Classification and Chemistry
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))
- Flucytosine: a pyrimidine analog
- Griseofulvin: an oxaspiro compound (a cyclic structure in which 1 of the ring components is an oxygen molecule)
- 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 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.
- 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
- 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%
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 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.
|Metabolism||Metabolized intracellularly by yeasts to its active form, 5-FU|
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.
- Not active against:
- Endemic mycoses: Histoplasma, Blastomyces, Coccidioides
- 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:
- Urinary tract infections
- Pulmonary infections
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
- GI and hepatic effects:
- GI distress (6% of individuals): nausea, vomiting, and/or diarrhea
- ↑ Serum transaminases
- Hepatic necrosis has been reported, but is rare.
- Hypersensitivity to flucytosine (only absolute contraindication)
- Use with extreme caution in individuals with:
- Bone marrow depression
- Hepatic impairment
- Renal impairment
- Avoid use as monotherapy.
- 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 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.
Overall, griseofulvin has a relatively low level of toxicity. Adverse effects may include:
- GI symptoms: nausea, vomiting, and/or diarrhea
- Histamine reactions:
- Skin reactions:
- Stevens-Johnson syndrome
- Porphyria crisis
- Systemic lupus erythematosus (SLE) exacerbation
- Hepatotoxicity (rare, but may be severe)
- Possible cross-allergenicity with penicillins
- Hypersensitivity to griseofulvin
- Hepatic failure
- 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 are usually mild and self-limiting.
- GI distress: nausea, vomiting, and/or diarrhea
- Histamine reactions:
- SLE exacerbation
- Rare cases of hepatic and hematologic toxicity have been reported.
- 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
|Drug class (examples)||Mechanism of action||Clinical 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|
|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:|
|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|
|Terbinafine||Inhibits the squalene epoxidase enzyme → blocks the production of squalene epoxide, which is a precursor to ergosterol and a critical component of the cell membrane|
|Flucytosine||A pyrimidine analog with metabolites:|
- 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.
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- 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
- Padda, I. (2021). Flucytosine. In StatPearls. Retrieved July 23, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/21829/
- Olson, J. (2020). Griseofulvin. In StatPearls. Retrieved July 23, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/22435/
- Maxfield, L. (2021). Terbinafine. In StatPearls. Retrieved July 23, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/42970/
- Lexicomp Drug Information Sheets (2021). In UpToDate. Retrieved July 22, 2021, from:
- Griseofulvin, https://www.uptodate.com/contents/griseofulvin-drug-information
- Terbinafine (systemic), https://www.uptodate.com/contents/terbinafine-systemic-drug-information
- Flucytosine, https://www.uptodate.com/contents/flucytosine-drug-information