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ANTIFUNGAL AGENTS. subhash k. mohan. UHN – TML & Mount Sinai Hospital. What are they? Empirical Use Antifungal Susceptibility Testing Interpretation. antifungal agents. antifungal agents. What are they?. Griseofulvin Polyenes Azoles 5-FC Terbinafine Echinocandins. antifungal agents.

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  1. ANTIFUNGAL AGENTS subhash k. mohan UHN – TML & Mount Sinai Hospital

  2. What are they? Empirical UseAntifungal Susceptibility Testing Interpretation antifungal agents Subhash K. Mohan

  3. antifungal agents What are they? Griseofulvin Polyenes Azoles 5-FC Terbinafine Echinocandins Subhash K. Mohan

  4. antifungal agents Mode of action Amphotericin B binds to plasma membrane creating pores Azoles inhibits cytochrome P450 enzymes in the fungal cell 5FC converts to 5FU, incorporated into RNA, abnormal proteins Griseofulvin binds microtubule proteins, inhibit cell wall synthesis Terbinafine is an ergosterol inhibitor useful for systemic mycosis Echinocandins target their action on fungal cell wall Subhash K. Mohan

  5. antifungal agents Griseofulvin Source Penicillium griseofulvum Produced in 1939 Not used until 1958 Spectrum Dermatophytes Gentles first used orally in guinea pigs prior to its use in humans Anti-inflammatory properties Inhibits keratolytic action Subhash K. Mohan

  6. antifungal agents Polyenes VERY TOXIC Polyenes are produced from Streptomyces Cyclic molecules Nystatin Amphotericin B Natamycin Mepartricin Broad spectrum Subhash K. Mohan

  7. antifungal agents Amphotericin B Yellow powder, water insoluble Bile salt allows solubility (weak association) Floats free in the aqueous medium, causes toxic effects Broad spectrum, binds to sterol in the cell membrane Fungicidal activity @ 3 h with 1 µg/ml Azole-amphotericin B is never synergistic Amphotericin B and 5FC gives synergy Candida lusitaniae is usually resistant to Amphotericin B Subhash K. Mohan

  8. antifungal agents Amphotericin B Toxicity • early intolerance reaction • thrombophlebitis • nephrotoxicity • hematotoxic effects The liposomal preparation of Amphotericin B reduces the risk of nephrotoxicity Subhash K. Mohan

  9. antifungal agents Azole Derivatives A chemical pentacyclic structure with 2 nitrogen atoms Water insoluble except fluconazole Preferentially inhibit cytochrome P450 enzymes Fungistatic, Modify cytochrome P450 enzyme First generation Imidazoles: Clotrimazole & Miconazole Clotrimazole requires high doses – poorly tolerated Parenteral dosages no longer available forMiconazole Subhash K. Mohan

  10. antifungal agents Cytochrome P 450 (CYP 450) CYP is a host of enzymes that use iron to oxidize things CYP disposes harmful substances by making them water-soluble CYP is something like a hydroxyl group P450-mediated oxidation is referred to as "Phase I metabolism” CYP in man is found in the liver, small intestine CYP is vital to the formation of cholesterol & steroids NADPH + H+ + O2 + RH ==> NADP+ + H2O + R-OH Subhash K. Mohan

  11. antifungal agents CYP 450 ….. Fungal plasma membranes have nonpolar sterol (ergosterol) Amphotericin B binds to ergosterol permitting rapid leakage Cytochrome P450 catalyzes synthesis of ergosterol Azole antifungal agents interfere with cytochrome P450 Subhash K. Mohan

  12. antifungal agents Ketoconazole Orally well absorbed imidazole of second generation Ketoconazole is the only imidazole for systemic use CSF penetration is very weak Hepatotoxicity restricts its use Also interacts with other molecules Subhash K. Mohan

  13. antifungal agents Third generation azoles Triazole derivatives (contain three nitrogen atoms) Fluconazole Itraconazole Voriconazole Posaconazole Revuconazole Satisfactory tolerability, Suitable for systemic use Subhash K. Mohan

  14. antifungal agents Fluconazole & Itraconazole Fluconazole has been extensively used for yeast infections Useful for systemic infections Readily and completely absorbed by gastrointestinal tract Distributed equally in different organs and tissue Candida krusei Intrinsically resistant to fluconazole Itraconazole is used to treat aspergillus infections Entirely metabolized in the liver Eliminated in the feces and urine Subhash K. Mohan

  15. antifungal agents Voriconazole is a modified fluconazole A broad spectrum antifungal agent Rapid absorption after oral administration Distributes in tissues and body fluids Metabolized in the liver Eliminated in the urine in unchanged form Azoles carry some side effects Hepatotoxicity, gastrointestinal and endocrine toxicity Skin rash, pruritis and other hypersensitivity Subhash K. Mohan

  16. antifungal agents Clinical Indication Miconazole has poor tolerability given by intravenous Ketoconazole used for endemic & superficial mycosis Fluconazole useful for C. albicans and Cryptococcus neoformans Voriconazole & Posaconazole have similar spectrum as other azole Itraconazole is used to treat bronchopulmonary aspergillosis Adverse effects: gastrointestinal, hypersensitivity & hepatotoxicity Subhash K. Mohan

  17. antifungal agents Echinocandins Caspofungin Caspofungin is semisynthetic, synthesized from Glarea lozyensis Whitish powder, water & methanol soluble, fungicidal Fungicidal against, Aspergilli, Candida and P. carinii No cross resistance amongst strains resistant to Ampho B or azoles No activity against Cryptococcus neoformans, Fusarium & Rhizopus Effective against Pneumocystis carinii Micafungin and Anidulafungin – are under investigation Subhash K. Mohan

  18. antifungal agents Terbinafine Terbinafine belongs to allylamines, synthetic, highly lipophilic Oral and topical (cream) formulations Terbinafine inhibits ergosterol biosynthesis Used to treat superficial mycosis Also useful against systemic mycosis (yeast & other fungi) Adverse reactions to terbinafine are in general transient and mild Subhash K. Mohan

  19. antifungal agents Antifungal susceptibility testing Based on NCCLS M27-A document Macrodilution Microdilution Disk diffusion Agar dilution E test Variables: inoculum, medium, PH, incubation & temperature, MIC Subhash K. Mohan

  20. antifungal agents Macrodilution read after 48h – more stable – useful for low volume Major problem “trailing point” Microdilution read after 24h (high values @ 48h) Colorimetric method better for Azoles Redox reaction of Alamar blue eliminates trailing point Colorimetric MIC high for Itraconazole and low for Fluconazole Spectrophotometer reading micro platesis useful after agitated Blank disks soaked in antifungals applied on agar surface Agar dilution faster – more data needed for evaluation E-test based on diffusion of concentration gradient - investigational Useful for isolates being resistant to Amphotericin B Subhash K. Mohan

  21. antifungal agents Medium RPMI 1640 buffered, pH 7.0 Inoculum 0.5 McFarland (1 x 103 to 5 x 103 CFU/ml) Drug dilution 10x macrodilution, 2x microdilution Range Fluconazole 0.12 to 64 µg/ml, others 0.03 to 16 µg/ml Macrodilution 0.9 ml inoculum & 0.1 ml of 10x drug Microdilution 100 µl inoculum & 100 µl of 2x drug Growth control Macrodilution 0.9 ml inoculum & 0.1 ml drug free medium Microdilution 100 µl inoculum & 100 µl drug free medium Interpretation Amphotericin B – lowest concentration prevents growth 5-FC & Azoles 80% inhibition macrodilution & 50% microdilution Subhash K. Mohan

  22. antifungal agents Interpreting antifungal test results (MIC: mg/L) Antifungal Susceptible Susceptible – dose dependent Intermediate Resistant Fluconazole = or < 8 16 - 32 = or > 64 Itraconazole = or < 0.125 0.25 – 0.5 = or > 1 5-FC = or < 4 8 - 16 = or > 32 Voriconazole* = or < 1 2 = or > 4 * Tentative approval Guidelines have not been established for Amp. B and Ketoconazole Subhash K. Mohan

  23. antifungal agents Question Does empiric use of antifungal agents trigger resistance? Antifungals show resistance more than they did in the past Some fungi become resistant after exposure to antifungals Are we going to hit MRSA like situation in mycology? Highly unlikely Antifungals are not over prescribed as antibiotics Subhash K. Mohan

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