Dr. James Antifungal Flashcards
What to be careful of when administering Antifungals?
-Electrolytes
-Renal function (Azole)
Types of Fungi
Non-invasive: mushrooms, rusts, smuts, puffballs, truffles, morels
Invasive (threats to humans): Yeast (unicellular), Molds, Dimorphics
How is a fungal cell different from a mammalian cell?
-Bacteria is prokaryotic (before nucleus - no nucleus)
-Fungal are eukaryotes, the difference to mammalian cells is the cell wall (mammalian cells have a cell membrane)
-> Newer drugs target the cell wall, rather than cell membrane to reduce toxicity
What are the most common fungi to cause infections?
Candida
-> Candida albicans (species)
for Molds: Aspergillus
-> A. fumigatus
How is the outer cell compartment of fungi structured?
-Cell wall: ß-(1,6)-glucan and ß-(1.3)-glucan
-Cell membrane: phospholipid bilayer -> Ergosterol embedded in the cell membrane
How is Ergosterol produced?
From Squalene
What is one MOA of Triazoles?
Triazoles
-Inhibition of 14-alpha-methylation of lanosterol -> reducing production of ergosterol
Resistance through efflux pumps and altered demethylase
Why is toxicity associated with Ketoconazole?
Interfere with Cholesterol pathway
-not seen in newer Azoles
How are newer Azoles different from the older ones?
They have less hormonal inhibition and a broader spectrum
Does Fluconazole need renal adjustment?
Yes
IV, PO available
Adverse effects of Fluconazole
Monitor LFT
-Prolonged QT
-rash
-SJS
What is a Contraindication of Itraconazole?
It is a negative inotrope
-> contraindicative in pt with heart failure
Adverse effects of Voriconazole
-Visual toxicity !!!
-Flourid, Bone, and Neurotoxicity
-rash
-hepatic
-QT prolongation
Why is Voriconazole dangerous in pt with renal impairment?
The IV form is compounded in Cyclodextrin,
Cyclodextrin is eliminated through the kidney, it accumulates in pt with renal impairment (CrCl less than 50)
Posaconazole
first to treat Myco category of fungal
-Adverse effects: hepatic, QT prolongation
Isavuconazonium
Prodrug, which increased it solubility
Which drug interactions are important to check when Azoles are administered?
CYP Interactions
Which diseases are treated with Fluconazole (Diflucan®)
-Candida species (except for C. krusei, and C. glabrata)
-Cryptococcus (starting with Amphotericin and flucytosine -> Fluconazole is used as a step down or when the fungi is in the brain)
-good penetration to CNS and urinary tract
Is IV to PO switch for Flucanozole possible?
Yes
Which organisms are not covered by Fluconazole?
Treatment gap
C. krusei, and C. glabrata
Itraconazole (Sporanox®)
-Broader spectrum than Flucanozole (includes molds and dimorphic fungi)
-IV to PO possible
-AVOID in heart failure patients !!! bc it is a negative inotrope
How is the capsule formulation of Itraconazole different from the suspension?
-Capsule: erratic absorption, has to be given with food/cola (to stimulate acid production of the stomach)
proton pump inhibitor raises the pH and decreases the absorption of Itraconazole -> switch to suspension
-Suspension: contains Cyclodextrin enhancing the absorption -> has to be given on an empty stomach - doesn’t matter if pt is on PPI
How is Itraconazole Tolsura different from Sporanox?
-Tolsura uses the SUBA Technology
-utilizes a solid dispersion of drug, improves the dissolution of poorly soluble drugs - compared to their normal crystalline form
-not interchangeable with Sporanox in terms of dosing
What Antifungal drug can be used in a patient who is on an acid-suppressive drug and additionally can’t use a suspension?
Itraconazole Tolsura
Voriconazole (Vfend®)
-Spectrum similar to itraconazole
-DOC for Aspergillus (before it Amphotericin Amphoterrible)
-weight-based dosing
-drug interaction with cyclosporine and tacrolimus
-changing from IV to PO is possible, but has to be discussed with the ID
-requires renal and hepatic adjustment
-> IV vehicles can accumulate!!!! EXAM
-for UTI: little efficacy
Where is Posaconazole (Noxafil®) used?
-Immunocompromised prophylaxis (AML/MDS)
-Potential use for zygomycosis
Posaconazole(Noxafil®)
-Suspension must given with a meal
-dosing depends on if for treatment or prophylaxis
-DR is more convenient, and more often used
-It is not interchangeable!!!
Isavuconazonium (Cresemba®)
-covers Aspergillus/mucormycosis
-broad coverage
-few drug interactions and fewer side effects
-requires load
Echinocandins
-Caspofungin (Cancidas®)
-Micafungin (Mycamine®)
-Anidulafungin (Eraxis®)
-Rezafungin (Phase III
Echinocandins
Inhibit 1,3-beta-glucan
-Covers most yeasts as well as some molds; Candida and Aspergillus (not the best for Aspergillus)
-Concentration dependant killing
-IV only
-Minimal drug interactions
-Minimal adverse effects
Difference between Echinocandins
-Caspofungin requires load, hepatic adjustment needed, and few drug interactions (Rifampin, cyclosporine, tacrolimus)
-Anidulafungin requires load
-all IV
Echinocandins
empiricall over Fluconazole
-severe candidiasis
-recent azole exposure
-pt with neutropenic (despite broad-spectrum antibiotics
pt can not tolerate other agents
Micafungin has 3 different doses
Polyenes
-Nystatin (swish and swallow)
-Amphotericin B (works systemically)
-MOA: inserts into the membrane and creates pores
What is the purpose of the 3 lipid-associated formulations of Amphotericin B?
-Lipid complex (Abelcet®) - common
-Liposomal (AmBisome®) - common
-Cholesteryl Sulfate Complex (Amphotec®)
to reduce toxicity
When is the conventional formulation of Amphotericin used?
-Symptomatic candiduria
-Extemporaneous compounds
BUT
-multiple adverse events
-Saline dosing to reduce nephrotoxicity
Where are Lipid Associated Amphotericin used?
-Life-threatening fungal infections
-Category D: avoid in pregnants
Advantages of Life-threatening fungal infections
-Can give higher doses
-Reduced nephrotoxicity
-Limited use in urine
Disadvantage: Expensive
Adverse effects of Amphotericin
-Flu-like symptoms: chills, fever,
headache, malaise
-Hypotension
-Electrolyte imbalances (must be replaced)
-Arrhythmias
-LFTs go up
-and more
Pharmacist role in Amphotericin
weight-based dosing
-not compatible with saline alone, saline -> dextrose -> Amphotericine -> Dextrose -> saline
-monitor: K, Mg, Ca, HCO3, CBC
Flucytosine (5-FC)
5-FC gets converted into 5-FU -> phosphorylation and incorporated into Thymidylate synthase -> Inhibition of DNA synthesis
- Substition for Uracil -> Inhibition of protein synthesis
How is Flucytosine used?
-Given in combination with Amphotericin for Candida and Cryptococcus
-sometimes monotherapy for UTIs, bc it gets in the urine so well - Candi
Important to know - Flucytosine
Weight-based dosing
-Renal adjustment
Side effects:
-Diarrhea, abdominal cramping -> dose is too high
-skin diseases
MOA Ibrexafungerp
-inhibits glucan synthase, an enzyme involved in the
formation of 1,3-β-D-glucan
Terbinafine
-Oral and topical Allylamine
-Onychomycosis of the toenail or fingernail
-inhibits squalene epoxidase (biosynthesis ergosterol)
Side effects: Terbinafine
-Skin reactions, SJS/TENS
-liver toxicity - not for pt with liver disease
Broad overview:
-DNA synthesis/protein inhibition: Flucytosine
-Squalene epoxidase inhibition: Terbinafine
-Inhibit Ergosterol formation: Azoles
-Insertion and pore-formation into the cell membrane: Amphotericin B, nystatin
-disrupting the cell wall: Ibrexifungerp, Echinocandins
Natamycin
-Antifungal eyedrop
Topical Antifungals
-Imidazoles
-Triazoles
-Allylamines
-Ciclopirox
-Tolnaftate - similare to Terbinafaine
