In this article, we will study the details about various antifungal drugs, their mechanism of action, adverse effects/toxicity, contraindications, drug interactions and drugs of choice. Other important pharmacological and therapeutic aspects of individual drugs will also be discussed.

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This Sabouraud's dextrose agar plate culture is growing the fungus Sporothrix schenckii.

Image: “Sporotrix schenckii on Sabouraud” by CDC. Licence: Public Domain


Definition

Antifungal are the drugs that treat fungal infections by acting on the synthesis of the cell membrane of the fungi, cell wall components, on membrane permeability, synthesis of nucleic acids and on the mitotic spindle function of the fungi during the cell division.

Overview of Fungal Infections

Fungi are non-motile eukaryotic cells organisms which cannot perform photosynthesis and hence majorly they are parasitic in nature. Thousands of species have been identified out of which some are the cause for local or systemic fungal infection (mycoses) in patients of AIDS or humans whose immune system is compromised.

Most infection caused by fungi are prevalent in patients whose immune systems are compromised by drug therapy and introduction into the host’s body is mainly through wounds, or into the lungs and nasal passages when inhaled which cause serious, sometimes life-threatening infections in the immunocompromised host. Diseases caused by fungi are mainly due to the Microsporum, Trichophyton or Epidermophyton genera.

Various Types of Fungal infections

Athlete’s Foot

Tinea pedis (Athlete’s foot): The infection is caused by Trichophyton mentagrophytes, and Trichophytonrubrum. It is often located between the toes, with the space between the fourth and fifth digits most commonly afflicted; however, it can spread if not treated in time.

Athlete's Food

Image: “A severe case of athlete’s foot.” by James Heilman, MD. License: CC BY-SA 3.0

Ringworm Infection

Tinea corporis (ringworm): The infection is caused by Microsporum canis, Trichophyton mentagrophytes via direct skin contact with an infected individual or by using the personal care products of the affected individual.

Ringworm Infection

Image: “Ringworm on the arm, or tinea corporis due to Trichophyton mentagrophytes.” by CDC.

Brazilian Blastomycosis

It is caused by Paracoccidioides brasiliensis and is a systemic infection involving mucous membranes, lymph nodes, bone, and lungs and prevalent in South America. Amphotericin B or Itraconazole and ketoconazole are more effective in treating the infection.

Candidiasis

oral candidiasis

Image: “Human tongue infected with oral candidiasis.” by James Heilman, MD. License: CC BY-SA 3.0

Candidiasis is caused by yeast Candida Albicans. It is commonly present in the GI tract and genitourinary system of human beings. However, it can cause local fungal infection to serious systemic infection with multisystem organ failure.

Mucormycosis

The infection is caused by the Mucor, Rhizopus, Absidia, and Cunninghamella genera with the affected areas being sinuses, eyes, blood and brain.

Mucormycosis

Image: “Mucormycosis” by Ran Yuping et al. License: CC BY-SA 3.0

Classification of Anti Fungal Drugs

These agents are categorized as:

  • Topical or systemic (acting in the blood stream) on the basis of their site of action
  • Based on the Source
  • Naturally occurring Antibiotics

Polyenes: Amphotericin B (AMB)

  • Synthetic Agents
  1. Azoles
  2. Imidazole: Clotrimazole, Econazole, Miconazole, Oxiconazole, Ketoconazole
  3. Triazole: Fluconazole, Itraconazole, Voriconazole
  4. Anti-metabolite: Flucytosine (5-FC)
  • Heterocyclic Benzofuran: Griseofulvin
  1. Allylamine: Terbinafine
  • Newest antifungals: Echinocandins

Antifungal Drugs

Below you can find different kinds of antifungal drugs.

Amphotericin B (AMB)

It is derived from cultures of Streptomyces Nodosus and is very large (‘macrolide’) molecule belonging to the polyene group of antifungal agents.

Mechanism of Action

The molecule has high affinity for ergosterol present in fungal cell membrane and combine with it in such a way to make a ‘micropore’. The basic mechanism of the drug is to disrupt the cell membrane. It is fungicidal at high and static at low concentrations.

Important: Amphotericin is not active against human and bacterial sterols as the predominant sterol found in bacteria and humans is cholesterol.

Indication

Amphotericin B is active against a wide range of yeasts and fungi: Candida Albicans, Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioidesimmitis, Torulopsis, Rhodotorula, Aspergillus, Sporothrix, etc. It does not have any anti-bacterial property. It is the most effective drug for resistant cases of kala azar and mucocutaneous leishmaniasis.

Pharmacokinetics

Amphotericin B is not absorbed orally that is why it administered intravenously and rarely intrathecally (for fungal meningitis). Amphotericin B has a half life of 15 days. The excretion through urine requires long time, although excretion occurs slowly both in urine and bile. Penetration into the CNS is poor. About 60% of AMB drug gets metabolized in the liver.

Side Effect

Nephrotoxicity is the most important side effect. Acute reaction may be triggered with symptoms consisting of chills, fever, aches and pain, nausea, vomiting and dyspnoea lasting for 1 hour, probably due to release of cytokines. To reduce the side effects and improve the tolerability of infusion, lipid complex, colloidal dispersion and small unilamellar vesicles formulation have been introduced.

Important: Irreversible renal toxicity can result on prolonged administration (more than 4 g cumulative dose).

AmBisome (liposome based), Amphotec (complex of amphotericin B and cholesteryl sulfate), Abelcet (consists of amphotericin B complexed with two phospholipids) are the lipidic formulations available to reduce the renal toxicity of the conventional amphotericin B; however, these are very costly.

Nystatin

It is also called as fungicidin with similar structure as that of Amphotericin B. It is derived from Streptomyces noursei and has high systemic toxicity, hence commonly used as topical agent.

Mechanism of Action

The molecule also has high affinity for ergosterol present in fungal cell membrane disrupts the cell membrane.

Indication

It is used against monilial vaginitis, corneal, conjunctival and cutaneous candidiasis in the form of an ointment and is ineffective in dermatophytosis. Nystatin can be combined with tetracycline to prevent monilial overgrowth caused by the destruction of bacterial microflora of the intestine during tetracycline therapy.

Pharmacokinetics

It is given in the form of vaginal tablets, pastilles, for local application only. Nystatin will treat gut candidiasis, and is used in a “swish and swallow” routine for oral candidiasis.

Side Effect

The common side effects associated are itching, irritation and burning. Rarely nystatin can cause diarrhea and nausea.

Azoles and Triazole Agents

These are synthetically derived antifungal agents both used orally and topically. They are used for treating a large number of infections caused by dermatophytes, Candida, other fungi involved in deep mycosis, Nocardia, some gram positive and anaerobic bacteria, e.g. Staphylococcus aureus, Enterococcus faecalis, Bacteroides fragilis and Leishmania.

Mechanism of Action

The azoles consitute imidazoles and triazoles subgroups and act by inhibiting CYP P450 14 α- demethylase enzyme in fungi which causes the conversion of lanosterol to ergosterol. Other P450s in sterol biosynthesis may also be affected. The nitrogen of the azole ring forms bond with the heme iron of the fungal P450 preventing substrate and oxygen binding leading to changes in shape and physical properties of the fungi membrane leading to permeability and fluidity changes. They also inhibit the transformation of yeast cells into hyphae, the invasive and the pathogenic form of the parasite.

Ketoconazole (KTZ)

It is available in the form of cream or in shampoos at a strength of one- or two-percent, for treating tinea pedis, tinea corporis, tinea cruris and cutaneous candidiasis. It can also be administered orally.

Pharmacokinetics

The oral absorption of KTZ is improved by gastric acidity because it is more soluble at lower pH. Hepatic metabolism is extensive for the drug; metabolites are excreted through urine and faeces. The half life is short and varies from l.5 to 6 hours.

Side Effect

The drug causes inhibition of adrenocortical steroid and testosterone synthesis with high doses, leading to gynecomastia, loss of hair and libido in male patients. In females, menstrual irregularities may occur. Hepatotoxicity is also a side effect but is rarely fatal.

Clotrimazole

The topical application of the drug is useful in treating tinea pedis, ring worms, otomycosis and oral/ cutaneous vaginal candidiasis. It is preferred drug for treating the vaginitis because of a long residual effect after once daily application. The drug is also combined sometimes with glucocorticoids, which are anti-inflammatory in nature.

Side Effect

The drug is well tolerated; however, causes local irritation with stinging and burning sensation occurs in some. No systemic toxicity is seen after topical use.

Fluconazole

It is marketed in the form of the tablet or suspension to treat yeast infections of the vagina,

mouth, throat, esophagus, abdomen and lungs.

Important: It is a drug of choice for esophageal and invasive candidiasis and coccidioidomycoses.

Pharmacokinetics

Fluconazole is 94% absorbed; oral bioavailability is unaffected by food or gastric pH. It is

primarily excreted unchanged in urine with a t1/2 of 25-30 hours.

Side Effect

Prominent side effects are nausea, vomiting, abdominal pain, rash and headache. Elevation of hepatic transaminase has been noted in AIDS patients. As compared to other azoles it has least effect on liver microsomal enzymes.

Voriconazole

The drug is present in the form of oral suspension, tablets or parenteral injection. It is used to treat serious fungal infections and may be used in patients who have not responded to other antifungal agent.

Rashes, visual disturbances, QT prolongation and an acute reaction on i.v. injection are the significant adverse effects.

Flucytosine (5-FC)

It is an antifungal drug, which act by blocking the pyrimidine and DNA synthesis in fungus. It is converted to its active metabolite (5-FU) by fungal cells.

The pathway of conversion if below:

Flucytosine → (5-FC) →5-Fluorouracil (5-FU) → 5-fluorodeoxyuridine monophosphate

No toxicity in human due to 5-FC as human cells can’t convert 5-FC to 5-FU.

It is not used as a single agent for the fungal infection but used with other antifungal agents such as amphotericin B (cryptococcal meningitis) and itraconazole (chromoblastomycosis).

Side-effects are reversible bone marrow depression, liver dysfunction and alopecia.

Terbinafine

It is a fungicidal and is given in shorter course therapy and the relapse rates are low. It is particularly useful against Dermatophytes specially nail infections along with treatment of candida infection.  It is available for oral as well topical use.

Mechanism of Action

It acts as a non-competitive inhibitor of ‘squalene epoxidase’, an enzyme in ergosterol biosynthesis by fungi. Accumulation of toxic squalene within fungal cells leads to the fungicidal action.

Pharmacokinetics

Approximately 75% of oral terbinafine is absorbed. The drug is lipophilic, widely distributed

in the body, strongly plasma protein bound and concentrated in sebum, stratum corneum and nail plates. Elimination t1/2 of l l-16 hour is prolonged to 10 days after repeated dosing schedule.

Side Effects

Common side effects are gastric upset, rashes, taste disturbance. Some cases of hepatic dysfunction, hematological disorder and severe cutaneous reaction also occur.

Griseofulvin

Griseofulvin is a narrow-spectrum antifungal agent isolated from cultures of Penicillium griseofulvum and is active against dermatophytes, including Epidermophyton, Trichophyton, Microsporum, but not against fungi causing deep mycosis.

Mechanism of Action

Mechanism of action of griseofulvin is not clear. It is thought to interfere with mitosis during the fungal hyphae formation. It also causes abnormal metaphase in the division of cells by acting in a way that the daughter nuclei fail to move apart or move only a short distance during division. It does not inhibit polymerization of tubulin, but binds to polymerized microtubules and disorients them.

Pharmacokinetics

Absorption of the drug is improved by taking it with fatty meal and by microfining the drug particles. Griseofulvin gets deposited in keratin forming cells of skin, hair and nails; concentrating in tinea infected cells because it is fungistatic and not cidal. The newly formed keratin is not affected by the fungus.

Side Effects

Effects with griseofulvin use are infrequent, but the drug causes gastrointestinal upsets, headache and photosensitivity. Allergic reactions (rashes, fever) may occur. The drug is contraindicated in pregnant women.

Echinocandins

These are recently discovered antifungal drugs. Examples of drugs in this class are capsofungin, micafungin, and dulafungin.

They act by blocking the synthesis of β (1-3)-glucan in fungus.

They are active against Candida spp., Aspergillus spp., pneumocystis carinii; however, they are not active against Cryptococcus neoformans.

They are poorly absorbed from GI tract, thus they are only available as intravenous formation.

They are well tolerated and have only minor gastrointestinal side-effects such as nausea, and vomiting. Other side-effects are headache and flushing.

Review Questions

The right answers can be found below the references

1. Which of the following is the drug of choice for the treatment of Chromomycosis?

  1. Griseofulvin
  2. Itraconazole
  3. Amphotericin B
  4. Hamycin

2. Which of the following causes athlete’s foot?

  1. Tinea capis
  2. Tinea pedis
  3. Tinea cruis
  4. Tinea unguium

3. Which of the following is the source for Amphotericin B?

  1. Streptomyces nodosus
  2. Echinococcus granulosus
  3. Streptomyces noursei
  4. Corynebacteria
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