Antifungals

Question 1

Amphotericin B

Answer 1

• sub family: polyene
• mechanism: Binds to ergosterol in fungal cell membranes, forming “leaky pores”
• kinetics: Multiple forms, IV for systemic infections (liposomal forms less nephrotoxic); topical for ocular/bladder infections, oral
• clinical: Candidemia and infections caused by Aspergillus, Blastomyces, Cryptococcus, Histoplasma, Mucor, etc
• toxicity/interactions: Nephrotoxicity is dose-limiting, additive with other nephrotoxic drugs; infusion reactions (chills, fever, muscle spasms, hypotension)
• misc: usually given with flucytosine to reduce the toxicity of it, broadest of all anti-fungals

Question 2

Nystatin

Answer 2

• sub family: polyene
• mechanism: Binds to sterols in fungal cell membrane, changing the cell wall permeability allowing for leakage of cellular contents
• kinetics: Topical and Oral; Absorption: Poorly absorbed; Excretion: Feces (as unchanged drug)
• clinical: Treatment of susceptible cutaneous, mucocutaneous, and oral cavity fungal infections normally caused by the Candida species
• toxicity/interactions: Gastrointestinal: Diarrhea, nausea, stomach pain, vomiting; Hypersensitivity reactions, toxic to the body, usually given only orally or topically to avoid GI absorption

Question 3

Miconazole

Answer 3

• sub family: azole
• mechanism: Inhibits biosynthesis of ergosterol, damaging the fungal cell wall membrane, which increases permeability causing leaking of nutrients
• kinetics: Inhibits biosynthesis of ergosterol, damaging the fungal cell wall membrane, which increases permeability causing leaking of nutrients
• kinetics: Oral and topical: Duration: Buccal adhesion: 15 hours, minimal absorption;
• clinical: Treatment of oropharyngeal candidiasis
• toxicity/interactions: “Application site reaction; including burning, discomfort, edema, glossodynia, pain, pruritus, toothache, ulceration; Central nervous system: Headache (5% to 8%), fatigue (3%), pain (1%); Dermatologic: Pruritus (2%); Gastrointestinal: Diarrhea; best topically since so toxic”

Question 4

Clotrimazole

Answer 4

• sub family: azole
• mechanism: Binds to phospholipids in the fungal cell membrane altering cell wall permeability resulting in loss of essential intracellular elements
• kinetics: Distribution: Oral (troche) and topical : Inhibitory concentrations remain in the saliva for up to 3 hours after dissolution of the troche, excreted via feces
• clinical: Treatment of susceptible fungal infections, including oropharyngeal candidiasis; limited data suggest that clotrimazole troches may be effective for prophylaxis against oropharyngeal candidiasis in neutropenic patients
• toxicity/interactions: Hepatic: Abnormal liver function tests; Dermatologic: Pruritus; Gastrointestinal: Nausea, vomiting

Question 5

Fluconazole

Answer 5

• sub family: azole
• mechanism: Inhibit fungal P450-dependent enzymes blocking ergosterol synthesis; resistance can occur with long-term use
• kinetics: oral, IV
• clinical: prophyactically used to reduce fungal infections in bone marrow transplant recipients; cryptococcus neoformans, candidemias, coccidioidomycosis; mucocutaneous candidiasis
• toxicity/interactions: no endocrine side effects; reduced dose with compromised renal function; nausea, vomiting, rashes; caution for patients with liver dysfunction; not to be used in pregnancy

Question 6

Itraconazole

Answer 6

• sub family: azole
• mechanism: Inhibit fungal P450-dependent enzymes blocking ergosterol synthesis; resistance can occur with long-term use
• kinetics: oral but requires acid for dissolution
• clinical: blastomycosis, sporotrichosis, paracoccidioidomycosis, histoplasmosis; AIDs associated histoplasmosis
• toxicity/interactions: no endocrine side effects; nausea, vomiting, rash, hypokalemia, hypertension, edema, and headache; not to be taken in pregnancy, CHF, or ventricular dysfunction

Question 7

Ketoconazole

Answer 7

• sub family: azole
• mechanism: Inhibit fungal P450-dependent enzymes blocking ergosterol synthesis; resistance can occur with long-term use
• kinetics: Various topical and oral forms for dermatophytose, Oral, parenteral forms for mycoses (fluconazole, itraconazole, posaconazole, voriconazole), Most azoles undergo hepatic metabolism; fluconazole eliminated in urine unchanged
• clinical: Aspergillosis (voriconazole); blastomycosis (itraconazole, fluconazole); mucormycosis (posaconazole); alternative drugs in candidemia and infections caused by Aspergillus, Blastomyces, Cryptococcus, and Histoplasma
• toxicity/interactions: Ketoconazole rarely used in systemic fungal infections owing to its inhibition of hepatic and adrenal P450s; other azoles are less toxic, but may cause GI upsets and rash;

Question 8

Griseofulvin

Answer 8

• mechanism: Inhibits fungal cell mitosis at metaphase; binds to human keratin making it resistant to fungal invasion; inhibits the microtubules
• kinetics: Oral; Absorption: enhanced by ingestion of a fatty meal Distribution: Excretion: Urine, feces; perspiration
• clinical: Treatment of susceptible tinea infections of the skin, hair, and nails, this is because the drug distributes ONLY to places with keratin, topical dermatophytic infections
• toxicity/interactions: Penicillin allergy: Hypersensitivity cross reaction between penicillins and griseofulvin is possible.; Photosensitivity: Avoid exposure to intense sunlight to prevent photosensitivity reactions, GI problems, hepatitis

Question 9

Flucytosine

Answer 9

• mechanism: Inhibits DNA and RNA polymerases
• kinetics: Oral; enters cerebrospinal fluid; renal elimination
• clinical: Synergistic with amphotericin B in candidemia and cryptococal infections
• toxicity/interactions: Bone marrow suppression

Question 10

Caspofungin

Answer 10

• sub family: echinocandin
• mechanism: echinocandin prototype, inhibitor of (1-3)-glucan synthesis, a cell wall component.
• kinetics: IV
• clinical: Used IV for disseminated Candida and Aspergillus infections
• toxicity/interactions: GI effects, flushing. Increases cyclosporine levels (avoid combination)