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Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Chapter 91 Antifungal Agents.

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Presentation on theme: "Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Chapter 91 Antifungal Agents."— Presentation transcript:

1 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Chapter 91 Antifungal Agents

2 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.2 Systemic Mycoses  Treatment can be difficult.  Infections often resist treatment.  Treatment may require prolonged therapy with drugs that frequently prove toxic.

3 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.3 Major Groups of Antifungal Agents 1.Drugs for systemic mycoses infections 2.Drugs for superficial mycoses infections Note: A few drugs are used for both.

4 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.4 Antifungal Agents 1.Systemic mycoses infections  Opportunistic Immunocompromised host Immunocompromised host  Candidiasis, aspergillosis, cryptococcosis, mucormycosis  Nonopportunistic Can occur in any host Can occur in any host  Sporotrichosis, blastomycosis, histoplasmosis, coccidioidomycosis

5 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.5 Antifungal Agents 2. Superficial mycoses infections  Candidiasis  Dermatophytes

6 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.6 Four Classes of Antifungal Drugs 1.Polyene antibiotics 2.Azoles 3.Echinocandins 4.Pyrimidine analogs

7 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.7

8 8 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

9 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.9 Amphotericin B  Mechanism of action  Binds to ergosterol (much more than cholesterol) in fungal cell membrane Bacterial cell membranes lack sterols Bacterial cell membranes lack sterols Fungi damaged more than human cells Fungi damaged more than human cells  Increases the permeability  Cell leaks intracellular cations (especially potassium)  Fungistatic or fungicidal

10 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.10 Amphotericin B  Adverse effects  Infusion reactions  Nephrotoxicity  Hypokalemia

11 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.11 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

12 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.12 Amphotericin B  Infusion reaction (cont’d)  Mild reactions – pretreatment options Diphenhydramine plus acetaminophen Diphenhydramine plus acetaminophen Aspirin can help – may increase renal damage Aspirin can help – may increase renal damage  IV meperidine or dantrolene can be given if rigors occur.  Hydrocortisone can be given with caution.

13 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.13 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

14 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.14 Amphotericin B  Nephrotoxicity (cont’d)  Avoid other nephrotoxic drugs concurrently. Aminoglycosides, cyclosporins Aminoglycosides, cyclosporins  NSAIDs should also be avoided.  Monitor serum creatinine q 3-4 days. Reduce dosage if >3.5 mg/dL Reduce dosage if >3.5 mg/dL

15 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.15 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 Anemia – monitor hematocrit

16 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.16 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

17 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.17

18 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.18 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

19 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.19 Itraconazole (Sporanox)  Side effects (well tolerated in usual doses)  Cardiosuppression Transient decrease in ventricular ejection fraction Transient decrease in ventricular ejection fraction  Liver damage Watch for signs of liver dysfunction Watch for signs of liver dysfunction  Can inhibit drug metabolizing enzymes  GI effects Nausea, vomiting, diarrhea Nausea, vomiting, diarrhea

20 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.20 Fluconazole (Diflucan)  Azole group of antifungal agents  Fungistatic  Same mechanism of action as itraconazole  Oral absorption good  IV and oral dosage the same

21 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.21 Fluconazole (Diflucan)  Adverse effects  Nausea  Headache  Vomiting  Abdominal pain  Diarrhea

22 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.22 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

23 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.23 Voriconazole (Vfend)  Adverse effects  Hepatotoxicity  Visual disturbances, hallucinations  Fetal injury  Hypersensitivity reactions  Nausea, vomiting, and abdominal pain  Headache  Drug interactions

24 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.24 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

25 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.25

26 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.26 Ketoconazole (formerly Nizoral)  Adverse effects (generally well tolerated)  GI (can be reduced if given with food)  Hepatotoxicity Rare but potentially fatal hepatic necrosis Rare but potentially fatal hepatic necrosis  Effect on sex hormones Can inhibit steroid synthesis in humans Can inhibit steroid synthesis in humans  Other adverse effects Rash, itching, dizziness, fever, chills, constipation, diarrhea, photophobia, and headache Rash, itching, dizziness, fever, chills, constipation, diarrhea, photophobia, and headache

27 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.27 Flucytosine (Ancobon)  Pyrimidine analog  Uses  Serious infections of susceptible strains of Candida and Cryptococcus neoformans  Resistance common  Often used with ampho B  Extreme caution in patient with renal impairment or hematologic disorders

28 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.28 Flucytosine (Ancobon)  Adverse effects  Hematologic Bone marrow suppression Bone marrow suppression  Hepatotoxicity Inhibits hepatic drug-metabolizing enzymes Inhibits hepatic drug-metabolizing enzymes

29 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.29 Drugs for Superficial Mycoses  Mycoses caused by two groups of organisms  Candida species Usually in mucous membranes and moist skin Usually in mucous membranes and moist skin Chronic infections may involve scalp, skin, and nails Chronic infections may involve scalp, skin, and nails  Dermatophytic infections (eg, ringworm) Usually confined to skin, hair, and nails Usually confined to skin, hair, and nails More common than Candida infections in nails More common than Candida infections in nails

30 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.30 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 Pregnancy, obesity, diabetes, debilitation, HIV, oral contraceptives, systemic glucocorticoids, anticancer agents, and systemic antibiotics  Onychomycosis

31 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.31

32 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.32

33 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.33 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

34 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.34 Griseofulvin (Grifulvin)  Uses  Superficial mycoses  Ineffective systemic mycoses  Inhibits fungal mitosis  Adverse effects  Transient headache  Rash  Gastrointestinal  Insomnia  Tiredness

35 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.35 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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