ANTI-FUNGAL AGENTS

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Antifungal agents are antimicrobial agents that kill or inhibit the growth of pathogenic fungi. Fungal infection is treated using antifungal drugs. Some of the drugs used for the treatment of mycoses (i.e., fungal infections) in humans include:

  1. Polyenes (e.g., amphotericin B and nystatin) – which are cidal in action and binds to the fungal ergosterol membranes to disrupt the integrity of the fungal cell membrane;
  2. Azoles (e.g., itraconazole, ketoconazole, voriconazole, fluconazole, miconazole) – which are static in action and inhibit the synthesis of ergosterol;
  3. Griseofulvin – which is static in action and inhibits fungal growth by binding to microtubules during mitosis;
  4. 5-fluorocytosine (5-FC) or flucytosine – which is an antimetabolite and inhibits nucleic acid synthesis and protein synthesis;
  5. Echinocandins (e.g., caspofungin, micafungin) – which are static in action and inhibits the synthesis of chitin and glucan in fungal cell wall; and
  6. Allylamines (e.g., terbinafine) – which are static in action and inhibit the synthesis of ergosterol like the azoles.

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Mycoses are known as fungal infections. Antimicrobial agents that inhibit the growth of pathogenic fungi are generally known as fungistatic agents while those that kill fungi are known as fungicidal agents. There are fewer antifungal agents than antibacterial agents because fungi like the mammalian cells are eukaryotic organisms. Both fungi and mammals are classified as eukaryotes because they posses membrane bound organelles which allows them to be classified as eukaryotes. Prokaryotes (e.g., bacteria) lack membrane bound organelles. Antibiotics used for the treatment of fungal infections or human mycoses have profound untoward effects on their recipient human hosts because both humans and fungi have eukaryotic cells. Since fungi and human cells share similar cellular and metabolic similarities because they are both eukaryotes, it is difficult to find suitable antifungal agents with little or no toxicity.

Many antifungal agents are too toxic for the clinical management of human mycoses. Antifungal agents have poor selective toxicity compared to antibacterial drugs which target prokaryotic cells (e.g., bacteria) with different cellular makeup from humans. Due to this fact, a considerable amount of antifungal agents 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. This is because most antifungal agents disrupts metabolic functions found not only in ‘target’ pathogenic fungi but also in the animal or human host cells taking the antifungal agent (as a form of therapy). The reason for this is because of similarities in the cellular makeup of fungi and animal or human cells. Therefore, most antifungal agents are produced in topical application forms – in which they are applied on the skin. And such topical applications are used to treat fungal infections caused by dermatophytes. 

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 of some human mycoses even in the face of potent antifungal agents. This is why people with compromised immune system (such as people living with 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 as aforementioned. They are only used on the skin surfaces as antimicrobial lotions or solutions. Most 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 of 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 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. Typical examples of azoles include fluconazole, ketoconazole, itraconazole, miconazole, voriconazole and clotrimazole. Ergosterol is the sterol that lines the cell membrane of fungi. (The human cell membrane is majorly made up of cholesterol, a different type of sterol). Polyenes include amphotericin B and nystatin. The main antimicrobial function of the polyenes 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, an enzyme that promote the formation of squalene metabolites in fungi. Typical examples of 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. This disrupts the synthesis of ergosterol in the target 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) found in the environment. They are usually incorporated into fungal culture media (e.g., Sabouraud dextrose agar, SDA) to prevent the growth of saprophytic fungi.

Echinocandins are antifungal agents that block the synthesis of glucan (polysaccharide polymers found in fungal cells) layers in pathogenic fungi. 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. They are mainly used for topical antifungal applications  

FURTHER READING

Ashutosh Kar (2008). Pharmaceutical Microbiology, 1st edition. New Age International Publishers: New Delhi, India. 

Block S.S (2001). Disinfection, sterilization and preservation. 5th edition. Lippincott Williams & Wilkins, Philadelphia and London.

Courvalin P, Leclercq R and Rice L.B (2010). Antibiogram. ESKA Publishing, ASM Press, Canada.

Denyer S.P., Hodges N.A and Gorman S.P (2004). Hugo & Russell’s Pharmaceutical Microbiology. 7th ed. Blackwell Publishing Company, USA. Pp.152-172.

Ejikeugwu Chika, Iroha Ifeanyichukwu, Adikwu Michael and Esimone Charles (2013). Susceptibility and Detection of Extended Spectrum β-Lactamase Enzymes from Otitis Media Pathogens. American Journal of Infectious Diseases. 9(1):24-29.

Finch R.G, Greenwood D, Norrby R and Whitley R (2002). Antibiotic and chemotherapy, 8th edition. Churchill Livingstone, London and Edinburg.

Russell A.D and Chopra I (1996). Understanding antibacterial action and resistance. 2nd edition. Ellis Horwood Publishers, New York, USA.

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