1. opportunistic mycoses (immunocompromised patients); aspergillus, candida, cryptococcus, phycomycetes

2. Endemic mycoses; blastomycosis, histoplasmosis, coccidiodomycosis, sporotrichosis  (These are the things that are in certain parts of the world and affect certain regions).

Polyene antimycotics

1. Characteristics

2. Method of action

1. lipophilic, chemical structure resembling polyunsaturated fatty acids

2. the drugs affiliate with ergosterol-rich membranes, where they exert a detergent-like action (remove ergosterol from membrane) that causes loss of membrane integrity, leakage of cell contents, and killing of the fungal cells.

Nystatin

1. Type

2. Uses

3. Other Notable characteristics

4. Dosage forms

1. Polyene

2. Topical fungal infections, especially for Candida albicans.

3. Dry powder storage, no resistance, IV is too toxic (Never give as an IV!!!), Oral administration = most of drug excreted unchanged in feces

4. suspension or lozenges are common. also as an ointment, cream, vaginal tablets, oral tablets.  Nystatin, Swish and Swallow...

Amphotericin B (amphoterrible)

1. Type of antifungal

2. Uses

3. Method of administration

4. Toxicity

5. Dosage forms available

6. Other notable characteristics

1. Polyene "drug of choice"

2. systemic fungal infections (progressive, potentially life-threatening fungal infections)

3. IV injection

4. hypotension, fever and delirium, nausea and vomiting, anemias, allergic reactions, and ALL patients have some degree of renal damage (AMPHOTERRIBLE)

5. ointment, cream, lotion, oral suspension, IV use (unlike Nystatin)

6. fungistatic or fungicidal, resistance is rare, no absorbed from skin or mucous membranes, nephrotoxicity may be reduced by sodium loading with normal saline, safe for use in pregnant women suffering from life threatening fungal infections.

Azoles

1. Method of action

2. fungicidal or fungistatic

3. Toxicity

4. Uses

5. Administration

1. azole drugs inhibit ergosterol biosynthesis by inhibiting the fungal enzyme lanosterol 14-alpha-demethylase. therefore, fungal membranes are not functional

2. fungicidal

3. liver damage. The drug inhibits the fungal form of cytochrome P450 and it can also inhibit some human P450 enzymes. Therefore, they can interact with drugs the patient is taking.

4. Systemic fungal infections, oral candidiasis, fungal infections of skin and nails

5. Topical: Miconazole and Clotrimazole

Oral/IV (mostly Ora)l: fluconazole, ketoconazole, itraconazole, vorioconazole, posaconazole

Clotrimazole

1. Type

2. Uses

1. azole antifungal (ergosterol biosynthesis inhibitor)

2. topical only; and troche for oral candidiasis. This is one of the older drugs.  This is too toxic for systemic use.

Fluconazole

1. Type

2. Uses

3. Toxicity

4. Other notable characteristics

5. Drug interactions

1. Azole antifungal

2. Orally effective for a variety of systemic fungal infections; preferred drug for oropharyngeal and esophageal candidiasis; highest activity against cryptococcus (meningitis) esp. in AIDS patients; mucosal candidiasis; prophylaxis against mucosal candidiasis (HIV patients)

4. not active against most molds; well absorbed orally but also available for IV use; long half life; excreted unchanged by kidneys.  Lowest incidence of adverse effects.

5. inhibitor of CYP3A4 = increased concentrations of cyclosporine, tacrolimus, simvastatin, and lovastatin; strong inhibitor of CYP2C9 = increased serum concentrations of phenytoin, zidovudine, warfarin

Itraconazole

1. Type

2. Uses

3. Spectrum of activity

4. Toxicity

5. Drug interactions

6. Other notable characteristics

1. Azole antifungal

2. active against wide variety of fungi = cryptococcus neoformans, aspergillus, blastocymes dermatitidis, coccidioides, histoplasma capsulatum, paracoccidioides brasiliensis, pseudoallescheria boydii, sporothrix.  broader spectrum than fluconazole.

3. active against wide variety of fungi

4. nausea, rash, hepatic toxicity, not for heart failure or ventricular dysfunction, pregnancy category C

5. inhibitor of CYP3A4 = increased serum concentrations of drugs metabolized by this enzyme, increased serum concentrations of digoxin and some HIV protease inhibitors; may decrease contraceptive effect of oral contraceptives.  contraindicated for patients taking cisapride, dofetilide, ergot alkyloids, lovastatin, simvastatin

Voriconazole

1. Type

2. Uses

3. Toxicity

4. Method of administration

5. Drug interactions

1. Azole antifungal

2. similar to intraconazole; aspergillus, candida, C. krusei, C glabrata; fusarium (not itraconazole); not active against zygomycetes; invasive aspergillosis and esophageal candidiasis

3. visual disturbances, rash, photosensitivity, hallucinations; mild to moderate hepatic insufficiency = normal loading dose but half of maintenance dose

4. orally to renally-impaired patients but IV to others.

5. contraindicated in patients on rifamycins, barbiturates, carbamazepine, and others; can cause torsades de pointes and/or increase the risk of QT prolongation; contraindicated in preg (cat. D); patients on warfarin, sulfonylureas, statins, benzodiazepines, HIV protease inhibitors

Ketoconazole

1. Type

2. Uses

3. Toxicity

4. Drug interactions

1. Azole antifungal (inhibitor of ergosterol synthesis)

2. treatment of infections with histoplasmosis, blastomycosis, coccidioidomycosis; not recommended for treatmet of meningitis because it doesn't cross the blood-brain barrier; paracoccidioidomycosis, candidiasis, severe cutaneous dermatophyte infections that do not respond to topical therapy

3. inhibits testosterone and estradiol synthesis = gynecomastia and menstrual irregularities.  it has limited use because of high incidence of side effects.  Also, liver toxicity, gingival bleeding, anorexia...

4. similar to intraconazole

Clotrimazole

1. type

2. uses

3. other characteristics

1. azole antifungal

2. only used topically; binds to oral mucosa; drug of choice for oral candidiasis in AIDS patients. This is too toxic for systemic use.

Posaconazole

1. type

2. uses

3. spectrum compared to others

4. other characteristics

1. azole antifungals

2. similar to intraconazole but has activity against zygomycetes (the only one)... new drug - approve 2006

3. prophylaxis of invasive aspergillus and disseminated candidiasis in severely immunocompromised hosts; candida species that are resistant to other azoles; active against zygomycetes (other azoles are not); oropharyngeal and esophageal candidiasis refractory to treatment with fluconazole or itraconazole

4. optimal absorption when taken with high fat meals; adverse effects similar to fluconazole; pregnancy cat. C.; inhibits cytochrome P450 enzyme CYP3A4

Terbinafine

1. type

2. method of action

3. uses

4. drug interactions

5. toxicity

1. synthetic allylamine

2. inhibits ergosterol biosynthesis by inhibiting fungal squalene oxidase

3. used for onychomychosis of toenail or fingernails, used topically or orally

4. less potential for drug interactions than with the azole antifungals; it is an inhibitor of CYP2D6 = may increase effect or toxicity of tricyclic antidepressants

5. liver injury less common than azoles; headache, gi symptoms, altered taste and toxic epidermal necrolysis and erythema multiforme

Griseofulvin

1. Type

2. Method of action

3. Uses

4. Toxicity

5. Drug interactions

6. Other characteristics

1. orally effective fungistatic agents

2. binds to mitotic spindle and blocks fungal mitosis

3. treat persistant infections of the nail and scalp that do not respond to topical treatment. microsporum, epidermophytum, trichophyton.  peeling the fungus off your "toe", sis...

4. drug allergies, metabolized by liver

5. induces P450 enzymes in the liver and as a result can decrease the effectiveness of warfarin and oral contraceptives

6. taken with a fatty meal.  this doesn't kill the fungus (bacteriostatic)

Flucytosine

1. type

2. Method of action

3. Uses

4. Toxicity

5. Drug interactions

6. other notable characteristics

1. Miscellaneous

2. inhibits fungal nucleic acid synthesis and function after it is metabolized to 5-fluorouracil.

3. fungi rapidly become resistant, most commonly combined with amphotericin B for treatment of severe systemic candidal or cryptococcal infections (you can use lower dose of toxic ampho B)

4. bone marrow depression and nephrotoxicity, nausea, vomiting, rarely enteroclititis, anemia, leucopenia, thrombocytopenia (like other anti-metabolite/anti-DNA, it effects rapidly dividing cells)

5. can increase hepatic enzymes

6. excreted unchanged in urin; gets into CSF well; widely distributed throughout body; well absorbed through GI

Echinocandins

1. Type

2. Method of action

3. fungicidal or fungistatic

4. Other characteristics

1. new class of antifungal drugs - parenteral use only!

2. target a fungal enzyme called 1,3-beta-D-glucan synthease that is required for the biosyntheis of (1,3)-beta-D-glucan, an essential polysaccharide component of the fungal cell wall.

3. fungicidal

4. None of the three echinocandins on market   require dose adjustments for patients with renal failure (okay for renally-impaired patients), do not significantly interact with other drugs, and appear to be similar in efficacy and safety

Caspofungin

1. type of antifungal

2. uses

3. toxicity

4. Other characteristics

1. echinocandins

2. parenteral use preferred drug; candida, pneumocystis, aspergillus, histoplasma; in patients who cannot tolerate amphotericin B or azole compounds; esophageal candidiasis, candidemia, intra-abdominal abscesses, peritonitis, pleural space infections due to candida.  excellent for life-threatening systemic fungal infs. in pts that cannot tolerate ampho B.

3. rash, facial swelling, pruritis, sensation of warmth, hepatic toxicity

4. do not use with pregnancy, a lot of drugs increase the clearance of this drug.

Micafungin

1. Type

2. Uses

3. Toxicity

4. Other characteristics

1. echinocandin

2. esophageal candidiasis and prophylaxis of invasive candida infections in patients undergoing hematopoietic stem cell transplantation; candida and aspergillus; candida albicans

3. fever, headache, nausea, vomiting, diarrhea, leukopenia, hepatic enzyme abnormalities

4. no major drug interactions (does not have major effects on CYP450 system or drugs metabolized by it); pregnancy category C

Anidulafungin

1. type

2. uses

3. toxicity

4. other characteristics

1. echinocandin

2. intravenous, esophageal candidiasis, candidemia, candida infections (intra-abdominal abscess or peritonitis)

3. histamine mediated rxns = due to infusion rate; fever, nausea, vomiting, hypokalemia; liver abnormalities, hepatitis and worsening hepatic failure reported; pregnancy category C

4. Not clear when this drug is advantageous to other echinocandins

1. clotrimazole troche - highly effective in most cases. when swallowed can give some hepatic toxicity (use nystatin oral pastilles or rinses in this case).

Oral options for AIDs patients: 1. ketoconazole 2. ketoconazole + topical nystatin 3. oral fluconazole 4.

itraconazole IV option: amphotericin B with flucytosine

1.  Patients at high risk for neutropenia (fluconazole, intraconazole, micafungin)

2.  HIV patients with severe, recurrent oral or esophageal candidiasis (fluconazole, intraconazole)

3.  recurrent vaginal candidiasis (flucanzole)

What are the antifungal agents that are used for superficial fungal infections?