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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 completely specific, cross-reacting with mammalian sterols such as cholesterol. This is the basis for the considerable toxicity that limits their use. Almost all fungi are susceptible to amphotericin B, and the development of resistance is rare.
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✺ Amphotericin B binds ergosterol and forms membrane channels
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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, observed in virtually every patient receiving a prolonged 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. 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 cell membrane. This leads to ergosterol depletion and lanosterol accumulation, forming defective membranes. All antifungal azoles have the same mechanism of action. The differences among them are in avidity of enzyme binding, pharmacology, and side effects. Azoles can also affect the precursors of some hormones and may therefore cause endocrinological side effects, restricting their use in pregnancy.
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✺ Inhibit enzyme crucial for synthesis of membrane ergosterol
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The systemic azoles are generally grouped based on antifungal spectrum. Fluconazole is primarily active against yeasts, including many Cryptococcus and Candida species. In contrast, newer azole compounds have extended activity against molds such as Aspergillus species, as well as the thermally dimorphic fungi (eg, Coccidioides, Blastomyces, Histoplasma). These mold-active azoles include itraconazole, voriconazole, posaconazole, and isavuconazole. Most of these agents can be given orally or parenterally. Although generally well-tolerated, the antifungal azoles can cause varying degrees of liver toxicity. Additionally, all systemic azoles, except isavuconazole, can adversely affect cardiac myocyte repolarization and therefore prolong the QTc interval on an EKG, placing patients at increased risk for cardiac arrhythmias. Topical agents such as ketoconazole, clotrimazole, and miconazole are available in over-the-counter topical preparations for superficial mycoses.
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Less toxic than amphotericin B
Systemic azoles divided between yeast-active and mold-active 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 RNA transcription.
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Enzymatically modified form makes defective RNA
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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 it 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 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
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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. 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, similar to the effect of β-lactams on bacteria. The first such agent to be licensed was 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 anidulafungin, have the same mode of action and a similar spectrum.
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✺ Inhibits enzyme crucial for glucan synthesis
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Current indications for Candida, Aspergillus
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Nikkomycins target fungal cell wall components similar to echinocandins. These compounds inhibit chitin synthases, 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 Blastomyces dermatitidis but not against yeast or Aspergillus. However, chitin synthesis remains an interesting strategy for novel antifungal development.
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✺ Inhibits chitin synthesis
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Other Antifungal Agents
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Griseofulvin is a product of one of the Penicillium species of molds. 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. It is active only against the agents of superficial mycoses. Clinical effectiveness has been demonstrated for many causes of dermatophyte infection, but the response is slow. Prolonged therapy may be required.
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✺ Microtubule disruption interferes with cell division
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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