Antifungals

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3 classes of antifungals

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Azoles - fluconazole, itraconazole, voriconazole
Polyenes - amphotericin B deoxycolate, lipid-based amphotericin B
Echinocandins - caspofungin

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3 morphological fungi classifications

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Yeast
Mold
Dimorphic

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Unicellular, reproduce by budding (may form pseudohyphae) and look like bacteria on typical growth plates

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Yeast

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Multicellular, have hyphae and conidia, and look cottony on culture

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Mold

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Dimorphic fungi take what form at body and room temp?

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Yeast at body temp; mold at room temp

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Which type of fungi tend to have specific geographic distributions?

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Dimorphic fungi - histoplasma, blastomyces, and coccidiodes - most commonly seen in immunocompromised

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Antigenic structure in fungi (boht yeasts and molds)

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cell wall

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Primary component of fungus cell wall

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polysaccharides (10% proteins and glycoproteins)

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Primary component of fungus cell membrane

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ergosterol

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Drugs that target ergosterol

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azoles and polyenes

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Drugs that target the cell wall

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Echinocandins (e.g. caspofungin)

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Azole action

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inhibit the rate-limiting step in ergosterol synthesis

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Azole drug-drug interactions

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Azole is a Cyp450 enzyme inhibitor. It increases levels of cyclosporine, tacrolimus, antihistamines, oral hypoglycemics, and warfarin. Its drug levels are lowered by rifampin.

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Azole adverse effects

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GI upset, hepatitis, rash, HA

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Azole elimination

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Hepatic (glucuronidation more than p450)

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Most important adverse effect of azoles

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possible hepatitis

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fluconazole administration

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IV, PO (close to 100% bioavailability) - also has great CNS penetration (50-60% serum levels)

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Least toxic of all azoles

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fluconazole

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adverse effects of fluconazole

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HA, alopecia, N/V, anorexia, hepatitis (rare,) rash

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Uses of fluconazole

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Covers most yeast and some dimorphics. DOC for Candida albicans, and mild-moderate Cryptococcus neoformans. No activity against molds. Some yeast are resistant.

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Itraconazole administration

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IV, PO (poor GI absorption and CNS penetration)

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Most drug interactions of all azoles

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Itraconazole

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Adverse effects of itraconazole

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HA, N/V/D, rash, hypokalemia, adrenal insufficiency, impotence, gynecomastia, leg edema, hepatitis (rare,) CHF (rare.)

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Uses of itraconazole

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Covers most yeast, many molds, and most dimorphics. DOC for Histoplasma.

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Azole w/ activity against molds

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Voriconazole

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Voriconazole administration

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IV and PO, 100% oral bioavailability, excellent CNS penetration

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Toxicity of Voriconazole

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visual disturbances (24%,) hepatitis (13,) rash (6%)

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Azole that causes gynecomastia

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Itraconazole

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Azole that causes visual disturbance

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Voriconazole

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DOC for invasive aspergillosis

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Voriconazole

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Uses of Voriconazole

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DOC for invasive aspergillosis, prophylaxis during neutropenia and GVHD

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Azole w/ non-linear PK

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Voriconaozle

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Azole most useful against C. albicans

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Fluconazole

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Azole with widest coverage

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Voriconazole

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Polyene activity

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Bind to ergosterols, allowing leakage of intracellular components across membrane

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Visual disturbance associated w/ voriconazole

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reversible color-change

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Polyene coverage

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Candida, Cryptococcus neoformans, dimorphics, Aspergillus, mucormycosis

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Amphotericin B deoxycholate administration

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IV

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Amphotericin B drug interactions

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Nephrotoxicity

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Amphotericin B pharmacokinetics

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Highly plasma-bound (poor CNS penetration,) wide distribution

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Amphotericin B toxicities

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Renal, infusion-related reactions, anemia (decreased epo)

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Tx for amphotericin B nephrotoxicity

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Slow infusion, administer salt load

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Unique aspects of lipid-based Amphotericin B

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Decreased ADRs (same spectrum of activity,) requires higher doses to achieve the same therapeutic effect

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Activity of echinocandins (caspofungin)

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Inhibition of beta (1,3)-D-glucan synthesis in the fungal cell wall

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Uses of echinocandins (caspofungin)

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Covers Candida, Aspergillus

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Caspofungin administration

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IV

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Caspofungin adverse reactions

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Fever, rash, N/V, phlebitis, hepatitis

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Elimination of caspofungin

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Hepatic clearance

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Uses of Caspofungin

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3rd-line tx for invasive Aspergillus, option for Candida species resistant to azoles (or in pt intolerant of azoles.)

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JR is a 30 y/o non-neutropenic clinically stable diabetic trauma patient with a central line in place in whom blood cultures have grown Candida albicans on hospital day #10. Your attending asks you to remove the central line and treat the patient with an appropriate systemic antifungal agent . Which one is the best antifungal treatment for this patient?

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Fluconazole is the drug of choice for treatment of sensitive Candida (which C. albicans almost always is) infections.

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A 48 y/o female who has been diagnosed with pulmonary histoplasmosis develops fever, chills and rigors after receiving the first dose of amphotericin B deoxycholate. Which one of the following is the best course of management to minimize infusion toxicity in this patient?

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Itraconazole is the only one of the listed agents with good activity against Histoplasma.

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BB is a 32 y/o male with ALL who underwent allogeneic BMT 6 months ago. Over the past 6 month the patient has had several episodes of GVHD and most recently has been diagnosed with invasive cerebral asperillosis. What is the most appropriate treatment for this patient?

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Voriconazole is the drug of choice for the treatment of aspergillosis (especially cerebral, due to excellent CNS penetration).

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KB is a 73 y/o white female with diabetes who has been receiving fluconazole 400mg IV daily for fungal peritonitis (C. albicans) for the past 5 days. Today you notice that her CrCl, which has been decreasing over the past week, is now 25ml/min. What is the most appropriate course of action?

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Fluconazole isn’t nephrotoxic, so no need to change the drug.