Antifungal Treatment

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Antifungal Treatment

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Antifungal Treatment

  1. 1. Antifungal Treatment
  2. 2. Fungi for generalists <ul><li>Superficial (skin, nails, oral, vaginal) </li></ul><ul><ul><li>Very common in otherwise healthy people </li></ul></ul><ul><ul><li>Frequent episodes suggest interference with immune defenses as in diabetes, antibiotic Rx </li></ul></ul><ul><li>Systemic </li></ul><ul><ul><li>rare except in severely immune- compromised </li></ul></ul>
  3. 3. Antifungals Lamisil Terbinafine Allylamine Triazoles Imidazoles SUBCLASS Griseofulvin Fluconazole Itraconazole Ketoconazole GENERIC Grisactin Fulvicin Gris-PEG Griseofulvin Diflucan Sporanox Nizoral Azoles TRADE CLASS
  4. 4. General Indications <ul><li>Ketaconazole </li></ul><ul><ul><li>Systemic fungal infections (candidiasis, blastomycosis, coccidioidomycosis, histoplasmosis) </li></ul></ul><ul><ul><li>Severe recalcitrant dermatophyte infections unresponsive to topical </li></ul></ul><ul><li>Fluconazole </li></ul><ul><ul><li>Candidiasis, including vaginal </li></ul></ul><ul><ul><li>Cryptococcal meningitis </li></ul></ul><ul><li>Itraconazole </li></ul><ul><ul><li>Blastomycosis, histoplasmosis, apergillosis </li></ul></ul><ul><ul><li>Onychomycosis </li></ul></ul><ul><li>Terbinafine </li></ul><ul><ul><li>Onychomycosis </li></ul></ul><ul><li>Griseofulvin </li></ul><ul><ul><li>Tinea infections of skin, hair, nails unresponsive to topical </li></ul></ul><ul><ul><li>NOT candidiasis, blastomycosis, coccidioidomycosis, histoplasmosis </li></ul></ul>
  5. 5. Azoles: Patient Variables <ul><li>Geriatrics </li></ul><ul><ul><li>More susceptible to hepatotoxicity </li></ul></ul><ul><ul><li>Require lower dosing in reduced renal function </li></ul></ul><ul><li>Pediatrics </li></ul><ul><ul><li>S&E NOT established </li></ul></ul><ul><li>Pregnancy </li></ul><ul><ul><li>Category C: Benefit > risk to fetus </li></ul></ul><ul><li>Lactation </li></ul><ul><ul><li>Excreted in breast milk. Do NOT use in nursing women. </li></ul></ul>
  6. 6. Azoles: Monitoring <ul><li>Assess LFTs prior to initiating Tx and periodically (baseline & Q2wk x 2 mo, then Q1-2 mo) </li></ul><ul><li>Assess for s/s of hepatitis </li></ul><ul><ul><li>Fatigue, anorexia, N/V, jaundice, dark urine, pale stools </li></ul></ul><ul><li>Assess for interference with steroidgenesis </li></ul><ul><ul><li>High-dose ketoconazole: adrenal suppression </li></ul></ul><ul><ul><li>High-dose itraconazole: hypokalemia & secondary V-fib </li></ul></ul><ul><li>Assess response to Tx with repeat cultures </li></ul>
  7. 7. Azoles: Patient Education <ul><li>Food enhances absorption of itraconazole, variably affects ketoconazole, no effect on fluconazole </li></ul><ul><li>Administer antacids, H2-blockers, proton pump inhibitors, or anticholinergics at least 2 hours after ketoconazole or itraconazole </li></ul><ul><li>Immediately report any s/s of hepatitis </li></ul><ul><ul><li>Fatigue, anorexia, N/V, jaundice, dark urine, pale stools </li></ul></ul><ul><li>Take as prescribed. Inadequate treatment  poor response or early recurrence of symptoms </li></ul><ul><li>Women of childbearing age: USE CONTRACEPTION OR ABSTINENCE </li></ul>
  8. 8. Ketoconazole <ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>Fungal meningitis (poor CNS penetration) </li></ul></ul><ul><ul><li>Use with Propulsid  serious cardiac arrhythmias </li></ul></ul><ul><li>Warnings / Precautions </li></ul><ul><ul><li>Hepatic toxicity: clinically significant / fatal hepatitis  D/C immediately if s/s, effects usually reversible may take weeks to months </li></ul></ul><ul><ul><li>Steroidgenesis: directly inhibit adrenal cortisol and testosterone synthesis  low sperm counts, decreased libido, impotence, gynecomastia, menstrual irregularities </li></ul></ul><ul><ul><li>Hypersensitivity & anaphylaxis </li></ul></ul><ul><ul><li>Weak bases require gastric acidity for dissolution/absorption  do NOT take with antacids, anticholinergics, or H2-blockers </li></ul></ul>
  9. 9. Ketoconazole: Pharmacokinetics <ul><li>Bioavailability varies depending on gastric pH </li></ul><ul><li>Ketoconazole absorption variable with food </li></ul><ul><li>Itraconazole 2-3 x greater bioavailability with food esp lipids </li></ul><ul><li>Hypochlohydria in AIDS  decreased bioavailability </li></ul>
  10. 10. Ketoconazole <ul><li>Adverse Effects </li></ul><ul><ul><li>Mild / transient – don’t require D/C </li></ul></ul><ul><ul><li>Most common: N/V </li></ul></ul><ul><li>Drug Interactions </li></ul><ul><ul><li>Least favorable toxicity profile </li></ul></ul><ul><ul><li>Inhibits P450 3A4, also inhibits 1A2, 2C, 3A4 </li></ul></ul><ul><ul><li>Propulsid  serious cardiac arrhythmias </li></ul></ul><ul><ul><li>Do NOT take with antacids, anticholinergics, or H2-blockers  decreases bioavailability </li></ul></ul>
  11. 11. Triazole <ul><li>Indications </li></ul><ul><ul><li>Oropharyngeal & esophogeal candidiasis </li></ul></ul><ul><ul><li>Single dose Tx of vulvovaginal candidiasis </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><li>Warnings / Precautions </li></ul><ul><ul><li>Hepatotoxicity </li></ul></ul><ul><ul><li>Allergic / Dermatologic reaction – anaphylaxis & exfoliative dermatitis (rare) </li></ul></ul><ul><ul><li>Dose reduction for renal dysfunction </li></ul></ul><ul><ul><li>Use care in use with elderly </li></ul></ul>
  12. 12. Triazoles: Pharmacokinetics <ul><li>Absorption & bioavailability NOT affected by food or gastric pH </li></ul><ul><li>Excreted renally with therapeutic concentrations achieved in urine </li></ul><ul><li>UNIQUE among azoles in that it crosses the blood-brain barrier & has good CSF penetration </li></ul>
  13. 13. Triazoles <ul><li>Pediatrics </li></ul><ul><ul><li>S&E NOT established </li></ul></ul><ul><li>Adverse Effects </li></ul><ul><ul><li>Most Common (single dose): headache, nausea, abdominal pain, diarrhea, dyspepsia, dizziness </li></ul></ul><ul><ul><li>Most Common (multidose): nausea, headache, skin rash, vomiting, abdominal pain, diarrhea </li></ul></ul><ul><ul><li>SERIOUS: seizures, exfoliative skin disorders, leukopenia, thrombocytopenia, serious hepatic reactions </li></ul></ul>
  14. 14. Triazoles <ul><li>Drug Interactions </li></ul><ul><ul><li>P450 2C and 3A4 inhibitor </li></ul></ul><ul><ul><li>Decreases blood levels of OCPs </li></ul></ul><ul><li>Overdose </li></ul><ul><ul><li>Gastric lavage & hemodialysis </li></ul></ul>
  15. 15. Itraconazole (Sporonox) <ul><li>Indications </li></ul><ul><ul><li>Wide spectrum of antifungal activity </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Coadministration with propulsid & halcion </li></ul></ul><ul><ul><li>Use with caution in patients with hypersensitivity to to other azoles </li></ul></ul><ul><li>Warnings / Precautions </li></ul><ul><ul><li>Obtain culture prior to Tx </li></ul></ul><ul><ul><li>Hepatitis – monitor hepatic enzymes </li></ul></ul><ul><ul><li>HIV – decreased absorption of drug </li></ul></ul><ul><ul><li>Absorption decreased with decreased gastric acidity </li></ul></ul>
  16. 16. Itraconazole (Sporonox) <ul><li>Pharmacokinetics </li></ul><ul><ul><li>Reduced absorption with decreased stomach acidity </li></ul></ul><ul><ul><li>Therapeutic concentrations may persist in fingernails & toenails for up to 6 mo after D/C </li></ul></ul><ul><li>Adverse Effects </li></ul><ul><ul><li>Greater specificity for P450 3A4 enzyme system </li></ul></ul><ul><li>Overdose </li></ul><ul><ul><li>NOT removed by dialysis </li></ul></ul><ul><ul><li>Gastric lavage & sodium bicarbonate </li></ul></ul>
  17. 17. Terbinafine <ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><li>Warnings </li></ul><ul><ul><li>Hepatic failure: worse in Hx of liver disease Assess liver function BEFORE prescribing </li></ul></ul><ul><ul><li>Ophthalmic: changes in ocular lens & retina </li></ul></ul><ul><ul><li>Neutropenia: reversible if D/C’d </li></ul></ul><ul><ul><li>Dermatologic: SJS, toxic epidermal necrolysis </li></ul></ul><ul><ul><li>Renal: do not use with significant renal impairment </li></ul></ul>
  18. 18. Griseofulvin <ul><li>Indications </li></ul><ul><ul><li>Tinea infections of skin, hair, nails </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity (5-7%) </li></ul></ul><ul><ul><li>Hepatocellular failure </li></ul></ul><ul><ul><li>Porphyria </li></ul></ul>
  19. 19. Griseofulvin: Warnings/Precautions <ul><li>Hypersensitivity (5-7%) </li></ul><ul><ul><li>Skin rash, urticaria, angioneurotic edema  D/C </li></ul></ul><ul><li>Prophylaxis </li></ul><ul><ul><li>S&E NOT established </li></ul></ul><ul><li>Prolonged therapy </li></ul><ul><ul><li>Monitor renal, hepatic, hematopietic function periodically </li></ul></ul><ul><li>PCN cross sensitivity </li></ul><ul><ul><li>Derived from PCN </li></ul></ul><ul><li>Lupus erythematosus </li></ul><ul><ul><li>Exacerbation or lupuslike syndromes </li></ul></ul><ul><li>Photosensitivity </li></ul><ul><ul><li>Use sunblock & protective clothing </li></ul></ul>
  20. 20. Griseofulvin <ul><li>Pharmacokinetics </li></ul><ul><ul><li>Better absorption when taken with meals high in fat content </li></ul></ul><ul><ul><li>Variable GI absorption </li></ul></ul><ul><ul><li>Peak: 4 hrs </li></ul></ul><ul><li>Pediatrics </li></ul><ul><ul><li>May produce estrogen-like effects in children: enlarged breasts, hyperpigmentation of areola, nipple & external genitalia </li></ul></ul><ul><li>Pregnancy </li></ul><ul><ul><li>Category C: embryotoxic & teratogenic </li></ul></ul><ul><li>Monitor </li></ul><ul><ul><li>Baseline & periodic: renal, liver, hematopoietic function </li></ul></ul>
  21. 21. Griseofulvin <ul><li>Adverse Effects </li></ul><ul><ul><li>Common: hypersensitivity – skin rashes, urticaria, angioneurotic edema (rare) </li></ul></ul><ul><ul><li>Oral thrush, N/V, epigastric distress, diarrhea, headache, fatigue, dizziness, insomnia, mental confusion, impairment of performance of routine acitivities </li></ul></ul><ul><ul><li>High dose or prolonged Tx: interference with porphyrin metabolism, proteinuria, leukopenia, hepatic toxicity, GI bleed, menstrual irregularities, paresthesias of hands and feet, granulocytopenia </li></ul></ul><ul><li>Drug Interactions </li></ul><ul><ul><li>NOT metabolized by P450 </li></ul></ul><ul><ul><li>Decreases activity of OCPs & anticoagulants </li></ul></ul>
  22. 22. Griseofulvin: Pt Education <ul><li>Bioavailability improves when given with food </li></ul><ul><li>Headaches disappear with continued Tx or taken with food </li></ul><ul><li>Continue for entire course of Tx – effects not immediately noticeable </li></ul><ul><li>Photosensitivity – avoid prolonged exposure to sunlight or sunlamps; use sun block and protective clothing </li></ul><ul><li>Notify provider of rash or sore throat </li></ul><ul><li>May potentiate effects of alcohol </li></ul>
  23. 23. Fungi Morphology <ul><li>Yeast </li></ul><ul><ul><li>Unicellular fungi </li></ul></ul><ul><ul><li>Typically round or oval </li></ul></ul><ul><ul><li>Reproduce by budding </li></ul></ul><ul><ul><li>May form pseudohyphae (long chains) </li></ul></ul><ul><li>Molds </li></ul><ul><ul><li>Multicellular colonies composed of tubular structures (hyphae) </li></ul></ul><ul><ul><li>Grow by branching & longitudinal extension </li></ul></ul><ul><li>Dimorphism </li></ul><ul><ul><li>Fungi may be yeast or mold depending on env conditions </li></ul></ul>
  24. 24. Mycosis <ul><li>Presence of parasitic fungi in or on the body </li></ul><ul><li>Most pathogenic fungi are yeast, are nonmotile, and are nontransmissible </li></ul><ul><li>May be superficial, subcutaneous, or deeply invasive </li></ul><ul><li>Fungi are eukaryocytes like mammalian cells </li></ul><ul><ul><li>Key difference b/w is the sterol used to make the cell membrane </li></ul></ul><ul><ul><li>Fungi: ergosterol VS. Mammals: cholesterol </li></ul></ul><ul><li>Mechanism of action = interaction with / inhibition of ergosterol synthesis </li></ul>
  25. 25. Mechanisms of Action <ul><li>Azoles </li></ul><ul><ul><li>Fungistatic (vs. fungicidal) </li></ul></ul><ul><ul><li>Inhibition of ergosterol synthesis  cell membranes becomes more permeable & leak cell contents  inhibits cell growth & replication </li></ul></ul><ul><li>Griseofulvin </li></ul><ul><ul><li>Deposited in keratin of diseased tissue making it resistant to fungal infection </li></ul></ul><ul><ul><li>Diseased tissue gradually exfoliated & replaced with healthy tissue </li></ul></ul>

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