III/ Antifungal agents:Antifungals should exhibit selective toxicity; they should be able to inhibit the growth of the fungus without adversely affecting the host. Based on the mechanism of action and the degree of toxicity to target fungal cells, antifungal agents can kill cells (fungicidal) or reversibly inhibit their growth (fungistatic). Antifungal agents may be naturally derived (antibiotic) or chemically synthesized (synthetic) compounds.The classes of currently available drugs include:

• Flucytosine • Polyenes (amphotericin B and nystatin)• Azoles• Allylamines• Echinocandins• Griseofulvin

Successful antifungal therapy depends on:

• Quick and correct identification of the fungus, • Susceptibility testing of positive cultures • Controlling underlying medical or immunosuppressive condition(s) • Understanding potential drug interactions and pharmacokinetics • Awareness of allergic reactions • Following primary therapy with maintenance therapy

1. Flucytosine Flucytosine or 5-fluorocytosine (5-FC) Is one of the oldest antifungal agents in use, it is a synthetic fluorinated pyrimidine used as an oral antimycotic agent Flucytosine, a fluorinated pyrimidine, inhibits both DNA and RNA synthesis. Flucytosine may have some effectiveness against dematiaceous fungi.

Adverse Reactions There is a relationship between flucytosine plasma concentrations and bone marrow toxicity. Neutropenia and thrombocytopenia

Mechanism of Action Fungal cells take up Flucytosine by a unique fungal-specific cytosine permease. Two important and independent pathways for fungal cell injury occur:

Protein synthesis inhibition: Flucytosine is converted by intracellular deamination to 5-fluorouracil and ultimately processed into 5-fluorourindine triphosphate, which is incorporated into fungal RNA. This results in miscoding during translation from RNA into amino acid sequencing, causing structural abnormalities during protein synthesis.

DNA synthesis inhibition: characterized by the conversion of 5-fluorouracil to 5- fluorodeoxyuridine monophosphate, which inhibits thymidylate synthetase and subsequently DNA biosynthesis

2. Polyene antifungal agents:Amphotericin B: (Fungizone®) . AmB is a polyene antifungal agent and the natural product of soil actinomycete Streptomyces nodosus. Chemically it is a heptaene, that face of the molecule is the lipophilic face. The hydrophilic face contains six hydroxyl groups. amphoteric properties on the molecule due to the presence of both basic (hexosamine) and acidic (carboxyl) residues.

Mode of Action . By intercalating with ergosterol in the fungal cell membrane, AmB creates a channel through which K+ and other cell constituents leak out, with resultant death of the fungal cell. AmB has much higher affinity for ergosterol than for cholesterol and that is the basis of its selective toxicity in both yeasts and molds.

Spectrum of Activity . AmB is active against all sterol-containing microbes including yeasts. AmB is a fungicidal drug against most yeasts and molds

Nystatin: (fungicidin) . is a tetraenediene macrolide polyene, Produced by Streptomyces noursei nystatin behaves as a heptaene, like amphotericin B and having a similar mode of action, used to treat candidal infections. The macrolide ring contains 37 carbons with a series of double bonds.

Lipid Formulations of AmB (liposomes): . Formulations of AmB compounded with lipids were developed to decrease the potentially harmful side effects of AmB-deoxycholate. Lipid formulations are less nephrotoxic but more expensive than AmB-deoxycholate. Their advantages are increased stability, solubility, and absorption of AmB. The different lipid

Polyene Fluorocytosine

formulations of AmB include:

Amphocil. ABCD has a toxicity profile that is similar to AmB-deoxycholate. As such, it is seldom used.

Abelcet

AmBisome

The liposomes are less than 100 nm in diameter. The FDA approved lipid-AmB drugs for systemic mycoses, particularly invasive Aspergillosis.

3. Azole antifungal agent: . Pure chemical synthesis successfully developed increasingly effective compounds. More than 40 derivatives are known to treat systemic fungal infections such as: Imidazoles, Clotrimazole and ketoconazole. Miconazole and ketoconazole are imidazoles, and the latter was the first orally administered azole capable of treating endemic mycoses, such as histoplasmosis. Newer, second generation triazoles, principally voriconazole (Pfizer), but also posaconazole and ravuconazole, have been developed to have a broader spectrum of activity especially against mold infections

Mechanism of Action

Azole antifungal drugs inhibit fungal cytochrome P450-dependent enzymes (lanosterol 14 α-demethylase); the enzyme convert lanosterol to ergosterol, the major sterol in the fungal cell membrane. Depletion of ergosterol in fungal membrane disrupts the structure and many functions of fungal membrane leading to inhibition of fungal growth

Spectrum of Activity

As a class, the azoles possess a broad spectrum of activity that includes most of the fungal pathogens associated with systemic infections

4. Allylamines and thiocarbamates (Terbinafine, Lamisil®, Novartis)Terbinafine (TRB) is an oral and topical agent in the allylamine class of synthetic compounds. Terbinafine is a newly developed oral and topical antifungal agent in the allylamine class of antifungal compounds. Discovered in 1983, it is closely related to naftifine.

Mode of Action

Terbinafine inhibits squalene epoxidase, the enzyme which catalyzes the conversion of squalene to squalene-2,3 epoxide, a precursor of lanosterol, which in turn is a direct precursor of ergosterol. A deficiency of ergosterol is detrimental to the integrity of the cell membrane resulting in a fungistatic effect similar to that seen with the azole antifungal compounds.

Antifungal Spectrum

Terbinafine is a very broad-spectrum antifungal agent, against the dermatophytes and some of the dimorphic fungi

5. EchinocandinsEchinocandins are lipopeptides, that is, cyclic hexapeptides N-acylated with an aliphatic chain of differing lengths. Echinocandins differ in having different substituents in the hexapeptide ring or a distinct fatty acid chain, many members of the family have been discovered, the natural products of several different fungal species.

Mode of Action

The echinocandins bind to ß-(1→3)-d-glucan synthase, blocking the synthesis of ß-(1→3)-d-glucan, a fibrillar structural component of the cell walls of yeasts and many molds. The result is that fungal cells cannot maintain their shape and become osmotically fragile. ß-(1→3)-d-glucan is not present in mammalian cells; consequently, its mechanism is analogous to the role of penicillin in blocking the synthesis of bacterial peptidoglycan.

Spectrum of Activity

Echinocandins have good efficacy in treating candidemia and invasive candidiasis.

Caspofungin (CASF) (Cancidas®, MERCK)

Caspofungin (CASF) was the first echinocandin derivative licensed for human use. Currently, CASF is a natural product of the fungus Glarea lozoyensis. Micafungin (MCF) and anidulafungin (ANF) are semisynthetic lipopeptides modified from fermentation products of Aspergillus species. This class of parenteral antifungal agents inhibits a novel target: blocking the synthesis of fungal cell-wall fibrils composed of ß-(1→3)-d-glucan.

Action Spectrum .

CASF is regarded as fungicidal for many yeasts and fungistatic for molds. CASF is highly active against all Candida species.

Mechanism of Action . The echinocandins act by noncompetitive inhibition of the synthesis of 1,3-beta-glucan, a polysaccharide in the cell wall of many pathogenic fungi. Together with chitin, the rope-like glucan fibrils are responsible for the strength and shape of the cell wall. They are important in maintaining the osmotic integrity of the fungal cell and play a key role in cell division and cell growth.

Anidulafungin (ANF) . ANF is a semisynthetic product of echinocandin B, itself a fermentation product of Aspergillus nidulans. It received approval from the U.S. Food and Drug Administration in 2006.

Anidulafungin has potent and broad-spectrum in vitro antifungal activity against most Candida spp., Aspergillus spp., phaeohyphomycetes and against dimorphic fungi.

Micafungin Micafungin has potent and broad spectrum in vitro activity against Candida spp.

Nikkomycin Z . Nikkomycin Z has been shown to have particularly good activity both in vitro and in vivo against the chitinous dimorphic fungi.

6. GriseofulvinGriseofulvin is a spiro-benzo [b] furan natural product, produced by Penicillium griseofulvum, dermatophytoses.

Mode of Action . Griseofulvin has been used for many years to treat dermatophytoses. The mechanism of action was thought to involve the inhibition of fungal cell mitosis, by interfering with the spindle microtubule function, arresting fungal cells in metaphase. The antimitotic effect of griseofulvin in mammalian cells is very weak, accounting for its selective toxicity for dermatophytes. Now appears that griseofulvin acts indirectly on microtubules by inhibiting gene expression.

Spectrum

Effective to treat ringworm. Griseofulvin has no activity against yeasts.

7. Cycloheximide:Is an inhibitor of protein biosynthesis in eukaryotic organisms, produced by the Streptomyces griseus. Used for isolation of pathogenic fungi.

Griseofulvin Cycloheximide

Drug resistance Mechnisms:

Microorganisms can exhibit their resistance in various ways:

1. Stop producing the drug-sensitive structure or modify the structure so that it is no longer sensitive to the drug.

2. Change the structure of the plasma membrane so that the antibiotic cannot pass to the cytoplasm.

3. Efflux pump