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

31. 31

32. 32

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