Anti-Fungal Agents Flashcards
What has the broadest spectrum of all anti-fungal agents?
Amphotericin B
Amphotericin B ROA
IV - not orally absorbed
What is Amphotericin B standard of care for?
Life threatening fungal infections
What are the problems with Amphotericin B?
It has significant adverse side effects
Amphotericin B MOA
- Ampho B binds to ergosterol in fungal membrane
- Forms pore in the membrane thereby increasing membrane permeability
How is amphotericin B specific for fungi?
Binds to ergosterol but only weakly to cholesterol so it does not affect host cells as much
What is the only fungi amphotericin B is not effective against?
Pseudallescheria boydii
What is amphotericin B resistance associated with?
Decreased ergosterol in the cell membrane
What is the typical regimen of therapy for amphotericin B?
Used as an initial induction therapy (typically 4 weeks) to reduce fungal burden, then replaced by newer, less toxic AZOLE drugs for consolidation therapy and prevention of relapse
What is the treatment of choice for Zygomycosis/mucormycosis?
Amphotericin B
What is the only anti-fungal agent approved for pregnant and breastfeeding women?
Amphotericin B
Amphotericin B SE
- Fever, chills, muscle spasms, vomiting, headache and hypotension
- Nephrotoxicity
- Hepatotoxicity
- Anemia
Flucytosine Pharmokinetics
- Good oral bioavailability
- Good penetration into the CSF
What does the CSF penetration of flucytosine make it useful in treating?
Cryptococcus meningitis
Is dosage adjustment of Flucytosine required in renal failure?
Dosage adjustment required in presence of renal insufficiency
Flucytosine MOA
Taken up via cytosine permease and converted by fungal-specific cytosine deaminase to 5-FU analogs that inhibit thymidylate synthase (DNA synthesis) and RNA synthesis
Spectrum of Action of Flucytosine
- Cryptococcus neoformans
- Candida sp
- Agents of chromoblastomycosis
Why is the use of flucytosine restricted?
Acquired resistance is very high
How does amphotericin B interact with flucytosine?
Ampho B enhances fungal cell uptake of flucytosine as it generates pores in the fungal cell wall
Flucytosine SE
- GI effects
- Bone marrow toxicity
- Anemia
- Teratogenic
What are the 2 groups of -azole drugs and what are the drugs in each class?
Imidazoles
- Ketoconazole (prototype)
Triazoles
- Fluconazole
- Itraconazole
- Voriconazole
- Posaconazole
What is the general spectrum of activity of all of the -azoles?
All have some activity against Candida and Cryptococcus
What is the order of the azoles from narrowest in spectrum to broadest spectrum?
Fluconazole - Itraconazole - Voriconazole - Posaconazole
Why do -azoles have a large potential for drug interactions?
They are all major inhibitors of CYP450
-azole MOA
Inhibit 14α-sterol demethylase involved in the biosynthesis of ergosterol, an essential component of fungal membranes
-azole SE
- GI Distress
- Hepatotoxicity- requires hepatic enzyme monitoring
- Can cause fetal abnormalities
Which -azoles are related to the most drug interactions?
Most drug interactions are associated with Itraconazole and Voriconazole
Itraconazole and Voriconazole Contraindications
Itraconazole and Voriconazole should NEVER be given to a patient taking STATINs due to increased risk of developing fatal Rhabdomyolysis
Ketoconazole Pharmokinetics
- Oral ketaconazole requires acidic environment for absorption
- Poor penetration into CSF and urine
Fluconazole Pharmokinetics
Good oral bioavailability and Excellent penetration into the CSF
What drug has the fewest drug interactions of all the -azoles?
Fluconazole
Fluconazole SE
- Nausea, headache, skin rash and GI
- Alopecia (reversible) associated with long duration/high dose therapy
Why is fluconazole useful for fungal bladder infections?
80% of drug eliminated unchanged in the urine
Itraconazole Pharmokinetics
Poor penetration of CSF, urine and eye
Itraconazole SE
- Triad of Hypertension, Hypokalemia and Peripheral Edema
- Can cause CHF in patients with ventricular dysfunction
Voriconazole Pharmokinetics
Well absorbed, broadly distributed into tissues including CSF - bioavailability is unpredictable and affected by genetic polymorphisms
What is unique about the metabolism of voriconazole?
Non-linear metabolism - 50% increase in dose = 150% increase in serum concentration
What is the treatment of choice for invasive Aspergillus?
Voriconazole
Voriconazole SE
- Periostitis
- Transient vision changes
- Photosensitivity/Rash- rarely Stevens Johnson syndrome
ONLY with very high doses
- Visual/Auditory hallucinations
- Seizures
Posaconazole Pharmokinetics
Readily distributes to tissues, but POOR penetration of CSF and URINE
What is the only azole effective VS Zygomycosis/Murcormycosis?
Posaconazole
What are the Echinocandins?
Caspofungin
Micafungin
Anidulafungin
Echinocandin Pharmokinetics
Poor penetration of CSF
Echinocandin SE
Well tolerated- few adverse effects
- Histamine-like effect (skin itching)- associated with rapid infusion
- Embryotoxic- NOT TO BE USED IN PREGNANCY
Echinocandin MOA
Echinocandins competitively inhibit ß(1-3)-D-glucan synthase complex involved in the biosynthesis of the principal building block of the fungal cell wall
- impairs structural integrity of fungal cell wall
- increases osmotic instability leading to cell death
What do echinocandins lack activity against?
Cryptococcus or dimorphic fungi
Griseofulvin Clinical Use
Only clinical use is for the treatment of mycotic infections of the skin, nail and hair due to dermatophytes:
Microsporum, Epidermophyton & Trichophyton
Griseofulvin MOA
The drug is fungistatic and binds to fungal microtubules, preventing the formation of the mitotic spindle and inhibiting fungal mitosis
Terbinafine Clinical Use
- Activity is limited to dermatophytes and Candida albicans
* Used in the treatment of tinea captis, tinea corpis, tinea cruis, tinea pedis and onchomycosis
Terbinafine MOA
Inhibition of fungal SQUALENE EPOXIDASE in membrane synthesis which leads to a build up of squalene which is toxic to the fungal cells
Nystatin MOA
Binds to ergosterol and forms pores in the fungal membrane - like ampho B
Nystatin ROA
Too toxic for IV - only in gels, creams and ointments
What is nystatin not active against?
Not active against dermatophytes
opical Azoles: Clotrimazole, Miconazole and Terconazole Clinical Uses
Oral and Vulvovaginal candidiasis
Dermatophyte infections
Topical Allylamines: Terbinafine and Naftifine and Benzylamines: Butenafine Clinical Uses
Candida albicans and dermatophytes
- Used in the treatment of tinea cruris, tinea corporis and tinea pedis