Antifunals Flashcards
Amphotericin B Mechanism
Binds ergosterol - disrupts wall function and creates small pores.
Echinocandin Mechanism
Inhibits B-(1,3)-glucan synthase
- Responsible for cross-linking
- Required for cell wall synthesis
Azole Mechanism
Inhibits Cytochrome P450 lanosterol 14-a demethylase
- Required for ergosterol biosynthesis
Amphotericin B Toxicities
“Shake and bake”
Nephrotoxicity
- Renal artery vasoconstriction
- Binds to renal tissues
Advantages of LFAB ( FWAB or Bacontericin B)
Delays delivery to kidney due to lipophilicity.
Agents - Cidal or static?
Ampho - cidal
Azole - static
Echino - cidal against Candida
Major drug interaction with Azoles
They inhibit CYP enzymes - 3A4!
Also, PGP
Low end of Fluconazole dose
6-12 mg/kg/day in the ICU
Fluconazole Strengths
C. albicans
Fluconazole weaknesses
Does not cover molds
Often under dosed
Voriconazole strengths
Broad spectrum
- Candida
- Aspergillus *
- NOT Mucorales or Zygomycetes
IV and PO
Generic
Gold standard for Aspergillus
Voriconazole
Voriconazole weaknesses
Metabolite and cancer risk Dosing strategy concerns Toxicities - LFT increases - Hallucinations
Posaconazole strengths
Broadest spectrum
- Candida
- Aspergillus
- Zygomycetes
IV and delayed release tablet have reliable PK
- QD as oral
Posaconazole weaknesses
Very expensive
Isavuconazole (Cresemba) strengths
Decent spectrum
- Aspergillus
- Mucorales (limited data)
- NO CANDIDA
IV and oral
- QD as oral
- IV : no cyclodextrin (accum. in renal failure)
Isavuconazole weaknesses
No prophylaxis data
Very long t1/2 - IV needs loading dose
“Advanced” Azole Indications
Voriconazole - TREATMENT of IA and IC
Posaconazole - PROPHYLAXIS in high risk patients
Isavuconazole - TREATMENT of IA & Mucormycosis
Echinocandins include
“Whatever-a-fungin”
Echinocandin strengths
Potent against Candida (cidal) Really well tolerated Great PK Few interactions No cross-resistance with Azoles
Echinocandin weaknesses
Limited spectrum: Candida >>> Aspergillus (combo) - That's about it. - Not C. neoformans No oral form High cost
Flucytosine (5-FC)
Think Cryptococcal meningitis
Terbinafine
Toe nails
Greatest risk for Invasive Candidiasis
GI-Perforation
Also being in the ICU > 3 days
- Really when you have something put inside you.
Increasingly prevalent Candida species resistant to fluconazole:
C. glabrata
Candida species completely resistant to fluconazole:
C. krusei
What to use for C. krusei
Echinocandins: Whatever-a-fungin
Maybe Vori or Posa
Only candida species with resistance to Echinocandins
C. parapsilosis
What to use for C. glabrata
Echinocandinds: Whatever-a-fungin IF resistant to Fluconazole.
- If resistant to one azole, resistant to all azoles.
Two Candida species that don’t show resistance yet:
C. albicans and C. tropicalis
Poor prognosis in Candidemia
Older age
APACHE > 2
Immunosuppressive therapy
C. tropicalis infection (seems weird)
Predictors of good outcome from study:
Removal of central venous catheter
Treatment with echinocandin
Initial treatment recommendation for Candidemia in non-neutropenic adults:
Echinocandin 1st line
or
Fluconazole 800mg followed by 400mg
What’s the deal with Candida auris?
It causes severe illness.
It can be resistant to all three antifungal options.
It is increasing in prevalence.
It is difficult to identify.
It is showing up in hospitals and nursing homes.
When would you worry about IFI (Aspergillosis)
Severyly immunocomprimised; bone marrow/blood cancer.
Common species involved in IFI
A. fumigatus
A. flavus
Where do you see IFI show up?
Lung and sinuses mostly
CNS most common secondary site
Treatment for IFI
Voriconazole
- isavu and posa probably work too
- addition of Echinocandin may be seen in future
- Isavu less SE’s
Alternative: Lipid-AmpB
What do you do if someone gets a mold infection while on an Azole
Ampho
Prophylaxis for IA
Posa > Vori > micafungin
Therapeutic drug monitoring for Voriconazole:
Stay above: 2
Stay below: 5-6
