Block 3

• Amphotericin B (AMB) DOC

  treatment of severe life threatening mycoses
• Amphotericin B (AMB) - MOA

  1. AMB binds to Ergosterol in fungal cell membrane
  2. Poke holes in cell membrane
  3. Leakage of cell contents out of fungal cell
• Fungus can impair AMB binding by (resistance)

  • decreasing the concentration
  • decrease the affinity of drug
• Can AMB be used alone to treat meningitis?

  no, Poor penetration into CNS - give intrathecally for CNS infection for fungal meningitis
• Amphotericin B (AMB) uses

  • Cryptococcus - fungal meningitis - Flucytosine + AMP
  • Sporotrichosis
  • Resistant leishmaniasis
• Amphotericin B (AMB) - Used as initial induction regimen for serious fungal infections, then replaced by azole drugs for chronic therapy
• Amphotericin B (AMB) Adverse effects

  • Infusion related - acute reaction - fever, chills -
  • due to release of histamine
• Amphotericin B (AMB) Adverse effects

  • Thrombophlebitis - inflammatory process that causes a blood clot to form
  • Use heparin to help with infusion
• Amphotericin B (AMB) Adverse effect

  • Anaphylaxis and convulsion
• Amphotericin B (AMB) adverse effect

  • Nephrotoxicity - hypokalemia and hypomagnesemia
  • Need to monitor level of ions
• Nephrotoxicity caused by AMB can be minimized by

  • liposomal preparation
  • Slow infusion
  • combine with flucytosine to reduce dosage of AMB
• Amphotericin B (AMB) adverse effect

  • Anemia - through decrease in erythropoietin production
• Nystatin - use is restricted to topical treatment of candida infection because of severe systemic infection
• Nystatin uses

  • Oral and Vaginal candidiasis
• Flucytosine - used with AMB for treatment of systemic mycosis and fungal meningitis due to crypt or candida
• How does Flucytosine work with AMB to cause a synergistic effect?

  AMB poke hole into the membrane, allowing more flucytosine into the cell to inhibit DNA
• Flucytosine MOA

  • Flucytosine is taken up by fungal cell via enzyme cytosine permease
  • Converted to 5-FU by cytosine deaminase then to FdUMP and FUTP
  • FdUMP inhibits DNA and FUTP inhibits RNA synthesis
• is flucytosine toxicity to human cells?

  no, humans cell are unable to convert flucytosine to active metabolite
• Flucytosine adverse effects

  • Bone marrow suppression
  • Hepatic dysfunction
  • GI disturbance
• Azoles MOA - Interfere with ergosterol synthesis

  • Inhibit 14-alpha demethylase - blocks demethylation of lanosterol to ergosterol
  • Disruption of membrane function and increase permeability
• Ketoconazole uses

  • shampoo for seborrheic dermatitis
  • Dermatophyte infection
  • ** 2nd line drug for treatment of mucocutaneous candidiasis - given orally
• Ketoconazole - Absorption of decreases by antacids
• Ketoconazole - inhibit activity of human CYP450 - increasing the level of multiple drugs
• Ketoconazole ADE

  • Gastric upset
  • Endocrine effect - block androgen and adrenal steroid synthesis
  • Hepatic dysfunction
  • ** Disulfiram like reaction with alcohol
• Fluconazole - Advantages

  • Excellent CNS permeability
  • Lack of endocrine adverse effects
  • good concentration in urine for candidal cystitis
• why is fluconazole a better choice for meningitis than AMB?

  good CNS permeability
• Fluconazole Uses

  • Cryptococcal meningitis
  • Candidal infection
  • Coccidioidomycosis
• Itraconazole

  • Azole choice for Blasto, sporotri, Paracocc and histo
• why isn't Itraconazole used for meningitis?

  poor CNS permeability
• Itraconazole ADE

  • Rash - Steven Johnson syndrome
  • Hepatic toxicity
  • GIT - N/V and diarrhea
• Itraconazole should be avoided in pregnancy
• Voriconazole - Approved for treatment of invasive aspergillosis
• Voriconazole

  • Inhibits CYP3A4 - reducing clearance of many drug - causing other to accumulate and become toxic
  • When giving voriconazole - reduce the dose of other drugs
• Voriconazole ADE

  • Transient visual disturbance - blurring and changes in color vision
• toxicities of high concentration of voriconazole

  • visual and auditory hallucination
  • hepatotoxicity
• Posaconazole uses

  • Candida and aspergillus in severely IC patients
  • Mucor
• why is Posaconazole preferred in candida and aspergillus infection over AMB?

  used in severely immunocompromised patients
• Posaconazole - Improved absorption by low pH and fatty food

  • drugs that increase pH will decrease absorption
• Posaconazole

  • Inhibitor of CYP3A4 - for drugs such as tacrolimus and cyclosporine
• • Isavuconazole
  • Less food drug interaction
  • Approved for invasive aspergillosis and mucor