Antifungals

Last updated: February 8, 2023

Summary

Antifungals are a class of medications that destroy or inhibit the growth of fungal organisms and are, accordingly, used to treat fungal infections (mycoses) such as candidiasis, cryptococcal disease, aspergillosis, and dermatophytosis. They are divided into three major groups according to chemical structure and spectrum of efficacy: polyenes (used for the treatment of systemic fungal infections), azoles (broad-spectrum antifungals), and allylamines (used for the treatment of onychomycosis). Topical agents (e.g., clotrimazole) generally have a more limited scope of action. Common adverse effects include hepatotoxicity, skin reactions, headaches, and gastrointestinal upset.

Overview

Overview of antifungals and their mechanisms of action ^[1]^[2]^[3]^[4]^[5]^[6]^[7]
Class		Examples	Mechanism of action	Clinical use	Adverse effects
Polyenes		Amphotericin B	Bind to ergosterol in the fungal cell membrane → formation of pores in the fungal membrane → disruption of electrolyte balance → cell lysis → cell death	Severe systemic mycoses Invasive candidiasis Cryptococcal disease Aspergillosis Blastomycosis Coccidioides Histoplasmosis Mucormycosis	Arrhythmias Nephrotoxicity Fever, chills IV phlebitis (“amphoterrible”) Hypokalemia, hypomagnesemia
Polyenes		Nystatin		Vaginal candidiasis Diaper rash Oropharyngeal candidiasis	Gastrointestinal symptoms Contact dermatitis Stevens-Johnson syndrome
Azoles	Triazoles	Fluconazole	Inhibit fungal cytochrome P450 → ↓ fungal synthesis of ergosterol from lanosterol → ↓ levels of ergosterol → membrane instability → cell death Ketoconazole: inhibition of 17α-hydroxylase/17,20-lyase	Cryptococcal meningitis (in AIDS patients) Candidiasis Coccidioidomycosis Histoplasmosis/blastomycosis Blastomycosis	Hepatotoxicity Cytochrome P450 inhibition Important contraindications: Cardiac arrhythmias (e.g., prolonged QT) Local burning sensation, pruritus if used topically Ketoconazole: gynecomastia
		Voriconazole		Drug of choice for invasive aspergillosis
		Itraconazole		Histoplasmosis Blastomycosis Coccidioidomycosis Sporotrichosis Allergic bronchopulmonary aspergillosis
		Isavuconazole		Invasive aspergillosis Invasive mucormycosis
	Imidazoles	Ketoconazole		Tinea versicolor Prostate cancer Psoriasis Hypercortisolism (e.g., Cushing syndrome)
	Imidazoles	Clotrimazole Miconazole		Vaginal candidiasis Oropharyngeal candidiasis
Allylamines		Terbinafine	Inhibit fungal squalene epoxidase → ↓ synthesis of ergosterol → accumulation of squalene → ↑ membrane permeability → cell death	Dermatophytosis (especially onychomycosis) Tinea infections	Headache Hepatotoxicity Dysgeusia Gastrointestinal upset
Echinocandins		Caspofungin Anidulafungin Micafungin	Inhibit the synthesis of β-glucan → disruption of fungal cell wall synthesis → ↓ resistance against osmotic forces → cell death	Invasive aspergillosis Invasive candidiasis	Flushing Hepatotoxicity Gastrointestinal upset
Pyridone derivatives		Ciclopirox	Not fully understood	Tinea versicolor Dermatophytosis Seborrheic dermatitis of the scalp	Ventricular tachycardia
Benzofurans		Griseofulvin	Bind to keratin → interference with microtubule function → disruption of fungal mitosis → inhibition of fungal growth	Dermatophyte infections (e.g., tinea pedis)	Hepatotoxicity Carcinogenic Teratogenic Cytochrome P450 induction Confusion, headaches Disulfiram-like reaction
Antimetabolites		Flucytosine	Converted to 5-fluorouracil by fungal cytosine deaminase → inhibition of DNA and RNA synthesis → inhibition of fungal growth	Monotherapy: select cases of non-life-threatening infections such as genitourinary candida infections that are not covered by alternative drugs Combination with amphotericin B (e.g., especially cryptococcal meningitis)	Bone marrow suppression Hepatic injury Renal failure

Mechanism of action: antifungals

Polyenes

Overview
- Used mainly for the treatment of systemic fungal infections
- Considered a subgroup of macrolide antibiotics ^[8]
Mechanism of action: bind to ergosterol in the fungal cell membrane → formation of pores in the fungal membrane → disruption of electrolyte balance → cell lysis → cell death

Amphotericin B Burrows nice (nystatin) holes in the fungal cell membrane.

Amphotericin B

Routes of administration
- Intravenous
- Intrathecal
- Bladder irrigation
Clinical use ^[9]
- Severe systemic mycoses, such as:
  - Cryptococcal disease (in combination with flucytosine for cryptococcal meningitis)
  - Sporotrichosis
  - Aspergillosis
  - Blastomycosis
  - Candidiasis
  - Coccidioides (administered intrathecally for coccidioidal meningitis)
  - Histoplasmosis
  - Mucormycosis
- Fungal cystitis
- Fungal meningitis
Adverse effects ^[9]
- Nephrotoxicity: Lipid-based formulations of the drug and IV hydration reduce nephrotoxicity.
- IV phlebitis
- Impaired renal tubule permeability → hypokalemia and hypomagnesemia (restoring K⁺ and Mg²⁺ while administering the drug can counter this effect)
- Fever, chills; (amphotericin B is sometimes referred to as “shake and bake”)
- Bone marrow suppression, anemia
- Arrhythmias
- Hypotension
Contraindications ^[9]
- Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia)
- Renal dysfunction
- Pregnancy

Amphotericin B has amphoterrible side effects, including nephrotoxicity, arrhythmias, and IV phlebitis.

Nystatin

Routes of administration (too toxic for intravenous use)
- Topical
  - Vaginal candidiasis
  - Diaper rash
- Oral (swish and swallow): oropharyngeal candidiasis
Adverse effects
- Gastrointestinal symptoms (e.g., diarrhea, nausea, pain)
- Contact dermatitis
- Stevens-Johnson syndrome
Contraindications: pregnancy

Nystatin is too toxic for intravenous use. For oropharyngeal candidiasis, the medication should be swished around in the mouth, gargled, and then swallowed (swish and swallow).

Azoles

Definition: a group of antifungal agents with a broad spectrum of activity that can be divided into triazoles and imidazoles
Routes of administration
- Imidazoles: topical, oral
- Triazoles: oral, IV
Mechanism of action
- Inhibition of 14-alpha demethylase, a fungal cytochrome P450 → ↓ fungal synthesis of ergosterol from lanosterol → ↓ levels of ergosterol → membrane instability → cellular death. ^[10]
- Ketoconazole: inhibition of 17α-hydroxylase/17,20-lyase

Overview of azoles
	Active substance	Clinical use	Adverse effects
	Active substance	Clinical use	Topical use	Systemic use
Imidazole derivatives	Clotrimazole	Primarily topical fungal infections Vaginal candidiasis Tinea infections Oropharyngeal candidiasis	Local burning sensation Pruritus	Hepatotoxicity: inhibits cytochrome P450 → ↑ concentration of many drugs metabolized by CYP450 (e.g., warfarin, simvastatin, cyclosporine, theophylline) Gynecomastia due to inhibition of testosterone synthesis (especially seen with ketoconazole) Gastrointestinal upset QT prolongation → torsade de pointes Hypokalemia Ketoconazole: adrenal cortex insufficiency Voriconazole: dose-dependent, reversible visual disorders (e.g., photosensitivity)
	Miconazole
	Ketoconazole	Tinea versicolor Prostate cancer Psoriasis Hypercortisolism (e.g., Cushing syndrome)
Triazole derivatives	Fluconazole	Drug of choice maintenance therapy of cryptococcal meningitis in patients with AIDS ^[11] Candidiasis (all forms) Coccidioidomycosis Histoplasmosis Blastomycosis
	Voriconazole	Drug of choice for invasive aspergillosis Some forms of Candida
	Itraconazole	Histoplasmosis Blastomycosis Coccidioidomycosis Sporotrichosis Allergic bronchopulmonary aspergillosis, aspergilloma Particularly effective in dermatophytosis (e.g., onychomycosis) Oropharyngeal/esophageal candidiasis
	Posaconazole	Oropharyngeal candidiasis Prophylactic treatment of invasive aspergillosis and Candida infections in immunocompromised patients
	Isavuconazole	Invasive aspergillosis Invasive mucormycosis

Contraindications
- Cardiac arrhythmias
- Severe cardiac insufficiency
Special considerations
- Inhibition of cytochrome P450 can influence serum concentrations of other medications
- Cautious use in patients with renal and/or hepatic dysfunction
- PPIs must be discontinued (azoles require a low pH to be absorbed)

Voriconazole is the drug of choice for inVasive aspergillosis.

The FLU easily penetrates the blood-brain barrier: FLuconazole has good CNS penetration.

Allylamine derivatives (terbinafine)

Route of administration: oral
Mechanism of action: inhibition fungal squalene epoxidase → ↓ synthesis of ergosterol → accumulation of squalene → ↑ membrane permeability → cell death
Clinical use
- Dermatophytosis (most commonly onychomycosis)
- Tinea infections (e.g., tinea pedis)
Adverse effects
- Hepatotoxicity
- Dysgeusia
- Gastrointestinal upset
- Headache
- Exacerbation of autoimmune diseases (e.g., systemic lupus erythematosus)
Contraindications
- Impaired liver function
- Systemic lupus erythematosus
- Breastfeeding

Echinocandins

Drugs
- Caspofungin
- Anidulafungin
- Micafungin
Route of administration: IV
Mechanism of action: inhibition of β-glucan synthesis → disruption of fungal cell wall synthesis → ↓ resistance against osmotic forces → cell death
Clinical use
- Invasive aspergillosis
- Invasive candidiasis (particularly biofilm-embedded Candida )
Adverse effects
- Flushing (due to release of histamine)
- Hepatotoxicity
- Gastrointestinal upset
- Hypotension
- Phlebitis/pain at the injection site
- Fever, shivering

Pyridone derivatives (ciclopirox)

Route of administration: topical
Mechanism of action
- Not fully understood
- Likely disruption of DNA, RNA, and protein synthesis
Clinical use
- Tinea versicolor
- Dermatophytosis (e.g., onychomycosis)
- Seborrheic dermatitis of the scalp
Adverse effects
- Facial edema
- Ventricular tachycardia
- Skin irritations
- Pruritus

Benzofurans (griseofulvin)

Route of administration: oral
Mechanism of action: griseofulvin binds to keratin precursor cells → accumulation in keratin-rich tissues (e.g., nails, hair) → entry into the fungal cell → interference with microtubule function → disruption of fungal mitosis
Clinical use: dermatophyte infections (e.g., tinea pedis)
Adverse effects
- Hepatotoxicity
- Carcinogenicity
- Teratogenicity
- Enzyme induction → ↓ concentration of many drugs metabolized by cytochrome P450 (e.g., warfarin)
- Confusion, headaches
- Disulfiram-like reaction
  - A reaction similar to the disulfiram-ethanol reaction triggered by the concomitant intake of alcohol and another drug (e.g., procarbazine)
  - Clinical signs of a disulfiram-like reaction include flushing, tachycardia, and hypotension.
- Urticaria and severe skin reactions (e.g., Stevens-Johnson syndrome)
Contraindications
- Porphyria
- Hepatic failure
- Pregnancy and breastfeeding

Antimetabolites (flucytosine)

Route of administration: oral
Mechanism of action: converted to 5-fluorouracil by fungal cytosine deaminase, thereby inhibiting DNA and RNA synthesis
Clinical use
- Combination with amphotericin B: systemic fungal infections (especially cryptococcal meningitis)
- Monotherapy: non-life-threatening infections, such as genitourinary candida infections, that do not respond to other drugs
Adverse effects
- Bone marrow suppression with pancytopenia
  Hepatic injury
- Renal failure
- Gastrointestinal upset
Contraindications
- Renal impairment
- Pregnancy and breastfeeding

Treatment of common fungal infections

Treatment of common fungal infections
		Treatment
Candidiasis	Oropharyngeal	Oral clotrimazole (troches) Oral nystatin (swish and swallow)
	Esophageal	Fluconazole
	Vaginal	Topical clotrimazole/miconazole
	Cutaneous	Topical nystatin (powder)
	Systemic	IV amphotericin B (sometimes in combination with flucytosine)
Invasive aspergillosis		Voriconazole (first-line) Caspofungin IV amphotericin B
Cryptococcosis		First 2 weeks: IV amphotericin B in combination with flucytosine After 2 weeks (maintenance therapy): oral fluconazole
Blastomycosis Histoplasmosis Coccidioidomycosis Sporotrichosis		Oral itraconazole/fluconazole Severe cases: IV amphotericin B
Tinea versicolor		Topical ciclopirox Topical ketoconazole Topical miconazole Selenium sulfide
Dermatophytosis		Topical ciclopirox Topical azoles Oral itraconazole Oral griseofulvin Terbinafine: onychomycosis

References

Antifungal Drugs. https://www.merckmanuals.com/professional/infectious-diseases/fungi/antifungal-drugs. Updated: January 1, 2014. Accessed: February 20, 2017.
FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. https://www.fda.gov/Drugs/DrugSafety/ucm362415.htm. Updated: July 26, 2013. Accessed: February 20, 2017.
FDA Drug Safety Communication: FDA warns that prescribing of Nizoral (ketoconazole) oral tablets for unapproved uses including skin and nail infections continues; linked to patient death. https://www.fda.gov/Drugs/DrugSafety/ucm500597.htm. Updated: May 19, 2016. Accessed: February 20, 2017.
Terbinafine. https://www.drugs.com/pro/terbinafine.html. Updated: February 20, 2017. Accessed: February 20, 2017.
Griseofulvin. https://www.drugs.com/pro/griseofulvin.html. Updated: February 20, 2017. Accessed: February 20, 2017.
Nystatin. https://www.drugs.com/monograph/nystatin.html. Updated: June 1, 2007. Accessed: January 29, 2018.
Castinetti F, Guignat L, Giraud P, et al.. Ketoconazole in cushing's disease: is it worth a try?. J Clin Endocrinol Metab. 2014; 99 (5): p.1623-1630. doi: 10.1210/jc.2013-3628 . | Open in Read by QxMD
Hamilton-Miller JM. Chemistry and biology of the polyene macrolide antibiotics.. Bacteriol Rev. 1973; 37 (3): p.166-96.
Ashley ED, Perfect JR. Pharmacology of azoles. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. http://www.uptodate.com/contents/pharmacology-of-azoles?source=search_result&search=itraconazole&selectedTitle=6~150#H19.Last updated: January 3, 2017. Accessed: February 20, 2017.
Abassi M, Boulware DR, Rhein J. Cryptococcal Meningitis: Diagnosis and Management Update.. Current tropical medicine reports. 2015; 2 (2): p.90-99. doi: 10.1007/s40475-015-0046-y . | Open in Read by QxMD
Amphotericin B. https://www.drugs.com/mtm/amphotericin-b.html. Updated: March 2, 2020. Accessed: September 30, 2020.

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