Antifungal Drugs
Pharmacology · Antimicrobials · lean revision notes
Antifungal Drugs
Antifungals are a high-frequency Pharmacology topic where almost every question pivots on mechanism of action, drug of choice (DOC) for a named mycosis, and a signature toxicity. Master the ergosterol pathway and the four "attack points" on the fungal cell, and most MCQs collapse into pattern recognition.
The fungal target: why ergosterol matters
Fungi are eukaryotes, so selective toxicity is hard. The exploitable difference is the cell membrane sterol: fungi use ergosterol where human cells use cholesterol. Add the cell wall (β-1,3-glucan + chitin, absent in humans) and nucleic acid metabolism, and you have the four druggable targets that organise the entire class.
Ergosterol synthesis flow (the spine of this topic):
Acetyl-CoA → squalene → (squalene epoxidase) → lanosterol → (lanosterol 14-α-demethylase, a CYP450 enzyme) → ergosterol → fungal membrane integrity
High-yield: Allylamines (terbinafine) block squalene epoxidase; azoles block lanosterol 14-α-demethylase (CYP51); amphotericin B binds preformed ergosterol to punch pores. Three different points on one pathway/membrane — examiners love distinguishing them.
Classification by mechanism
| Class | Drugs | Molecular target | Effect |
|---|---|---|---|
| Polyenes | Amphotericin B, Nystatin | Binds ergosterol → membrane pores | Fungicidal |
| Azoles (imidazole) | Ketoconazole, Clotrimazole, Miconazole | Lanosterol 14-α-demethylase (CYP51) | Fungistatic |
| Azoles (triazole) | Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazole | Lanosterol 14-α-demethylase (CYP51) | Fungistatic (cidal vs Aspergillus for some) |
| Echinocandins | Caspofungin, Micafungin, Anidulafungin | β-1,3-glucan synthase (cell wall) | Fungicidal vs Candida, static vs Aspergillus |
| Allylamines | Terbinafine, Naftifine | Squalene epoxidase | Fungicidal |
| Antimetabolite | Flucytosine (5-FC) | Inhibits DNA/RNA synthesis (→ 5-FU) | Fungistatic |
| Antimitotic | Griseofulvin | Disrupts microtubules (mitotic spindle) | Fungistatic |
| Others | Nikkomycin, Tavaborole, Ciclopirox | Chitin synthase / leucyl-tRNA / chelation | Varies |
High-yield: Only polyenes, echinocandins and terbinafine are fungicidal; azoles, flucytosine and griseofulvin are fungistatic. Echinocandins are the only class acting on the cell wall — a frequent one-liner.
Polyenes — Amphotericin B
Mechanism: A large polyene macrolide that binds ergosterol in the fungal membrane and inserts to form transmembrane pores/channels, causing leakage of K⁺ and Mg²⁺, depolarisation and cell death. It binds cholesterol with lower affinity — the basis of its host toxicity.
Spectrum: Broadest of all antifungals — most yeasts and moulds, including Candida, Cryptococcus, Histoplasma, Blastomyces, Coccidioides, Mucor/Rhizopus (mucormycosis), and Aspergillus. Resistant organisms worth remembering: Candida lusitaniae (intrinsic resistance), Aspergillus terreus, Scedosporium and Trichosporon.
Pharmacokinetics: Not absorbed orally (oral form used only for gut decontamination); given IV. Poor CSF penetration, yet still used in fungal meningitis because of activity. Long terminal half-life; renally and hepatically cleared slowly.
Amphotericin B toxicity and management
Two patterns: infusion-related (immediate) and dose-dependent nephrotoxicity (cumulative).
| Toxicity | Mechanism | Prevention / management |
|---|---|---|
| Infusion reaction — fever, rigors, chills ("shake and bake") | Cytokine release | Premedicate with paracetamol + antihistamine ± hydrocortisone; pethidine abolishes rigors; slow infusion |
| Nephrotoxicity (azotaemia, ↓GFR) | Renal afferent vasoconstriction | Sodium loading (saline preload); avoid other nephrotoxins |
| Hypokalaemia & hypomagnesaemia | Distal tubular K⁺/Mg²⁺ wasting (RTA type I) | Monitor and replace K⁺/Mg²⁺ |
| Normocytic normochromic anaemia | ↓ Erythropoietin | Usually reversible |
| Thrombophlebitis | Local irritation | Central line / heparin |
High-yield: Nephrotoxicity is the dose-limiting toxicity of amphotericin B; sodium (saline) loading before infusion is the single best preventive step. The classic electrolyte triad is hypokalaemia + hypomagnesaemia (distal RTA).
Lipid formulations — Liposomal amphotericin B (L-AmB), amphotericin B lipid complex (ABLC), and colloidal dispersion (ABCD) — deliver drug preferentially to reticuloendothelial cells, allowing higher doses with markedly less nephrotoxicity (but far costlier). Liposomal amphotericin B is now standard for mucormycosis and as the polyene of choice when renal function is precarious.
Azoles
Mechanism: Inhibit the fungal CYP450 enzyme lanosterol 14-α-demethylase (CYP51), blocking conversion of lanosterol to ergosterol. Result: ergosterol depletion + accumulation of toxic 14-α-methyl sterols → membrane dysfunction. Triazoles are more fungal-selective (less host CYP inhibition) than imidazoles, hence the systemic shift to triazoles.
High-yield: Azoles are CYP enzyme inhibitors — this drives both their antifungal action and their drug interactions (they raise levels of warfarin, statins, cyclosporine, etc.). Ketoconazole's inhibition of human steroidogenesis (it blocks 17,20-lyase/11-β and 17-α-hydroxylase) causes gynaecomastia and adrenal suppression and is exploited therapeutically in Cushing's syndrome and prostate cancer.
| Triazole | Key spectrum niche | Distinctive point |
|---|---|---|
| Fluconazole | Cryptococcus, Candida (non-krusei) | Best CSF penetration, water-soluble, oral = IV bioavailability; no activity vs moulds/Aspergillus |
| Itraconazole | Dimorphic fungi — Histoplasma, Blastomyces, Sporothrix | Needs acid for absorption (avoid PPIs); negative inotrope → avoid in CHF |
| Voriconazole | DOC for invasive aspergillosis | Visual disturbances (photopsia), hepatotoxicity, phototoxicity/skin Ca, periostitis; needs therapeutic drug monitoring |
| Posaconazole | Broadest azole — incl. Mucorales (prophylaxis & salvage) | Widest mould cover |
| Isavuconazole | Aspergillosis & mucormycosis | Well-tolerated; shortens QT (unique) |
High-yield: Azoles in general prolong the QT interval — isavuconazole is the exception (shortens QT). Candida krusei is intrinsically fluconazole-resistant; C. glabrata is dose-dependently resistant.
Common azole adverse effects: hepatotoxicity (monitor LFTs), GI upset, rash, QT prolongation, and CYP-mediated interactions. Itraconazole and (historically) ketoconazole carry the strongest cardiac/hepatic warnings; ketoconazole systemic use is now largely abandoned because of fatal hepatotoxicity.
Echinocandins
Mechanism: Non-competitively inhibit β-1,3-glucan synthase, the enzyme building the fungal cell wall glucan polymer → osmotically unstable wall → lysis.
Spectrum: Fungicidal against most Candida (including azole-resistant C. glabrata/krusei) and active (fungistatic) against Aspergillus. No activity against Cryptococcus, Mucor/Rhizopus, or Fusarium — a high-yield gap.
Pharmacology: IV only, large molecules, excellent safety profile (minimal nephro/hepatotoxicity, few interactions). Now the first-line empirical therapy for invasive candidiasis/candidaemia, especially in unstable or azole-exposed patients.
High-yield: Echinocandins are DOC for candidaemia/invasive candidiasis and are the "safe" antifungals (no renal dose adjustment for caspofungin in renal failure). They do not cover Cryptococcus or mucormycosis — remember the holes.
Flucytosine (5-FC)
Mechanism: A pyrimidine analogue taken up by fungal cytosine permease and deaminated by fungal cytosine deaminase to 5-fluorouracil (5-FU) → (a) 5-FdUMP inhibits thymidylate synthase (blocks DNA synthesis) and (b) FUTP is incorporated into RNA. Human cells lack cytosine deaminase, giving selectivity.
Use: Narrow spectrum (Cryptococcus, Candida). Never used alone — rapid resistance develops. Combined with amphotericin B for cryptococcal meningitis (synergy: AmB pores let 5-FC enter).
Toxicity: Gut flora convert it to 5-FU → bone marrow suppression (neutropenia, thrombocytopenia) and enterocolitis; dose-related, worse in renal impairment.
High-yield: Induction therapy for cryptococcal meningitis = amphotericin B + flucytosine (then fluconazole for consolidation/maintenance). Flucytosine's toxicity is bone marrow suppression via conversion to 5-FU by gut bacteria.
Griseofulvin
Mechanism: Disrupts the mitotic spindle by binding microtubules/tubulin, arresting fungal mitosis; also deposits in keratin precursor cells, making new keratin resistant to dermatophyte invasion.
Spectrum: Dermatophytes only (Trichophyton, Microsporum, Epidermophyton) — no yeast/mould activity. Oral; absorption improved by fatty meals; concentrates in keratin.
Use: Tinea capitis (still a useful oral agent in children), and extensive/nail dermatophytosis when terbinafine is unsuitable. Treatment is prolonged until infected keratin is shed.
Toxicity & interactions: Headache (common), GI upset, disulfiram-like reaction with alcohol, photosensitivity, and it is a CYP inducer (↓ warfarin, ↓ oral contraceptive efficacy). Teratogenic — avoid in pregnancy.
High-yield: Griseofulvin = microtubule disruptor, dermatophytes only, take with fatty food, enzyme inducer. Contrast with terbinafine (squalene epoxidase, also dermatophyte-focused but fungicidal and now first-line for onychomycosis).
Terbinafine and topical agents
Terbinafine (allylamine) inhibits squalene epoxidase, causing toxic squalene accumulation; fungicidal, DOC for onychomycosis/dermatophyte nail infection. Hepatotoxicity and rare taste disturbance are notable.
Topicals: Nystatin (polyene — oral/vaginal/cutaneous candidiasis, too toxic for IV), clotrimazole/miconazole (topical candidiasis & tinea), ciclopirox and tavaborole (nail lacquers), and selenium sulphide/ketoconazole shampoo for pityriasis versicolor.
Drug of choice — the exam table
| Condition | Drug of choice |
|---|---|
| Invasive aspergillosis | Voriconazole (isavuconazole alternative; L-AmB if azole-intolerant) |
| Cryptococcal meningitis (induction) | Amphotericin B + flucytosine → fluconazole maintenance |
| Invasive candidiasis / candidaemia | Echinocandin (caspofungin/micafungin) |
| Oesophageal/oropharyngeal candidiasis | Fluconazole |
| Mucormycosis | Liposomal amphotericin B + surgical debridement (posaconazole/isavuconazole salvage) |
| Dermatophytosis (tinea corporis/cruris) | Topical azole/terbinafine; oral terbinafine if extensive |
| Onychomycosis / tinea unguium | Terbinafine (oral) |
| Tinea capitis | Griseofulvin or terbinafine (oral) |
| Histoplasmosis / Blastomycosis (mild-mod) | Itraconazole (severe → amphotericin B) |
| Sporotrichosis | Itraconazole |
| Pityriasis (tinea) versicolor | Topical ketoconazole/selenium sulphide |
| Coccidioidomycosis | Fluconazole/itraconazole |
High-yield: Three "must-not-miss" DOCs repeatedly tested — voriconazole for invasive aspergillosis, L-AmB for mucormycosis, echinocandin for candidaemia, and AmB + 5-FC for cryptococcal meningitis.
Stepwise approach to a suspected invasive mycosis
- Stabilise & sample: blood cultures, tissue/biopsy, galactomannan (Aspergillus), serum/CSF cryptococcal antigen (CrAg), 1,3-β-D-glucan (pan-fungal except Mucor/Crypto).
- Empirical cover in the unstable neutropenic patient → echinocandin (Candida) or mould-active azole/L-AmB if mould suspected.
- Identify the organism → switch to the targeted DOC from the table.
- Optimise host: reverse neutropenia, control diabetes/DKA (mucormycosis), reduce immunosuppression.
- Source control: debride mucormycosis, remove infected lines in candidaemia.
- Monitor toxicity — renal/electrolytes (AmB), LFTs and visual symptoms (voriconazole), marrow (flucytosine).
Key resistance & "gaps" to memorise
- Candida krusei → intrinsic fluconazole resistance.
- Candida lusitaniae → amphotericin B resistance.
- Aspergillus terreus → amphotericin B resistance.
- Echinocandins fail against Cryptococcus, Mucor/Rhizopus, Fusarium.
- Fluconazole has no mould activity (no Aspergillus, no Mucor).
Complications & monitoring summary
- Amphotericin B: nephrotoxicity, K⁺/Mg²⁺ wasting, anaemia, infusion rigors.
- Azoles: hepatotoxicity, QT prolongation, teratogenicity, CYP interactions; voriconazole → visual disturbance & phototoxic skin cancer; itraconazole → CHF.
- Echinocandins: histamine-mediated infusion flush, mild LFT rise (very safe overall).
- Flucytosine: marrow suppression, hepatotoxicity, GI.
- Griseofulvin/terbinafine: hepatotoxicity; griseofulvin disulfiram-like reaction + enzyme induction.
Key differentials in mechanism (the classic confusion set)
- Squalene epoxidase = terbinafine (NOT azoles).
- Lanosterol 14-α-demethylase = azoles (NOT terbinafine).
- Binds ergosterol/forms pores = amphotericin (acts on preformed sterol, not synthesis).
- β-1,3-glucan synthase = echinocandins (cell wall, not membrane).
- Microtubules = griseofulvin (also vinca/colchicine/taxanes act on microtubules — disambiguate carefully).
- Cytosine deaminase → 5-FU = flucytosine.
Recently asked / exam angle
- "Mechanism of voriconazole?" → inhibits lanosterol 14-α-demethylase; and "characteristic side effect?" → visual/photopsia.
- "DOC for mucormycosis?" → liposomal amphotericin B + surgical debridement (often paired with a poorly controlled diabetic ketoacidosis vignette).
- "Antifungal acting on the cell wall?" → echinocandins (β-1,3-glucan synthase).
- "Which antifungal causes hypokalaemia & nephrotoxicity, and how to reduce it?" → amphotericin B; saline/sodium loading.
- "Griseofulvin mechanism?" → microtubule/mitotic spindle disruption, deposits in keratin.
- "Why is flucytosine combined with amphotericin in cryptococcal meningitis?" → synergy — AmB pores enhance 5-FC entry; prevents resistance.
- "Antifungal used in Cushing's syndrome?" → ketoconazole (steroidogenesis inhibition).
- Image/clinical-feature questions on tinea/onychomycosis mapping to terbinafine.
Mnemonics
- "AmB blows holes" — Amphotericin Binds ergosterol and Bores pores; toxicity = Bad kidneys + low K⁺/Mg²⁺.
- Echinocandins → "echino-WALL" — the only cell-WALL agents (glucan synthase).
- "Vori sees Aspergillus" — Voriconazole = aspergillosis DOC, with visual side effects.
- Azole interactions: "Azoles inhibit, Griseofulvin/Rifampin induce."
Rapid revision
- Ergosterol = fungal membrane sterol; basis of selective toxicity.
- Amphotericin B binds preformed ergosterol → pores; fungicidal, broadest spectrum.
- Dose-limiting AmB toxicity = nephrotoxicity; prevent with saline loading; expect hypokalaemia + hypomagnesaemia.
- Liposomal AmB = less nephrotoxic and DOC for mucormycosis (+ debridement).
- Azoles inhibit lanosterol 14-α-demethylase (CYP51); fungistatic; QT prolongation + CYP interactions.
- Voriconazole = DOC invasive aspergillosis; side effect = visual disturbance.
- Fluconazole = best CSF penetration, no mould cover; C. krusei resistant.
- Echinocandins inhibit β-1,3-glucan synthase (cell wall); DOC for candidaemia; no Crypto/Mucor cover.
- Flucytosine → 5-FU (via cytosine deaminase); marrow suppression; combine with AmB for cryptococcal meningitis.
- Griseofulvin = microtubule disruptor, dermatophytes only, take with fatty food, enzyme inducer.
- Terbinafine inhibits squalene epoxidase; DOC for onychomycosis; fungicidal.
- Ketoconazole = abandoned systemically (hepatotoxic); used in Cushing's; isavuconazole shortens QT (azole exception).