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Fungal infections are caused by eukaryotic organisms and for that reason they generally present more difficult therapeutic problems than do bacterial infections. There are relatively few agents that can be used to treat fungal infections. The fungal cell wall may be considered to be a prime target for selectively toxic antifungal agents because of its chitin structure, absent from human cells. It was only in 2006 that antifungals targetting this structure became available. Other targets are also being exploited currently. |
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Polyene antibiotics bind to sterols within the fungal membrane, disrupting its integrity. This makes the membrane leaky, leading to a loss of small molecules from the fungal cell. Polyene antibiotics include nystatin, used topically for candida infections and amphotericin B. |
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Chemical structure of nystatin
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Chemical structure of amphotericin B
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Amphotericin B is an important polyene antifungal drug administered parenterally and widely used to treat systemic mycoses. It is usually administered in a preparation complexed with lipid, as this reduces toxicity in comparison to the "conventional" formulation (amphotericin B deoxycholate), which causes significant nephrotoxicity, fever, chills and hypotension. Around 95% of the drug binds to plasma proteins and leaves the circulation. There is poor penetration into body fluids such as CSF and treatment of central nervous system infections usually requires alternative antifungal agents (with the exception of cryptococcal meningitis, for which amphotericin B is effective). Amphotericin B is used in combination with flucytosine (5-FC) for the treatment of cryptococcal meningitis, based on clinical evidence of improved efficacy. However, the addition of 5-FC to amphotericin B has not been proven to improve its efficacy in other fungal infections, and it is usually used as monotherapy. |
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The azoles are a large group of synthetic compounds that include two clinically useful families employed in the treatment of systemic fungal infections: the imidazoles and triazoles. They typically have a broad spectrum of antifungal activity although there is some variation of activity between thae various compounds. They act by inhibiting lanosterol 14-a demethylase, which is an enzyme component of the biosynthetic pathway for ergosterol, the predominant sterol in the fungal cell membrane. Lanosterol 14-a demethylase is a fungal cytochrome P450 enzyme, and one of disadvantages of this group of compounds is that most of them inhibit human cytochrome P450-dependent biosynthetic pathways to some extent. The majority of azoles can only used topically, and a few may be used to treat systemic infections. There are azoles that may be prescribed for oral administration whilst others may be given parenterally. The older (imidazole) agents clotrimazole, miconazole, econazole and ketoconazole are nowadays considered too toxic to be used systemically, and are used topically (although ketoconazole is used occasionally in resource-poor settings, e.g. to treat eumycetoma). The newer (triazole) agents fluconazole, itraconazole, voriconazole and posaconazole are used widely for a number of indications: fluconazole is active against yeasts and dimorphic fungi only, whereas the other triazoles are also active against moulds. Only posaconazole has significant activity against the Mucorales. Emergence of resistance in yeasts has occurred following therapy with fluconazole, and certain yeast species, for example Candida krusei, are not sensitive to this compound.
Chemical structure of myconazole
Chemical structure of ketoconazole
Chemical structure of fluconazole
Chemical structure of itraconazole
TerbinafineTerbinafine is a synthetic antifungal agent introduced into the UK in 1991 and is used to treat skin and nail infections. It inhibits ergosterol biosynthesis.
Chemical structure of terbinafine
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The drug griseofulvin is a naturally occurring compound and so is a true antibiotic with antifungal properties. It binds to the proteins involved in microtubule formation and prevents separation of chromosomes at mitosis. Why griseofulvin does not affect human cells is not known. It is used in the treatment of ringworm and other fungal infections of the skin or nails.
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The synthetic pyrimidine 5-flucytosine is a synthetic compound that is primarily active against yeasts. It is an analogue of naturally occurring nucleotides and acts by interfering with nucleic acid synthesis. Because of its analogue status, the drug is actively taken up by the fungal cells where it is metabolised to fluorouracil. It has been administered both orally and parenterally for the treatment of systemic yeast infections, either as a single agent or in combination with amphotericin B. Flucytosine is excreted via the kidneys and good drug levels are achieved in body fluids such as CSF. Since it is renally excreted, the dose must be modified in patients with renal impairment. Flucytosine is relatively safe although bone marrow depression can occur in patients with very high serum levels. Serum levels should therefore be monitored closely, particularly in patients with kidney problems. White blood cell and platelet counts should also be carefully monitored. One of the major drawbacks with flucytosine is the occurrence of resistance following therapy. If it is used, sensitivity testing of fungal isolates is necessary both before and during therapy. With the exception of cryptococcal meningitis, for which it has proven efficacy when given in combination with amphotericin B, it is now rarely used, as there is very little evidence for efficacy.
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Page edited October 2009
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