Advancements in Systemic Antifungal Agents.

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.