Chapter 37  ·  Module 6
Allylamines, Flucytosine, and Griseofulvin
Three distinct mechanisms, three narrow clinical niches
CYP = cytochrome P450  ·  5-FU = 5-fluorouracil  ·  TDM = therapeutic drug monitoring  ·  DNA = deoxyribonucleic acid  ·  RNA = ribonucleic acid  ·  CBC = complete blood count  ·  GI = gastrointestinal
Mechanism and Spectrum
Allylamines
Terbinafine
  • Target: Squalene epoxidase (early ergosterol pathway)
  • Effect: Ergosterol depletion + squalene accumulation (toxic)
  • Activity: Fungicidal against dermatophytes
  • Spectrum: Dermatophytes only — no Candida, Aspergillus
  • Niche: Onychomycosis; tinea capitis (Trichophyton)
Flucytosine
5-Fluorocytosine
  • Target: Fungal cytosine deaminase → 5-FU
  • Effect: 5-FU blocks DNA synthesis; disrupts RNA
  • Activity: Fungicidal (combination)
  • Spectrum: Cryptococcus, Candida; never use alone
  • Niche: Cryptococcal meningitis induction (+ amphotericin B)
Griseofulvin
Griseofulvin
  • Target: Microtubules — inhibits polymerization
  • Effect: Disrupts fungal mitotic spindle
  • Activity: Fungistatic
  • Spectrum: Dermatophytes only
  • Niche: Tinea capitis in children (Microsporum canis)
Clinical Properties at a Glance
Property Terbinafine Flucytosine Griseofulvin
Route Oral or topical Oral (IV available) Oral only
Key toxicity Hepatotoxicity (rare); taste disturbance; GI effects Bone marrow suppression; GI effects — concentration-dependent Headache; GI effects; photosensitivity; teratogenic
Drug interaction Inhibits CYP2D6 — check tricyclics, beta-blockers, antiarrhythmics Accumulates in renal failure; amphotericin B worsens renal function → monitor levels Induces CYP3A4 — reduces warfarin, oral contraceptives, cyclosporine
Monitoring Liver function tests for prolonged courses TDM (peak 50–100 mg/L); CBC twice weekly; renal function None routine; counsel on alcohol (disulfiram-like reaction)
Special caution Avoid in severe hepatic impairment Never use as monotherapy — resistance in days Avoid in pregnancy (teratogenic); take with fatty food
Flucytosine + Amphotericin B Synergy
Why the Combination Works
Synergistic Fungicidal Effect
  • Amphotericin B increases membrane permeability
  • Enhanced flucytosine entry via cytosine permease
  • Lower concentrations of both drugs achieve fungicidal killing
  • Mortality benefit vs. monotherapy in cryptococcal meningitis
Resistance Warning
Never Use Flucytosine Alone
  • Resistance emerges within days to weeks as monotherapy
  • Mechanisms: loss of cytosine permease or cytosine deaminase
  • Combination with amphotericin B slows resistance emergence
  • One-week induction (WHO 2022) reduces toxicity while preserving benefit
Clinical Niche Summary — When to Use Each Agent

Terbinafine: drug of choice for dermatophyte onychomycosis and tinea capitis from Trichophyton tonsurans. Flucytosine: use only in combination with amphotericin B for cryptococcal meningitis induction — never alone. Griseofulvin: tinea capitis in children, especially Microsporum canis where terbinafine is less effective. Outside these niches, none of the three agents offers advantages over the polyenes, azoles, or echinocandins for invasive fungal disease.