma, Blastomyces, Coccidioides, Mucor/Rhizopus (mucormycosis), Sporothrix, Leishmania (yes — also antiprotozoal).
- Resistant/poor: Candida lusitaniae (intrinsic Amp B resistance — high-yield!), Aspergillus terreus, Scedosporium/Pseudallescheria, dermatophytes (not used topically for ringworm systemically).
Toxicity (heavily tested)
- Infusion (immediate) reaction → fever, chills, rigors, hypotension ("shake and bake"). Pre-medicate with paracetamol/antihistamine ± hydrocortisone.
- Nephrotoxicity (dose-limiting) → afferent arteriolar vasoconstriction (↓GFR) + distal tubular damage → renal tubular acidosis (type 1), hypokalaemia, hypomagnesaemia, polyuria (nephrogenic DI). Mitigate with saline pre-loading (sodium loading).
- Normochromic normocytic anaemia (↓erythropoietin).
- Thrombophlebitis at infusion site.
High-yield: Amphotericin B nephrotoxicity is reduced by lipid formulations (liposomal Amp B) and sodium/saline loading. Liposomal Amp B is DOC for mucormycosis and for severe cryptococcal meningitis (with flucytosine).
Nystatin = too toxic for systemic use (not absorbed orally) → topical only: oral/oesophageal/cutaneous Candida (e.g., oral thrush "swish and swallow", denture stomatitis, candidal intertrigo).
Azoles — the CYP51 inhibitors
Azoles inhibit fungal lanosterol 14-α-demethylase (CYP51), a cytochrome-P450 enzyme. This causes ↓ergosterol and accumulation of 14-α-methylsterols → membrane dysfunction. Because they act on a P450 enzyme, azoles also inhibit human CYP enzymes → many drug interactions (especially ketoconazole, itraconazole, voriconazole).
Two chemical sub-groups: imidazoles (2 nitrogens — ketoconazole, clotrimazole, miconazole; mostly topical) and triazoles (3 nitrogens — fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole; systemic, more selective, safer).
| Azole | Best-for spectrum highlight | Key clinical pearl |
|---|---|---|
| Fluconazole | Cryptococcus, most Candida (NOT C. krusei; C. glabrata dose-dependent) | Best CSF penetration; DOC maintenance/consolidation in cryptococcal meningitis; oral candidiasis, vaginal candidiasis (single 150 mg dose) |
| Itraconazole | Dimorphics: Histoplasma, Blastomyces, Sporothrix, dermatophytes, onychomycosis | DOC for sporotrichosis and mild-moderate histo/blasto; needs acid for absorption (capsule) |
| Voriconazole | Aspergillus (DOC), Scedosporium, Fusarium, Candida | Toxicities: visual disturbance (photopsia), phototoxicity/skin cancer, hepatotoxicity, periostitis (fluoride); levels affected by CYP2C19 polymorphism |
| Posaconazole | Broadest azole incl. Mucorales (zygomycetes) | Prophylaxis in neutropenia/GVHD; salvage for mucormycosis |
| Isavuconazole | Aspergillus + Mucorales | Alternative to Amp B in mucormycosis; less QT effect |
| Ketoconazole | Largely historical/topical | Most hepatotoxic; inhibits steroidogenesis (↓testosterone → gynaecomastia; ↓cortisol → used in Cushing's); many interactions — systemic use abandoned |
High-yield: Fluconazole does NOT cover moulds (no Aspergillus, no Mucor) and is intrinsically poor against C. krusei (resistant) and C. glabrata (reduced susceptibility). Voriconazole = DOC invasive aspergillosis.
High-yield: Azole-specific tox flashcards — Voriconazole → visual disturbances; Ketoconazole → gynaecomastia + adrenal suppression; Itraconazole → negative inotrope (avoid in CHF) + needs gastric acid.
Mnemonic for triazole spectrum ladder: "Fluconazole the Floor (yeasts), Itraconazole adds dimorphics, Voriconazole adds Aspergillus, Posa/Isa add the Mucorales Peak."
Allylamines — Terbinafine
Terbinafine inhibits squalene epoxidase, an early step in ergosterol synthesis. Squalene accumulates (directly fungicidal) and ergosterol falls. It is concentrated in skin, nails and sebum, making it ideal for dermatophytoses.
- DOC for onychomycosis (dermatophyte nail infection) and tinea (especially tinea pedis, tinea capitis in many guidelines) — fungicidal, shorter courses than griseofulvin, better cure rates.
- Oral terbinafine adverse effects: hepatotoxicity, taste/smell disturbance (dysgeusia), rare neutropenia, Stevens–Johnson.
High-yield: Terbinafine > griseofulvin for onychomycosis (higher cure, shorter duration). Terbinafine hits squalene epoxidase — a favourite single-best-answer pairing.
Echinocandins — the cell-wall "fungins"
Caspofungin, micafungin and anidulafungin non-competitively inhibit 1,3-β-D-glucan synthase, crippling cell-wall synthesis. Given IV only (large molecules, poorly absorbed orally).
- Fungicidal against Candida (incl. azole-resistant C. glabrata, C. krusei) → DOC/first-line for invasive candidiasis & candidaemia, especially in haemodynamically unstable or recently azole-exposed patients.
- Fungistatic against Aspergillus — second-line/salvage, not first-line.
- No activity against Cryptococcus, Mucorales/Zygomycetes, Fusarium, Trichosporon (these lack the relevant glucan or have low content) — a classic "which is NOT covered" question.
- Excellent safety profile (no nephrotoxicity); minimal CYP interactions → favoured in renal failure and ICU.
High-yield: Echinocandins are first-line for invasive candidiasis but have no activity against Cryptococcus or Mucor. The (1→3)-β-D-glucan assay is also a serum diagnostic marker for invasive candidiasis/PCP.
Griseofulvin
Griseofulvin disrupts the mitotic spindle by binding microtubules / tubulin, arresting fungal mitosis. It deposits in newly formed keratin (skin, hair, nails), making it active only against dermatophytes (Trichophyton, Microsporum, Epidermophyton) — i.e., ringworm/tinea. No activity against Candida or systemic fungi.
- Classic indication: tinea capitis (esp. Microsporum — griseofulvin still favoured) and widespread tinea; long courses (weeks–months) until keratin replaced.
- Absorption ↑ with fatty meal; it is a CYP450 inducer (↓ warfarin, ↓ oral contraceptive efficacy).
- Adverse effects: headache, disulfiram-like reaction with alcohol, photosensitivity, may exacerbate porphyria and SLE.
High-yield: Griseofulvin = microtubule/spindle disruptor, deposits in keratin, used for dermatophytes only. Terbinafine has largely superseded it for nails; griseofulvin retains a role in Microsporum tinea capitis.
Flucytosine (5-FC)
A pyrimidine analogue taken up by cytosine permease and converted by cytosine deaminase to 5-fluorouracil (5-FU) → 5-FdUMP inhibits thymidylate synthase (↓DNA) and is incorporated into RNA. Human cells lack cytosine deaminase → relative selectivity. Never used alone (rapid resistance) — always combined, classically with Amphotericin B.
- Spectrum: Cryptococcus, Candida. Combined with Amp B for cryptococcal meningitis induction.
- Toxicity: bone-marrow suppression (5-FU effect, worse with renal impairment / high levels), hepatotoxicity, GI upset, colitis.
High-yield: Cryptococcal meningitis (HIV) induction = liposomal Amphotericin B + Flucytosine (≈2 weeks) → then consolidation/maintenance with Fluconazole. This sequence is repeatedly tested.
Drug-of-choice quick map (most-tested)
Stepwise approach to "DOC for X fungal infection":
- Invasive aspergillosis → Voriconazole (Amp B / isavuconazole / echinocandin = alternatives).
- Invasive candidiasis / candidaemia → Echinocandin first-line → step-down to fluconazole if susceptible.
- Cryptococcal meningitis → Liposomal Amp B + Flucytosine → fluconazole maintenance.
- Mucormycosis (Rhizopus/Mucor) → Liposomal Amp B + urgent surgical debridement + control diabetes/DKA → posaconazole/isavuconazole step-down.
- Histoplasmosis / Blastomycosis → Itraconazole (mild–moderate); Amp B if severe.
- Sporotrichosis → Itraconazole (DOC for cutaneous/lymphocutaneous; potassium iodide is the cheap classical alternative).
- Dermatophytosis (tinea) → topical azole/terbinafine; onychomycosis → oral terbinafine; tinea capitis → griseofulvin or terbinafine.
- Oral/oesophageal candidiasis → fluconazole (nystatin topical for mild oral).
- Pneumocystis jirovecii (PCP) → Co-trimoxazole (NOT a classic antifungal — important trap; echinocandins/azoles ineffective).
- Tinea versicolor (Malassezia) → topical selenium sulphide / ketoconazole shampoo; oral itra/fluconazole if extensive.
| Infection | DOC | Key alternative |
|---|---|---|
| Invasive aspergillosis | Voriconazole | Isavuconazole, L-Amp B |
| Candidaemia | Echinocandin | Fluconazole (if stable/susceptible) |
| Cryptococcal meningitis | L-Amp B + 5-FC | Fluconazole (maintenance) |
| Mucormycosis | L-Amp B + surgery | Posaconazole/Isavuconazole |
| Histoplasma/Blastomyces | Itraconazole | Amp B (severe) |
| Sporotrichosis | Itraconazole | Potassium iodide |
| Onychomycosis | Terbinafine | Itraconazole pulse |
| Tinea capitis | Griseofulvin/Terbinafine | — |
| Mucosal candidiasis | Fluconazole | Nystatin (topical) |
High-yield: PCP is NOT treated with conventional antifungals — DOC is co-trimoxazole (TMP-SMX), second-line pentamidine/atovaquone/clindamycin-primaquine. Steroids added if PaO₂ <70 mmHg or A–a gradient >35.
Resistance — mechanisms worth knowing
- Azole resistance: point mutations/overexpression of ERG11 (CYP51 target); efflux pumps (CDR/MDR) — prominent in C. glabrata, C. krusei, and Candida auris (multidrug-resistant nosocomial yeast, high exam relevance).
- Echinocandin resistance: mutations in FKS1/FKS2 genes (glucan synthase) — rising in C. glabrata.
- Amphotericin resistance: ↓ergosterol content / altered sterol — intrinsic in C. lusitaniae, A. terreus.
- Flucytosine resistance: loss of cytosine permease/deaminase → develops fast as monotherapy → always combine.
Key differentials & "which is NOT covered" traps
- No mould cover (no Aspergillus/Mucor): fluconazole, echinocandins (Mucor), flucytosine.
- No Cryptococcus cover: echinocandins.
- Mucor (zygomycetes) coverage only by: Amp B, posaconazole, isavuconazole (NOT voriconazole, NOT echinocandins, NOT fluconazole). Voriconazole prophylaxis can even precipitate breakthrough mucormycosis — classic vignette.
- Dermatophyte-only agent: griseofulvin.
- Fungistatic vs fungicidal: Fungicidal → Amp B, echinocandins (vs Candida), terbinafine. Fungistatic → azoles (mostly), griseofulvin, flucytosine.
Recently asked / exam angle
- "Which antifungal inhibits squalene epoxidase?" → Terbinafine (distinguish from azoles = 14-α-demethylase).
- "Mechanism of caspofungin?" → β-1,3-glucan synthase inhibition (cell wall).
- "DOC for invasive aspergillosis?" → Voriconazole; with the toxicity twist → visual disturbances/photopsia.
- "Antifungal causing renal tubular acidosis + hypokalaemia?" → Amphotericin B; mitigation → sodium loading / liposomal form.
- "Cryptococcal meningitis induction regimen?" → Amp B + flucytosine.
- "Which Candida is intrinsically resistant to fluconazole?" → C. krusei (and C. lusitaniae to Amp B — frequently swapped to trip you).
- "Antifungal acting on microtubules / used in ringworm?" → Griseofulvin.
- "Antifungal with disulfiram-like reaction + CYP inducer?" → Griseofulvin (contrast: ketoconazole = CYP inhibitor + gynaecomastia).
- Microbiology cross-link: (1→3)-β-D-glucan and galactomannan serum assays — galactomannan = Aspergillus marker; β-D-glucan = pan-fungal (Candida/PCP/Aspergillus, NOT Mucor/Crypto).
- Pharmacology trap: Ketoconazole inhibits steroidogenesis → used therapeutically in Cushing's syndrome.
Rapid revision
- Polyenes (Amp B/nystatin) bind ergosterol → fungicidal; nystatin topical only.
- Azoles inhibit 14-α-demethylase (CYP51); cause many drug interactions; mostly fungistatic.
- Terbinafine inhibits squalene epoxidase → DOC onychomycosis.
- Echinocandins inhibit β-1,3-glucan synthase → first-line invasive candidiasis; NO Crypto/Mucor cover; IV only.
- Griseofulvin disrupts microtubules, deposits in keratin → dermatophytes only; alcohol disulfiram reaction; CYP inducer.
- Flucytosine → 5-FU, inhibits thymidylate synthase; never alone; marrow suppression.
- Amp B tox: nephrotoxicity (RTA, ↓K⁺, ↓Mg²⁺), infusion rigors, anaemia → reduce by sodium loading + liposomal form.
- Voriconazole = DOC aspergillosis; tox = visual disturbance, phototoxicity, hepatotoxicity.
- Mucormycosis = Liposomal Amp B + surgery; only Amp B, posaconazole, isavuconazole cover Mucor.
- Cryptococcal meningitis = Amp B + flucytosine → fluconazole maintenance.
- C. krusei = fluconazole-resistant; C. lusitaniae / A. terreus = Amp B-resistant; C. auris = MDR.
- PCP = co-trimoxazole, NOT a conventional antifungal — classic distractor.