53-Antifungal Therapy

Question 1

Unique targets in antifungal therapy?

Answer 1

fungal cell membrane (ergosterol and ergosterol synthesis–versus cholesterol)
fungal cell wall (glucans)

Question 2

Shared targets in antifungal therapy?

Answer 2

DNA/RNA synthesis

cell division

Question 3

Amphotericin B
(use, mechanism, resistance, adverse)

Answer 3

antifungal (poor CNS penetration requires intrathecal administration for fungal meningitis)
binds ergosterol and makes pores in membrane
resistance if decrease membrane concentrations of ergosterol or sterol is modified to reduce binding affinity
nephrotoxic (less toxicity if liposomal packaged)

Question 4

Azoles MOA?

Answer 4

bind to the enzyme responsible for converting lanosterol to ergosterol. The inhibition of ergosterol synthesis leaves too few ergosterol for the membrane and decreases the integrity of the fungal cell membrane

Question 5

Resistance to azoles? (3)

Answer 5

efflux pumps
mutations in target enzyme
decreased ergosterol content in cell membrane

Question 6

Ketoconazole

Answer 6

first oral azole clinically used

high CYP450 inhibition

Question 7

Fluconazole

Answer 7

Largest therapeutic index of azoles

first line 3 Cs: candidiasis, cryptococcosis, coccidiomycosis

Question 8

Intraconazole

Answer 8

broader spectrum of activity than fluconazole, but worse therapeutic index.
Requires low gastric pH for absorption, no CNS activity

Question 9

Voriconazole

Answer 9

replaced Amphotericin B for aspergillosis

CYP450 interactions

Question 10

Posaconazole

Answer 10

broadest spectrum of azoles
treats aspergillus and agents of mucormycoses
strong inhibitor of CYP450s

Question 11

Flucytosine

MOA, use, resistance, adverse

Answer 11

converted to 5-FU and blocks protein and DNA synthesis
used for cryptococcal meningitis
altered metabolism of flucytosine
bone marrow toxicity

Question 12

echinocandins

names, MOA, use

Answer 12

caspofungin, micafungin, anidulafungin
inhibit synthesis of beta-glucans (essential in fungal cell wall)
used in nonresponsive infections of candida and aspergillus

Question 13

Griseofulvin

Answer 13

used for dermatophyte infections
concentrates in keratin precursor cells
increases warfarin metabolism

Question 14

Allylamines (use, MOA)

Answer 14

dermatophyte infections

inhibit squalene epoxidase (ergosterol synthesis)

Question 15

Terbinafine (use, MOA)

Answer 15

onychomycosis
oral (topical doesn't penetrate nail bed very well) that concentrates in keratin cells like griseofulvin

Question 16

nystatin (use)

Answer 16

topical polyene related to amphotericin B

usually used against candida

Question 17

topical azoles (names, use)

Answer 17

clotrimazole and miconazole

vaginal candidiasis and dermatophyte infections

Question 18

topical allylamines (names, use

Answer 18

Terbinafine, naftifine
tinea cruris (jock itch), tinea corporis (ringworm), etc..