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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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1.
Drugs for systemic mycoses infections
2.
Drugs for superficial mycoses infections
Note: A few drugs are used for both.
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1.
Systemic mycoses infections
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Opportunistic
•
Immunocompromised host
 Candidiasis, aspergillosis, cryptococcosis, mucormycosis
Nonopportunistic
•
Can occur in any host
 Sporotrichosis, blastomycosis, histoplasmosis, coccidioidomycosis
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2.
Superficial mycoses infections
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Candidiasis
Dermatophytes
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1.
Polyene antibiotics
2.
Azoles
3.
Echinocandins
4.
Pyrimidine analogs
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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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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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Adverse effects
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Infusion reactions
Nephrotoxicity
 Hypokalemia
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Infusion reaction
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Fever, chills, rigors, nausea, and headache
Caused by release of proinflammatory cytokines
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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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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.
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Nephrotoxicity
 Extent of kidney damage related to total dose administered over the full course of treatment
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If total dose >4 g, residual impairment likely
Damage minimized by infusing 1 L of saline on days of treatment
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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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Hypokalemia
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Results from damage to the kidneys
May need potassium supplements
 Monitor serum levels
Hematologic effects
 Can cause bone marrow suppression
•
Anemia – monitor hematocrit
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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
 Inhibit P450 drug-metabolizing enzymes and can increase the levels of many other drugs
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Azole group of antifungal agents
Lower toxicity level
Uses
 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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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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Azole group of antifungal agents
Fungistatic
Same mechanism of action as itraconazole
Oral absorption good
 IV and oral dosage the same
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Adverse effects
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Nausea
Headache
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Vomiting
Abdominal pain
Diarrhea
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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
 Suppresses synthesis of ergosterol
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Adverse effects
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Hepatotoxicity
Visual disturbances, hallucinations
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Fetal injury
Hypersensitivity reactions
Nausea, vomiting, and abdominal pain
Headache
Drug interactions
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Azole group of antifungal agents
Mechanism of action
 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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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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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
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Adverse effects
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Hematologic
•
Bone marrow suppression
Hepatotoxicity
•
Inhibits hepatic drug-metabolizing enzymes
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Mycoses caused by two groups of organisms
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Candida species
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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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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
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Dermatophytic infections (eg, ringworm)
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Tinea pedis (feet)
Tinea corporis (body)
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Tinea cruris (groin)
Tinea capitis (scalp)
Drugs
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Clotrimazole – topical
Griseofulvin – oral
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Uses
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Superficial mycoses
Ineffective systemic mycoses
Inhibits fungal mitosis
Adverse effects
 Transient headache
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Rash
Gastrointestinal
Insomnia
Tiredness
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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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