Antifungal Therapy

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Chapter: Pharmaceutical Microbiology : Fungi

The choice and dose of an antifungal will depend upon the nature of the condition, whether there are any underlying diseases, the health of the patient and whether antifungal resistance has been identified as compromising therapy.




The choice and dose of an antifungal will depend upon the nature of the condition, whether there are any underlying diseases, the health of the patient and whether antifungal resistance has been identified as compromising therapy. Part of the difficulty in designing effective antifungal agents lies in the fact that fungi are eukaryotic organisms so agents that will kill fungi may also have a deleterious effect on human tissue. The ideal antifungal drug should target a pathway or process specific to the fungal cell, so reducing the possibility of damaging tissue and inducing unwanted side effects.



Polyene antifungals



Polyene antifungals are characterized by having a large macrolide ring of carbon atoms closed by the formation of an internal ester or lactone (Figure 4.3). In addition, polyenes have a large number of hydroxyl groups distributed along the macrolide ring on alternate carbon atoms. This combination of highly polar and nonpolar regions within the molecule renders the polyenes amphiphatic, i.e. having hydrophobic and hydrophilic regions in the one molecule, which assists solubility in lipid membranes.



The principal polyenes are amphotericin B and nystatin. Amphotericin B is produced by the bacterium Streptomyces nodosus and its activity is due to the ability to bind ergosterol, which is the dominant sterol in fungal cell membranes, and consequently increases membrane permeability by the formation of pores (Figure 4.4). The action of amphotericin B seems to rely on the formation of pores through which intracellular contents can escape from the cell. Amphotericin B can lead to renal damage during prolonged antifungal therapy. Amphotericin B is active against a broad range of fungal pathogens and is considered the ‘gold standard’ against which the activity of other antifungal agents is measured. Because of its renal toxicity amphotericin B tends to be reserved for severe cases of systemic fungal disease but recent formulations in which the drug is encapsulated within liposomes have been shown to have reduced toxicity.




Nystatin was discovered in 1950 and exhibits the same mode of action as amphotericin B but tends to have lower solubility, which has restricted its use to the treatment of topical infections. Although nystatin was effective for the treatment of conditions such as oral and vaginal candidosis, its use has been overtaken by the introduction of azole antifungal drugs.


Azole antifungals



The first generation of azole antifungals revolutionized the treatment of mucosal and invasive fungal infections, and azoles are still the most widely used group of antifungal agents. The azole derivatives are classified as imidazoles or triazoles on the basis of whether they have two or three nitrogen atoms in the fivemembered azole ring (Figure 4.3). The azoles in current clinical use are clotrimazole, miconazole, econazole and ketoconazole; newer drugs such as itraconazole, fluconazole and voriconazole have important applications in the treatment of systemic infections. Azoles function by interfering with ergosterol biosynthesis by binding to the cytochrome P450 mediated enzyme known as 14αdemethylase  (P450DM). This blocks the formation of ergosterol by preventing the methylation of lanosterol (a precursor of ergosterol) (Figure 4.4). This result in a reduction in the amount of ergosterol in the fungal cell membrane which leads to membrane instability, growth inhibition and cell death. An additional consequence of the block in ergosterol biosynthesis is the build up of toxic intermediates which can prove fatal to the fungal cell.


Azoles exhibit a broad spectrum of activity in vitro, being capable of inhibiting the growth of most Candida, Cryptococcus and Aspergillus species, and dermatophytes. Miconazole was the first azole used to treat systemic fungal infections but demonstrated a number of toxic side effects. Ketoconazole produced high serum concentrations upon oral administration but had poor activity against aspergillosis. In addition, ketoconazole was associated with a range of side effects which limited its applicability. Newer triazoles such as fluconazole and itraconazole have increased the options for dealing with fungal infections. Fluconazole was introduced for clinical use in 1990, is water soluble and shows good penetration and deposition into the pulmonary tissues; it also reaches high levels in the cerebrospinal fluid and the peritoneal fluids. Fluconazole has proved highly effective in the treatment of infections caused by C. albicans but shows limited activity against Aspergillus. Itraconazole became available for clinical use in the late 1980s and was the first azole with proven efficacy against Aspergillus. Itraconazole is effective in treating severe Aspergillus infections and exhibits both fungicidal and fungistatic effects. Upon ingestion itraconazole undergoes extensive hepatic metabolism which yields up to 30 metabolites, a number of which retain antifungal activity. Itraconazole is currently available as an intravenous formulation and is widely used for the treatment of severe Aspergillus infection in this form. Fluconazole and itraconazole demonstrate significantly reduced side effects compared to ketoconazole. Novel azole drugs with increased ability to inhibit the fungal 14α demethylase are also becoming available. These agents, which include voriconazole, posaconazole and ravuconazole, have a wider spectrum of activity than fluconazole and it has been suggested that some of them show fungicidal effects to some species (e.g. Aspergillus spp.). Voriconazole is one of the newest secondgeneration triazole antifungal drugs and it shows good activity against pulmonary aspergillosis and cerebral aspergillosis.






The echinocandins are a relatively new group of antifungal drug and are semisynthetic lipopeptides comprising a cyclic hexapeptide core connected to a lateral fatty acid chain. Three compounds of this group are currently in use: caspo-fungin, micafungin and anidulafungin (Figure 4.5 ). Unlike conventional antifungal therapy that targets ergosterol or its synthesis, the echinocandins target the synthesis of β-1-,3-glucan, the major polymer of the fungal cell wall. The cell wall is essential to the fungus as it provides physical protection, maintains osmotic stability, regulates cell shape, acts as a scaffold for proteins, mediates cell–cell communication and is the site of a number of enzymatic reactions. Inhibition of β-1-,3-glucan synthesis disrupts the structure of the growing cell wall, resulting in osmotic instability and ballooning out of the intracellular contents as a result of high osmotic pressure, and ultimately ends in cell lysis.




Caspofungin has demonstrated in vitro antifungal activity against various filamentous fungi and yeasts. It has activity against different Aspergillus species including A. fumigatus, A. flavus, A. niger and A. terreus but is considered to be more fungistatic than fungicidal. Conversely, caspofungin is particularly fungicidal against a range of Candida species including species that are resistant (e.g. C. krusei) or isolates that are less susceptible (e.g. C. dubliniensis, C. glabrata) to azoles, or resistant to amphotericin B.


The fungal cell wall represents an attractive target and the echinocandins have proven to offer a safer alternative to conventional antifungal therapies. (i.e. polyenes and azoles). Echinocandins display an unique mode of action which results in defects in cell wall morphology and osmotic instability. As the cell wall is an essential component for stability and ultimately virulence, the targeting of the wall by echinocandins results in the efficient destruction of the fungal cell. To avoid future problems with resistance, researches need to clarify the precise interactions of the echinocandins with the target enzyme, and fully examine the cell’s complex response to this agent.


Synthetic antifungal agents



Flucytosine is a synthetic fluorinated pyrimidine which has been used as an oral antifungal agent and demonstrates good activity against a range of yeast species and moderate levels of activity against Aspergillus species. Two modes of action have been proposed for flucytosine. One involves the disruption of protein synthesis by the inhibition of DNA synthesis while the other possible mode of action is the depletion in the amino acid pools within the cell as a result of inhibition of protein synthesis. In general yeast cells increase in size when exposed to levels of flucytosine lower than the minimum inhibitory concentration (MIC) and display alterations in their surface morphology, both of which can be interpreted as a result of an imbalance in the control of cellular growth. Many fungi are inherently resistant to flucytosine or develop resistance after a relatively short exposure and resistance has been attributed to alteration in the enzyme (cytosine deaminase) required to process flucytosine once inside the cell or to an elevation in the amount of pyrimidine synthesis. The problem of resistance has limited the use of flucytosine so that now it is generally used in combination with an antifungal agent (e.g. amphotericin B) where it can potentiate the effect of the second agent.


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