Antifungal therapy week 4 Flashcards
What drug class is amphotericin B in?
polyene
Amphotericin B
MOA
administration
What can be combined with this drug to increase drug delivery?
Clinical use
Toxicities
What things are often coadministered to reduce side effects?
Is this drug protein bound? Where in the body does it concentrate?
MOA: binds ergosterol in cell membrane (ergosterol unique to fungi)forming membrane pores that allow leakage of contents, oxidative damage, and cell death. Amphotericin tears holes in the fungal membrane by forming pores.
Administration: IV, topical, and oral formulations (oral form not absorbed systemically)
Combinations to increase drug delivery: Acidic and basic properties (amphoteric), insoluble in H20 - needs to be combined with deoxycholate and bile salts to increase solubility. Lipid formulations of AmB: drug “wrapped” in phospholipids- more efficient transfer of drug to fungal cell membranes leading to less nephrotoxicity, more costly
Clinical use: Serious, systemic mycoses. Systemic Candida infections, Severe pneumonia and extrapulmonary Blastomyces, Coccidiodes, Histoplasma, Paracoccidiodes. Also used for Mucormycosis. Combined with flucytosine in treatment of Cryptococcal meningitis. Used intrathecall for fungal meningitis. Also used for invasive Aspergillosis, invasive Sporothricosis.
Toxicities:
- Nephrotoxicity: dose dependent azotemia (increase in BUN and creatinine)-REVERSIBLE if drug is stopped. Intra-renal vasospasm with decreased GFR and K+ and Mg2+ wasting. Hydration with normal saline reduces nephrotoxicity.
- Fevers, chills (“shake and bake”)
- hypotension, nausea, vomiting
2 and 3 due to IL-1 and TNFa release. Coadministration with ASA, acetaminophen, chlorpheniramine, hydrocortisone reduces these effects
- Anemia due to reduced erythropoietin production. Usually reversible.
- IV phlebitis
- Degraded in situ, no dose change for liver or renal disease
- Highly protein bound, concentrates in liver, spleen, kidneys; minimal in CSF
Flucytosine
What drug class is flucytosine in?
MOA
how does it get into fungal cells? what happens once it gets there?
clinical use
toxicities
administration
route of elimination-what does this mean for dosage adjustment?
Flucytosine-antimetabolite
MOA: Inhibits DNA and RNA synthesis. Taken into fungal cells by cytosine permease. Deaminated by cytosine deaminse to 5FU then 5-UTP. 5-UTP is incorporated into DNA/RNA
Clinical use: Mainly Cryptococcal meningitis in combination with Amphotericin B. When used alone, resistance develops quickly. AmB and flucytosine are synergistic-AmB permits uptake of flucytosine into fungal cells for it to perform its job.
Toxicities: Bone marrow suppression-leukopenia, thrombocytopenia. Remeber that most antimetabolite drugs will do this (methotrexate, sulfa drugs, 5-FU, etc). Clinical microbio-also get N/V/D. Reaons for these side effects in the DNA damage occuring in rapidly dividing cells such as bone marrow and GI epithelial cells.
Administration: Oral form only; well absorbed from GI tract; good CNS penetration
Elimination: 80% of drug excreted unchanged in the urine. Monitor serum levels- more toxicity seen with high serum levels. Dose reduction required with renal insufficiency (reduced renal elimination)
What drugs are in the azole family?
What drug(s) are in the imidazole family? Triazole family? What is the difference?
Clotrmazole, fluconazole, itraconazole, ketoconazole, miconazole, voriconazole, posaconazole
•Two classes of azoles: imidazoles and triazoles
Imidazoles: ketoconazole, miconazole, clotrimazole.
Triazoles: Fluconazole, Itraconazole, Voriconazole, Posaconazole
•Triazoles have 3 nitrogen atoms in their azole ring conferring greater affinity for fungal rather than mammalian CYP450 enzymes, thus fewer side effects compared with imidazoles (2 nitrogen atoms in azole ring)
Azoles-Clotrimazole, fluconazole, itraconazole, ketoconazole, miconazole, voriconazole, posaconazole
MOA
clinical use
toxicities
Clotrmazole, fluconazole, itraconazole, ketoconazole, miconazole, voriconazole, posaconazole
MOA: Inhibits lanosterol demethylase which convers lanosterol to ergosterol. Renders membrane leaky.
Clinical use: Local and less serious systemic mycoses. Ketoconazole used topically to treat Tinea skin infections (concentrates in keratinocytes). Fluconazole used for skin, mucosal, and systemic Candida infections, chronic supresion of Cryptococcal meningits in AIDS pts, Coccidiomycosis, Histoplasmosis, Blastomycosis, Paracoccidiomycosis (less active against Histo and Blasto). Itraconazole for Blastomyces, Coccidioides, Histoplasma, Paracoccidioides, Sporthrix, Tinea, onychomycosis. Clotrimazole and miconazole for topical fungal infections-pityriasis versicolor, cutneous candidiasis, tinea, corporis, etc. Voriconale is treatment of choice for Aspergillus infections, also activity against Candida, Cryptococcus, Dimorphic fungi but no activity agains Zygomycetes. Posaconazole is broadest spectrum azole available and active against Candida, Cryptococcus, dimorphs, Aspergillus, and Zyomycetes (unlike Voriconazole). Posaconaole used for prophylaxis against invasive fungal infections in high risk pts and for tx of oro-esophageal Candida infections
Toxicites: Testosterone synthesis inhibition (gynecomastia, esp with ketoconazole), liver dysfunction (inhibits CYP-450)
Echinocandins
Drugs in this class
MOA
Clinical use
toxicities
Echinocandins: Capsofungin, Anidulafungin, Micafungin
MOA: Inhibit cell wall synthesis by inhibiting synthesis of β-glucan, a cell wall component.
Clinical use: Invasive Aspergillosis, mucosal or systemic Candida
Toxicity: GI upset, flushing (by histamine release)
