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An Introduction to Anti-fungal Pharmacology

An Introduction to Anti-fungal Pharmacology. The following slides were generously supplied by Professor Russell E. Lewis, Pharm.D., BCPS University of Houston College of Pharmacy, University of Texas M.D. Anderson Cancer Center.

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An Introduction to Anti-fungal Pharmacology

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  1. An Introduction to Anti-fungal Pharmacology The following slides were generously supplied by ProfessorRussell E. Lewis, Pharm.D., BCPS University of Houston College of Pharmacy, University of Texas M.D. Anderson Cancer Center. With lecture notes written by Hannah Woodcock and Jenny Bartholomew, University of Manchester, UK.

  2. Types of fungal infections - Mycoses • Superficial mycoses • Affect the skin, hair and nails • Subcutaneous mycoses (tropical) • Affect the muscle and connective tissue immediately below the skin • Systemic (invasive) mycoses • Involve the internal organs • Primary vs. opportunistic • Allergic mycoses • Affect lungs or sinuses • Patients may have chronic asthma, cystic fibrosis or sinusitis There is some overlap between these groups

  3. What are the targets for antifungal therapy? Cell membrane Fungi use principally ergosterol instead of cholesterol DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis. Cell Wall Unlike mammalian cells, fungi have a cell wall Atlas of fungal Infections, Richard Diamond Ed. 1999 Introduction to Medical Mycology. Merck and Co. 2001

  4. Cell Membrane Active Antifungals Cell membrane • Polyene antibiotics - Amphotericin B, lipid formulations - Nystatin (topical) • Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Miconazole, clotrimazole (and other topicals)

  5. Azole Antifungals for Systemic Infections Imidazole • Ketoconazole (Nizoril) • Itraconazole (Sporanox) • Fluconazole (Diflucan) • Voriconazole (Vfend) Triazoles “2nd generationtriazole” Fluconazole Ketoconazole

  6. Azoles - Mechanism • In fungi, the cytochrome P450-enzyme lanosterol 14-a demethylase is responsible for the conversion of lanosterol to ergosterol • Azoles bind to lanosterol 14a-demethylase inhibiting the production of ergosterol • Some cross-reactivity is seen with mammalian cytochrome p450 enzymes • Drug Interactions • Impairment of steroidneogenesis (ketoconazole, itraconazole)

  7. Effect of azoles on C. albicans Before exposure After exposure

  8. Azoles - Pharmacodynamics • Concentration-independent fungistatic agents • Dosage escalation may be necessary when faced with more resistant fungal species (e.g. Candida glabrata) • Goal of dosing is to maintain AUC:MIC >50 • i.e. maintain concentrations 1-2xMIC for the entire dosing interval

  9. Ketoconazole • Spectrum: yeasts and moulds - poor absorption limits its role for severe infections, generally used in mucosal infections only • Pharmacokinetics • Variable oral absorption, dependent on pH (often given with cola or fruit juice) • T1/2 7-10 hours • Protein binding > 99% • Hepatic, bile and kidney elimination

  10. Ketoconazole - Adverse effects • Adverse effects • N&V, worse with higher doses (800 mg/day) • Hepatoxicity (2-8%), increase in transaminases, hepatitis • Dose related inhibition of CYP P450 responsible for testosterone synthesis • Gynecomastia, oligosperma, decreased libido • Dose-related inhibition of CYP P450 responsible for adrenal cortisol synthesis

  11. Ketoconazole - Drug Interactions • Potent inhibitor of cytochrome P450 3A4 • Rifampin and phenytoin decrease ketoconazole levels • Ketoconazole increases cyclosporin, warfarin, astemizole, corticosteroid, and theophyllinelevels • Many of these drug interactions aresevere • Drugs that increase gastric pH will decrease blood levels of ketoconazole • Antacids, omeprazole, H2 blockers

  12. Ketoconazole - Dose • Serious infections 800 mg/day PO • Other: 200-400 mg/day PO Cost $2.50 per 200 mg tablet

  13. Well tolerated IV/PO formulations Favorable pharmacokinetics Fungistatic Resistance is increasing Narrow spectrum (Drug interactions) Fluconazole Advantages Disadvantages

  14. Fluconazole - spectrum • Good activity against C. albicans and Cryptococcus neoformans • Non-albicansCandida species more likely to exhibit primary resistance Always resistant Sometimes resistant C. krusei > C. glabrata > C. parapsilosis C. tropicalis C. kefyr

  15. Fluconazole - resistance • Primary resistance (seen in severely ill or immunocompromised patients) • Selection of resistant species or subpopulations • Replacement with more resistant strain • Secondary resistance (seen in patients with AIDS who experienced recurrent orophayrngeal candidiasis and received long-term fluconazole therapy) • Genetic mutation • Upregulation of efflux pumps

  16. Mechanisms of antifungal resistance • Target enzyme modification • Ergosterol biosynthetic pathway • Efflux pumps • Drug import White TC, Marr KA, Bowden RA. Clin Microbiol Review 1998;11:382-402

  17. Fluconazole - What is not covered • Candida krusei • +/- Candida glabrata • Aspergillus species and other moulds

  18. Fluconazole - Pharmacokinetics • Available as both IV and PO • Bioavailibility > 90% • Linear pharmacokinetics • t 1/2 = ~24 hours • Cmax (400 mg IV) = 20 µg/ml (steady state) • Protein binding < 12% • Vd 0.85 L/kg (widely distributed) • >90% excreted unchanged through the kidney

  19. Fluconazole - adverse effects/monitoring • N&V, rash: • More likely with high doses and in AIDS patients • Asymptomatic increase in LFTs (7%) • Drug interactions: • May increase phenytoin, cyclosporin, rifabutin, warfarin, and zidovudine concentrations • Rifampin reduced fluconazole levels to half (even though FLU is not a major substrate)

  20. Fluconazole - Dosing • Mucosal candidiasis • 100-200 mg/day (150 mg tablet vulvovaginal candidiasis) • Systemic fungal infections • 400-800 mg q24h • > 800 mg q24h in unstable patient, S-DD isolate, or if non-albicans spp. (except C. krusei) • Maintenance for cryptococcal meningitis • 400 mg q24h

  21. Key Biopharmaceutical Characteristics of the Triazole Antifungals R.E. Lewis 2002. Exp Opin Pharmacother 3:1039-57.

  22. Itraconazole Solution - Side Effects • Taste disturbances • Nausea and vomiting • Osmotic diarrhea (especially at doses > 400 mg/day) • Long-term compliance often difficult

  23. Voriconazole - Side Effects • Visual disturbances (~ 30%) • Decreased vision, photophobia, altered color perception and ocular discomfort • IV > oral • No evidence of structural damage to retina • Reversible alterations in function of retinal rods and cones • Testing 2 weeks after the end of treatment demonstrates a return to normal function • Long term effects?..caution against night-time driving • Effects may be intensified by hallucinations (2-5%)

  24. Amphotericin B • Polyene antibiotic • Fermentation product of Streptomyces nodusus • Binds sterols in fungal cell membrane • Creates transmembrane channel and electrolyte leakage. • Active against most fungi except Aspergillus terreus, Scedosporium spp.

  25. Lipid Amphotericin B Formulations Abelcet ® ABLC Amphotec ® ABCD Ambisome ® L-AMB Ribbon-like particles Carrier lipids: DMPC, DMPG Particle size (µm): 1.6-11 Disk-like particles Carrier lipids: Cholesteryl sulfate Particle size (µm): 0.12-0.14 Unilaminarliposome Carrier lipids: HSPC, DSPG, cholesterol Particle size (µm) : 0.08 DMPC-Dimyristoyl phospitidylcholine DMPG- Dimyristoyl phospitidylcglycerol HSPC-Hydrogenated soy phosphatidylcholine DSPG-Distearoyl phosphitidylcholine

  26. Amphotericin B • Classic amphotericin B deoxycholate (Fungizone™) formulation: serious toxic side effects. • Less toxic preparations: 1) Liposomal amphotericin B 2) Amphotericin B colloidal dispersion 3) Amphotericin B lipid complex

  27. Amphotericin B - Pharmacokinetics • Absorption from the GI tract is negligible • Oral solution sometimes used to decontaminate gut; few side effects • Only reliable method of administration is IV • Selective distribution into deep tissue sites, with slow release of drug High Low kidney > liver > spleen > lung > heart > skeletal muscle > brain > bone > CSF > eye

  28. Amphotericin B - Metabolic elimination • Metabolic fate is unknown, drug accumulates in tissues and then is slowly released • Drug levels can be measured in the kidney, liver, and spleen up to 1 year after receiving drug • Dosages of amphotericin B are generally not altered due to decreased elimination of the drug in kidney dysfunction • Hemodialysis does not alter serum drug concentrations except in hyperlipidemic patients

  29. Amphotericin B - Elimination • Inverse correlation between patient age and elimination of AmB, • á Age, â elimination, á side effects • Paediatric patients often tolerate amphotericin B better than adults

  30. Amphotericin B - Nephrotoxicity • Most significant delayed toxicity • Renovascular and tubular mechanisms • Vascular-decrease in renal blood flow leading to drop in GFR, azotemia • Tubular-distal tubular ischemia, wasting of potassium, sodium, and magnesium • Enhanced in patients who are volume depleted or who are on concomitant nephrotoxic agents

  31. Amphotericin B - Manoeuvers employed to blunt nephrotoxicity… • Sodium loading-> blunt the vasoconstriction and tubular-glomerular feedback • Administration of 500 ml -1000 ml of NaCl before and after amphotericin B infusion

  32. Amphotericin B - Drug Interactions • Enhanced nephrotoxicity • Nephrotoxic drugs • Cyclosporine, aminoglycosides, foscarnet, pentamidine • Antineoplastic agents • Cisplatin, nitrogen mustards

  33. Amphotericin B - Clinical Uses The drug of choice for: • Cryptococcal meningitis • Mucormycosis (zygomycosis) • Invasive fungal infection, not responding to other therapy

  34. Amphotericin B - Dosing andAdministration • “Test dose” 1.0 mg in 25-100ml 5% dextrose infused over 10 minutes used to evaluate possibility of anaphylactic reaction • No longer recommended, current product has fewer impurities • Current recommendation- Start with ~30% of target dose, infuse for 15 minutes, stop infusion, and monitor patient for adverse effects before resuming infusion • Rapidly escalate to full dosages within 48-72 hours • Delay in giving full dose=worse clinical outcome

  35. Cell Wall Active Antifungals Cell membrane • Polyene antibiotics • Azole antifungals DNA/RNA synthesis • Pyrimidine analogues - Flucytosine Cell wall • Echinocandins -Caspofungin acetate (Cancidas)

  36. Flucytosine Fluorinated pyrimidine related to flurouracil.

  37. Flucytosine • Restricted spectrum of activity. • Acquired Resistance. > result of monotherapy > rapid onset Due to: 1) Decreased uptake (permease activity) 2) Altered 5-FC metabolism (cytosine deaminase or UMP pyrophosphorylase activity)

  38. Flucytosine - pharmacokinetics

  39. Flucytosine - side effects • Infrequent – include D&V, alterations in liver function tests and blood disorders. • Blood concs need monitoring when used in conjunction with Amphotericin B.

  40. Flucytosine – Clinical uses • Candidiasis • Cryptococcosis • ?Aspergillosis Monotherapy : now limited } In combination with amphotericin B or fluconazole.

  41. Cell Wall Active Antifungals Cell membrane • Polyene antibiotics • Azole antifungals DNA/RNA synthesis • Pyrimidine analogues - Flucytosine Cell wall • Echinocandins -Caspofungin acetate (Cancidas) Atlas of fungal Infections, Richard Diamond Ed. 1999 Introduction to Medical Mycology. Merck and Co. 2001

  42. mannoproteins b1,3 b1,6 glucans Cell membrane b1,3 glucan synthase chitin ergosterol The Fungal Cell Wall Atlas of fungal Infections, Richard Diamond Ed. 1999 Introduction to Medical Mycology. Merck and Co. 2001

  43. Cyclic lipopeptide antibiotics that interfere with fungal cell wall synthesis by inhibition of ß-(1,3) D-glucan synthase Loss of cell wall glucan results in osmotic fragility Spectrum: Candida species including non-albicans isolates resistant to fluconazole Aspergillus spp. but not activity against other moulds (Fusarium, Zygomycosis) No coverage of Cryptococcus neoformans HO OH H H O H NH HO H NH H O N H NH HO O H H C O H 3 H H CH O OH NH 3 N O OH HO H NH N H 2 H H H H O OH OH Echinocandins - Pharmacology

  44. Highly active Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei Candida kefyr Pneumocystis cariniiLow MIC ,with fungicidal activity and good in-vivo activity. Echinocandins - spectrum Very activeCandida parapsilosisCandida gulliermondiiAspergillus fumigatusAspergillus flavusAspergillus terreusCandida lusitaniaeLow MIC, but without fungicidal activity in most instances. Some activityCoccidioides immitisBlastomyces dermatididisScedosporium speciesPaecilomyces variotiiHistoplasma capsulatumDetectable activity, which might have therapeutic potential for man (in some cases in combination with other drugs).

  45. Echinocandins act at the apical tips of Aspergillus hyphae DiBAC Bowman et al. Antimicrob Agent Chemother 2002;46:3001-12

  46. Active against Aspergillus species Glucan synthase localized in apical tips Activity against other yeast and moulds is less well described or variable Mycelial forms of endemic mycoses? Staining with antisera to glucan synthase subunit (Fks1p) Echinocandins-Spectrum vs. Moulds Aniline blue staining of β (1-3) glucans –stains only at apex Beauvais et al. J. Bacteriol 2001;183:2273-79

  47. Caspofungin - Pharmacokinetics

  48. Caspofungin acetate • IV only Indication: • Invasive candidiasis • Invasive aspergillosis refractory to other therapies Dosage and administration • 70 mg day 1, followed by 50 mg daily • Increase to 70 mg per day in non-responders • Decrease to 35 mg per day in moderate-severe hepatic dysfunction (Child-Pugh 7-9) Antiviral Drug Products Advisory Committee, January 10, 2001- www.FDA.gov

  49. Caspofungin - Adverse effects • Most common AEs are infusion related: • Intravenous site irritation (15-20%) • Mild to moderate infusion-related AE including fever, headache, flushing, erythema, rash (5-20%) • Symptoms consistent with histamine release (2%) • Most AEs were mild and did not require treatment discontinuation • Most common laboratory AE • Asymptomatic elevation of serum transaminases (10-15%) • Clinical experience to date suggests that these drugs are extremely well-tolerated Antiviral Drug Products Advisory Committee, January 10, 2001- www.FDA.gov

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