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Advancements in Systemic Antifungal Agents.

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This article reviews the rising need for antifungals in the pharmaceutical armamentarium and its innovations and risks. Read on to know more.

Medically reviewed by

Dr. Dhepe Snehal Madhav

Published At October 7, 2022
Reviewed AtFebruary 23, 2024

Introduction:

Systemic fungal infections are diseases that can often be fatal. The prevalence of these diseases is increasing. The increase in the use of antibiotics, the rise in the number of immunocompromised patients, and the increase in the number of patients with AIDS have led to the rise in fungal infections. New advances are being made in this domain, such as reducing the toxicity of the current drugs, formulation of more recent, less toxic drugs, and use of nanotechnology, among others.

What Are Antifungals?

Antifungals, by definition, are drugs that selectively destroy fungal organisms without causing side effects to the patient. There is a significant need for antifungals at this age, as the prevalence of infections is increasing. These drugs include sub-types such as:

  • Polyenes - Amphotericin B.

  • Azoles - Itraconazole, Fluconazole, etc.

  • Nucleoside analogs.

  • Echinocandins.

  • Allylamines - Terbinafine.

What Is the Need for Advances?

The progress made in antifungal agents was significantly lagging behind compared to the extensive research and development in antibiotics. This was primarily due to the increased threat of bacterial infection and the low incidence of fungal infections. However, in recent times, there has been an increasing rate of morbidity and mortality due to the lack of efficiency of traditional antifungals. They are associated with high toxicity and resistance to fungi.

Amphotericin B was the only antifungal drug available for many years. But it had several disadvantages, such as side effects, renal toxicity, and electrolyte imbalance. It could also only be administered intravenously because of the need for high sustained doses.

These factors led to the need for alternative drugs that were nontoxic, wide spectrum, well tolerated, and easy to administer.

What Are the Advances?

  • New formulations are being developed.

  • Increasing use of nanoparticles as carriers.

  • Modification of the chemical structure of traditional antifungals improves drug efficacy.

What Are Some of the Newer Antifungals?

1) Flucytosine:

It is of a relatively narrow spectrum of activity, with only strains of Candida species and Cryptococcus neoformans.

Advantages:

  • Excellent absorption through oral administration.

  • Tissue penetration.

  • Good diffusion.

Disadvantages:

  • Toxicity.

  • Resistance can emerge.

  • Leukopenia.

  • Diarrhea.

The resistance caused by Flucytosine can cause clinical deterioration. Toxicity associated with Flucytosine is gastrointestinal in nature and bone marrow aplasia. This medication is excreted through the kidneys, leading to severe kidney damage; this further reduces the elimination of the drug from the system and causes an increase in serum concentration.

2) Imidazoles:

The discovery of the imidazole group of antifungals turned out to be a major advantage. Some drugs like Miconazole were approved in Canada but not in the United States. However, Ketoconazole has been largely commercialized. It was, in fact, the first drug in the azole group that was commercialized. The main advantage was the ability to be orally administered when compared to Amphotericin B.

However, Ketoconazole was not without its drawbacks:

  • Histamine blocking agents and antacids reduce the blood levels of the drug if given together.

  • Several other drug interactions were also noticed, such as cardiotoxicity when administered with antihistamine drugs (Terfenadine, Astemizole).

  • Rifampin accelerated the metabolism of Ketoconazole, causing a decrease in blood levels of Ketoconazole.

  • Cyclosporine blood levels increase when administered with Ketoconazole, which worsens its nephrotoxicity (kidney toxicity).

  • It reduces the levels of testosterone and adrenocorticoids.

  • Administration of acidic food can help prevent the blocking action of Ketoconazole by antacids, but it is not a long-standing solution.

3) Fluconazole:

Some of the drawbacks of Ketoconazole were addressed by Fluconazole. It is water soluble and can be administered orally and intravenously. Oral administration is not dependent on gastric activity and can be completely absorbed. Fluconazole is not susceptible to the increased metabolism that occurs in Ketoconazole when administered with Rifampin. Cyclosporine blood levels do not increase with Fluconazole unless it is given in a high dose.

Other advantages of Fluconazole include the following:

  • It can be used for the treatment of cryptococcal meningitis in AIDS patients.
  • Chronic candidiasis may be treated with Fluconazole. It can be used as a prophylactic measure in bone marrow transplants and leukemia patients to prevent candidiasis.

4) Itraconazole:

It is a broad-spectrum antifungal when compared to other azoles. It is effective against Aspergillus. It is similar to Ketoconazole but without its disadvantages. It is safer than Ketoconazole due to its specificity to fungal cytochrome and not human enzymes.

Drawbacks include mild gastrointestinal irritation, an increase in lipid profile, and an increase in potassium levels. One major concern is cardiac problems may arise due to the combined administration of Itraconazole with antihistamines.

5) Polyenes:

Amphotericin B:

It was the first antifungal drug developed and was effective against aspergillosis, candidiasis, blastomycosis, cryptococcosis, histoplasmosis, and mucormycosis, among others. Despite the severe side effects, Amphotericin B is still the mainstay for severe systemic fungal infections, especially in immunocompromised patients. Efforts have been made to reduce the toxicities associated with Amphotericin B. New formulations have been developed for this purpose.

But the cost-benefit, efficacy, tolerance, and safety of the new formulations are still to be analyzed if proper clinical trials have to be properly conducted to address the problem of severe systemic antifungals, especially in immunocompromised patients.

Azole group of drugs was the answer to the side effects of Amphotericin B. First-generation azole groups were better tolerated and were effective against candidiasis but were not as effective as Amphotericin for treating aspergillosis and mucormycosis. The second generation was a more broad spectrum in nature. The newest azole group has better pharmacological efficacy, bioavailability, and fewer drug interactions.

Some less common fungal infections and their treatment include:

  • Onychomycosis is a fungal infection affecting nails and can be treated using Griseofulvin, Itraconazole, Terbinafine, and Ketoconazole.

  • Tinea cruris is a contagious fungal infection in the groin area. Clotrimazole, Miconazole, Terbinafine, or Tolnaftate can be used to treat it.

What Are the Disadvantages of Systemic Antifungals?

Systemic antifungals are still not completely free of concerns. Some of the problems include the following:

  • Additive drug interactions, some of which could be fatal.

  • Antifungals could be modified by other drugs if given combined.

  • Pharmacological aspects of different medications may be affected by antifungals.

  • Kidney toxicity.

  • Cardiac rhythm discrepancies.

  • Anti-epileptic medications can cause rapid excretion of antifungals.

Conclusion:

Systemic fungal infections are increasing in frequency, especially in immunocompromised patients. And with it, the need for antifungals is also growing. However, the concerns associated with antifungals include drug interaction and toxicity. Therefore newer formulations of former drugs and newer medications are being introduced. If this is correctly done, accompanied by clinical trials to assess the pharmacological aspects of these medications, it will help reduce opportunistic infections and other fungal diseases.

Frequently Asked Questions

1.

What Is the Classification of Antifungal Medications?

Polyenes (such as Amphotericin B), azoles (such as the Imidazoles Ketoconazole and Miconazole and the Triazoles, Itraconazole, and Fluconazole), Allylamines (such as Terbinafine), and Echinocandins constitute the four major classes of antifungal medications. Moreover, a novel class of antifungal medications called Echinocandin kills fungi by preventing the production of an enzyme that builds the fungal cell wall, rupturing the fungal cell. And, Orotomides are a class of antifungal drugs that target a crucial enzyme in the pathway of de novo pyrimidine production. These drugs are currently being studied. Additionally, Flucytosine and Griseofulvin are systemic antifungals.

2.

What Medication Combats a Systemic Fungus the Most Effectively?

For more than 50 years, invasive fungal infections have been treated with Amphotericin B. It was initially discovered as a byproduct of a soil Actinomycete species. The FDA has approved Amphotericin B Deoxycholate for the treatment of aspergillosis, cryptococcosis, blastomycosis, systemic candidiasis, coccidioidomycosis, histoplasmosis, mucormycosis, all of which are life-threatening or potentially life-threatening fungi.

3.

What Antifungal Medication Has Recently Been Made Available to Treat Systemic Fungal Infections?

Rezafungin for injection, also known as REZZAYOTM, is now licensed by the U.S. Food and Drug Administration as a treatment for candidemia and invasive candidiasis. The new therapy is the first to be authorized for an invasive fungal infection in more than ten years. It is a brand-new antifungal treatment administered intravenously once every week. In addition, three new azole medications such as Voriconazole, Ravuconazole, and Posaconazole, that may be useful for systemic and superficial fungal infections have been discovered.

4.

Which Newer Oral Antifungals Are Available?

In general, the more recent oral antifungal medications, such as Fluconazole, Itraconazole, and Terbinafine, are successful and well-tolerated in treating fungal infections.

5.

What New Antifungal Medications Are Being Developed?

Rezafungin, Olorofim (Orotomides), Opelconazole, and Ibrexafungerp (Enfumafungin derivative oral Triterpene antifungal for vulvovaginal candidiasis) are some of the antifungals in the pipeline or in the later phases of clinical research. Two of these have just obtained FDA approval: Rezafungin and Ibrexafungerp.

6.

What Is an Alternative to Fluconazole?

Fluconazole-refractory candidiasis was defined as that which failed to clear up with 14 days of treatment with Fluconazole, at a minimum dosage, can be treated with Amphotericin B, Caspofungin, Micafungin, Anidulafungin, Itraconazole, and Voriconazole (Azole antifungals).

7.

What Is the First-Line Treatment for a Fungal Infection on the Skin?

Fungal infections are usually treated using antifungal drugs. The affected area is treated topically with these drugs. Topical drugs include but are not limited to, creams, gels, lotions, shampoos, and solutions. Additionally available are oral antifungal medicines. Clotrimazole cream or lotion, Miconazole cream, Selenium sulfide lotion, Terbinafine cream or gel, and Zinc Pyrithione are a few of the first-line topical treatments for fungal skin infections.

8.

Why Is It Difficult to Treat Systemic Fungal Infections?

For instance, candida grows unharmed on the skin and in the gastrointestinal tract. But Candida can get into the bloodstream and make people sick causing invasive candidiasis, as it enters the bloodstream, it spreads to the bones, brain, and central nervous system. Invasive candidiasis is a hazardous fungal condition that can become life-threatening if it is not properly diagnosed and treated. Even in healthy people, fungal infections can be challenging to treat since antifungal drugs are challenging to develop and some fungi are adept at developing resistance to existing antifungal treatments.

9.

What Are Second-Generation Antifungal Drugs?

Voriconazole, Posaconazole, and Ravuconazole are three brand-new second-generation drugs that appear to have more antifungal action than older azoles.

10.

What Exactly Is the Latest Pandemic Fungus?

A type of fungi known as Candida auris, or C. auris, can cause significant infection in those with weakened immune systems. An alarming rate of C. auris spread in U.S. healthcare facilities in 2020 to 2021, according to data from the Centers for Disease Control and Prevention that were published in the Annals of Internal Medicine. C. auris is a new fungus that is considered an urgent threat due to antimicrobial resistance.

11.

What Are the New Drugs for Aspergillosis?

Aspergillosis is a condition caused by Aspergillus, a type of fungus that can be found both indoors and outdoors. The majority of people habitually breathe in Aspergillus spores without getting sick. Voriconazole, a more contemporary antifungal drug, is the best treatment. If it causes signs of invasive pulmonary aspergillosis, that is the recommended line of action.

12.

Which Medications Are Prescribed for Systemic Fungal Infections?

Systemic fungal infections are treated using the following drugs: Amphotericin B and its lipid formulations, Polyene Macrolides, other azole derivatives including Fluconazole, Isavuconazole, and Itraconazole and Echinocandins including Anidulafungin, Caspofungin, and Micafungin.
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Dr. Dhepe Snehal Madhav
Dr. Dhepe Snehal Madhav

Venereology

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