Review articleClinical pharmacology of antifungal compounds
Section snippets
Amphotericin B deoxycholate
Amphotericin B is a natural polyene macrolide antibiotic and consists of seven conjugated double bounds, an internal ester, a free carboxyl group, and a glycoside side chain with a primary amino group (Fig. 1). It is not orally or intramuscularly absorbed. For parenteral use, AmB has been solubilized with deoxycholate as micellar suspension.
Flucytosine
Flucytosine (5-fluorocytosine [5-FC]) is a low-molecular-weight water-soluble synthetic fluorinated pyrimidine analogue (Fig. 3). It is taken up by the fungus-specific enzyme cytosine permease and converted in the cytoplasm by cytosine deaminase to 5-fluorouracil, which causes RNA miscoding and inhibits DNA synthesis [37]. 5-FC is relatively nontoxic to mammalian cells because of the absence or very low level of activity of cytosine deaminase. In the United States, 5-FC is available only as
Antifungal triazoles
The antifungal azoles are a class of synthetic compounds that have one or more azole rings and, attached to one of the nitrogen atoms, a more or less complex side chain. The imidazoles miconazole and ketoconazole were the first azoles developed for systemic treatment of human mycoses. Two subsequently developed triazoles, fluconazole and itraconazole, are in current use (Fig. 4).
Echinocandin lipopeptides: anidulafungin, caspofungin, and micafungin
The echinocandins are a novel class of semisynthetic amphiphilic lipopeptides composed of a cyclic hexapeptide core linked to a variably configured lipid side chain. The echinocandins act by noncompetitive inhibition of the synthesis of 1,3-β-glucan, a polysaccharide in the cell wall of many pathogenic fungi (Fig. 5). Together with chitin, the rope-like glucan fibrils are responsible for the cell wall's strength and shape. They are important in maintaining the osmotic integrity of the fungal
Future directions
The past decade has seen a considerable expansion in antifungal drug research and the clinical development of several new compounds and strategies targeted against invasive fungal infections. ITC, voriconazole, and liposomal AmB are acceptable alternatives to AmB-D in neutropenic fever. The newer triazoles offer the tantalizing possibility of oral prophylaxis of mold infections, and seem a viable option to AmB in many cases of aspergillosis. Combination therapy of echinocandins with triazoles
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