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Antifungal Agents in Ophthalmology

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Fungal infections of eye cause one of the most dangerious infections. Accurate diagnosis and proper institution of anti-fungal therapy is essential. Here we discuss the various anti-fungal agents available to be used in ophthalmology.

Published in: Health & Medicine, Education

Antifungal Agents in Ophthalmology

  1. 1. Dr. Mrinmayee Ghatak Dept of Ophthalmology, K.I.M.S. Hospital, Bangalore (India) [email_address]
  2. 3. Polyenes <ul><li>1 st effective antifungals </li></ul><ul><li>Bind preferentially to ergosterol in the fungal plasma membrane > alters membrane permeability > disrupts the fungal cell </li></ul><ul><li>Use is restricted due to insolubility, irritation on application and instability </li></ul>
  3. 4. Nystatin <ul><li>1 st polyene antibiotic in 1950 </li></ul><ul><li>Derived from Streptomyces noursei </li></ul><ul><li>Affective against Candida infections </li></ul><ul><li>Topical ointment 100,000 IU, 4-5 times/day </li></ul><ul><li>Allergic hypersensitivity reactions </li></ul>
  4. 5. Amphotericin B <ul><li>Streptomyces nodosus </li></ul><ul><li>Insoluble in water, unstable at 37 degree </li></ul><ul><li>Degrades rapidly is exposed to light </li></ul><ul><li>Effective against Candida, Aspergillus, Cryptococcus, Coccidioides, Sporothrix, Blastomycosis, Histoplasma, Mucormycosis </li></ul><ul><li>Topical/s.c./intracameral/i.v. </li></ul><ul><li>Topical – 0.075%-0.3% hourly </li></ul><ul><li>S.c. 0.8-1.0mg 1-2 doses </li></ul><ul><li>i.v. 1-1.5mg/kg/day in 5% dextrose over 4 hrs with pretreatment with hydrosortisone </li></ul><ul><li>Adverse reactions: anaphylaxis, headache, nausea, vomoting, fever, nephrotoxicity </li></ul>
  5. 6. Natamycin <ul><li>Only antifungal commercially available for topical administration </li></ul><ul><li>Derived from Streptomyces natalenses </li></ul><ul><li>Most effective against filamentous fungi </li></ul><ul><li>Also for fusarium, aspergillus and most of other fungi </li></ul><ul><li>5% topical suspension drops 4-6 times/day </li></ul><ul><li>Adverse reactions: irritation, burning, PEK, allergic reactions </li></ul>
  6. 7. Imidazoles <ul><li>1 st imidazole was Clotrimazole </li></ul><ul><li>Inhibition of fungal ergosterol synthesis </li></ul><ul><li>Interference with mitochondrial oxidative and peroxisomal enzymes resulting in accumulation of lethal by-products </li></ul><ul><li>Affinity for fungal cytochrome P450 </li></ul>
  7. 8. Clotrimazole <ul><li>Chlorinated trityl imidazole </li></ul><ul><li>Borad antifungal activity </li></ul><ul><li>Specially for aspergillus </li></ul><ul><li>Also for Candida, fusarium, penicillium, clasporium and actenomyces </li></ul><ul><li>1% eye drops to be used hourly </li></ul><ul><li>Sckin cream 1% well tolerated by eye </li></ul><ul><li>Poorly soluble in water </li></ul><ul><li>Can not be given parenterally </li></ul><ul><li>Irritation, punctate keratopathy, hepatotoxicity, diarrhoea </li></ul>
  8. 9. Miconazole <ul><li>Phenethyl imidazole </li></ul><ul><li>Broad spectrum </li></ul><ul><li>Causes alteration in fungal cell wall > induces permeability changes </li></ul><ul><li>1% Topical instilled every hourly </li></ul><ul><li>Sub conj 5-10mg every 48 hrs for 2-3 doses </li></ul><ul><li>Conjunctival injection, PEE, pruritus, erythema, local irritation </li></ul>
  9. 10. Econazole <ul><li>Dichlorimidazole </li></ul><ul><li>Broad spectrum </li></ul><ul><li>Low toxicity </li></ul><ul><li>Interference with membrane sterol formation </li></ul><ul><li>1% ointment and drops 4-6times daily </li></ul><ul><li>Effective in only superficial infections of the eye </li></ul>
  10. 11. Ketoconazole <ul><li>Highly effective for treatment of keratomycosis </li></ul><ul><li>Inhibits ergosterol synthesis </li></ul><ul><li>More water soluble </li></ul><ul><li>Enhanced absorption capacity </li></ul><ul><li>Affective against Candida, Aspergillus, Fusarium </li></ul><ul><li>Oral: 200-800mg/24hrs single daily dose for a week </li></ul><ul><li>Topical 1-5% drops </li></ul><ul><li>Reactions: relatively safe, GIT upset, abnormal LFT, hypersensitivity </li></ul><ul><li>Reversible hepatotoxicity </li></ul><ul><li>Topical well tolerated </li></ul>
  11. 12. Fluconazole <ul><li>1 st antifungal with good pharmacokinetic profile & relative low side effect </li></ul><ul><li>Water soluble </li></ul><ul><li>Exhibits low binding to proteins </li></ul><ul><li>Most effective against yeasts. </li></ul><ul><li>Also few dimorphic fungi </li></ul><ul><li>Most important application : systemic use in Candida endophthalmitis in combination with Amphotericin B </li></ul><ul><li>Oral 200-600mg/day for 3 weeks for candida and 10-12 weeks in cryptococcus infection </li></ul><ul><li>Topically 0.3% eye drop every 4hrly </li></ul>
  12. 13. Voriconazole <ul><li>Good bioavailability </li></ul><ul><li>Good tolerability </li></ul><ul><li>Good therapeutic concentrations </li></ul><ul><li>Completely inhibits ergosterol synthesis, more effectively than fluconazole </li></ul><ul><li>Commonly used for invasive systemic and ocular infections specially aspergillosis and candidiasis </li></ul><ul><li>200-400mg BD with maintaininace with half dose </li></ul><ul><li>Transient visual disturbances, fever, rash, vomiting, headache, abdominal pain, rare but serous hepatotoxicity </li></ul>
  13. 14. <ul><li>Faster and deeper penetration </li></ul><ul><li>Highly effective in fungal keratitis with deep abscess </li></ul><ul><li>Outclasses all other antifungals </li></ul><ul><li>IV 100ug at conc of 1000ug/ml in candida endophthalmitis – non-toxic to retina </li></ul>
  14. 15. Itraconazole <ul><li>Well distributed in lipid-rich tissues </li></ul><ul><li>Lack of intravenous preparation </li></ul><ul><li>Primarily for aspergillus, histoplasma, blastomycosis, onychomycosis </li></ul><ul><li>Moderate for candida & fusarium </li></ul><ul><li>Orally 200mg BD for a week </li></ul><ul><li>Topically – to be freshely prepared </li></ul><ul><li>Subconj is safe </li></ul><ul><li>GI upset and hypersensitivity </li></ul>
  15. 16. FLUCYTOSINE <ul><li>Fluorinated pyrimidine </li></ul><ul><li>Effective against Candida, Cryptococcus, Aspergillus, Clasporium, Penicillium </li></ul><ul><li>Transported across fungal cell membrane by a specific permease </li></ul><ul><li>In cell it is deaminated to fluorouracil that blocks fungal thymidine synthesis </li></ul><ul><li>Orally 50-150mg/kg/day divided in 4 doses for a week </li></ul><ul><li>Topically 1% drops every hourly </li></ul><ul><li>Not used alone as poor penetration in certain fungal cell membranes </li></ul><ul><li>Topically causes irritation, itching, burning. Systemically causes nausea, vomiting, diarrhoea </li></ul>
  16. 17. Caspofungin <ul><li>Inhibits 1,3 beta glucan synthase </li></ul><ul><li>Disrupts the integrity of fungal cell wall </li></ul><ul><li>Administered IV </li></ul><ul><li>Effective for invasive aspergillosis, candidemia </li></ul><ul><li>Initial dose 70mg iv-infusion followed by 50mg iv daily </li></ul><ul><li>Relatively low incidence of side effects including GI disturbances, headache, fever, anemia, hypokalemia, tachycardia, hypersensitivity </li></ul>
  17. 18. SILVER COMPOUNDS <ul><li>Silver Sulphadiazine </li></ul><ul><li>Highly effective against Candida, Aspergillus, Fusarium </li></ul><ul><li>Topically well tolerated </li></ul><ul><li>Fungistatic </li></ul><ul><li>For both superficial and deep infections </li></ul><ul><li>1% drops hourly </li></ul><ul><li>Local irritation, FB sensation, tching </li></ul>
  18. 19. NEWER HORIZONS <ul><li>TERBINAFINE (LAMISIL) </li></ul><ul><ul><li>Allylamine </li></ul></ul><ul><ul><li>Broad spectrum, highly effective </li></ul></ul><ul><ul><li>Low toxicity, high cure rates </li></ul></ul><ul><ul><li>Primary fungicidal action even at low conc </li></ul></ul><ul><ul><li>Highly selective for single fungal enzyme </li></ul></ul><ul><ul><li>Highly lipophilic </li></ul></ul><ul><ul><li>Mycological cure achieved before clinical cure </li></ul></ul><ul><ul><li>250mg/day for 2-4 weeks </li></ul></ul><ul><ul><li>Topical 1% ointment </li></ul></ul><ul><ul><li>Systemic side effect include GI upset, skin reactions, taste disturbances, liver dynfunction, blood disorders. </li></ul></ul><ul><ul><li>Topical may cause irritaiton, itching, redness </li></ul></ul>
  19. 20. Caspofungin

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