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Chapter 91

Chapter 91. Antifungal Agents. Systemic Mycoses. Treatment can be difficult. Infections often resist treatment. Treatment may require prolonged therapy with drugs that frequently prove toxic. Major Groups of Antifungal Agents. Drugs for systemic mycoses infections

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Chapter 91

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  1. Chapter 91 Antifungal Agents

  2. Systemic Mycoses • Treatment can be difficult. • Infections often resist treatment. • Treatment may require prolonged therapy with drugs that frequently prove toxic.

  3. Major Groups of Antifungal Agents • Drugs for systemic mycoses infections • Drugs for superficial mycoses infections Note: A few drugs are used for both.

  4. Antifungal Agents • Systemic mycoses infections • Opportunistic • Immunocompromised host • Candidiasis, aspergillosis, cryptococcosis, mucormycosis • Nonopportunistic • Can occur in any host • Sporotrichosis, blastomycosis, histoplasmosis, coccidioidomycosis

  5. Antifungal Agents 2. Superficial mycoses infections • Candidiasis • Dermatophytes

  6. Four Classes of Antifungal Drugs • Polyene antibiotics • Azoles • Echinocandins • Pyrimidine analogs

  7. Amphotericin B • Broad-spectrum antifungal agent (also used against some protozoa) • Highly toxic • Infusion reaction and renal damage occur in all patients to varying degrees • Must be given IV – no oral administration • Uses • Drug of choice for most systemic mycoses • Before ampho B, systemic fungal infections were usually fatal

  8. Amphotericin B • Mechanism of action • Binds to ergosterol (much more than cholesterol) in fungal cell membrane • Bacterial cell membranes lack sterols • Fungi damaged more than human cells • Increases the permeability • Cell leaks intracellular cations (especially potassium) • Fungistatic or fungicidal

  9. Amphotericin B • Adverse effects • Infusion reactions • Nephrotoxicity • Hypokalemia

  10. Amphotericin B • Infusion reaction • Fever, chills, rigors, nausea, and headache • Caused by release of proinflammatory cytokines • Symptoms begin 1-3 hours after starting infusion and last for about 1 hour • Less intense with lipid-based ampho B formulations

  11. Amphotericin B • Infusion reaction (cont’d) • Mild reactions – pretreatment options • Diphenhydramine plus acetaminophen • Aspirin can help – may increase renal damage • IV meperidine or dantrolene can be given if rigors occur. • Hydrocortisone can be given with caution.

  12. Amphotericin B • Nephrotoxicity • Extent of kidney damage related to total dose administered over the full course of treatment • If total dose >4 g, residual impairment likely • Damage minimized by infusing 1 L of saline on days of treatment

  13. Amphotericin B • Nephrotoxicity (cont’d) • Avoid other nephrotoxic drugs concurrently. • Aminoglycosides, cyclosporins • NSAIDs should also be avoided. • Monitor serum creatinine q 3-4 days. • Reduce dosage if >3.5 mg/dL

  14. Amphotericin B • Hypokalemia • Results from damage to the kidneys • May need potassium supplements • Monitor serum levels • Hematologic effects • Can cause bone marrow suppression • Anemia – monitor hematocrit

  15. Azoles • Broad-spectrum antifungal drugs • 5/14 – can be an alternative to ampho B for most systemic mycoses • Lower toxicity • Can be given orally • Disadvantage • Inhibit P450 drug-metabolizing enzymes and can increase the levels of many other drugs

  16. Itraconazole (Sporanox) • Azole group of antifungal agents • Lower toxicity level • Uses • Systemic mycoses (alternative to ampho B) • Mechanisms of action • Inhibits the synthesis of ergosterol • Inhibits fungal cytochrome P450-dependent enzymes

  17. Itraconazole (Sporanox) • Side effects (well tolerated in usual doses) • Cardiosuppression • Transient decrease in ventricular ejection fraction • Liver damage • Watch for signs of liver dysfunction • Can inhibit drug metabolizing enzymes • GI effects • Nausea, vomiting, diarrhea

  18. Fluconazole (Diflucan) • Azole group of antifungal agents • Fungistatic • Same mechanism of action as itraconazole • Oral absorption good • IV and oral dosage the same

  19. Fluconazole (Diflucan) • Adverse effects • Nausea • Headache • Vomiting • Abdominal pain • Diarrhea

  20. Voriconazole (Vfend) • Azole group of antifungal agents • Broad spectrum of fungal pathogens • Uses • Candidemia • Invasive aspergillosis • Esophageal candidiasis • Scedosporium apiospermum–resistant infections • Mechanism of action • Suppresses synthesis of ergosterol

  21. Voriconazole (Vfend) • Adverse effects • Hepatotoxicity • Visual disturbances, hallucinations • Fetal injury • Hypersensitivity reactions • Nausea, vomiting, and abdominal pain • Headache • Drug interactions

  22. Ketoconazole (formerly Nizoral) • Azole group of antifungal agents • Mechanism of action • Inhibits ergosterol • Uses: Alternative to ampho B for systemic mycoses • Less toxic and only somewhat less effective • Slower effects • More useful in suppressing chronic infections than in treating severe, acute infections

  23. Ketoconazole (formerly Nizoral) • Adverse effects (generally well tolerated) • GI (can be reduced if given with food) • Hepatotoxicity • Rare but potentially fatal hepatic necrosis • Effect on sex hormones • Can inhibit steroid synthesis in humans • Other adverse effects • Rash, itching, dizziness, fever, chills, constipation, diarrhea, photophobia, and headache

  24. Flucytosine (Ancobon) • Pyrimidine analog • Uses • Serious infections of susceptible strains of Candida and Cryptococcusneoformans • Resistance common • Often used with ampho B • Extreme caution in patient with renal impairment or hematologic disorders

  25. Flucytosine (Ancobon) • Adverse effects • Hematologic • Bone marrow suppression • Hepatotoxicity • Inhibits hepatic drug-metabolizing enzymes

  26. Drugs for Superficial Mycoses • Mycoses caused by two groups of organisms • Candida species • Usually in mucous membranes and moist skin • Chronic infections may involve scalp, skin, and nails • Dermatophytic infections (eg, ringworm) • Usually confined to skin, hair, and nails • More common than Candida infections in nails

  27. Drugs for Superficial Mycoses • Oral candidiasis (thrush) • Vulvovaginal candidiasis • 75% of women experience at least once • Risk factors • Pregnancy, obesity, diabetes, debilitation, HIV, oral contraceptives, systemic glucocorticoids, anticancer agents, and systemic antibiotics • Onychomycosis

  28. Drugs for Superficial Mycoses • Dermatophytic infections (eg, ringworm) • Tinea pedis (feet) • Tinea corporis (body) • Tinea cruris (groin) • Tinea capitis (scalp) • Drugs • Clotrimazole – topical • Griseofulvin – oral

  29. Griseofulvin (Grifulvin) • Uses • Superficial mycoses • Ineffective systemic mycoses • Inhibits fungal mitosis • Adverse effects • Transient headache • Rash • Gastrointestinal • Insomnia • Tiredness

  30. Nystatin (Mycostatin) • Polyene antibiotic • Used only for candidiasis • Drug of choice for intestinal candidiasis • Also used for candidal infections in skin, mouth, esophagus, and vagina • Can be administered orally or topically

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