Antifungals

Question 1

Flucytosine

Answer 1

MOA: prodrug converted by fungus to 5-FdUMP which inhibits thymidylate synthetase which blocks synthesis of dTMP, and 5-FUTP inhibits protein synthesis
Spectrum: narrow (fungistatic)
Use: synergistic when used w/ Amphotericin B to tx serious Candida and Cryptococcus infections
SE: BM suppression d/t metabolism to 5-fluorouracil

Question 2

Caspofungin

Answer 2

MOA: inhibit synthesis of β(1,3)-D-glucans in fungal CW
Effect: disruption in cell wall = cell death
PK: only IV
Use: tx Candida and Aspergillus

Question 3

Amphotericin Infusion-related SEs

Answer 3

Fever, chills, muscle spasm, HA, hypotension

- slow rate or decrease dose, or pre-treat w/ antihistamine/glucocorticoids

Question 4

Azoles

Answer 4

MOA: inhibit 14-α-sterol demethylase (fungal CYP450 enzyme) prevents ergosterol synthesis
Effect: disrupts membrane function and increases permeability
*specificity results from affinity for fungal rather than human CYP450 enzymes (triazoles more specific than imidazoles)

Question 5

Fluconazole

Answer 5

PK: sorta inhibits CYP3A4, strong inhibitor of CYP2C9 (increase levels of Phenytoin, Zidovudine and Warfarin)
DOC: esophageal, vulvovaginal or urinary Candidiasis, Candidemia, Coccidiomycosis, Cryptococcal meningitis

Question 6

Voriconazole

Answer 6

DOC: invasive aspergillosis
SE: transient visual disrurbances, inhibition of CYP2C19, CYP2C9, CYP3A4

Question 7

Topical Azoles

Answer 7

Clotrimazole and Miconazole

Question 8

Itraconazole

Answer 8

PK: metabolized CYP3A4, inhibits CYP3A4 (so potential for arrhythmias when given concurrently w/ Cisapride or Quinidine), poor bioavailability and CSF penetration, absorption reduced by antacids, H2RBs and PPIs
Use: preferred for Blastomyces, SPorothrix and Hisotplasma infections, effective against Aspergillus (but has been replaced by voriconazole), tx dermatophytoses and onychomycosis

Question 9

Griseofulvin

Answer 9

MOA: disrupts mitosis spindle and inhibits mitosis
Use: tx severe dermatophytosis of skin/hair/nails (replaced by newer antifungals like Itraconazole and Terbinafine)
SE: induces CYP450 enzymes (increases concentration of Warfarin)

Question 10

Azoles names

Answer 10

Imidazoles: Ketoconazole / Miconazole / Clotrimazole

Triazoles: Itraconazole / Fluconazole / Voriconazole / Posaconazole

Question 11

PCP Tx options

Answer 11

Clindamycin + Primaquine
Dapsone + Trimethoprim
Atovaquone
Pentamidine

Question 12

Nystatin

Answer 12

(Structurally similar to amphotericin B)
Use: candidiasis
PK: cutaneous, vaginal and PO administration

Question 13

Posaconazole

Answer 13

Use: tx Zygomycetes (ie Mucormycoses)
SE: inhibits CYP3A4

Question 14

Terbinafine

Answer 14

MOA: inhibits squareness epoxidase preventing synthesis of ergosterol, and accumulation of toxic levels of squalene
Use: onychomycosis
SE: GI sx’s, rash, HA, taste disturbances, elevated LFTs, inhibits CYP2D6

Question 15

Amphotericin B

Answer 15

MOA: binds ergosterol forming pores in cell membrane = cell death
Spectrum: broad AF (yeasts, mycoses, molds)
PK: IV only, low CSF penetration so intrathecal tx for meningeal dz
Use: life-threatening fungal infections, initial drug to rapidly reduce fungal burden then continue pt on Azole, topical use for Candidiasis, tx deep infections during pregnancy

Question 16

Amphotericin Slower Toxicity SEs

Answer 16

Renal toxicity, azotemia, decreased GFR, renal tubular acidosis w/ Mg2+ and K+ wasting
- co-administer NaCl infusion to attenuate renal damage
LFT abnormalities, decreased EPO

Question 17

Amphotericin Lipid Formulations

Answer 17

Packaged in lipid carriers to reduce exposure to nephron = reduce nephrotoxicity

Question 18

Co-Trimoxazole

Answer 18

DOC: tx PCP and prevention of PCP in immunocompromised pt’s

Question 19

Terbinafine

Answer 19

Use: tx Tinea curis and Tinea corporis (topical cream)

Question 20

Ketoconazole

Answer 20

PK: inhibits CYP3A4 (potentials toxicity of Warfarin and Cyclosporine), best absorbed at low pH
Uses: superficial mycoses
SE: decrease plasma testosterone levels = decreased libido, gynecomastia, menstrual irregularities in women
(High doses may inhibit adrenal steroid synthesis and decrease plasma cortisol)
CI: coadministration w/ antacids, PPIs, H2RBs