Antifungal Therapy Flashcards
Mechanism of action of amphotericin B?
- Binds ergosterols in cell membrane of fungal organisms
- Increases cell permeability
- Leakage of nutrients and electrolytes
What is the route by which Amphotericin B is administered?
IV occ. SQ (not absorbed well orally)
What are the acute side effects of Amphotericin B when giving the infusion? How can these side effects be decreased?
fever, vomit, myalgia, muscle tremors, phlebitis, anaphylaxis
Give the infusion slowly
What are the chronic side effects of Amphotericin B?
NEPHROTOXICITY
weight loss
Non-regen anemia
What is the spectrum of action of Amphotericin B?
Most systemic antifungals (blasto, histo, crypto, coccidiosis, asper)
In which species of fungal organisms is resistance being reported to Amphotericin B?
Aspergillosis
What are the four formulations of Amphotericin B?
Amphotericin deoxycholate (Fungizone®)
Amphotericin cholesteryl sulfate (Amphocil®)
Liposome encapsulated amphotericin (AmBisome®)
Lipid complexed amphotericin (Abelcet ®)
Which Lipid complexed amphotericin formulation has the best CSF penetration?
Liposome encapsulated amphotericin (AmBisome®)
Which amphotericin formulation is predominantly protein bound and NOT lipid complexed?
Amphotericin deoxycholate (Fungizone®)
What is the MOA for flucytosine?
Fluorinated pyrimidine–> Converted to fluorouracil w/in fungal organism (yeasts)–> Interferes w/DNA synthesis
How is amphotericin administered?
IV
What drug/s is/are synergistic with amphotericin B?
flucytosine
In which fungal oraganisms is flucytosine effective & ineffective?
Effective:
Crypto
Candida
Ineffective:
aspergillus
What are the side effects of flucytosine?
nephrotoxicity
Drug eruptions (dogs)
TCP (cats)
What is the MOA for azole derivatives?
Inhibit sterol synthesis
Also inhibit synthesis of nucleic acid, triglycerides and fatty acids
With the concentrations that can be achieved systemically with Azole derivatives, are they fungistatic or fungicidal?
fungistatic
How are azole derivatives metabolized? Why is this important?
CP450 in liver
affects metabolism of other drugs
When administering ketoconazole to a dog, what two things can help increase its absorption?
small fatty meal
avoid antacids (better absorbed in acidic env.)
What are the side effects of ketonazole?
Nausea/Vomiting
Decr. appetite
Hepatotox (incr. ALT, AST, SAP, usually reversible*)
TCP, anemia
Teratogenic
Suppress cortisol production
Spectrum of action of ketoconazole?
candida
malassezia
histo
blasto
coccidiosis
Because relapse of fungal dz is common with ketoconazole, what can be done to try to prevent this relapse?
TX 4 weeks past resolution of clinical disease
What are the side effects of itraconazole?
Less toxic than ketoconazole
Nausea, vomiting
Inappetence
Hepatotoxicity
Ulcerative dermatitis*
Does NOT suppress cortisol production*
What is the spectrum of action of itraconazole?
Histo
Blasto
Crypto
Coccidio
Aspergillus
Compar CNS penetration for ketoconazole, itraconazole, & fluconazole?
ketoconazole & itraconazole= poor penetration
fluconazole= good penetration in CNS, CSF, and eye
How is fluconazole metabolize?
Renal excretion of ACTIVE drug
What are the side effects of fluconazole?
V/D
Spectrum of action for fluconazole?
crypto (TX of choice is in CNS/eye)
Candida
Blast & histo (less effective than itraconazole)*
Min effective against asper
If a canine is DX with systemic blasto or histo, which antifungal is a better choice fluconazole or itraconazole?
itraconazole
How long do you typically TX with keto, itra, and fluconazole?
Keto: 1-9 mo
Itra: 60 days
Fluconazole: 8 mo (TX until Ag test neg), 2 mo past clinical resolution
Newer azoles (ex: voriconazole) are most effective against which fungal organisms?
Candida
crypto
Histo
Blasto
Asper
Some activity against zygomycetes
What is Posaconazole a derivative of? How does it’s spectrum of action differ?
Itraconazole
Both: Histo, blasto, Crypto, asper
POSA only: Candida, malassezia
What is voriconazole a derivative of? How does it’s metabolism differ?
fluconazole
metabolized by the liver (rather than excreted in active form by kidneys)
What is the benefit of using clotrimazole? What are the side effects?
TOPICAL
Irritating
Erythema
Airway obstruction secondary to inflammation caused by carrier
May prolong barbiturate anesthesia
what are the two methods of administering clotrimazole for nasal apsergillosis?
nasal infusion
trephination of frontal sinus and administration of cream into sinus
What are the two topical azole derivatives that treat fungal diseases?
clotrimazole
enilconazole
What is the MOA for terbinafine?
Where does the drug accumulate in the highest concentrations?
Allylamine–> Inhibits ergosterol synthesis (different enzyme than azoles)
High concentrations in skin and nails
What are the side effects of terbinafine?
V/D
hepatotox (hepatic metabolism)
neutropenia, pancytopenia
What is the spectrum of action of terbinafine?
Hyphal organisms (asper, sporothrix, dermatophytes)
Which fungal organisms is terbinafine ineffective against?
yeast or dimorphic organisms (blasto, histo)
What is the MOA of Echinocandins?
inhibit cell wall synthesis (glucan synthesis–> Caspofungin, Micafungin, Anidulafungin)
What is the spectrum of action of Echinocandins?
Effective against invasive candidiasis and aspergillus (esp if resistant to AMB and/or triazoles)
Some efficacy against pythium
What are the side effects of Echinocandins?
Fever, urticaria, pruritis
Vomiting, diarrhea
Increased liver enzymes (hepatic metab)
What is often the limiting factor in being able to use Echinocandins?
VERY $$$$
What is the MOA for Mefenoxam? What is it proposed to be effective against?
Agricultural fungicide–> Inhibits RNA polymerase
o Plant pathogen oomycetes (pythium)
