Antifungal Drugs



Antifungal Drugs


Objectives


When you reach the end of this chapter, you will be able to do the following:



Drug Profiles



Key Terms


Antimetabolite A drug that is a either a receptor antagonist or that resembles a normal human metabolite and interferes with its function in the body, usually by competing for the metabolite’s usual receptors or enzymes. (p. 684)


Dermatophyte One of several fungi that are often found in soil and infect the skin, nails, or hair of humans. (p. 683)


Ergosterol The main sterol in fungal membranes. (p. 684)


Fungi A very large, diverse group of eukaryotic microorganisms that require an external carbon source and that form a plant structure known as a thallus. Fungi consist of yeasts and molds. (p. 683)


Molds Multicellular fungi characterized by long, branching filaments called hyphae, which entwine to form a complex branched structure known as a mycelium. (p. 683)


Mycosis The general term for any fungal infection. (p. 683)


Pathologic fungi Fungi that cause mycoses. (p. 683)


Sterols Substances in the cell membranes of fungi to which polyene antifungal drugs bind. (p. 684)


Yeasts Single-celled fungi that reproduce by budding. (p. 683)


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Anatomy, Physiology, and Pathophysiology Overview


Fungal Infections


Fungi are a very large and diverse group of microorganisms that include all yeasts and molds. Yeasts are single-celled fungi that reproduce by budding (in which a daughter cell forms by pouching out of and breaking off from a mother cell). These organisms have common practical uses in the baking of breads and the preparation of alcoholic beverages. Molds are multicellular and are characterized by long, branching filaments. Some fungi are part of the normal flora of the skin, mouth, intestines, and vagina.


An infection caused by a fungus is called a mycosis. A variety of fungi can cause clinically significant infections or mycoses. These are called pathologic fungi, and the infections they cause range in severity from mild infections with annoying symptoms (e.g., athlete’s foot) to systemic mycoses that can become life-threatening. These infections are acquired by various routes: the fungi can be ingested orally; can grow on or in the skin, hair, or nails; and, if the fungal spores are airborne, can be inhaled. There are four general types of mycotic infection: systemic, cutaneous, subcutaneous, and superficial. The latter three are infections of various layers of the integumentary system (skin, hair, or nails). Fungi that cause integumentary infections are known as dermatophytes, and such infections are known as dermatomycoses. The most severe systemic fungal infections generally affect people whose host immune defenses are compromised. Commonly, these are patients who have received organ transplants and are taking immunosuppressive drug therapy, cancer patients who are immunocompromised as a result of their chemotherapy, and patients with acquired immunodeficiency syndrome (AIDS). In addition, the use of antibiotics, antineoplastics, or immunosuppressants such as corticosteroids may result in colonization of Candida albicans, followed by the development of a systemic infection. When the infection affects the mouth, it is referred to as oral candidiasis, or thrush. It is common in newborns and immunocompromised patients. Vaginal candidiasis, commonly called a yeast infection, often affects pregnant women, women with diabetes mellitus, women taking antibiotics, and women taking oral contraceptives. The characteristics of some of the systemic, cutaneous, and superficial mycotic infections are summarized in Table 42-1.



Pharmacology Overview


Antifungal Drugs


Drugs used to treat fungal infections are called antifungal drugs. Systemic mycotic infections and some cutaneous or subcutaneous mycoses are treated with oral or parenteral drugs. Antifungals are a fairly small group of drugs. There are few such drugs because the fungi that cause these infections have proved to be very difficult to kill, and research into new and improved drugs has occurred at a slow pace. One difficulty is that often the chemical concentrations required for experimental drugs to be effective cannot be tolerated by human beings. The drugs that proved successful in the treatment of systemic mycoses as well as severe dermatomycoses include amphotericin B, caspofungin, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, micafungin, nystatin, terbinafine, posaconazole, anidulafungin, and voriconazole. These drugs are the focus of this chapter.


Topical antifungal drugs are the most commonly used drugs in this class and are often administered without prescription for the treatment of dermatomycoses as well as oral and vaginal mycoses. Although topical drug therapy is usually sufficient for these conditions, systemic oral medications are sometimes used, especially for more severe or recurrent cases. Antifungal drugs available for topical use are discussed further in Chapter 56. There is also a single antifungal drug (natamycin) for ophthalmic use (see Chapter 57).


Two antifungal drugs, flucytosine and griseofulvin, are individually listed and are not specifically classified according to their chemical structures. The remaining drugs currently include four specific chemical classes: polyenes (amphotericin B and nystatin), imidazoles (ketoconazole), triazoles (fluconazole, itraconazole, voriconazole, and posaconazole), and the echinocandins (caspofungin, micafungin, and anidulafungin). The imidazoles and triazoles are sometimes referred to by the more general term azole antifungals. Also included in some of these classes are drugs for topical use.


Mechanism of Action and Drug Effects


The mechanisms of action of the various antifungal drugs differ between drug subclasses. Flucytosine, also known as 5-fluorocytosine (5-FC), acts in much the same way as the antiviral drugs. It is an antimetabolite, which is a drug that disrupts critical cellular metabolic pathways of the fungal cell. Once inside a susceptible fungal cell, the drug is deaminated by the enzyme cytosine deaminase to 5-fluorouracil (5-FU). Because human cells do not have this enzyme, they are not harmed by this antimetabolite. Once the 5-FU is generated inside the fungal cell, it interferes with fungal deoxyribonucleic acid (DNA) synthesis, which results in both inhibition of cell growth and reproduction, and cell death. 5-FU is also available as an antineoplastic (anticancer) drug and is discussed in more detail in Chapter 45.


Griseofulvin, like flucytosine, is one of the older types of antifungal drugs. It works by preventing susceptible fungi from reproducing. It enters the fungal cell through an energy-dependent transport system and inhibits fungal mitosis (cell division) by binding to key structures known as microtubules. It has also been proposed that griseofulvin causes the production of defective DNA, which is then unable to replicate. Although both griseofulvin and flucytosine are still currently available in the U.S. market, their use has been largely replaced by the newer antifungal drug classes.


The polyenes (amphotericin B and nystatin) act by binding to sterols in the cell membranes of fungi. The main sterol in fungal membranes is ergosterol. Human cell membranes have cholesterol instead of ergosterol. Because polyene antifungals have a strong chemical affinity for ergosterol instead of cholesterol, they do not bind to human cell membranes and therefore do not kill human cells. Once the polyene drug molecule binds to the ergosterol, a channel forms in the fungal cell membrane that allows potassium and magnesium ions to leak out of the fungal cell. This loss of ions causes fungal cellular metabolism to be altered, which leads to death of the cell.


Imidazoles and triazoles (ketoconazole, fluconazole, itraconazole, voriconazole, and posaconazole) act as either fungistatic or fungicidal drugs, depending on their concentration in the fungus. They are most effective in combating rapidly growing fungi and work by inhibiting fungal cell cytochrome P-450 enzymes. These enzymes are needed to produce ergosterol. The allylamine terbinafine is believed to act by a similar mechanism. When the production of ergosterol is inhibited, other sterols called methylsterols are produced instead, which results in a defect similar to that caused by the polyene antifungals, namely, a leaky cell membrane that allows needed electrolytes to escape. The fungal cells die because they cannot carry on cellular metabolism.


The echinocandins (caspofungin, micafungin, and anidulafungin) act by preventing the synthesis of glucans, essential components of fungal cell walls that are not present in mammalian cells. This also contributes to fungal cell death. Some of the fungi that are susceptible to these drugs are the pathogens involved in the various mycoses listed in Box 42-1.



Indications


Indications for the use of the various antifungal drugs are specific to the drug. The adverse effects of the newer antifungals are fewer and less serious than those of the older drugs. However, the drug of choice for the treatment of many severe systemic fungal infections remains one of the oldest antifungals, amphotericin B, which does have major adverse effects. Amphotericin B is effective against a wide range of fungi. It is sometimes given with flucytosine in the treatment of Candida and cryptococcal infections because of the synergy of the two drugs. Amphotericin B is also effective for treating aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, fungal endocarditis, histoplasmosis, zygomycosis, fungal septicemia, and many other systemic fungal infections. The activity of nystatin is similar to that of amphotericin B, but its usefulness is limited because of its toxic effects when given in the dosages required to accomplish the same antifungal actions as amphotericin B. It is also not available in parenteral form. Nystatin is most commonly used to treat oropharyngeal candidiasis, commonly referred to as thrush.


Fluconazole and itraconazole are synthetic azole antifungals. Fluconazole can pass into the cerebrospinal fluid (CSF) and inhibit the growth of cryptococcal fungi. This makes it effective in the treatment of cryptococcal meningitis. Both drugs are active against oropharyngeal and esophageal Candida infections. Itraconazole is capable of only poor CSF penetration but can be widely distributed throughout other areas of the body. It is indicated for the treatment of fungal infections in immunocompromised and nonimmunocompromised patients with disseminated candidiasis, histoplasmosis, blastomycosis, and aspergillosis. Ketoconazole, a systemic imidazole, inhibits many dermatophytes and fungi that cause systemic mycoses, but it is not active against Aspergillus organisms or Phycomycetes (common molds) such as Mucor species (spp.). Fortunately, the newest triazole antifungal drug, voriconazole, does have activity against some of these more tenacious fungi, including Aspergillus spp. causing invasive infection, Scedosporium spp., and Fusarium spp.


Of the azole antifungals, fluconazole is the most effective for combating infections with Candida, Cryptococcus, Blastomyces, and Histoplasma organisms. Fluconazole is very effective against vaginal candidiasis. One dose of 150 mg of fluconazole can cure many vaginal candidal infections.


Flucytosine inhibits Cryptococcus neoformans, C. albicans, and many Cladosporium and Phialophora spp. It does not inhibit Aspergillus, Sporothrix, Blastomyces, or Histoplasma spp. or Coccidioides immitis.


Griseofulvin inhibits dermatophytes of Microsporum, Trichophyton, and Epidermophyton spp. It has no effect on filamentous fungi such as Aspergillus, yeasts such as Candida spp., or dimorphic species such as Histoplasma. Terbinafine is a synthetic allylamine derivative used in a systemic oral form for treatment of onychomycoses—fungal infections of the fingernails or toenails. Topical forms of terbinafine are also used for various skin infections (see Chapter 56).


Contraindications


Drug allergy, liver failure, kidney failure, and porphyria (for griseofulvin) are the most common contraindications for antifungal drugs. Itraconazole should not be used to treat onychomycoses in patients with severe cardiac problems. Voriconazole can cause fetal harm in pregnant women.


Adverse Effects


The major adverse effects caused by antifungal drugs are encountered most commonly in conjunction with amphotericin B treatment. Drug interactions and hepatotoxicity are the primary concerns in patients receiving other antifungal drugs, but the intravenous administration of amphotericin B is associated with a multitude of adverse effects. The most common and problematic of the adverse effects of the various antifungal drugs are listed in Table 42-2. With amphotericin B treatment in particular, prescribers commonly order various premedications (including antiemetics, antihistamines, antipyretics, and corticosteroids) to prevent or minimize infusion-related reactions. The likelihood of such reactions can also be reduced by using longer-than-average drug infusion times (i.e., 2 to 6 hours) for this particular drug.



TABLE 42-2


SELECTED ANTIFUNGAL DRUGS: COMMON ADVERSE EFFECTS AND CAUTIONS

















































































































BODY SYSTEM ADVERSE EFFECTS CAUTIONS
Amphotericin B (Sy)
Cardiovascular Cardiac dysrhythmias Recheck dosage and type of amphotericin B being administered
Central nervous Neurotoxicity; tinnitus; visual disturbances; hand or feet numbness, tingling, or pain; convulsions  
Renal Renal toxicity, potassium loss, hypomagnesemia  
Pulmonary Pulmonary infiltrates  
Other (infusion related) Fever, chills, headache, malaise, nausea, occasional hypotension, gastrointestinal upset, anemia  
Fluconazole (Sy)
Gastrointestinal Nausea, vomiting, diarrhea, stomach pain Use with caution in patients with renal or hepatic dysfunction
Other Increased liver enzyme levels, dizziness  
Caspofungin (Sy)
Central nervous Fever, chills, headache Adjust dose for patients with hepatic dysfunction
Cardiovascular Hypotension, peripheral edema, tachycardia  
Gastrointestinal Nausea, vomiting, diarrhea, hepatotoxicity  
Hematologic Decreased hemoglobin and hematocrit, leukopenia, anemia  
Integumentary Rash, facial edema, itching  
Voriconazole (Sy)
Central nervous Hallucinations  
Gastrointestinal Nausea, vomiting  
Hepatic Increased liver enzyme levels  
Integumentary Rash  
Other Photophobia, hypokalemia  
Nystatin (T)
Gastrointestinal Nausea, vomiting, diarrhea, cramps Local irritation may occur
Integumentary Rash, urticaria  
Terbinafine (Sy, T)
Central nervous Headache, dizziness Rarely causes irritation
Gastrointestinal Nausea, vomiting, diarrhea  
Integumentary Rash, pruritus  
Other Alopecia, fatigue  

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May 9, 2017 | Posted by in NURSING | Comments Off on Antifungal Drugs

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