Antifungal

Fungi

Fungi are more complex than bacteria and require a different approach to anti infective therapy—Fungal diseases are called mycoses.

Fungi

Fungi
Classifying fungal infections. Superficial mycoses Affect scalp, skin, nails, mucous membranes (oral cavity, vagina) Treated with topical agents (Low incidence of side effects). Systemic mycoses Affect internal organs (lungs, brain, digestive organs)less common than superficial mycoses Sometimes fatal to clients with suppressed immune systems Treated with oral or parenteral agents(More side effects).

Types of fungal infections

Superficial Infections . Tinea (dermatophyte) infections: Fungi that affect keratin layer of skin, hair, nail. Tinea pedis, cruris, capitus, etc Onychomycosis Infection of finger/toenails by dermatophytes

Fungal cell.

The most important fungus of relevance in dentistry is a yeast belonging to the genus Candida. Oropharyngeal (thrush) and Esophageal candidiasis Infection can spread from oral mucosa into esophagus Risk factors include antibiotics, inhaled steroids, dentures, smoking, immunocompromised patients

Classification of Antifungal Drugs

1- Antifungal Antibiotics : Griseofulvin Polyene macrolide : Amphotericin- B & Nystatin 2- Synthetic Antifungal : Azoles : A) Imidazoles : Ketoconazole , Miconazole B) Triazoles : Fluconazole , Itraconazole Flucytosine Squalene epoxidase inhibitors : e.g. Terbinafine & Naftifine.


Systemic Antifungal Drugs
Systemic antifungal drugs are used for serious infections. A number of drugs available due to opportunistic fungal disease in AIDS patients.

Classification According to Route of Administration

Systemic : Griseofulvin , Amphotericin- B , Ketoconazole , Fluconazole , Terbinafine. Topical In candidiasis : Imidazoles : Ketoconazole , Miconazole. Triazoles : Terconazole. Polyene macrolides : Nystatin , Amphotericin-B

Antifungal agents

Anti fungal agent can be classified according mechanism of action into: Agent form pores in the cell membrane polyenes ( amphotericin B and Nystatin) 2. Agents disrupt ergosterol synthesis. a. Azole. Include Imidazole and triazole b. Allylamines. As terbinafine 3. gents disrupts the mitotic spindle as Grisofulvin 4. Agents inhibiting DNA synthesis As Fluorocytosine

Antifungal mechanism of action

Antifungal agent

1- Agent form pores in the cell membrane

Polyenes: Amphotericin B Amphotericin B has a broad spectrum of antifungal activity and is effective against Candida species. amphotericin B is obtained from Streptomyces Nodosus and is the gold standard for the treatment of many invasive or life-threatening mycoses.

Mechanism of action

The primary mechanism of antifungal action of Amphotericin B results from its binding to ergosterol, a component of the cell membrane of sensitive fungi. This binding forms channels in the membrane, altering its permeability and causing leakage of Na+, K+, and H+ ions.

Resistance to amphotericin B is associated with a replacement of ergosterol with other sterols in the fungal plasma membrane. amphotericin B is either fungistatic or fungicidal.


Dosage and administration Amphotericin is not absorbed when given orally, and intravenous formulation must be used to treat systemic disease. So it is administered by slow intravenous infusion (over a period of 2 to 6 hours each day) Amphotericin B applied topically as a 3% cream, ointment, or lotion is useful in the treatment of superficial Candida infections.

Adverse Effects

1- Immediate reactions ( Infusion –related toxicity ).Local phlebitis at the injection site can occur.Fever, muscle spasm, vomiting ,headache, hypotension. Can be avoided by :A. Slowing the infusionB. Decreasing the daily dose C. Premedication with antipyretics, antihistamincs or corticosteroids.D. A test dose.

2- Slower toxicity

Most serious is renal toxicity (nearly in all patients ). Hypokalemia Hypomagnesaemia Impaired liver functions Thrombocytopenia Anemia

Nystatin

Nystatin has a spectrum of activity slightly narrower than that of amphotericin B. it obtained from Streptomyces Noursei. As with amphotericin B, Nystatin is either fungi static or fungicidal. Nystatin is used primarily to treat candidal infections of the mucosa, skin, intestinal tract, and vagina. Although the efficacy of oral nystatin for enteric candidiasis has been questioned, topical nystatin remains a drug of choice for the treatment of candidal infections of the oral cavity (oral moniliasis, thrush, denture stomatitis.

Dosage and administration For the treatment of oral candidiasis, 2 to 3 ml of a suspension containing 100,000 units/ml of Nystatin are placed in each side of the mouth, and held for at least 5 minutes before swallowing. This regimen is repeated every 6 hours for at least 10 days or for 48 hours after remission of symptoms. Alternatively, one to two lozenges (200,000 units per each) may be used four to five times per day. For denture stomatitis, Nystatin ointment (100,000 units/g) can be applied topically every 6 hours to the tissue surface of the denture

Clinical uses

Prevent or treat superficial candidiasis of mouth, esophagus, intestinal tract. Vaginal candidiasis Can be used in combination with antibacterial agents & corticosteroids.


Side effect Nystatin is well tolerated, and only mild and transient gastrointestinal disturbances such as nausea, vomiting, and diarrhea have occurred after oral ingestion. The major complaint associated with Nystatin is its bitter, foul taste

2. Agents disrupt Ergosterol synthesis

a. Azole. Include Imidazole and triazole A group of synthetic fungistatic agents with a broad spectrum of activity . b. Allylamines. As terbinafine a. Azole antifungal drugs Include Imidazole (e.g ketoconazole, Miconazole, Clotrinazole) and Triazole (e.g Itraconazole, fluconazole) Azole agents has broad spectrum of activity against common fungal pathogens (e.g., Candida species, Cryptococcus neoformans, Blastomyces dermatitidis). Azole agents are synthetic compounds.


Mechanism of Action
Azoles inhibit C-14 α-demethylase (a cytochrome P450 enzyme), thereby blocking the demethylation of lanosterol to ergosterol, the principal sterol of fungal membranes. The inhibition of ergosterol biosynthesis disrupts membrane structure and function, which, in turn, inhibits fungal cell growth.

Mechanism of action of Azole Group

Clotrimazole
Indication Clotrimazole is an imidazole antifungal drug used for various mucosal and cutaneous infections. Clotrimazole also appears to be highly effective and is the is the drug of choice for the treatment of oral candidiasis in patients with AIDS.

Dosage and administration For the treatment of oral candidiasis, clotrimazole is available as a 10-mg troche. Slow dissolution in the mouth results in the binding of clotrimazole to the oral mucosa, from which it is gradually released to maintain at least fungistatic concentrations for several hours. The swallowed drug is variably but poorly absorbed. It is metabolized in the liver and eliminated in the feces along with unabsorbed drug.

the more pleasant taste of clotrimazole compared with nystatin. Side effect The adverse effects are usually Irritation associated with topical Clotrimazole. occasionally minor gastrointestinal upset may follow oral ingestion of the drug .

Fluconazole

Indications It is effective in the treatment of mucosal candidiasis, including oropharyngeal and esophageal candidiasis. Side effect Nausea, vomiting, gastric pain, headache, and rashes.

b. Allylamines

Terbinafine It is a synthetic allylamine. It is fungicidal. Like the azole drugs it interferes with ergosterol biosynthesis. Is available in an oral formulation and is used at a dosage of 250 mg/d. It is used in the treatment of dermatophytoses, especially onychomycosis. Side effect Adverse effects are rare, consisting primarily of gastrointestinal upset and headache.

3. Agents disrupts the mitotic spindle

Mechanism of action These agent interacts with polymerized microtubules, causing the disruption of the mitotic spindle and eventually fungal mitosis. Griseofulvin It was first isolated from Penicillium griseofulvum Indication griseofulvin readily reaches the skin, hair, and nails, where it binds avidly to newly synthesized keratin and inhibits fungal invasion through surface keratin. So it indicated in dermatophyte infections for which topical therapy is ineffective, principally that involving hair or nails

Caspofungin

Inhibits the synthesis of fungal cell wall by inhibiting the synthesis of β(1,3)-D-glucan, leading to lysis & cell death.PharmacokineticsGiven by IV route onlyExcretion primarily by hepatic metabolism Elimination half-life 9 to 12 hours

Clinical uses

Effective in aspergillus & candida infections. Second line for those who have failed or cannot tolerate amphotericin B or itraconazole. Adverse effects : Nausea, vomiting Flushing( release of histamine from mast cells) Very expensive

4.Agents inhibiting DNA synthesis

Fluorocytosine Mechanism of action flucytosine is a small molecule is transported into susceptible fungal cells by a specific enzyme cytosine permease and converted in the cytoplasm by cytosine deaminase to 5-fluorouracil (5-FU). 5-FU is phosphorylated and incorporated into RNA where it causes miscoding and halts protein synthesis. Additionally, phosphorylated 5-FU is converted to its deoxynucleoside, which inhibits DNA synthesis by blocking the functions of a key enzyme in DNA replication.

Mechanism of action flucytosine

Indication indicated for the treatment of systemic candidiasis and cryptococcosis. Side effect The major toxicity of flucytosine is depression of the bone marrow, resulting in anemia, leukopenia, and thrombocytopenia. Also flucytosine may cause nausea, vomiting, diarrhea, and (rarely) severe enterocolitis