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The polyenes nystatin and amphotericin B are lipophilic and bind to ergosterol, the dominant sterol in the cytoplasmic membrane of fungal cells. After binding, they form annular channels, which penetrate the membrane and lead to leakage of essential small molecules from the cytoplasm and cell death. Their binding affinity for the ergosterol of fungal membranes is not absolute and includes sterols such as cholesterol, which are present in human cells. This is the basis of the considerable toxicity that limits their use. Almost all fungi are susceptible to amphotericin B, and the development of resistance is too rare to be a consideration in its use.
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Ergosterol binding forms membrane channels
Active against most fungi
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At physiologic pH, amphotericin B is insoluble in water and must be administered intravenously as a colloidal suspension. It is not absorbed from the gastrointestinal tract. The major limitation to amphotericin B therapy is the toxicity created by its affinity for mammalian as well as fungal membranes. Infusion is commonly followed by chills, fever, headache, and dyspnea. The most serious toxic effect is renal dysfunction and is observed in virtually every patient receiving a therapeutic course. Experienced clinicians learn to titrate the dosage for each patient to minimize the nephrotoxic effects. For obvious reasons, use of amphotericin B is limited to progressive, life-threatening fungal infections. In such cases, despite its toxicity it retains a prime position in treatment often by administration of an initial course of amphotericin followed by a less toxic agent. Preparations that complex amphotericin B with lipids have been used as a means to limit toxicity. The even greater toxicity of nystatin limits its use to topical preparations.
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Insoluble compound must be infused in suspension
Therapy must be titrated against toxicity
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The azoles are a large family of synthetic organic compounds, which includes members with antibacterial, antifungal, and antiparasitic properties. The important antifungal azoles for systemic administration are ketoconazole, fluconazole, itraconazole, and voriconazole. Clotrimazole and miconazole are limited to topical use. Other azoles are under development or evaluation. Their activity is based on inhibition of the enzyme (14 α-demethylase) responsible for conversion of lanosterol to ergosterol, the major component of the fungal cytoplasmic membrane. This leads to lanosterol accumulation and the formation of a defective membrane. Effects on the precursors of some hormones may cause endocrine side effects and restricts use in pregnancy. All antifungal azoles have the same mechanism of action. The differences among them are in avidity of enzyme binding, pharmacology, and side effects.
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Inhibit enzyme crucial for synthesis of membrane ergosterol
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Ketoconazole, the first azole, has now been supplanted by the later azoles for most systemic mycoses. Although nausea, vomiting, and elevation of hepatic enzymes complicate the treatment of some patients, the azoles are much less toxic than amphotericin B. Fluconazole was the first azole with good central nervous system penetration, but itraconazole is now generally preferred for fungal meningitis. Azoles are also effective for superficial and subcutaneous mycoses in which the initial therapy either fails or is not tolerated by the patient. In general, itraconazole and, more recently, voriconazole are the primary azoles used together with, or instead of, amphotericin B for serious fungal infections. Clotrimazole and miconazole are available in over-the-counter topical preparations.
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Less toxic than amphotericin B
Itraconazole and voriconazole prime systemic agents
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The allylamines are a group of synthetic compounds that act by inhibition of an enzyme (squalene epoxidase) in the early stages of ergosterol synthesis. The allylamine group includes an oral and topical agent, terbinafine used in the treatment of dermatophyte (ringworm) infections.
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Inhibit ergosterol synthesis
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NUCLEIC ACID SYNTHESIS
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5-Flucytosine (5FC) is an analog of cytosine. It is a potent inhibitor of RNA and DNA synthesis. 5FC requires a permease to enter the fungal cell, where its action is not direct but through its enzymatic modification to other compounds (5-fluorouracil, 5-fluorodeoxyuridyic acid, 5-fluoruridine). These metabolites then interfere with DNA synthesis and cause aberrant RNA transcription.
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Enzymatically modified form makes defective RNA
Inhibits DNA synthesis
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Flucytosine is well absorbed after oral administration. It is active against most clinically important yeasts, including Candida albicans and Cryptococcus neoformans, but has little activity against molds or dimorphic fungi. The frequent development of mutational resistance during therapy limits its application to mild yeast infections or its use in combination with amphotericin B for cryptococcal meningitis. The combination reduces the probability of expression of resistance and allows a lower dose of amphotericin B to be used. The primary toxic effect of flucytosine is a reversible bone marrow suppression that can lead to neutropenia and thrombocytopenia. This effect is dose related and can be controlled by drug monitoring.
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Active against yeasts but not molds
Resistance develops during therapy if used alone
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The unique chemical nature of the fungal cell wall, with its interwoven layers of mannan, glucan, and chitin (Figure 44–1), makes it an ideal target for chemotherapeutic attack. Although such antifungal agents have only recently (2002) entered the armamentarium, they are most welcome. The echinocandins, which block glucan synthesis, are now in clinical use and the nikkomycins, which block chitin synthesis, are in development.
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Echinocandins act by inhibition of a glucan synthetase (1,3-β-D-glucan synthetase) required for synthesis of the principal cell wall glucan of fungi. Its action causes morphologic distortions and osmotic instability in yeast and molds that are similar to the effect of β-lactams on bacteria. The first such agent to be licensed is caspofungin, which has good activity against Candida and Aspergillus and a wide range of other fungi. Cryptococcus neoformans whose cell wall glucans have a slightly different structure is resistant. Since there are no similar human structures, toxicity is minimal. The newest echinocandins, micafungin and andiulafungin, have the same mode of action and a similar spectrum.
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Inhibit synthease crucial for glucan synthesis
Current use is Candida, Aspergillus
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Nikkomycins have a mechanism of action analogous to echinocandins. They inhibit chitin synthetase, which polymerizes the N-acetylglucosamine subunits that make up chitin. The result is inhibition of chitin synthesis. The agent in development, nikkomycin Z, has activity against dimorphic fungi such as Coccidioides immitis and Bastomyces dermatitidis but not against yeast or Aspergillus.
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Other Antifungal Agents
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Griseofulvin is a product of a species of the mold Penicillium. It is active only against the agents of superficial mycoses. Griseofulvin is actively taken up by susceptible fungi and acts on the microtubules and associated proteins that make up the mitotic spindle. It interferes with cell division and possibly other cell functions associated with microtubules. Griseofulvin is absorbed from the gastrointestinal tract after oral administration and concentrates in the keratinized layers of the skin. Clinical effectiveness has been demonstrated for all causes of dermatophyte infection, but the response is slow. Difficult cases may require 6 months of therapy to affect a cure.
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Microtubule disruption interferes with cell division
Active against dermatophytes
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Potassium iodide is the oldest known oral chemotherapeutic agent for a fungal infection. It is effective only for cutaneous sporotrichosis. Its activity is somewhat paradoxical, because the mold form of the etiologic agent, Sporothrix schenckii, can grow on medium containing 10% potassium iodide. The pathogenic yeast form of this dimorphic fungus appears to be susceptible to molecular iodine.
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Iodide inhibits Sporothrix