Indications

Fungi are eukaryotic organisms that exist in all environments worldwide. They exist in many forms, ranging from visible fungi, such as mushrooms, to microscopic yeasts and molds. While most fungi do not play a significant role in human disease, there are several hundred fungi that do, resulting in fungal infection or disease. Fungal infections (mycoses) range from common benign infections like 'jock itch' to severe, life-threatening illnesses such as cryptococcal meningitis V体育官网入口. The term 'antifungals' encompasses all chemical compounds, pharmacologic agents, and natural products used to treat mycoses.

Clinically, fungal infections are best categorized first by the site and extent of the infection, then by the route of acquisition, and finally, by the virulence of the causative organism. These classifications are essential when determining the most effective treatment regimen for a particular mycosis.  Mycoses are classified as local (superficial, cutaneous, subcutaneous) or systemic (deep, bloodborne). The acquisition of the fungal infection can occur through either an exogenous (airborne/inhalation, cutaneous exposure, or percutaneous inoculation) or an endogenous process (normal flora or reactivation of an existing infection) VSports在线直播. The virulence of the organism is classified as either a primary infection (a disease arising in a healthy host) or an opportunistic infection (a disease arising in human hosts with a compromised immune system or other defenses). [1].

Antifungal drugs represent a pharmacologically diverse group of drugs that are crucial components in the modern medical management of mycoses. While antimycotic pharmacology has advanced significantly, particularly over the last 3 decades, common invasive fungal infections still carry a high mortality rate: Candida albicans (20% to 40% mortality), Aspergillus fumigatus (50% to 90%), and Cryptococcus neoformans (20% to 70%).[2][3]

Amphotericin B deoxycholate, a polyene antibiotic, was the first antimycotic agent introduced in 1958 to treat systemic mycoses. While this drug is an effective agent, the demand for other efficacious topical, oral, and intravenous agents was apparent. Griseofulvin was introduced in 1959, representing the second class of antifungals. The next significant introduction would not occur until 1971 when the antimetabolite drug flucytosine entered the market. Azoles first became available in 1973 with the arrival of clotrimazole; additional azoles that have the pharmaceutical industry has rolled out over the past 5 decades: miconazole (1979), ketoconazole (1981), fluconazole (1990), itraconazole (1992), voriconazole (2002), posaconazole (2006), and most recently isavuconazonium (2015).[4] Terbinafine, an allylamine antifungal, was approved by the FDA in 1996 and has indications for treating local, non-systemic fungal infections. The next breakthrough in systemic therapy would be based on amphotericin B lipid formulations, which have more favorable adverse effect profiles.

In 2021, the FDA approved ibrexafungerp, a triterpenoid fungicidal agent, making it the first oral non-azole treatment option for vulvovaginal candidiasis.[5] Following lipid formulations of azoles, a new class of antifungal agents that are highly effective in treating some systemic mycoses, is the recently developed echinocandin class. While the echinocandins demonstrate less renal toxicity than amphotericin B, they cause significant hepatotoxicity and are more expensive than azoles; this effectively relegates this class to second- or third-line agents. Rezafungin was approved by the FDA in 2023.[6][7] Mechanistically, antifungal agents are diverse, yet due to the alarming and rapid increase in drug-resistant systemic fungal infections, new agents are more necessary than ever.[8][9][10][11] This discussion will focus on the currently available antifungal agents.[12][13][14][15]

Common, medically relevant fungal infections include, but are not limited to, the conditions and causative organisms listed below.[16][17][18][19]

• Aspergillosis - Aspergillus fumigatus, A. flavus
• Blastomycosis - Blastomyces dermatitidis
• Candidiasis - Candida albicans, C glabrata, C krusei, C parasilosis, C tropicalis
• Chromoblastomycosis (Chromomycosis) - Cladosporium carrionii, Phialophora verrucosa, Fonsecaea pedrosoi
• Coccidioidomycosis - Coccidioides imitis, C posadasii
• Cryptococcosis - Cryptococcus neoformans, C gattii
• Dermatophytosis (Tinea) - Microsporum spp, Epidermophyton spp, Trichophyton spp
• Fusariosis - Fusarium oxysporum, F proliferatum, F verticillioides
• Histoplasmosis - Histoplasma capsulatum
• Mucormycosis (Zygomycosis) - Mucor spp, Rhizopus spp
• Paracoccidioidomycosis - Paracoccidioides brasiliensis
• Pneumocystis pneumonia - Pneumocystis jirovecii (formerly called P. carinii)*

  • *While this is an essential and prevalent fungal disease, it is not treated with typical antifungal agents.
• Sporotrichosis - Sporothrix schenckii
• Tinea (Pityriasis) Versicolor - Malassezia furfur (also called Pityrosporum orbiculare), M globosa

Antifungal Drug Classification and Common Specific Drugs

• Loss of cell membrane integrity:

  • Polyenes: amphotericin B deoxycholate, liposomal amphotericin B, amphotericin B lipid complex, nystatin [4]
  • Azoles: ketoconazole, miconazole, clotrimazole, itraconazole, isavuconazonium sulfate (isavuconazole), fluconazole, voriconazole, posaconazole
  • Allylamines: terbinafine, naftifine [20]
• Loss of cell wall integrity:

  • Echinocandins: anidulafungin, caspofungin, micafungin, rezafungin V体育2025版 - [6]
• Mitotic inhibitors: griseofulvin
• Antimetabolites: flucytosine
• Ciclopirox
• Quinoline derivatives: iodoquinol, clioquinol
• Potassium iodide: saturated solution of potassium iodide (SSKI)
• Zinc pyrithione
• Triterpenoid antifungal agent: Ibrexafungerp VSports注册入口 - [21]

Indications

Various antifungal agents are indicated for the situations discussed below.[22][23][24][25]

Amphotericin B deoxycholate (AMB-d) is FDA indicated for treating life-threatening or potentially life-threatening fungal infections: aspergillosis, cryptococcosis, blastomycosis, systemic candidiasis, coccidioidomycosis, histoplasmosis, and mucormycosis. AMB-d is also approved for treating the parasitic disease American mucocutaneous leishmaniasis. AMB-d has an off-label use for esophageal candidiasis (both HIV infected and non-HIV-infected adults and adolescents; HIV-exposed and or infected infants and children), fluconazole-refractory oropharyngeal candidiasis, candidal endophthalmitis, candidal urinary tract infections, visceral leishmaniasis, and ophthalmic aspergillosis.

Liposomal amphotericin B (L-AMB) has FDA approval for treating systemic aspergillosis, candidiasis, and cryptococcosis in patients with renal impairment and those refractory to AMB-d therapy. Additionally, L-AMB is an empiric antifungal therapy in patients with febrile neutropenia or HIV with cryptococcal meningitis. Visceral leishmaniasis is a parasitic infection that is also treated with this agent. L-AMB has extensive off-label usage for patients infected or exposed to HIV, including candidiasis, coccidioidomycosis, cryptococcosis, and histoplasmosis.[26][27][28][29]

Amphotericin B lipid complex (ABLC), like L-AMB, is indicated for treating invasive mycoses in patients unable to tolerate AMB-d. Off-label use of ABLC is an indicated agent in HIV infected patients with coccidioidomycosis, cryptococcal meningitis, and histoplasmosis; empiric therapy for candidiasis and neutropenic fever; and in the treatment of the parasitic infection, visceral leishmaniasis.[30][31][32][33]

Nystatin has been approved as an oral "swish-and-swallow" suspension for treating cutaneous, mucocutaneous, and oral Candida infections. Topically, nystatin has been approved for treating mucocutaneous and cutaneous infections with Candida spp (most commonly C. albicans).

Ketoconazole, when applied topically, has been approved for the treatment of tinea corporis, tinea cruris, tinea pedis, tinea versicolor, cutaneous candidiasis, and seborrheic dermatitis. Off-label, topical ketoconazole is used to treat several oral candidal pathologies, including chronic mucocutaneous candidiasis and oral thrush. Ketoconazole is also a systemic agent, approved for treating blastomycosis, coccidioidomycosis, chromomycosis, histoplasmosis, and paracoccidioidomycosis. Off-label oral ketoconazole treatment is used to treat Cushing syndrome and prostate cancer.[34][35]

Miconazole in its topical form is approved to treat cutaneous and mucocutaneous mycoses, particularly vulvovaginal candidiasis. Oral formulations of miconazole are indicated for the treatment of oropharyngeal candidiasis.

Clotrimazole, in topical forms, is approved to treat tinea corporis, tinea pedis, tinea versicolor, cutaneous candidiasis, and vaginal yeast infections. Oral clotrimazole is indicated for the treatment of oropharyngeal candidiasis.

Itraconazole is an oral drug approved to treat aspergillosis (pulmonary and extrapulmonary), blastomycosis (pulmonary and extrapulmonary), and histoplasmosis (systemic/disseminated not involving the CNS, cavitary pulmonary histoplasmosis) in patients who are immunocompromised and immunocompetent. In immunocompetent patients, this drug is also approved for the treatment of oropharyngeal candidiasis, esophageal candidiasis, and onychomycosis (involving the toenails or fingernails).

Fluconazole indications include the treatment of esophageal, oropharyngeal, peritoneal, urinary tract, and vaginal candidiasis. Fluconazole may also help treat systemic fungal infections, including candidemia, candida pneumonia, and cryptococcal meningitis. Fluconazole serves as a first-line agent in prophylaxis for mycoses in allogeneic hematopoietic stem cell transplant patients. Off-label, fluconazole has a variety of applications, including blastomycosis, empiric antifungal therapy in non-neutropenic ICU patients, Candida prophylaxis (in ICU patients with a high risk of invasive Candida spp and transplant patients), and tinea.[36]

Voriconazole has approval for the following indications: invasive aspergillosis, candidemia in patients without neutropenia, esophageal candidiasis, and disseminated candidiasis. This drug also treats life-threatening mycoses caused by fungi, such as Fusarium spp Off-label uses for voriconazole are primarily aimed at prophylactic and suppressive therapy for fungal infections, including but not limited to aspergillosis, candidiasis, hematopoietic stem cell transplant patients with or without graft-versus-host disease, acute myelogenous leukemia, and empiric therapy in neutropenic fever.

Isavuconazole is approved to treat invasive aspergillosis and invasive mucormycosis in adult populations. 

Posaconazole is approved for prophylaxis of both invasive aspergillosis and invasive candidiasis. Additionally, it is used to treat oropharyngeal candidiasis, typically for patient populations refractory to treatment with fluconazole and itraconazole.

Terbinafine is approved for both topical and systemic (oral) use. Topical terbinafine is approved to treat tinea pedis, cruris, and corporis. When administered orally, this drug is indicated for the systemic treatment of onychomycosis (tinea unguium) and tinea capitis. Common off-label uses of oral formulations include treating tinea (cruris, corporis, penis, and manuum) as well as lymphocutaneous and cutaneous sporotrichosis. 

Anidulafungin is an echinocandin that is administered intravenously only. This drug has been approved for the treatment of Candida spp infections (esophageal candidiasis, candidemia, Candida spp peritonitis, and intrabdominal abscesses when Candida spp is grown in culture or the suspected organism).

Caspofungin is only administered intravenously. This agent is approved for treating invasive aspergillosis in patient populations refractory to amphotericin B and itraconazole. Caspofungin has also received approval for treating Candida spp infections (candidemia, esophageal, intra-abdominal abscess, peritonitis, and empiric therapy in patients with neutropenia). Off-label, this agent is used as an adjunct in the treatment of other severe Candida spp infections not listed above.

Micafungin is also approved for intravenous administration to treat esophageal candidiasis and for the prophylaxis of Candida spp infections, including candidemia, Candida spp peritonitis, Candida spp abscesses, and disseminated candidiasis.

Griseofulvin is only approved as a systemic (oral) agent. This drug is indicated for treating dermatophytoses of the skin, hair, and nails, which are severe or refractory to topical therapy. Specifically, this drug treats tinea (corporis, pedis, cruris, barbae, capitis, and unguium).

Flucytosine has been approved as an adjunct antifungal agent for treating systemic infections caused by Candida spp or Cryptococcus spp infections. Off-label, flucytosine is administered to treat pediatric endocarditis caused by Aspergillus spp; however, other antifungal agents, such as amphotericin B or voriconazole, are preferred for Aspergillus infections.

Ciclopirox is FDA-approved for the topical treatment of tinea corporis, tinea pedis, tinea cruris, tinea unguium (onychomycosis), tinea (pityriasis) versicolor, and Candida spp infection with moniliasis.

Iodoquinol (discontinued in the USA) was a topical agent approved for treating tinea capitis, tinea cruris, tinea corporis, tinea pedis, moniliasis, and candidal intertrigo.

Clioquinol is a combination product with hydrocortisone (availability in the U.S. is unclear). This combination topical agent was approved to treat the same spectrum of dermatoses as iodoquinol: tinea capitis, tinea cruris, tinea corporis, tinea pedis, moniliasis, and candidal intertrigo.

Potassium iodide, formulated as a saturated solution of potassium iodide (SSKI), has no official antifungal approvals, but is used in the off-label treatment of both cutaneous and lymphocutaneous sporotrichosis.

Zinc pyrithione is not officially approved for antifungal purposes but has been utilized as primary or adjunct therapy in the treatment of mycoses leading to hyperkeratotic skin conditions. A common off-label use is in treating tinea (pityriasis) versicolor.