Antifungals

Question 1

Amphotericin B
Class
Mechanism
Spectrum
Toxicity
Use

Answer 1

• Class - polyene
• Mechansim – binds w/ ergosterol → membrane disruption / porosity → loss of membrane potential / death. AmB also oxidaized by lipoxygenases → free radical damage. Fungicidal.
• Spectrum – Everything except Candida lusitaniae and Aspergillus terreus. Great for Cryptococcus, Endemic fungi (Histo, Blasto, Coccidiomycosis), and Zygomycetes.
• Toxicity – Main problem is renal toxicity (distal tubular acidosis / electrolyte wasting). Must monitor kidney function.
• Infusion fever, rigors, and SOB. Must pre-treat w/ Tylenol or acetaminophin and benedryl.
• Use – 1st line for cryptococcal meningitis, severe endemic disease, and zygomycosis.

Question 2

Are triazoles fungistatic or fungicidal?

Answer 2

Fungistatic against yeast

Fungicidal against molds

Question 3

Mechanism of azoles

Answer 3

Inhibition of fungal p450 enzyme 14-alpha-demethylase, interrupting conversion of lanosterol to ergosterol

Question 4

General side effects of azoles (3)

Answer 4

Liver toxicity
Endocrine effects such as low testosterone and glucocorticoids → gynecomastia and adrenal insufficiency.
Teratogens.

Question 5

Fluconazole
Spectrum
Distribution
Elimination
Toxicity
Use
Resistance mechanism

Answer 5

• Spectrum – Most Candida (not C glabrata or C krusei), Cryptococcus, and Coccidioidomycosis. NOT aspergillus or zygomycetes.
• Good distribution to CNS (cryptococcal meningitis) and urine (Candida cystitis).
• Renal elimination
• Toxicity – Overall very safe. Teratogen, QT prolongation w/ risk of Torsades (do ECG before and during use), and drug interactions (CYP450 inhibitor)
• Use – 1st line for mucosal Candidiasis (oral, esophageal, vaginal), Candida cystitis, and Coccidioidomycosis meningitis. 1st line step down therapy for invasive candidiasis (not glabrata or krusei) and cyrptococcal meningitis (start w/ Amphotericin B which is bactericidal).
• Resistance – due to alteration of target enzymes (14 demethylase) and efflux.

Question 6

Itraconazole
Spectrum
Absorption (2 forms)
Distribution
Toxicity
Use

Answer 6

• Spectrum – same as Fluconazole (Candida and Cryptococcus) + ENDEMICS, ASPERGILLUS, DERMATOPHYTES (tinea), sporothrix shenckii, penicillium, and pheohyphomycetes. NOT Zygomycetes.
• Absorption – liquid form is better than capsule form. Need acid and food for capsule. Do drug monitoring to make sure they’re actually absorbing enough of the drug.
• Poor CNS and urine distribution. Not good for meningitis.
• Toxicity – Drug interactions due to CYP450 inhibition. Need to do drug monitoring. QT prolongation and teratogenicity.
• Use – 1st line for dermatophytes (tinea). Step down for endemics.

Question 7

Voriconazole
Spectrum
Distribution
Metabolism
Toxicity
Use

Answer 7

• Spectrum – Itraconizole (CANDIDA, Cryptococcus, endemics, ASPERGILLUS, dermatophytes) + C GLABRATA and C KRUSEI. NOT zygomycetes.
• Good CNS distribution. Not urine.
• Variable metabolism speed due to CYP19 polymorphism. CYP450 inhibitor. Need to do drug monitoring.
• Toxicity – More issues than other azoles.
• Photopsia – see bright / blue lights. Benign and reversible, but should not drive at night.
• Hepatotoxicity
• Common photosensitivity w/ prolonged tx. Avoid sun exposure.
• Teratogen
• QT prolongation
• Rare hallucinations, mainly in elderly.
• Use – 1st line for invasive aspergillosis, Fusarium, and Scedosporium.

Question 8

Posaconazole
Spectrum
Absorption (2 types)
Distribution
Toxicity
Use

Answer 8

• Spectrum – Voraconazole (Candida, Cryptococcus, ENDEMICS, ASPERGILLUS, dermatophytes) + ZYGOMYCETES (rhizapus and mucor).
• Absorption
• Solution absorption is poor and saturable. Need acid and food. Avoid PPI’s and H2 inhibitors.
• Tablet absorption is much better. Best with food, especially fat.
• Poor CNS and urine distribution
• Toxicity – Drug interactions. Need drug monitoring.
• Use – 1st line prophylaxis for leukemia and bone marrow transplant. 2nd line zygomycetes (amphotericin B first).

Question 9

Isavuconazole
Spectrum
Absorption
Toxicity
Use

Answer 9

• Spectrum – Identical to posaconazole. Candida, Cryptococcus, Endemics, Aspergillus, Zygomycetes, and Dermatophytes. Good for empiric therapy.
• Great absorption. Do not need acid or food.
• No toxicity. Only azole that drug monitoring is NOT needed.
• Use – 1st line aspergillus (along w/ voriconazole) and zygomycetes. Also Fusarium and Scedosporium.

Question 10

Terbinafine
Class
Mechanism
Spectrum
Limitations
Toxicity
Use

Answer 10

• Class - Allylamine
• Mechanism – Inhibit ergosterol synthesis at level of squalene epoxidase. Fungicidal.
• Spectrum – DERMATOPHYTES, Aspergillus, endemics, and PCP
• Nonsatruable protein binding limits utility. Concentrates in stratum corneum, persisting long after drug is discontinued.
• No toxicity
• Use – Skin and anail dermatophyte infections.

Question 11

Flucytosine
Class
Abbreviation
Mechanism
Spectrum
Distribution
Elimination
Toxicity
Use

Answer 11

• Class - Pyrimidine
• Abbreviation - 5FC
• Mechanism – Enters cells via cytosine permease, converted to 5FU via cytosine deaminase, phosphorylated to FUMP → inhibits thymidylate and DNA synthesis. Fungistatic.
• Spectrum – Candida and CRYPTOCOCCUS.
• Great CNS and urine distribution
• Renal elimination. Dose adjust for renal insufficiency.
• Toxicity – High concentrations can be lethal. Nephrotoxicity, especially when combined w/ amphotericin B. Bone marrow suppression. Need drug monitoring.
• Use – 1st line combo w/ amphotericin for induction Cryptococcal meningitis. 2nd line for Candida glabrata cystitis.
• Combo w/ Amphotericin B is better than Amphotericin B alone.

Question 12

Echinocandins 
3 drugs
Mechanism
Spectrum
Distribution
Toxicity
Use

Answer 12

• Caspofungin, Micafungin, and Anidulafungin
• Mechanism – noncompetitive inhibition of beta-(1,3)-glucan synthetase in cell memberane, depleting glucan → osmotic instability / lysis.
• Spectrum – Cidal for Candida (except C parapsilosis). Static for aspergillus.
• Poor CNS, eye, and urine distribution
• No toxicity or drug interactions
• Use – 1st line for invasive candidiasis (not C parapsilosis or CNS / eye infections). Combine w/ mold-active triazole for invasive aspergillosis.

Question 13

Tx for invasive Candidiasis
Non C parapsilosis or CNS / eye infection?
C parapsilosis?
Step down?

Answer 13

• Use echinocandin unless C parapsilois or CNS / eye infection
• Use Flucoonazole or LAmB for C parapsilosis
• Fluconazole is good step down for all except glabrata or krusei
• Voriconazole is good step down for krusei

Question 14

Tx for oral / esophageal Candidiasis

Answer 14

Fluconazole. Voriconazle for glabrata or krusei. Echinocandins for triazole refractory disease.

Question 15

Tx for vaginal Candidiasis

Answer 15

Fluconazole. Systemic azoles are not allowed during pregnancy.

Question 16

Tx for Aspergillosis

Answer 16

Voriconazole (1st line), Isavuconazole, and Azole / Echinocandin combo

Question 17

Tx for Zygomycetes

Answer 17

LamB. Step down posaconazole and isavuconazole.

Question 18

Tx for endemic fungi
Initial tx
Step down

Answer 18

Start w/ LAmB. Step down itraconazole for 3-12 months. If CNS, step down w/ voriconazole or fluconazole.

Question 19

Tx for Cryptococcal meningitis

Answer 19

LAmB + 5FC. Step down w/ Fluconazole.

Question 20

Tx for Dermatophytes

Answer 20

Terbinafine (1st line) or Itraconazole