Anti-Fungal Drugs - Fitzpatrick Flashcards
Amphotericin B falls under what class of drugs?
polyenes
what is the MOA of Amphotericin B?
Penetrate cell membrane and bind to ergosterol to create pores thus disrupts membrane integritiy and increase osmotic fragility (allows nutrients and electrolytes to leak out and thus killing the cell. )
What AE are associated iwith Amphotericin B
Onset at infusion: chills, fever, anemia, hypotension
Later onset: nephrotoxicity
How does amphotericin B cause nephrotoxicity?
Direct damage to distal tubule membrane leading to Na, K, and Mg wasting and the drug induced hypokalmeia and hyponatremia leads to decreased GFR and arteriole constriction
Commonly what other drugs are affected due to nephrotoxicity caused by amphotericin B?
Cyclosporine, sirolimus, tacrolimus as used in transplant pts
Foscarnet, pentamidine as used in HIV pts
Aminoglycosides, vancomycin as used in MRSA and other gram negatives
what are the 1st generation Triazole drugs
Fluconazole and Itraconazole
What are the 2nd generation Triazoles
Voriconazole and posaconazole
Trizole and imidazole are azoles. what is the MOA of azoles?
Inhibits Lanosterol to ergosterol biosynthetic pathway. Thus creating a ergosterol deficit and disrupt sterol content of lipid bilayer. The specific enzyme blocked is 14-a-demethylase (cypP450)
what are the indications for Fluconazole?
- Narrow spectrum drug used to treat 1. Candida albican (candidemia, local candidiasis); 2) Cryptococcus (meningitis, with AMP-B)
what two triazoles have good CSF access?
Flu and voriconazole
which Triazole has strong drug interactions due to CYP450 inhibition
Itraconazole
which Triazole is mainly cleared by renal and thus effective against renal infections
Fluconazole
Fluconazole is usually finrst line for candida, but if it does not work, whats the next drug of choice?
Voriconazole
what drug is clearedly renal mostly and thus is used for candiduria
Fluconazole (renal excretiona nd high bioavailability)
Which azole is used for aspergillus?
Voriconazole. If that doent work then try Itraconazole as 2nd line
HIV pt presents with cyryptococus infection, what is the drug of choice?
Fluconazole
Mechanism of resistance to azoles
- Mutation or overexpression of lanosterol 14-a-demethylase
- efflux
- changes in sterol and/or phospholipid composition
what is the drug of choice for Histoplasmosis, cocidioides, blastomycoses?
Itraconazole
Caspifungin is an Echinocandins. what is the MOA of Echinocandins?
- Inhibit fungal Cell wall synthesis by blocking b(1,3) glucan synthase thus depleting b(1,3 glucan) and creating osmotic fragility
Is caspifungin given IV or PO?
IV. No PO meds available
Pertinent PK of caspofungin
- well tolerated
- Hepatic metabolism
- Few drug interactions
Indication for Caspofungin
- Opportunistic infections (serious): invasive candidiasis, candidemia, invasive aspergillosis
- Esp useful if refractory to other therapies. Active against most candida and aspergillus spp.
An AIDS pts with oropharyngeal candidiasis failed on fluconazole, Amphotericin B, and itraconazole. What is the next choice of drug?
Caspofungin
Will caspofungin work for Histoplasmosis, coccidiodomycosis or fusarium ssp?
NO
Pt presents with histoplasmosis who was treated with anti-TNFa therapy (9-infliximab, 1-etanercept) and did not recover. what else can be given?
Itracanazole
what is the drug of choice for invasive aspergillosis?
Voriconazole
what is the 3rd line therapy of Triazole that is given PO and requires gastric acid.
Ketoconazole
Which triazole is known to inhibit human adrenal and gonadal steroid synthesis causing gynecomastia and decreased libido
Ketoconazole.
A GERD pt who routinely takes an PPI develops a fungal infection and is given an oral antifungal drug. but symptoms did not improve. what drug was he most likely given?
Ketoconazole, an oral triazole. It requires gastric acid (low pH) and becuase this pt was taking an PPI, the drug did not work. Similar to Itraconazole, it also requires gastric acidity to dissolve.
What AE are associated with Triazoles?
- terotogenic thus avoid in pregnancy
- Liver damage
- Voricoanzole disturbs vision
What is the drug of choice for mucormycosis?
Amphotericin B
What is the drug of choice for cryptococcal meningitis?
Amphotericin B, given with 5-FC (5-fluorocytosine anti metabolite).
What is the role of 5-FC in treating cryptococcal meningitis?
It uses cytosine deaminase to ultimately inhibit DNA synthesis by blockign thymidyate synthase and also inhibits protein synthesis.
What is the mechanism of resistance to 5-FC
- mutated cytosine permease
- mutated cytosine deaminase
