OVERVIEW OF THE CLINICAL APPLICATIONS, TYPES AND USAGE OF ANTI-FUNGAL AGENTS

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Antifungal agents are antimicrobial agents that kill or inhibit the growth of pathogenic fungi. Antimicrobial agents that inhibit the growth of pathogenic fungi are generally known as fungistatic agents while those that kill pathogenic fungi are known as fungicidal agents. There are fewer antifungal agents than antibacterial agents because fungi like the mammalian cells are eukaryotic organisms, and drugs used for the treatment of fungal infections or human mycoses have profound untoward effects on their recipient human hosts. Since fungi and human cells share similar cellular and metabolic similarities because they are both eukaryotes, it is often difficult to find suitable antifungal agents with little or no toxicity on human cells. Many antifungal agents are too toxic for the clinical management of human mycoses because of similarities in the cellular and/or metabolic functions of human and animal cells – which are both regarded as eukaryotic cells.

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Antifungal agents have poor selective toxicity compared to antibacterial drugs which target prokaryotic cells (e.g., bacteria); and a considerable amount of these drugs or antibiotics have adverse pharmacological features which compromises their usage in clinical medicine. They also have low therapeutic index compared to antibacterial agents with higher therapeutic index; and this is because most antifungal agents disrupts metabolic functions found not only in pathogenic fungi but also in the animal or human host cells taking them because of similarities in the cellular makeup of fungi and animal or human cells. Some of the undesirable characteristics of antifungal agents can be clinically managed because of the fact that most fungal infections in humans (e.g., superficial and cutaneous mycoses) are self-limiting in nature, and may heal on their own even without formal antifungal chemotherapeutic measures.

A strong immune system is also critical to the effective management and treatment of some human mycoses even in the face of potent antifungal agents; and this is why people with compromised immune system (e.g., HIV/AIDS patients or cancer patients receiving chemotherapy) normally fall victims of opportunistic mycoses and other types of fungal infections which will by and large not affect a normal human being with intact immunity. Because of their notable toxicity, most fungal agents (except for those used for the treatment of systemic or deep mycoses) are usually in topical forms and are only used on the skin surfaces as antimicrobial lotions or solutions. Antifungal agents that are too toxic for systemic use (i.e., for treating deep mycoses) are available for topical administration. Antifungal agents like antibacterial agents target specific sites on their target pathogenic fungi including the fungal cell wall, nucleic acid and cell membranes, even though some of these agents have low selective toxicity when used for in vivo treatment.

THE MAIN GROUPS OF ANTIFUNGAL AGENTS INCLUDE THE AZOLES, POLYENES, FLUCYTOSINE, GRISEOFULVIN, CYCLOHEXIMIDE, THE ALLYLAMINES AND THE ECHINOCANDINS.

The azoles whose main function is to inhibit the synthesis of ergosterol in fungi are the largest antifungal agents, and typical examples include fluconazole, ketoconazole, itraconazole, miconazole, voriconazole and clotrimazole. Ergosterol is the sterol that lines the cell membrane of fungi. The human or animal cell membrane is majorly made up of cholesterol.

Polyenes include amphotericin B and nystatin; and their main antimicrobial function is to disrupt the integrity or cellular structure of the fungal cell membrane. Flucytosine is an antifungal agent that inhibits the biosynthesis of nucleic acid molecules (DNA and RNA) in pathogenic fungi.

The allylamines are synthetic antifungal agents that interfere with the activities of squalene synthase. Squalene synthase is an enzyme that promotes the formation of squalene metabolites in fungi. Typical examples of antifungal agents that are allylamines include terbinafine and naftifine. Allylamines generally inhibit fungal squalene metabolism; and they also reduce ergosterol synthesis in fungi. Increased levels of squalene are toxic to fungi.Allylamines are mainly used to treat fungal infections caused by dermatophytes.

Terbinafine is a broad-spectrum antifungal agent which interferes with the structural and functional integrity of fungal cell membrane by inhibiting the enzymesqualene 2, 3 epoxidase; and this disrupts the synthesis of ergosterol in the target pathogenic fungi. Terbinafine is used to treat cutaneous mycoses; and the agent can be used systemically or orally to treat some fungal infections (e.g., for treating nail infections). Gastrointestinal upset is usually a common side effect associated with the use of terbinafine.

Cycloheximide is an antifungal agent that inhibits the growth of saprophytic fungi (i.e., non-pathogenic fungi). They are usually incorporated into fungal culture media (e.g., Sabouraud dextrose agar) to prevent the growth of saprophytic fungi.

Echinocandins are antifungal agents that block the synthesis of glucan layers in pathogenic fungi. Glucan layers are polysaccharide polymers found in fungal cells. Caspofungin is a typical example of an echinocandin, and they have activity against Candida species and Aspergillus species.

Griseofulvin is an antifungal agent that inhibits cell division in pathogenic fungi by interfering with mitosis especially at the stage of microtubule development. Griseofulvin is mainly use for topical antifungal applications.

Further reading

Anaissie E.J, McGinnis M.R, Pfaller M.A (2009). Clinical Mycology. 2nd ed. Philadelphia, PA: Churchill Livingstone Elsevier. London.

Baumgardner D.J (2012). Soil-related bacterial and fungal infections. J Am Board Fam Med, 25:734-744.

Calderone R.A and Cihlar R.L (eds). Fungal Pathogenesis: Principles and Clinical Applications. New York: Marcel Dekker; 2002.

Champoux J.J, Neidhardt F.C, Drew W.L and Plorde J.J (2004). Sherris Medical Microbiology: An Introduction to Infectious Diseases. 4th edition. McGraw Hill Companies Inc, USA.       

Gladwin M and Trattler B (2006). Clinical Microbiology Made Ridiculously Simple. 3rd edition. MedMaster, Inc., Miami, USA.

Larone D.H (2011). Medically Important Fungi: A Guide to Identification. Fifth edition. American Society of Microbiology Press, USA.

Madigan M.T., Martinko J.M., Dunlap P.V and Clark D.P (2009). Brock Biology of Microorganisms, 12th edition. Pearson Benjamin Cummings Inc, USA.

Stephenson S.L (2010). The Kingdom Fungi: The Biology of Mushrooms, Molds and Lichens. First edition. Timber Press.

Sullivan D.J and Moran G.P (2014). Human Pathogenic Fungi: Molecular Biology and Pathogenic Mechanisms. Second edition. American Society of Microbiology Press, USA.

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