Antifungal Therapy

Question 1

Mechanism of action of amphotericin B?

Answer 1

1. Binds ergosterols in cell membrane of fungal organisms
2. Increases cell permeability
3. Leakage of nutrients and electrolytes

Question 2

What is the route by which Amphotericin B is administered?

Answer 2

IV occ. SQ (not absorbed well orally)

Question 3

What are the acute side effects of Amphotericin B when giving the infusion? How can these side effects be decreased?

Answer 3

fever, vomit, myalgia, muscle tremors, phlebitis, anaphylaxis

Give the infusion slowly

Question 4

What are the chronic side effects of Amphotericin B?

Answer 4

NEPHROTOXICITY

weight loss

Non-regen anemia

Question 5

What is the spectrum of action of Amphotericin B?

Answer 5

Most systemic antifungals (blasto, histo, crypto, coccidiosis, asper)

Question 6

In which species of fungal organisms is resistance being reported to Amphotericin B?

Answer 6

Aspergillosis

Question 7

What are the four formulations of Amphotericin B?

Answer 7

Amphotericin deoxycholate (Fungizone®)
Amphotericin cholesteryl sulfate (Amphocil®)
Liposome encapsulated amphotericin (AmBisome®)
Lipid complexed amphotericin (Abelcet ®)

Question 8

Which Lipid complexed amphotericin formulation has the best CSF penetration?

Answer 8

Liposome encapsulated amphotericin (AmBisome®)

Question 9

Which amphotericin formulation is predominantly protein bound and NOT lipid complexed?

Answer 9

Amphotericin deoxycholate (Fungizone®)

Question 10

What is the MOA for flucytosine?

Answer 10

Fluorinated pyrimidine–> Converted to fluorouracil w/in fungal organism (yeasts)–> Interferes w/DNA synthesis

Question 11

How is amphotericin administered?

Answer 11

IV

Question 12

What drug/s is/are synergistic with amphotericin B?

Answer 12

flucytosine

Question 13

In which fungal oraganisms is flucytosine effective & ineffective?

Answer 13

Effective:

Crypto

Candida

Ineffective:

aspergillus

Question 14

What are the side effects of flucytosine?

Answer 14

nephrotoxicity

Drug eruptions (dogs)

TCP (cats)

Question 15

What is the MOA for azole derivatives?

Answer 15

Inhibit sterol synthesis

Also inhibit synthesis of nucleic acid, triglycerides and fatty acids

Question 16

With the concentrations that can be achieved systemically with Azole derivatives, are they fungistatic or fungicidal?

Answer 16

fungistatic

Question 17

How are azole derivatives metabolized? Why is this important?

Answer 17

CP450 in liver

affects metabolism of other drugs

Question 18

When administering ketoconazole to a dog, what two things can help increase its absorption?

Answer 18

small fatty meal

avoid antacids (better absorbed in acidic env.)

Question 19

What are the side effects of ketonazole?

Answer 19

Nausea/Vomiting

Decr. appetite

Hepatotox (incr. ALT, AST, SAP, usually reversible*)

TCP, anemia

Teratogenic

Suppress cortisol production

Question 20

Spectrum of action of ketoconazole?

Answer 20

candida

malassezia

histo

blasto

coccidiosis

Question 21

Because relapse of fungal dz is common with ketoconazole, what can be done to try to prevent this relapse?

Answer 21

TX 4 weeks past resolution of clinical disease

Question 22

What are the side effects of itraconazole?

Answer 22

Less toxic than ketoconazole

Nausea, vomiting

Inappetence

Hepatotoxicity

Ulcerative dermatitis*

Does NOT suppress cortisol production*

Question 23

What is the spectrum of action of itraconazole?

Answer 23

Histo

Blasto

Crypto

Coccidio

Aspergillus

Question 24

Compar CNS penetration for ketoconazole, itraconazole, & fluconazole?

Answer 24

ketoconazole & itraconazole= poor penetration

fluconazole= good penetration in CNS, CSF, and eye

Question 25

How is fluconazole metabolize?

Answer 25

Renal excretion of ACTIVE drug

Question 26

What are the side effects of fluconazole?

Answer 26

V/D

Question 27

Spectrum of action for fluconazole?

Answer 27

crypto (TX of choice is in CNS/eye) Candida Blast & histo (less effective than itraconazole)\* Min effective against asper

Question 28

If a canine is DX with systemic blasto or histo, which antifungal is a better choice fluconazole or itraconazole?

Answer 28

itraconazole

Question 29

How long do you typically TX with keto, itra, and fluconazole?

Answer 29

Keto: 1-9 mo Itra: 60 days Fluconazole: 8 mo (TX until Ag test neg), 2 mo past clinical resolution

Question 30

Newer azoles (ex: voriconazole) are most effective against which fungal organisms?

Answer 30

Candida crypto Histo Blasto Asper Some activity against zygomycetes

Question 31

What is Posaconazole a derivative of? How does it's spectrum of action differ?

Answer 31

Itraconazole Both: Histo, blasto, Crypto, asper POSA only: Candida, malassezia

Question 32

What is voriconazole a derivative of? How does it's metabolism differ?

Answer 32

fluconazole metabolized by the liver (rather than excreted in active form by kidneys)

Question 33

What is the benefit of using clotrimazole? What are the side effects?

Answer 33

TOPICAL Irritating Erythema Airway obstruction secondary to inflammation caused by carrier May prolong barbiturate anesthesia

Question 34

what are the two methods of administering clotrimazole for nasal apsergillosis?

Answer 34

nasal infusion trephination of frontal sinus and administration of cream into sinus

Question 35

What are the two topical azole derivatives that treat fungal diseases?

Answer 35

clotrimazole enilconazole

Question 36

What is the MOA for terbinafine? Where does the drug accumulate in the highest concentrations?

Answer 36

Allylamine--\> Inhibits ergosterol synthesis (different enzyme than azoles) High concentrations in skin and nails

Question 37

What are the side effects of terbinafine?

Answer 37

V/D hepatotox (hepatic metabolism) neutropenia, pancytopenia

Question 38

What is the spectrum of action of terbinafine?

Answer 38

Hyphal organisms (asper, sporothrix, dermatophytes)

Question 39

Which fungal organisms is terbinafine ineffective against?

Answer 39

yeast or dimorphic organisms (blasto, histo)

Question 40

What is the MOA of Echinocandins?

Answer 40

inhibit cell wall synthesis (glucan synthesis--\> Caspofungin, Micafungin, Anidulafungin)

Question 41

What is the spectrum of action of Echinocandins?

Answer 41

Effective against invasive candidiasis and aspergillus (esp if resistant to AMB and/or triazoles) Some efficacy against pythium

Question 42

What are the side effects of Echinocandins?

Answer 42

Fever, urticaria, pruritis Vomiting, diarrhea Increased liver enzymes (hepatic metab)

Question 43

What is often the limiting factor in being able to use Echinocandins?

Answer 43

VERY $$$$

Question 44

What is the MOA for Mefenoxam? What is it proposed to be effective against?

Answer 44

Agricultural fungicide--\> Inhibits RNA polymerase o Plant pathogen oomycetes (pythium)