 |
|
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. No clinically available inhibitor of chitin synthesis analogous to the b-lactams exists at present, even though much effort is being directed towards developing such agents. Other targets are currently being exploited. |
|
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. |
|
Chemical structure of nystatin
 |
Chemical structure of amphotericin B
|
The antifungal drug Amphotericin B is administered parenterally and is widely used to treat systemic mycoses. It is most often given intravenously in a bile salt suspension and diluted with 5% dextrose. It penetrates poorly into cerebrospinal fluid and when used to treat meningitis it may be delivered directly into the brain ventricles. Amphotericin B is a very successful and widely used antifungal drug but its use is beset with problems of toxicity. It can cause unpleasant side effects including chills, fever and a lowering of blood pressure. It may also cause kidney damage. The side effects of amphotericin B therapy can mimic the clinical appearance of serious systemic infection, complicating patient management. The severity of side effects may cause interruption of antifungal infection. Amphotericin B remains the drug of choice for life-threatening fungal infections. It may often be administered together with flucytosine since in combination a lower dose may be used, reducing the risk of therapeutic complications. |
|
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
|
|
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.
|
|
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.
|
Page edited October 2009
The information on this web site is copyrighted.
© John Heritage 2006
The information is being released only for use by students of the University of Leeds.
It is solely for use by students of the University of Leeds. If any other party aside from students of the University of Leeds should access this information, the University of Leeds accepts no responsibility for any such unauthorised use.
