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Chapter 91 Antifungal Agents 1.

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Presentation on theme: "Chapter 91 Antifungal Agents 1."— Presentation transcript:

1 Chapter 91 Antifungal Agents 1

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

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

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

5 Antifungal Agents 2. Superficial mycoses infections Candidiasis
Dermatophytes 5

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

7 7

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 8

9 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

10 Amphotericin B Adverse effects Infusion reactions Nephrotoxicity
Hypokalemia 10

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 11

12 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

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 13

14 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

15 Amphotericin B Hypokalemia Hematologic effects
Results from damage to the kidneys May need potassium supplements Monitor serum levels Hematologic effects Can cause bone marrow suppression Anemia – monitor hematocrit 15

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 16

17 17

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 18

19 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 19

20 Fluconazole (Diflucan)
Azole group of antifungal agents Fungistatic Same mechanism of action as itraconazole Oral absorption good IV and oral dosage the same 20

21 Fluconazole (Diflucan)
Adverse effects Nausea Headache Vomiting Abdominal pain Diarrhea 21

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 22

23 Voriconazole (Vfend) Adverse effects Hepatotoxicity
Visual disturbances, hallucinations Fetal injury Hypersensitivity reactions Nausea, vomiting, and abdominal pain Headache Drug interactions 23

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 24

25 25

26 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 26

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 27

28 Flucytosine (Ancobon)
Adverse effects Hematologic Bone marrow suppression Hepatotoxicity Inhibits hepatic drug-metabolizing enzymes 28

29 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 29

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 Onychomycosis 30

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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 33

34 Griseofulvin (Grifulvin)
Uses Superficial mycoses Ineffective systemic mycoses Inhibits fungal mitosis Adverse effects Transient headache Rash Gastrointestinal Insomnia Tiredness 34

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 35

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