Antimycotic drugs

Antimycotic drugs, also known as antifungal drugs, are utilised to treat various fungal infections including yeast infections, athlete's foot, onychomycosis (fungal nail infections), ringworm, oropharyngeal, skin, vaginal and vulval fungal infections. These drugs exert their effects by targeting specific components of fungal cells, such as the cell wall or membrane, to inhibit their growth, survival, and reproductive capacity.

The administration of antimycotic drugs can be oral, topical, or intravenous, depending on the specific drug, as well as the severity and location of the infection. It is important to note that some antimycotic drugs may have side effects, such as liver toxicity or gastrointestinal upset, and may interact with other medications. Therefore, careful monitoring is necessary during treatment. The emergence of antimycotic drug resistance, exemplified by strains of Candida auris, is a growing concern. Appropriate use and monitoring of these drugs are crucial to prevent the development of resistant fungal strains. As with antibacterial medications, it is essential to complete prescribed drug courses.

Antimycotic drugs are commonly classified into four major categories:

1. Azole class drugs inhibit the synthesis of ergosterol, a vital component of fungal cell membranes.
2. Polyenes bind to ergosterol in the fungal cell membrane, causing it to become permeable and leading to fungal cell death.
3. Echinocandins target the fungal cell wall by inhibiting the synthesis of beta-glucan, an essential component of fungal cell wall formation.
4. The ‘other’ antimycotics group includes the pyrimidine analogue flucytosine (which interferes with fungal DNA and RNA synthesis), along with terbinafine, griseofulvin and ibrexafungerp.

This classification system helps categorise and understand the mechanisms of action of different antimycotic drugs.

1. Azole antimycotics:

Azole antimycotics are synthetic, fungistatic agents with broad-spectrum activity. They all share a common chemical structure called an azole ring and can be further subclassified into imidazoles (with two nitrogens in the azole ring), or triazoles (with three nitrogens in the azole ring)- as shown in the table below.

Additionally, oteseconazole is in a subclass of its own, as the first approved azole antifungal drug to possess a tetrazole moiety, which consists of an azole ring with four nitrogens.

Azole antimycotic drugs are widely utilised for the treatment of various fungal infections. They offer a broad spectrum of activity and are indicated for a wide range of clinical conditions. Below, we provide an overview of several frequently used azole antimycotics, detailing their clinical uses and potential side effects:

• Fluconazole: This drug is widely employed to treat a variety of fungal infections, including candidiasis, cryptococcosis, and dermatophytosis. It can be administered orally or intravenously and generally exhibits a relatively low incidence of side effects. Some possible side effects include gastrointestinal upset, rash, and headache.
• Itraconazole: Used for a range of fungal infections, such as candidiasis, aspergillosis, and histoplasmosis. Itraconazole can be administered orally or intravenously. Compared to fluconazole, it has a higher incidence of side effects, and these may include gastrointestinal upset, liver toxicity, and cardiovascular effects.
• Voriconazole: As a second-generation triazole. voriconazole is primarily employed to treat invasive aspergillosis and other serious fungal infections. It can be administered orally or intravenously. Voriconazole has a higher incidence of side effects than fluconazole, including visual disturbances, skin reactions, and liver toxicity.
• Posaconazole: This third-generation triazole treats a range of fungal infections, including candidiasis, aspergillosis, and mucormycosis. It can be administered orally or intravenously and generally has a relatively low incidence of side effects. Possible side effects may include gastrointestinal upset and headache.
• Isavuconazole: Acting as triazole, isavuconazole inhibits fungal cell division and disrupts ergosterol synthesis. It is utilised for the treatment of invasive aspergillosis and mucormycosis. It can be administered orally or intravenously and has a relatively low incidence of side effects. Possible side effects can include gastrointestinal upset and headache.

Each azole antimycotic drug has its own unique clinical use and potential side effects profile. It is important for healthcare professionals to carefully consider these factors when selecting the appropriate drug for each patient.

2. Polyene antimycotic drugs:

Polyene antimycotic drugs are a class of medications that have been used for several decades to treat fungal infections. Their primary mechanism of action involves binding to ergosterol, a key component of fungal cell membranes, resulting in membrane disruption and cell death. The following summary provides information on commonly used polyene antimycotics, their intended uses, and potential side effects:

• Amphotericin B: This broad-spectrum antimycotic drug has been in use since the 1950s to treat various systemic fungal infections. It is available in different formulations, including a conventional formulation (amphotericin B deoxycholate) and lipid formulations (amphotericin B lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B). The lipid formulations, which are less nephrotoxic, have replaced the conventional formulation in many clinical settings. Amphotericin B is administered intravenously and has a high incidence of side effects, such as fever, chills, hypotension, nephrotoxicity, and electrolyte imbalances.
• Nystatin: This topical antimycotic drug is used to treat fungal infections of the skin, mouth, and intestinal tract. It is not systemically absorbed, resulting in a low incidence of side effects. Nystatin is available in various forms, including creams, ointments, and oral suspensions.
• Natamycin: This topical antimycotic drug is used to treat fungal infections of the eye, including blepharitis, conjunctivitis, and keratitis caused by susceptible fungi, such as Fusarium solani. It is administered as an ophthalmic solution with a low incidence of side effects. However, its efficacy as a single agent for treating fungal endophthalmitis (infection of the vitreous and aqueous intraocular fluids) has not not been established.

The clinical use of polyene antimycotic drugs can be limited by their high incidence of side effects. Therefore, healthcare professionals must carefully consider the potential risks and benefits when prescribing these medications.

3. Echinocandin antimycotic drugs:

Echinocandins are a class of antimycotic drugs that target the fungal cell wall. They are lipopeptide molecules that noncompetitively inhibit a fungal enzyme crucial for 1,3-beta-D-glucan synthesis, disrupting cell wall formation. Due to poor absorption from the gastrointestinal tract these drugs are administered by slow intravenous infusion. A slow infusion rate is essential to minimise the risk of histamine-mediated reactions.

• Micafungin: A semisynthetic echinocandin that is used in the treatment of candidaemia (Candida infections in the blood), acute disseminated candidiasis, Candida peritonitis and abscesses, oesophageal candidiasis, and as prophylaxis of Candida infections in patients who are receiving haematopoietic stem cell transplants.
• Anidulafungin: Used to treat candidaemia and other invasive Candida infections such as those in the stomach and oesophagus.
• Caspofungin: Used to treat fungal infections of the stomach, lungs and oesophagus, including intra-abdominal abscess, peritonitis, and pleural space infections. Effective against C. albicans, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis.

4. Other antimycotic drugs:

• Terbinafine: An oral antimycotic drug that is used to treat dermatophyte infections of the fingernails or toenails (onychomycosis), and hair follicles. It is more active against dermatophytes than azole class drugs, but less active than azole antimycotics against Candida infections. Hepatotoxicity is an established severe side effect, so this drug is not suitable for patients with liver disease. Terbinafine inhibits CYP2D6; therefore pharmacokinetic interactions are possible with drugs that are substrates for CYP2D6 (e.g., tricyclic antidepressants, β-blockers, selective serotonin reuptake inhibitors [SSRIs], monoamine oxidase [MAO] inhibitors).
• Griseofulvin: An oral antimycotic antibiotic that is produced by Penicillium sp. It is administered orally to treat infections such as ringworm, athlete's foot, jock itch, and fungal infections of the scalp (Tinea capitis), fingernails, or toenails. Griseofulvin is not suitable for patients with porphyria or liver failure, nor should it be prescribed during the first 3 months of pregnancy as it is potentially embryotoxic and teratogenic and may harm the unborn baby. The primary use of griseofulvin is as a treatment for severe, chronic, or recalcitrant Tinea dermatophytoses, when topical antimycotic treatment has failed to clear the infection.
• Ibrexafungerp: An orally administered triterpenoid used to treat recurring (post-menarchal) vaginal yeast infections. It carries a high risk of embryo-fetal toxicity, so is contraindicated during pregnancy.
• Flucytosine: A fluorinated pyrimidine analogue. It is an oral antimycotic that is used to treat severe Candida infections of the blood, lungs, heart, central nervous system, and urinary tract (especially fluconazole-resistant strains), sometimes along with intravenous amphotericin B, and to treat serious cryptococcal infections (cryptococcosis) including pulmonary infections, septicaemia, and meningitis, again, usually in conjunction with intravenous amphotericin B.

The World Health Organization (WHO) Essential Medicines List (EML) includes several antimycotic drugs considered essential for addressing fungal infections in the global population.

The antimycotic drugs included in the WHO Essential Medicines List are:

• Amphotericin B
• Anidulafungin
• Caspofungin
• Clotrimazole
• Fluconazole
• Flucytosine
• Griseofulvin
• Itraconazole
• Micafungin
• Nystatin
• Potassium iodide
• Voriconazole