Flucytosine, Griseofulvin, and Terbinafine

In addition to the 3 other major classes of antifungal agents (azoles, polyenes, and echinocandins), several other clinically important antifungal agents are used, including flucytosine, griseofulvin, and terbinafine. Each drug has a distinct mechanism of action and unique characteristics and indications. Flucytosine is a pyrimidine analog that disrupts fungal DNA and RNA synthesis. Flucytosine is always used in combination with other antifungal agents and is primarily used to treat cryptococcal meningitis. Both griseofulvin and terbinafine act within the stratum corneum of the skin and are used to treat dermatophyte infections of the skin, hair, and nails.

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Classification and Chemistry

Classification

In addition to the 3 major classes of antifungal agents (azoles, polyenes, and echinocandins), there are several other clinically important antifungals agents. These drugs include:

  • Flucytosine (also known as 5-fluorocytosine (5-FC))
  • Griseofulvin
  • Terbinafine

Chemical structures

  • Flucytosine: a pyrimidine analog
  • Griseofulvin: an oxaspiro compound (a cyclic structure in which 1 of the ring components is an oxygen molecule)
  • Terbinafine:
    • An allylamine: contains a nitrogen atom and carbon-carbon double bond
    • Contains an alkynyl functional group (carbon-carbon triple bond)

Pharmacodynamics: Mechanisms of Action

Flucytosine

Flucytosine is a pyrimidine analog that disrupts both DNA and RNA synthesis.

  • Enters fungal cells via a protein known as cytosine permease
  • Inside the fungal cell, flucytosine is converted to its active form 5-fluorouracil (5-FU) by the enzyme cytosine deaminase.
    • Mammals lack cytosine deaminase → selective effects on microbial cells
    • Conversion to 5-FU by intestinal flora is thought to be responsible for toxicity in humans.
  • 5-FU:
    • Competes with uracil → incorporated into RNA strands, disrupting RNA synthesis → inhibits fungal protein synthesis
    • Irreversibly inhibits thymidylate synthases → inhibition of thymine production → inability to synthesize or correct DNA → DNA damage
  • May exert fungistatic or fungicidal effects depending on the organism
  • Synergistic effects with amphotericin B and azoles
  • Resistance:
    • Primary/intrinsic resistance: due to mutations in cytosine permease → ↓ 5-FC uptake into fungal cells
    • Secondary/acquired resistance:
      • Due to mutations in cytosine deaminase
      • Resistance is significant when flucytosine is used as monotherapy.
    • Resistance among C. albicans: approximately 10%
Antifungal agents and mechanisms of action

Antifungal agents and mechanisms of action

Image by Lecturio. License: CC BY-NC-SA 4.0

Griseofulvin

The exact mechanisms of griseofulvin are not completely understood, but 2 general mechanisms of action have been suggested:

  • Binds to keratin in newly forming skin, rendering new human cells resistant to invasion
    • Prevents infection of new skin structures → fungistatic agent
    • Over time (weeks to months), the new, uninfected hair/skin/nail structures will have replaced the old, infected ones.
  • Inhibits cell replication in dermatophytes:
    • Binds to tubulin, inhibiting microtubule assembly 
    • Leads to inhibition of the formation of the mitotic spindle → prevention of mitosis at metaphase

Terbinafine

Terbinafine exerts its effects by causing deterioration of the fungal cell membrane by inhibiting the production of squalene epoxide, a precursor to ergosterol.

  • Ergosterol synthesis:
    • Squalene is converted to squalene epoxide by the enzyme squalene epoxidase.
    • Squalene epoxide is converted to lanosterol.
    • Lanosterol is converted to ergosterol by the enzyme lanosterol 14-α-demethylase (14-α-demethylase is inhibited by azoles).
  • Terbinafine noncompetitively inhibits squalene epoxidase.
  • Effects include:
    • ↓ Squalene epoxide production → ↓ ergosterol
    • Fungi are unable to synthesize or maintain their cell membranes without ergosterol.
    • ↑ Fungal cell membrane permeability → cell lysis
  • Terbinafine exerts fungicidal effects in dermatophytes.

Pharmacokinetics

Table: Pharmacokinetics of azoles
DrugsFlucytosineGriseofulvinTerbinafine
Absorption
  • Well absorbed
  • Bioavailability: 75%‒90%
  • Not absorbed topically
  • Very poor water solubility
  • Improved oral absorption with fatty foods
  • Well absorbed
  • Bioavailability: 40% (due to 1st-pass metabolism)
Distribution
  • Minimal protein binding
  • Penetrates well into all body fluid compartments, including CSF
  • Stratum corneum (keratin layer) of skin, hair and nails
  • Also concentrates in:
    • Liver
    • Fat
    • Skeletal muscle
  • Stratum corneum
  • Protein binding: > 99%
MetabolismMetabolized intracellularly by yeasts to its active form, 5-FU
  • Extensive hepatic metabolism
  • CYP450 inducer (drug-drug interactions)
  • Hepatic metabolism via CYP450 enzymes to inactive metabolites
  • Moderate inhibitor of CYP2D6
Excretion
  • Renal elimination via glomerular filtration, primarily as unchanged drug
  • T1/2: 3‒6 hours
  • Adjust dose in renal impairment.
  • Elimination:
    • Fecal (33%)
    • Perspiration
  • T1/2: 9‒24 hours
  • Elimination:
    • Urine: 80%, primarily as inactive metabolites
    • Feces: 20%
  • Effective T1/2: approximately 36 hours
  • Terminal T1/2: 200‒400 hours (very slow drug release from skin and adipose tissue)
CYP450: cytochrome P450
5-FU: 5-fluorouracil
T1/2: half-life
Layers of the skin

Layers of the skin:
Griseofulvin and terbinafine are distributed to the stratum corneum.

Image by Lecturio. License: CC BY-NC-SA 4.0

Flucytosine

Indications

Flucytosine has a narrow spectrum of activity. Owing to its demonstrated synergy with other antifungal agents and the high risk for secondary resistance when used as monotherapy, flucytosine is not used as a single agent.

  • Active against:
    • Cryptococcus neoformans
    • Some Candida spp.
    • Chromoblastomycosis
  • Not active against:
    • Endemic mycoses: Histoplasma, Blastomyces, Coccidioides
    • Aspergillus
    • Zyomycetes
    • Most dermatophytes
  • Clinical uses:
    • Used in combination with amphotericin B to treat cryptococcal meningitis and pneumonia (primary use)
    • Used in combination with itraconazole to treat chromoblastomycosis
    • Used in combination with other agents for systemic, susceptible fungal infections, including:
      • Septicemia
      • Endocarditis
      • Urinary tract infections
      • Peritonitis
      • Pulmonary infections

Adverse effects

Flucytosine is often administered with the highly nephrotoxic agent amphotericin B. Amphotericin B-induced renal impairment can lead to the accumulation of 5-FC (which is renally cleared) and direct 5-FC toxicity, which includes:

  • Hematologic effects: due to bone marrow toxicity
    • Leukopenia
    • Thrombocytopenia
    • Anemia
  • GI and hepatic effects:
    • GI distress (6% of individuals): nausea, vomiting, and/or diarrhea
    • ↑ Serum transaminases
    • Hepatic necrosis has been reported, but is rare.

Contraindications

  • Hypersensitivity to flucytosine (only absolute contraindication)
  • Use with extreme caution in individuals with:
    • Bone marrow depression
    • Hepatic impairment
    • Renal impairment
  • Avoid use as monotherapy.

Monitoring

  • CBC with differential: to monitor for signs of hematologic toxicity
  • Liver function tests: to monitor for signs of hepatotoxicity
  • BUN and creatinine: to monitor for signs of renal dysfunction, which may necessitate dosing adjustments
  • Serum flucytosine concentrations: narrow therapeutic window

Griseofulvin

Indications

Griseofulvin is primarily used to treat dermatophyte infections of the hair, skin, or nails. However, griseofulvin is being replaced by newer agents such as terbinafine or itraconazole for many of its indications.

  • Active against:
    • Trichophyton spp.
    • Microsporum spp.
    • Epidermophyton floccosum
  • Clinical indications:
    • Tinea pedis: “athlete’s foot”
    • Tinea cruris: “jock itch,” typically affecting the groin
    • Tinea corporis: “ringworm,” anywhere on the body
    • Tinea barbae: an infection of the beard and mustached areas of the face, typically seen in adult men
    • Tinea capitis: infection of the scalp and hair shaft
      • Efficacy is improved when combined with a shampoo containing selenium sulfide.
    • Tinea unguium (onychomycosis): infection of the nails
  • Note: Griseofulvin is not effective for the treatment of tinea versicolor.

Adverse effects

Overall, griseofulvin has a relatively low level of toxicity. Adverse effects may include:

  • GI symptoms: nausea, vomiting, and/or diarrhea
  • Headaches
  • Histamine reactions:
    • Fever
    • Rash
    • Flushing
  • Skin reactions:
    • Photosensitivity
    • Rash
    • Stevens-Johnson syndrome
  • Porphyria crisis
  • Systemic lupus erythematosus (SLE) exacerbation
  • Hepatotoxicity (rare, but may be severe)
  • Possible cross-allergenicity with penicillins

Contraindications

  • Hypersensitivity to griseofulvin
  • Hepatic failure
  • Porphyria
  • Pregnancy

Terbinafine

Indications

  • Dermatophyte infections, especially onychomycosis
  • More effective than griseofulvin or itraconazole for onychomycosis
  • Available in both oral and topical forms (unlike griseofulvin, which is only available as an oral formulation)

Adverse effects

Adverse effects are usually mild and self-limiting.

  • GI distress: nausea, vomiting, and/or diarrhea
  • Histamine reactions:
    • Fever
    • Rash
    • Flushing
  • SLE exacerbation
  • Rare cases of hepatic and hematologic toxicity have been reported.

Contraindications

  • Hypersensitivity to terbinafine or other allylamines (e.g., naftifine)
  • Chronic or active liver disease
  • Use with caution in individuals with renal impairment.

Comparison of Antifungal Medications

Table: Comparison of antifungal medications
Drug class (examples)Mechanism of actionClinical relevance
Azoles (Fluconazole, Voriconazole)Inhibits the production of ergosterol (a critical component of the fungal cell membrane) by blocking the lanosterol 14-α-demethylase enzyme
  • Widely used antifungals with a relatively broad spectrum of activity
  • Many drug-to-drug interactions due to effects on the CYP450 system
  • Hepatotoxicity
  • Overall less toxic than amphotericin B
Polyenes (Amphotericin B, Nystatin)Binds to ergosterol in the fungal cell membrane creating artificial pores in the membrane → results in leakage of cellular components and leads to cell lysis (death)Amphotericin B:
  • Reserved for life-threatening fungal infections
  • Broad spectrum of activity
  • Relatively ↑ toxicity (especially nephrotoxicity)
  • Overall less toxic than amphotericin B

Nystatin:
  • Topical use only: skin, mucous membranes, GI lumen
Echinocandins (Caspofungin, Micafungin, Anidulafungin)Inhibits β-glucan synthase (the enzyme synthesizing β-glucan and an important structural component of the fungal cell wall) → weakened cell wall → cell lysis
  • Treats Candida and Aspergillus infections in critically ill and neutropenic patients
  • Minimal toxicity
  • Minimal drug-to-drug interactions
Griseofulvin
  • Binds to the keratin in newly forming skin, making the human cells resistant to invasion → over time the new, uninfected hair/skin/nail structures replace the old, infected structures
  • Inhibits the assembly of microtubules in dermatophytes → inhibits fungal cell replication
  • Treats dermatophyte infections of the hair, skin, and nails
  • Oral medication only (not topically active)
  • Affects the CYP450 system (more drug-to-drug interactions)
  • Largely replaced by newer agents (e.g., terbinafine)
TerbinafineInhibits the squalene epoxidase enzyme → blocks the production of squalene epoxide, which is a precursor to ergosterol and a critical component of the cell membrane
  • Treats dermatophyte infections of the hair, skin, and nails
  • Agent of choice for onychomycosis
  • Relatively low toxicity
FlucytosineA pyrimidine analog with metabolites:
  • Competing with uracil and disrupting RNA synthesis
  • Irreversibly inhibiting thymidylate synthase → fungus is unable to synthesize or correct DNA
  • Always used in combination with other agents due to:
    • Positive synergistic effects
    • ↑ Resistance with monotherapy
  • Major indications:
    • Cryptococcal meningitis
    • Chromoblastomycosis
  • Toxicity: myelosuppression

References

  1. Sheppard, D., Lampiris, H.W. (2012). Antifungal agents. In Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic and Clinical Pharmacology, 12th Ed., pp. 852‒853, 855‒856.
  2. Drew, R.H. (2020). Pharmacology of flucytosine (5-FC). In Bogorodskaya, M (Ed.), UpToDate. Retrieved July 23, 2021, from https://www.uptodate.com/contents/pharmacology-of-flucytosine-5-fc 
  3. Nivoix, Y., Ledoux, M., Herbrecht, R. (2020). Antifungal therapy: New and evolving therapies. Semin Respir Crit Care Med. 2020, 41, 158-174. Retrieved July 23, 2021, from https://www.medscape.com/viewarticle/924712_7 
  4. Padda, I. (2021). Flucytosine. In StatPearls. Retrieved July 23, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/21829/ 
  5. Olson, J. (2020). Griseofulvin. In StatPearls. Retrieved July 23, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/22435/ 
  6. Maxfield, L. (2021). Terbinafine. In StatPearls. Retrieved July 23, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/42970/ 
  7. Lexicomp Drug Information Sheets (2021). In UpToDate. Retrieved July 22, 2021, from:

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