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Chapter 91
Antifungal Agents
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Systemic Mycoses
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Treatment can be difficult.
Infections often resist treatment.
Treatment may require prolonged therapy
with drugs that frequently prove toxic.
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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.
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Antifungal Agents
1. Systemic mycoses infections
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Opportunistic
• Immunocompromised host
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Candidiasis, aspergillosis, cryptococcosis, mucormycosis
Nonopportunistic
• Can occur in any host
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Sporotrichosis, blastomycosis, histoplasmosis,
coccidioidomycosis
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Antifungal Agents
2. Superficial mycoses infections
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Candidiasis
Dermatophytes
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Four Classes of Antifungal Drugs
1.
2.
3.
4.
Polyene antibiotics
Azoles
Echinocandins
Pyrimidine analogs
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Amphotericin B
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Broad-spectrum antifungal agent (also used
against some protozoa)
Highly toxic
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Infusion reaction and renal damage occur in all
patients to varying degrees
Must be given IV – no oral administration
Uses
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Drug of choice for most systemic mycoses
Before ampho B, systemic fungal infections were
usually fatal
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Amphotericin B
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Mechanism of action
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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
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Amphotericin B
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Adverse effects
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Infusion reactions
Nephrotoxicity
Hypokalemia
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Amphotericin B
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Infusion reaction
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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
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Amphotericin B
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Infusion reaction (cont’d)
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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.
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Amphotericin B
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Nephrotoxicity
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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
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Amphotericin B
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Nephrotoxicity (cont’d)
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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
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Amphotericin B
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Hypokalemia
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Results from damage to the kidneys
May need potassium supplements
Monitor serum levels
Hematologic effects
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Can cause bone marrow suppression
• Anemia – monitor hematocrit
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Azoles
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Broad-spectrum antifungal drugs
5/14 – can be an alternative to ampho B for
most systemic mycoses
Lower toxicity
Can be given orally
Disadvantage
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Inhibit P450 drug-metabolizing enzymes and can
increase the levels of many other drugs
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Itraconazole (Sporanox)
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Azole group of antifungal agents
Lower toxicity level
Uses
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Systemic mycoses (alternative to ampho B)
Mechanisms of action
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Inhibits the synthesis of ergosterol
Inhibits fungal cytochrome P450-dependent
enzymes
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Itraconazole (Sporanox)
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Side effects (well tolerated in usual doses)
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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
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Fluconazole (Diflucan)
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Azole group of antifungal agents
Fungistatic
Same mechanism of action as itraconazole
Oral absorption good
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IV and oral dosage the same
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Fluconazole (Diflucan)
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Adverse effects
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Nausea
Headache
Vomiting
Abdominal pain
Diarrhea
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Voriconazole (Vfend)
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Azole group of antifungal agents
Broad spectrum of fungal pathogens
Uses
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Candidemia
Invasive aspergillosis
Esophageal candidiasis
Scedosporium apiospermum–resistant infections
Mechanism of action
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Suppresses synthesis of ergosterol
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Voriconazole (Vfend)
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Adverse effects
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Hepatotoxicity
Visual disturbances, hallucinations
Fetal injury
Hypersensitivity reactions
Nausea, vomiting, and abdominal pain
Headache
Drug interactions
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Ketoconazole (formerly Nizoral)
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Azole group of antifungal agents
Mechanism of action
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Inhibits ergosterol
Uses: Alternative to ampho B for systemic
mycoses
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Less toxic and only somewhat less effective
Slower effects
More useful in suppressing chronic infections than
in treating severe, acute infections
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Ketoconazole (formerly Nizoral)
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Adverse effects (generally well tolerated)
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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
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Flucytosine (Ancobon)
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Pyrimidine analog
Uses
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Resistance common
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Serious infections of susceptible strains of
Candida and Cryptococcus neoformans
Often used with ampho B
Extreme caution in patient with renal
impairment or hematologic disorders
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Flucytosine (Ancobon)
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Adverse effects
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Hematologic
• Bone marrow suppression
Hepatotoxicity
• Inhibits hepatic drug-metabolizing enzymes
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Drugs for Superficial Mycoses
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Mycoses caused by two groups of organisms
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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
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Drugs for Superficial Mycoses
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Oral candidiasis (thrush)
Vulvovaginal candidiasis
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75% of women experience at least once
Risk factors
• Pregnancy, obesity, diabetes, debilitation, HIV, oral
contraceptives, systemic glucocorticoids, anticancer
agents, and systemic antibiotics
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Onychomycosis
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Drugs for Superficial Mycoses
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Dermatophytic infections (eg, ringworm)
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Tinea pedis (feet)
Tinea corporis (body)
Tinea cruris (groin)
Tinea capitis (scalp)
Drugs
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Clotrimazole – topical
Griseofulvin – oral
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Griseofulvin (Grifulvin)
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Uses
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Superficial mycoses
Ineffective systemic mycoses
Inhibits fungal mitosis
Adverse effects
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Transient headache
Rash
Gastrointestinal
Insomnia
Tiredness
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Nystatin (Mycostatin)
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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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