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Amphotericin B continues to be an important drug for the treatment of systemic fungal infections. However, several azoles and echinocandins are proving to be just as effective in some systemic mycoses with less risk of toxic effects.
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1. Classification and pharmacokinetics
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Amphotericin B is a polyene antibiotic related to nystatin. Amphotericin is poorly absorbed from the gastrointestinal tract and is usually administered intravenously as a nonlipid colloidal suspension, as a lipid complex, or in a liposomal formulation. The drug is widely distributed to all tissues except the central nervous system (CNS). Elimination is mainly via slow hepatic metabolism; the half-life is approximately 2 wk. A small fraction of the drug is excreted in the urine; dosage modification is necessary only in extreme renal dysfunction. Amphotericin B is not dialyzable.
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2. Mechanism of action
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The fungicidal action of amphotericin B is due to its effects on the permeability and transport properties of fungal membranes. Polyenes are molecules with both hydrophilic and lipophilic characteristics (ie, they are amphipathic). They bind to ergosterol, a sterol specific to fungal cell membranes, and cause the formation of artificial pores (Figure 48–1). Resistance, though uncommon, can occur via a decreased level of or a structural change in membrane ergosterol.
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Amphotericin B is one of the most important drugs available for the treatment of systemic mycoses and is often used for initial induction regimens before follow-up treatment with an azole. It has the widest antifungal spectrum of any agent and remains the drug of choice, or codrug of choice, for most systemic infections caused by Aspergillus, Blastomyces, Candida albicans, Cryptococcus, Histoplasma, and Mucor. Amphotericin B is usually given by slow intravenous infusion, but in fungal meningitis intrathecal administration, though dangerous, has been used. Local administration of the drug, with minimal toxicity, has been used in treatment of mycotic corneal ulcers and keratitis.
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Adverse effects related to intravenous infusion commonly include fever, chills, muscle spasms, vomiting, and a shock-like fall in blood pressure. These effects may be attenuated by a slow infusion rate and by premedication with antihistamines, antipyretics, meperidine, or glucocorticoids.
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Amphotericin B decreases the glomerular filtration rate and causes renal tubular acidosis with magnesium and potassium wasting. Anemia may result from decreases in the renal formation of erythropoietin. Although concomitant saline infusion may reduce renal damage, the nephrotoxic effects of the drug are dose-limiting. Dose reduction (with lowered toxicity) is possible in some infections when amphotericin B is used with flucytosine. Liposomal formulations of amphotericin B have reduced nephrotoxic effects, possibly because of decreased binding of the drug to renal cells.
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Intrathecal administration of amphotericin B may cause seizures and neurologic damage.
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B. Flucytosine (5-Fluorocytosine [5-FC])
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1. Classification and pharmacokinetics
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5-FC is a pyrimidine antimetabolite related to the anticancer drug 5-fluorouracil (5-FU). It is effective orally and is distributed to most body tissues, including the CNS. The drug is eliminated intact in the urine, and the dose must be reduced in patients with renal impairment.
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2. Mechanism of action
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Flucytosine is accumulated in fungal cells by the action of a membrane permease and converted by cytosine deaminase to 5-FU, an inhibitor of thymidylate synthase (Figure 48–1). Selective toxicity occurs because mammalian cells have low levels of permease and deaminase. Resistance can occur rapidly if flucytosine is used alone and involves decreased activity of the fungal permeases or deaminases. When 5-FC is given with amphotericin B, or triazoles such as itraconazole, emergence of resistance is decreased and synergistic antifungal effects may occur.
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The antifungal spectrum of 5-FC is narrow; its clinical use is limited to the treatment, in combination with amphotericin B or a triazole, of infections resulting from Cryptococcus neoformans, possibly systemic candidal infections and chromoblastomycosis caused by molds.
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Prolonged high plasma levels of flucytosine cause reversible bone marrow depression, alopecia, and liver dysfunction.
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C. Azole Antifungal Agents
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1. Classification and pharmacokinetics
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The azoles used for systemic mycoses include ketoconazole, an imidazole, and the triazoles fluconazole, itraconazole, posaconazole, and voriconazole. Oral bioavailability is variable (normal gastric acidity is required). Fluconazole, posaconazole, and voriconazole are more reliably absorbed via the oral route than the other azoles. Most triazoles are available in both oral and intravenous formulations. The drugs are distributed to most body tissues, but with the exception of fluconazole, drug levels achieved in the CNS are very low. Liver metabolism is responsible for the elimination of ketoconazole, itraconazole, and voriconazole. Inducers of drug-metabolizing enzymes (eg, rifampin) decrease the bioavailability of itraconazole. Fluconazole is eliminated by the kidneys, largely in unchanged form.
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2. Mechanism of action
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The azoles interfere with fungal cell membrane permeability by inhibiting the synthesis of ergosterol. These drugs act at the step of 14α-demethylation of lanosterol, which is catalyzed by a fungal cytochrome P450 isozyme. With increasing use of azole antifungals, especially for long-term prophylaxis in immunocompromised and neutropenic patients, resistance is occurring, possibly via changes in the sensitivity of the target enzymes.
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Because it has a narrow antifungal spectrum and causes more adverse effects than other azoles, ketoconazole is now rarely used for systemic mycoses. The drug is not available in parenteral form. However, ketoconazole continues to be used for chronic mucocutaneous candidiasis and is also effective against dermatophytes.
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Fluconazole is a drug of choice in esophageal and oropharyngeal candidiasis and for most infections caused by Coccidioides. A single oral dose usually eradicates vaginal candidiasis. Fluconazole is the drug of choice for treatment and secondary prophylaxis against cryptococcal meningitis and is an alternative drug of choice (with amphotericin B) in treatment of active disease due to Cryptococcus neoformans. The drug is also equivalent to amphotericin B in candidemia.
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This azole is currently the drug of choice for systemic infections caused by Blastomyces and Sporothrix and for subcutaneous chromoblastomycosis. Itraconazole is an alternative agent in the treatment of infections caused by Aspergillus, Coccidioides, Cryptococcus, and Histoplasma. In esophageal candidiasis, the drug is active against some strains resistant to fluconazole. Itraconazole is also used extensively in the treatment of dermatophytoses, especially onychomycosis.
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Voriconazole has an even wider spectrum of fungal activity than itraconazole. It is a codrug of choice for treatment of invasive aspergillosis; some studies report greater efficacy than amphotericin B. Voriconazole is an alternative drug in candidemia with activity against some fluconazole-resistant organisms and in AIDS patients has been used in the treatment of candidial esophagitis and stomatitis.
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The broadest-spectrum triazole, posaconazole has activity against most species of Candida and Aspergillus. It is the only azole with activity against Rhizopus, one of the agents of mucormycosis and is used for prophylaxis of fungal infections during cancer chemotherapy and in salvage therapy in invasive aspergillosis.
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Adverse effects of the azoles include vomiting, diarrhea, rash, and sometimes hepatotoxicity, especially in patients with preexisting liver dysfunction. Ketoconazole is a notorious inhibitor of hepatic cytochrome P450 isozymes and may increase the plasma levels of many other drugs, including cyclosporine, oral hypoglycemics, phenytoin, and warfarin. Inhibition of cytochrome P450 isoforms by ketoconazole interferes with the synthesis of adrenal and gonadal steroids and may lead to gynecomastia, menstrual irregularities, and infertility. The other azoles are more selective inhibitors of fungal cytochrome P450. Although they are less likely than ketoconazole to cause endocrine dysfunction, their inhibitory effects on liver drug-metabolizing enzymes have resulted in drug interactions. Voriconazole causes immediate but transient visual disturbances including blurring of vision of unknown cause in more than 30% of patients. Based on animal studies voriconzole is a class D drug in terms of pregnancy risk. Visual dysfunction has not been reported with posaconazole, but the drug is an inhibitor of CYP3A4, increasing the levels of cyclosporine and tacrolimus.
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1. Classification and pharmacokinetics
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Caspofungin is an echinocandin, the first of a novel class of antifungal agents. Other echinocandins include anidulafungin and micafungin. Used intravenously, the drugs distribute widely to the tissues and are eliminated largely via hepatic metabolism. Caspofungin has a half-life of 9–12 h. The half-life of micafungin is slightly longer, and that of anidulafungin is 24–48 h.
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2. Mechanism of action
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The echinocandins have a unique fungicidal action, inhibiting the synthesis of β(1-3)glucan, a critical component of fungal cell walls.
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Caspofungin is used for disseminated and mucocutaneous Candida infections in patients who fail to respond to amphotericin B and in the treatment of mucormycosis. Anidulafungin is used for esophageal and invasive candidiasis. Micofungin is used for mucocutaneous candidiasis and for prophylaxis of Candida infections in bone marrow transplant patients.
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Infusion-related effects of caspofungin include headache, gastrointestinal distress, fever, rash, and flushing (histamine release). Micafungin also causes histamine release and elevates blood levels of the immunosuppressant drugs cyclosporine and sirolimus. Combined use of echinocandins with cyclosporine may elevate liver transaminases.