Anti-fungals

Question 1

Describe the mechanism of action of Amphotericin B

Answer 1

Fungicidal. Binds ergosterol (a cholesterol) so it isn’t properly incorporated into cell wall. Causes pores in cell wall and leakage.

Question 2

ADME and adverse effects of Amphotericin B

Answer 2

IV more common (poor oral absorption). Slow excretion leads to accumulation and toxicity (chills, fever, vomiting, hypotension). Longterm can injure kidneys.

Question 3

Pros and Cons of Amphoterin B Lipid Formulations

Answer 3

P: Less renal toxicity than conventional amphotericin, less severe infusion rxns (*one exception).
C: the 3rd lipid formulation (Amphotec) has more severe infusion rxn, greater hepatotoxicity risk, $$$

Question 4

Clinical use of Amphotericin B

Answer 4

Category B (preferred over azoles). Broadest spectrum of action, used for life-threatening mycotic infections.

Question 5

Clinical use of Nystatin

Answer 5

Can’t be given parenteral (too toxic), but similar to amphotericin B and used to tx thrush/yeast infections

Question 6

Mechanism of action of azoles

Answer 6

Blocks ergosterol synthesis (remember, a cholesterol in cell wall) by inhibiting P450 enzyme (14-a-sterol demethylase).
*Can cause drug interactions b/c it’s a P450 inhibitor.

Question 7

Clinical uses of fluconazole

Answer 7

Drug of choice for cryptococcal meningitis and as prophylaxis for high-risk immunocompromised. Highest therapeutic index of the azoles.

Question 8

Clinical uses of itraconazole

Answer 8

Drug of choice for dimorphic fungi histoplasma, blastomyces, and sporothrix. *Poor CNS penetration.

Question 9

Clinical uses of voriconazole

Answer 9

Drug of choice for invasive aspergillosis (better outcomes/less toxicity than amphotericin).
*Visual disturbances common (blurring/color and brightness changes; all reversible)

Question 10

Mechanism of action of caspofungin

Answer 10

An echinocandin- inhibits cell wall synthesis via inhibition of B(1-3) glucan synthesis

Question 11

Clinical use of caspofungin

Answer 11

Given IV to treat aspergillus and candida (when aspergillus doesn’t respond to voriconazole).
*Can cause hepatotoxicity

Question 12

Mechanism of action of griseofulvin

Answer 12

Fungistatic. Mitotic inhibitor- intereferes w/ microtubule assembly so it can’t proceed to metaphase and chromosome segregation.
*P450 inducer

Question 13

Clinical uses of griseofulvin

Answer 13

Deposits in newly growing keratin (skin/nails) where fungus likes to grow. Needs to be used for dermatophytosis only until infected tissue is completely gone (can be 6 months to a year)

Question 14

Mechanism of action of terbinafine

Answer 14

Fungicidal. Inhibits fungal enzyme (squalene epoxidase) resulting in high levels of squalene that is toxic

Question 15

Clinical use of terbinafine

Answer 15

Treats dermatophytoses, especially onychomycosis (fingernail/toenail infections)

Question 16

Mechanism of action of flucytosine

Answer 16

Taken up by cytosine permease (only in fungal cells) where it’s converted to 5-FU and goes on to inhibit DNA and RNA synthesis. Narrow spectrum, so only used in combo w/ amphotericin B or itraconazole
*Can cause hematotoxicity

Question 17

Is prophylactic anti-fungal use recommended in immunocompromised patients?

Answer 17

No way jose.