DOC-20241006-WA0006..pptx................

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1. Anti-Fungal Drugs INTRODUCTION:- Fungal infection is the raising prevalence in recently trends because of increased use of broad spectrum antibiotics, corticosteroids, anticancer, immunosuppressant drugs and emergence of AIDS. As a result of breakdown of host defence mechanisms by the above agents, saprophytic fungi easily invade the living tissues. A number of antifungal agents have become available in the recent years.

2. These can be broadly classified on the basis of their chemical structure into polyene antibiotics, imidazole derivatives, pyrimidines and silver compounds.

3. (A) Polyene antifungals It is the 1 st effective antifungals - These have been the mainstay of antifungal therapy. These are isolated from various species of Streptomyces and consist of a large, conjugated, double-bond system in a lactose ring linked to an amino acid sugar. - Mechanism of action:- They work by binding to the sterol groups ( ergosterol ) in fungal cell membranes , rendering them permeable followed by alters membrane permeability and disrupts the fungal cell, consecutive leads to lethal imbalances in cell contents.

4. Polyenes do not penetrate well into the cornea and are not beneficial in deep stromal keratitis . Use is restricted due to insolubility, irritation on application. This group includes following drugs-

5. (1) Nystatin 1 st polyene antibiotic in 1950, derived from Streptomyces noursei . It is fungistatic and is well tolerated in the eye as 3.5% ointment. It has a medium level of activity in ocular infections caused by Candida or Aspergillus isolates. Because of its narrow spectrum and poor intraocular penetration, its use is restricted .

6. (2) Amphotericin B ( Fungizone ) This antibiotic may act as fungistatic or fungicidal depending upon the concentration of the drug and sensitivity of the fungus. Topically, it is effective in superficial infections of the eye in the concentration of 0.075 to 0.3% drops. Sub- conjunctival injections are quite painful and more than 300 mg is Poorly tolerated.

7. Amphotericin B may be given intravitreally or/ and intravenously for treatment of intraocular infections caused by Candida,Histoplasma,Cryptococcus and some strains of Aspergillus and others. Total daily dosage may range up to 1.0 mg/kg per day or up to 1.5 mg/kg when given on alternate days.

8. 3. Natamycin ( Pimaricin ). Natamycin derived from Streptomyces natalenses . It is a broad-spectrum antifungal drug having activity against Candida,Aspergillus , Fusarium and Cephalosporium . Topical application of 5% pimaricin suspension produces effective concentrations within the corneal stroma but not in intraocular fluid. It is the drug of choice for fusarium solani keratitis .

9. It adheres well to the surface of the ulcer, making the contact time of the antifungal agent with the eye greater. It is not recommended for injection. 5% topical suspension drops 4-6 times/day Adverse reactions: irritation, burning, allergic reactions.

10. (B) Imidazole antifungal drugs Various imidazole derivatives available for use in ocular fungal infections include:- miconazole , clotrimazole , ketoconazole, econazole and itraconazole , voriconazole . (1) Miconazole . It possesses a broad antifungal spectrum and is fungicidal to various species of Candida, Aspergillus , Fusarium , Cryptococcus,Cladosporium , Trichophyton and many others. Topical (1%) instilled every hourly and subconjunctival (5-10 mg) every 48 hrs for 2-3 doses, application of miconazole produces high levels of the drug in the cornea which is more dramatic in the presence of epithelial defect.

11. (2) Clotrimazole It is fungistatic and is effective against Candida, Aspergillus and many others. Its 1% suspension is effective topically and is the treatment of choice in Aspergillus infections of the eye.

12. (3) Econazole . It also has broad-spectrum antifungal activity and is used topically as 1% ointment and drops 4-6 times daily. Because of its poor intraocular penetration, it is effective only in superficial infections of the eye.

13. (4) Ketoconazole . It is effective after oral administration and possesses activity against common fungi But highly effective for treatment of keratomycosis . It is an adjunctive systemic antifungal agent in fungal keratitis complicated by endophthalmitis .

14. It is given as single oral dose of 200-400 mg daily up to at least one week after the symptoms have disappeared. Topical 1-5% drops also used and well tolerated. Reactions: relatively safe, but GIT upset, abnormal LFT, hypersensitivity and Reversible hepatotoxicity is occurs.

15. (5) Fluconazole . 1 st antifungal with good pharmacokinetic profile & relative low side effect It is fungistatic drug active against Candida, Aspergillus and Cryptococcus. It is used Orally, 200-600mg/day for 3 weeks for candida and 10-12 weeks in cryptococcus infection and also for topical use 0.2% eye drops every 4hrly .

16. (6) Itraconazole . It is prescribed for treatment of fungal infections caused primarily by Aspergillus,Histoplasmosis , Blastomycosis . It has moderate effect against Candida and Fusarium infections. It is available for oral and topical use. Oral dose is 200 mg twice daily for a week and Topically it is used as 1% eye drops.

17. (7) Voriconazole Voriconazole is a new generation triazole antifungal agents, with broad-spectrum activity and high intraocular penetration. Voriconazole eye drops have been used for the treatment of ophthalmic fungal keratitis . The voriconazole eye drops used are of topically 1% concentration, well tolerated by the eye, and are stable..

18. Have Good bioavailability and Good therapeutic concentrations Completely inhibits ergosterol synthesis and more effective than fluconazole Commonly used for invasive systemic and ocular infections specially aspergillosis and candidiasis Oral dose of Voriconazole 200mg BD.

19. S/E- Transient visual disturbances, fever, rash, vomiting, headache, abdominal pain. Faster and deeper penetration Highly effective in fungal keratitis with deep abscess

20. (C) Pyridine This group includes flucystosine , which is fluorinated salt of pyrimidine . MOA- After uptake into fungal cells, it is converted into 5-fluorouracil and then to 5-fluorodeoxyuridylic acid which is an inhibitor of thymidylate synthesis. Thymidylic acid is a component of DNA. The drug is very effective against Candida species and yeasts. It is used as 1.5% aqueous drops hourly. It can also be given Orally 50-150mg/kg/day divided in 4 doses for a week.

21. (D) Silver compounds- Combination of silver with sulfonamides and with other anti-microbial compounds significantly increases the activity against bacterial and fungal infections. In this context several silver compounds have been synthesized. Most frequently used is silver sulphadiazine which is reported to be highly effective against Aspergillus and Fusarium species. It is used to 1% drops hourly.

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