Lecture 1 - Antifungal Agents Flashcards
Fungal Categories and which are more resistant to antifungals?
Yeasts (Unicellular)
Dimorphics ( Can be yeast or mold)
Molds (Multicellular & more resistant)***
Polyene Macrolide Antifungals
Amphotericin B
Nystatin
Polyene Macrolide Antifungal MOA
- Bind to ergosterol leading to pore formation and leakage of intracellular contents
Low conc of Polyene Macrolide Antifungal
selective for ergosterol-rich fungal cell membranes
High conc of Polyene Macrolide Antifungal
can damage cholesterol-rich mammalian cells
Amphotericin B Preparations info
Deoxycholate = rarely used
Liposomal ones = decrease ADE
Nystatin Preparations
Tabs
Suspension
Vag suppositories
Topical cream & powders
Amphotericin B Spectrum of Activity
Candida species (Except Lusitanae + auras)
Cryptococcus neoformans
Aspergillus species (Except terries)
Dimetacieous molds (inc rhizomes + mucorlaes)
Endemic fungi ( Blastomycosis, Histoplasma, Coccidiodes)
Liposomal (Ambisome) Dosing Adjustment
No adjustment for renal or hepatic insufficiency
Dose: 3-5mg/kg IV every 24hrs, can go higher if needed
Dose-limit toxicity of Amphotericin B?
Nephrotoxicity
rehydrate prior to admin
Monitoring for Ambisome
AST, ALT, ALP
K & Mg wasting
Acute pulmonary Tox
Infusion reactions
Drug interactions Amphotericin B
Nephrotoxicity accelerated by…
Calcineurin inhib (tacrolimus + cyclosporine) Aminoglycosides IV contrast Foscarne Cidofovir Tenofovir disoproxil fumarate
Meds that deplete K/Mg = Loop diuretics
Giving Amphotericin B infusion
Flush & Mix with D5W, incompatible w/ saline*****
premeditate with Benadryl/ APAP
Amphotericin B Nephrotoxicity Mechanism
- Reduces pre renal blood flow leading to decrease in GFR
- Binds to lipid bilayers of the proximal + distal tubules to cause direct toxicity
Effects Pre/Post Renal blood flow
Mitigating Nephrotoxicty Amphotericin B
Hydration, maintain euvolemia
Infuse 250-500ml NaCl 0.9% prior to infusion
Nystatin Spectrum of Activity
Candida Species
Tinea
Nystatin Toxicity
Limited due to minimal-low absorption
Oral associated with N/V/D
All potential hypersensitivity
Nystatin Oral susp
spit for oral candida
swallow for esophageal candida
Nystatin oral tabs
non absorbable
used for candida ppx only
5- Flucytosine (5-FC) MOA
Converted intracellularly from 5-FC -> 5-FU by fungal cytosine deaminase
Prevents fungal DNA/RNA synthesis
5- Flucytosine (5-FC) should only be used….
in combo with other antifungals given rapid resistance to monotherapy
often used corectal cancers
5- Flucytosine (5-FC) dose adjustment
Renal cleared
normal: Q6hr
CrCl 10-50 = dosing interval Q12-24hrs
CrCl < 10 = dosing interval Q24-48hrs
5- Flucytosine (5-FC) Spectrum of Activity
Candida Spp.
Cryptococcus neoformans
5- Flucytosine (5-FC) ADE
CBC w/ Diff (monitor for leukopenia)
N/V
Serum Drug lvls
5- Flucytosine (5-FC) Toxicity lvls
peak 50-100mcg/mL
Triazole Antifungals
Ketoconazole Fluconazole Itraconazole Voriconazole Posaconazole Isavuconazonium (pro-drug)
Triazole Antifungal MOA
Inhibit fungal 14-alpha demethylase-blocking ergosterol synthesis
Leads to dysfunctional fungal membrane synthesis
Fluconazole Spectrum of Activity
Candida albicans = + Candida glabrata = +/- Candida Krusei** = -- Aspergillus fumigateurs** = -- Cryptococcus neofromans= ++ Resistant mold Rhizomes Mucor** = --
Itraconazole Spectrum of activity
Candida albicans = + Candida glabrata = +/- Candida Krusei = +/- (small bump over fluc) Aspergillus fumigateurs** = + Cryptococcus neofromans = + Resistant mold Rhizomes Mucor** = --
Voriconazole Spectrum of Activity
Candida albicans = + Candida glabrata = + Candida Krusei = +/- Aspergillus fumigateurs** = ++ Cryptococcus neofromans = + Resistant mold Rhizomes Mucor** = --
Posaconazole Spectrum of Activity
Candida albicans = + Candida glabrata = + Candida Krusei = + Aspergillus fumigateurs = + Cryptococcus neofromans = + Resistant mold Rhizomes Mucor** = ++
Isavuconazole Spectrum of Activity
Candida albicans = + Candida glabrata = + Candida Krusei = + Aspergillus fumigateurs = + Cryptococcus neofromans = + Resistant mold Rhizomes Mucor = +
Which Tripazole has most Bioavial?
Fluconazole = ~ 100%, 80% Renal Elim unchanged
Fluconazole Dose Adjustments
Req dose adjustment
Reduce maintenance doses 50% for CrCl < 50mL/min
Fluconazole ADE + Monitoring Paramaters
Hepatotoxicity
Monitor AST,ALT, Alk phos
- torsades de pointes **
- EKG (Prolonged QT Interval) **
Itraconazole - Oral Spectrum of Activity
Candida albicans Cryptococcus neoformans Aspergillus spp histoplasmosis Blastomycosis Tines unguium (nail fungus)
Itraconazole admin recommendations
Take with an acidic beverage with drugs reducing gastric acidity
anything changing pH in Gut can cause issues
Itraconazole Bioavail
Difference between capsules and suspensions
Itraconazole ADE
**Hepatotoxicity **
** Ventricular dysfunction, CI in pts with CHF **
Hypersensitivity
Nause
Headache
Breast tenderness - gynecomastia
2nd Gen Triazoles
Voriconazole
Posaconazole
Isavuconazonium-isavuconazole
Ravuconazole - investigational
Albaconazole - investigational
Voriconazole Spectrum of Activity
Candida = including some fluconazole resistant
Aspergillus spp = Drug of choice for therapy for invasive disease
Resistant mold including Scedosporium, Fusarium
Less so other mold, Mucorales, Rhizopus
Dose adjustments req for Voriconazole
Requires Hepatic Dose adjustment
Load dose to reach Steady State
Notable ADE of Voriconazole
CNS: Hallucinations, agitation, anxiety, delirium
Hypersensitivity: Rash & phytotoxicity
Posaconazole Spectrum of Activity
Candida - including some fluconazole resistant
Aspergillus spp.
Resistant mold including Mucor, Rhizopus, Scedosporium, Fusarium
Posaconazole Dosing Adjustments
Suspension has erratic absorption, consider alternative dosing in pts with extreme weights
Distinc differences between oral suspension & oral delated release tabs/IV
Posaconazole ADE + Monitoring
Hepatotoxicity = AST/ALT, Alk Phos
torsades de pointes, prolonged QT interval
Hypersensitivity = rash + phototoxicity
No CNS
Isavuconazonium-Isavuconazole Spectrum of Activity
Candida - including some fluconazole resistant
Aspergillus spp.
Resistant mold including Mucor, Scedosporium, Fusarium
Isavuconazonium-Isavuconazole Dose adjustments
IV:PO is 1:1 ratio
Hepatic: no adjustment for Child-Pugh score A/B
Renal: no adjustment for insufficiency, including ESRD
Isavuconazonium-Isavuconazole notable ADE
** Shortens QT, unlike others which prolong ***
DI Itraconazole
H2 antagonist
PPI
Mg, Al, Ca antacid (space 1hr before, 2hrs after) or drink coca-cola or OJ
Triazole w/ most CYP interactions
Ketoconazole
Triazole w/ least CYP interactions
Fluconazole
DI Azoles ( Inhibitors)
HIV Protease Inhib
PK boosters 9Cobicistat
Will inc lvl of Azole, more tox
Interact with all, least with fluconazole
DI Azoles (Inducers)
Rifamycins
Carbamazepine
Phenobarbital
Efavirenz, Nevirapine, Rilpivirine
Will dec lvl of Azole, leading to potential failure
Interact with all, least with fluconazole
Ketoconazole MOA
Alters permeability of fungal cell wall, blocks CYP450 leading to build-up of toxic conc of hydrogen peroxide.
inhibits biosynthesis of phospholipids for cell membrane
Ketoconazole Spectrum of Activity
Not recommended, Systemic - No go = yeasts
Oral Salvage ONLY = Endemic Mold
Topical ONLY = Dermatophytes
Ketoconazole ADE
Hepatotoxicty
Liver function tests: AST, ALT, Alk Phos
Ketoconazole used topically for…
nail fungus or seborrheic dermatitis
Ketoconazole PO only as….
alternative for endemic fungi
Blastomycosis
coccidioidomycosis
histoplasmosis
paracoccidioidomycosis
Ketoconazole Severe Adverse effects
oral tab
potentially fatal liver injury and risk of DI + adrenal gland problems
Echinocandins
Caspofungin
Micafungin
Anidulafungin
Echinocandins MOA
Bind to (1,3)-B-D-glucan synthase preventing cell wall synthesis ultimately leading to cell lysis
Anidulfungin has Activity for….
Candida albicans
Candida glabrata
Candida Krusei
Candida parapsilopsis = +/-
Caspofungin has activity for…
Candida albicans
Candida glabrata
Candida Krusei
Candida parapsilopsis = +/-
Aspergillus fumigateurs = +/-
Micafungin has activity for…
Candida albicans
Candida glabrata
Candida Krusei
Candida parapsilopsis = +/-
Caspofungin Dose adjustment
Dec by 1/2 for Hepatotoxicity
None for renal issues
Micafungin Dose adjustment
none
Anidulagungin Dose adjustment
none
Echinocandin with most ADE
Caspofungin > Micafungin > Anidulafungin
DI Caspofungin
Rifampin, efavirenz, phenytoin, carbamazepine = dc lvls of caspo
Tacrolimus = dc lvl of taco
cyclosporine = inc lvl of caspo
DI Micafungin
Sirolimus + nifedipine = inc lvls of each
DI Anidulafungin
Cyclosporine = inc lvls of Anid, no dose adjust tho
Terbinafine MOA
inhibits squalene epoxidase- decrease sterol formation
early stage
Terbinafine indications
Topical superficial fungal infections
Oral use for onychomycosis
Terbinafine ADE
Cholestatic Hepatitis
** Onychomycosis, DONT use in pt with chronic or active liver disease **
Griseofulvin MOA
Inhibits fungal mitosis
Causes production of defective DNA which cannot replicate
Griseofulvin Indications
Treatment of ring worm infections of skin, hair and nails
Griseofulvin DI
Disulfiram reaction w/ alcohol
Decreased effect of oral contraceptives
Decrease warfarin effectiveness
Terbinafine Elim
Liver metabolism and 70% in urine
Griseofulvin Elim
liver metabolism + urine mostly metabolites
Ibrexafungerp MOA
inhibits (1,3)-B-D-glucan synthase but at different site than echinocandins
Ibrexafungerp Spectrum of activity
Bunch of Candida, including multiple azole-resistant and echinocandin-resistant including C auras + Aspergillus
No activity against Mucor + Fusarium
Ibrexafungerpy approved for…
Vulvovaginal candidiasis
** high fat meal inc bioavailability **
Ibrexafungerp ADE
GiI = D, Ab pain, N, V
CNS: Headache, dizziness,fatigue
D-Cateslytin Activity
In vitro activity against Candida albicans only
Topical only currently
Synergy w/ Voriconazole, isavuconazole, Amphotericin
APX001A activity
in Vitor against Candida, including….
Auris Cryptococcus Aspergillus Scedosporium Fusarium Mucor Coccidiomycosis
Synergy w/ Fluconazole
