Antifungals Dr. Cluck EXAM 4 Flashcards
What are the two broad categories of Fungi?
Yeast and Molds
Match the organism to the fungal category.
Aspergillus
Candida
Cryptococcus
Mucormycosis
Pneumoc. jirovecii
Dermatophytes
Aspergillus - Mold
Candida - Yeast
Cryptococcus - Yeast
Mucormycosis - Mold
Pneumoc. jirovecii - Yeast
Dermatophytes - Mold
Which organisms can exist in the Yeast and Mold form (depending on the temperature)?
Dimorphic Fungi
-Histoplasmosis
-Blastomycosis
-Coccidioidomycosis
Candida is a normal commensal of which part of the body?
GI
Genitourinary !! (especially seen in uncontrolled diabetes, catheters placed)
Respiratory tract !!
Candida in a sputum or respiratory culture is indicative of a disease (infection) and antifungals should be started. T/F
!!! EXAM
False
Candida found in a blood sample is never considered a contaminant and is indicative of an infection. T/F
EXAM !!!
True.
What are the five frequently isolated Candida species?
Candida albicans !!
Candida glabrata !!
Candida parapsilosis (hands of healthcare workers leading to catheter infections)
Candida tropicalis
Candida krusei !!
Which Candida species is resistant to Flucanozole and decreased susceptibility to Amphotericin?
!!!
Candida krusei
How should Candida in the urine be managed?
When is Candida in the urine a problem?
-doesn’t always need to be treated with antifungals
-Fluconazole
-treating the underlying cause of diabetes, catheter, uncontrolled diabetes, BPH
-it might be a problem with certain Candida species like C. krusei where drugs are limited
Candida glabrata is resistant to which antifungals?
all Azoles
maybe echinocandins
Which Aspergillus strain is the most pathogenic and seen most commonly with invasive aspergillosis?
Aspergillus fumigatus
Which drug can cause a false positive aspergillus galactomannan test?
ß-lactams (especially Pip/Tazo)
Invasive pulmonary aspergillosis (IPA) does not appear before how many days of neutropenia in an immunocompromised patient?
not before 10 days of neutropenia
What is the drug of choice for an Aspergillus infection? What is the duration?
!!!
- voriconazole (or other azole) !!!
- isavuconazole (no drug monitoring, less side effects)
- Amphotericin (if they dont tolerate azoles)
6-12 weeks minimum - duration not well-defined
What is the role of Echinocandin in Aspergillus therapy?
may combine it with Azoles for Candidemia
should not be used as monotherapy for Aspergillus
Mucormycosis is often referred to as _____?
What is the most common strain?
Zygomycetes
most common strain: Rhizopus
others:
-Rhizomucor
-Absidia (Lichtheimia)
-Cunninghamella
-Mucor
Which patients are at higher risk for Mucormycosis infection?
-DM particularly with DKA
-HSCT/SOT, transplant (prolonged neutropenia)
-iron overload: Chelation treatment with deferoxamine (deferasirox is protective
in vitro; see DEFEAT MUCOR)
-High-dose corticosteroid use (20 mg long-term)
-Prolonged voriconazole use
What is the drug of choice for a Mucormycosis infection?
!!!
- Surgical intervention (often rhinosinusitis, need to remove the tissue)
Antifungals:
-Amphotericin B
-posaconazole and isavuconazole have some activity
What temperature distinguishes the yeast and mold forms of dimorphic fungi?
yeast: 37°C
mold: 25°C
Dimorphic fungi, also referred to as endemic fungi
-Histoplasma capsulatum
-Blastomyces dermatitidis
-Coccidioides immitis
-Paracoccidioides brasiliensis
-Sporothrix schencki
What are the classes of Antifungals?
-Azoles
-Echinocandins (Caspofungin, Micafungin, Anidulalafungin,Rezafungin)
-Polyenes (Nystatin, Amphotericin B)
-Flucytosine
What is the MOA of Azoles?
OBJECTIVE !!!
inhibition of 14-α- demethylase resulting
in inhibition of fungal cell wall growth
Which of the Azoles is the most hydrophilic and is the only Azole used for candida in the urine (candiduria)?
!!!
Diflucan (Flucanozole)
IV and PO (1:1 conversion)
-covers multiple Candida species, also Cryptococci (except C. krusei)
What is the spectrum of activity of Itraconazole (Sporonox)?
-covers molds such as Aspergillus and dimorphic fungi
-metabolized by CYP enzymes
-ADE: heart failure (negative inotropic)
What is the unique side effect of Itraconazole (Sporonox)?
heart failure (negative inotropic)
How can capsules of Itraconazole be taken?
with food +/or acidic beverage
needs a loading dose -> then therapeutic drug monitoring (steady state reached after 2 weeks)
-better absorption with solution (but taste is terrible)
Which drug should be avoided because itraconazole requires an acidic environment?
PPIs
SUBA-itraconazole doesn’t need the acidic environment
What is the dosing approach for Voriconazole?
What is the pharmacokinetics behind it?
-Loading -> induction -> Maintenance
-CYP metabolism
-saturable (0-order) kinetics, like Phenytoin (build-up over time, may overdose when increasing the dose)
-IV and PO available
In which patients should Voriconazole be avoided?
What are the side effects?
-QTc prolongation
-use caution if history of arrhythmias
-IV is not recommended in CrCl < 50 ml/min (SBECD accumulation)
ADE: visual disturbances/hallucinations and skin rash, squamous carcinoma (long-term use)
-> need therapeutic drug monitoring (1-5 mcg/ml) to avoid ADEs
What does Posaconazole (Noxafil) require for its absorption?
How is it metabolized?
high-fat meal (high-fat meal needs an acidic environment -> avoid PPI)
metabolized by glucuronidation
What is the spectrum of activity for Posaconazole?
wide spectrum coverage
-but they don’t use it very often in the hospital
What is Isavuconazole (Cresemba) approved for?
Invasive Aspergillus and Mucormycosis
-less effective for invasive candida (IC)
Isavuconazole:
IV and PO
prodrug: activated by plasma esterases (doesn’t require a vehicle)
How does Isavuconazole affect QTc? How is it different from other azoles?
it shortens the QTc
(other azoles prolong it)
Which of the Azoles need therapeutic drug monitoring?
Itraconazole
Voriconazole
Antifungals coverage
Diflucan: multiple Candida species (also Cryptococci)
Itraconazole: molds such as Aspergillus and dimorphic fungi
Posaconazole: a wide spectrum of antifungal coverage
Which of the Azoles require an acidic environment and should not be given with PPIs?
Itraconazole
Posaconazole
When are Echinocandins started empirically?
-start Micafungin
in patients with risk factors for resistant Candida species or critically ill
-it has fungicidal activity against most Candida species + azole-resistant species
-less toxic than Azoles
For which type of infection should echinocandins be avoided?
fungal UTIs
(doesn’t get in the urine very well)
What is the MOA of Echinocandins?
!!! OBJECTIVE
beta(1,3) glucan synthase inhibitors
How is Caspofungin dosed?
requires loading dose
70 mg -> then 50 mg daily
only Candin that requires adjustment in mild hepatic impairment
What DDI should looked out for when using Caspofungin?
Cyclosporin
Tacrolimus
CYP inducers
What is the commonly used dose for Micafungin (Mycamine)?
100 mg daily
150 mg if esophageal candidiasis
How is Micafungin metabolized and what are possible drug interactions?
partially metabolized by CYP enzymes
DDIs with Cyclosporine
How is Anidulafungin dosed?
How is it metabolized?
loading dose of 200 mg then 100 mg daily
metabolized via chemical degradation (independent of the liver)
Which drug is a structural analog of Anidulafungin?
How is the dose different from Anidulafungin?
What is it approved for?
Rezafungin (Rezzayo)
-loading dose of 400 mg, then 200 mg weekly for 4 doses
-approved for invasive candidiasis (candidemia)
How should Rezafungin be dosed initially if switching from another candin?
EXAMQ !!!
still need the 400 mg loading dose
then 200 mg weekly
What are the two Polyenes?
Nystatin (used as topical)
Amphotericin B
What is the MOA of Amphotericin B?
binds to ergosterol (the sterol in the cell membrane of fungi) -> formation of ion channels and fungal cell death
What are the formulations of Amphotericin B?
-Deoxycholate formulation
Fungizone
-Lipid formulation
AmBiSome, Abelcet
What should be monitored when using Amphotericin B?
Amphotericin depletes K+ and Mg2+
-Nephrotoxic !!
Which of the formulations reaches the urine better?
Which one is more toxic?
the deoxycholate reaches the urine better and is more toxic
the lipophilic formulation reaches the tissues better
What are the adverse effects of Amphotericin B?
Infusion-related
-Chills/rigor (meperidine helps)
-fever
-headache
-muscle/joint pain
-N/V
-> use premeds: diphenhydramine, acetaminophen,
How is Flucytosine (5-FC) dosed?
weight-based dosing: 25 mg/kg/dose
-need renal dose adjustment
What are the side effects of Flucytosine?
bone marrow suppression
hepatoxicity
When is Flucytosine used as monotherapy?
recommenend in Candida UTI
-resistance develops after several days of monotherapy
(fungal UTIs may not need to be treated - Dr. Cluck)
When is Flucytosine used as an adjunct?
Candida endocarditis or meningitis
Cryptococcal infections
What is the MOA of Flucytosine?
-it is converted to 5-FU in the cell (chemo drug - bone marrow suppression)
-inhibition of protein synthesis (false Uracil base)
-inhibition of DNA synthesis (blocks thymidylate synthase)
What is Ibrexafungerp approved for?
only for Vulvovaginal Candidas (VVC)
Indication of Oteseconazole
VVC
has a long half-life
