Anti-Fungal Flashcards
Prokaryotic bacterial cell wall contain peptidoglycan while eukaryotic fungal cell wall contain ________
Chitin and B-1,3-glucan
Which two anti fungal agents are polyenes?
Polyene: bind to ergosterol in cell membrane and form pores, disrupt membrane function, allow K+ and small molecules to leak from the cell
Amphotericin B (IV)
Nystatin (oral, topical)
Amphotericin B is active against:
Candida
Histoplasmosis
Cryptococcus meningitis (in combi w 5-Flucytosine)
Aspergillus
Amphotericin is insoluble in water and hence must be formulated with _____ or ______
Conventional: sodium deoxycholate
Liposomal: form liposomes
Which of the 2 formulations of Amphotericin B has better CSF penetration
Liposomal
*Though both generally have poor CSF penetration
What are Amphotericin B adverse effects?
- Fever and chills (infusion-related toxicity)
- Nephrotoxicity - bc conventional formulation causes renal vasoconstriction, hence can cause renal dysfunction
**Hydration - Electrolyte imbalance, hypotension
- Hypokalemia
- Digoxin interactions
**Potassium supplement - Thromboplebitis
**Add heparin to infusion - Bone marrow suppression
5-flucytosine enters fungal cells through cytosine specific permeases, and is converted by _______ to ________
Converted by cytosine deaminase to 5-fluorouracil (5-FU)
What is the action of 5-FU?
- Converted to FUTP, incorporates into fungal RNA in place of uridylic acid, inhibit protein synthesis
- Metabolised to FdUMP, potent inhibitor of thymidylate synthase which is involved in DNA synthesis
5-FC has activity against _____ and _____
Candida
Cryptococcus meningitis (in combi w Amphotericin B)
*Also effective against yeast infection
5-FC is cleared via ______
Dose adjustment is required in _______
80% excreted unchanged in urine
Dose adjustment required in renal impairment
What adverse effects are associated with 5-FC?
- GI effects
- Hepatotoxicity
- Bone marrow suppression
Why must 5-FC be used in combi with Amp B for Cryptococcal meningitis?
Some fungal cells express decreased level of the enzymes involved in conversion of 5-FC to 5-FU (cytosine specific permease, cytosine deaminase)
Hence, Amp B can form pores in cell membrane, allow more 5-FC to penetrate the cell (synergistic effect)
Echinocandins bind to _________
B-1,3-glucan synthase, hence interfere with the structural intergrity of the cell wall => cell rupture
Echinocandins are active against ______ and _______
It is first line again which?
Candida (first-line)
Aspergillus
How is Echinocandin cleared?
Metabolised slowly by hydrolysis and N-acetylation, eliminated in urine and feces
NOT cleared renally, no dose adjustment required
Which systemic anti-fungal agent is generally well-tolerated?
Echinocandins
Azoles are _____ inhibitors
C-14a demethylase inhibitors
Block the demethylation of lanosterol to ergosterol, disrupt membrane function, increase membrane permeability
What might cause resistance to azoles?
- Mutation of C-14a demethylase gene
- Efflux pump
Triazoles are administered via ____ route
Oral/IV (except Itraconazole - oral only)
*Posaconazole
- Capsule, Syrup
*Itraconazole
- Capsule (after meal), Solution (empty stomach)
*Voriconazole
- Tablet, Syrup
What are Triazole spectrum of activity?
Fluconazole: Candida, Histoplasmosis, Cryptococcal meningitis
Posaconazole: Candida, Aspergillus
Itraconazole: Candida, Aspergillus, Histoplasmosis, Onychomycosis
Voriconazole: Candida, Aspergillus (1st line)
Which triazoles have good CSF penetration?
Fluconazole and Voriconazole
Which triazole is cleared renally?
When is dose adj required?
Fluconazole
*Require dose adj in renal impairment
For the rest, dose adj in renal impairment is required if given IV (due to cyclodextrin - nephrotoxic)
How are Posaconazole, Itraconazole, and Voriconazole cleared respectively?
Posaconazole:
- Feces
Itraconazole:
- Metabolized by liver, excreted in feces and urine
Voriconazole:
- Metabolized by CYP450, excreted via urine
Itraconazole and Posaconazole absorption are affected by _____
Antacids/PPI
incr in pH cause dcr absorption
Azoles are CYP450 ______
inhibitors
What are triazole adverse effects?
- GI effects
- Skin rash
- Headache
- Hepatotoxicity
- Prolong QT interval
Fluconazole: hair loss after 2months
Itraconazole: cardiotoxicity
Voriconazole: neurotoxicity (visual disturbances, hallucinations), periostitis with long term use due to fluoride excess
Name 2 imidazoles
- Clotrimazole
- Miconazole
Imidazoles have wide range of action, including activity against ___ and ____
Candida
Trichophyton (causes Tinea)
What is used to treat oropharyngeal candidiasis?
Itraconazole solution
Clotrimazole oral troche
Nystatin gargle (swish and swallow/spit)
What is used to treat vulvovaginal candidiasis?
Single oral dose fluconazole
Clotrimazole cream
Miconazole pessary
Nystatin pessary
What are some adverse effects with imidazole?
Topical use:
- contact dermatitis
- vulvar irritation
- edema
Oral use:
- GI disturbances
- Clotrimazole: elevated liver enzymes
Why can’t nystatin be used parenterally?
IV use is associated with systemic toxicity - acute-infusion related adverse effects + nephrotoxicity
Terbinafine is a _______ inhibitor
Squalene epoxidase
- Block conversion of squalene to lanosterol, thus inhibit biosynthesis of ergosterol
- Accumulation of toxic amount of squalene also causes increase membrane permeability
Terbinafine is active against:
Trichophyton, dermatophytes
*dermatophytes are fungi that require keratin for growth
What are the 2 drugs that can be used for dermatophyte onychomycosis and tinea capitis?
Oral Terbinafine (40% oral bioavailability)
Oral Itraconazole
=> require systemic absorption to accumulate in keratin in nails or scalp
How is terbinafine eliminated?
metabolized by CYP450 enzyme, excreted mainly via urine
*Avoid in renal and hepatic impairment
What drugs are metabolized by CYP450?
Metronidazole
Voriconazole
Terbinafine
Terbinafine adverse effects
GI
Headache
Rash
Elevated liver enzymes
Terbinafine should not be given to ______
Breastfeeding mothers as it accumulates in the breastmilk
