Systemic Antifungal Therapy Flashcards
What are the triazole antifungals? MOA? Is this fungicidal? What is the spectrum of activity? What is each the treatment of choice for? Adverse effects? Drug interactions?
Fluconazole, Itraconazole, Posaconazole, Vorionazole (F VIP). MOA: Inhibit 14-alpha-sterol-demethylase – an enzyme necessary in the formation of ergosterol synthesis. Inhibition of ergosterol synthesis impedes fungal growth, but will not kill existing fungi (this is left up to the host immune system). Fluconazole: Lowest spectrum of activity – Some Candida, Cryptococcus, endemic mycoses. Voriconazol & Itraconazole: Mid spectrum of activity – All Fluconazole + broader Candida coverage, Aspergillus. Posaconzole: Greatest spectrum of activity – All Vori/Itra/Fluconazole + Zygomocoses (Fusarium, Mucor). Fluconazole: DOC for susceptible candidiais (incl. thrush & esophageal), 2 for tx & prophylaxis of cryptococcal mening; Itraconazole: 2 for tx & prophylaxis of systemic histoplasmosis; Voriconazole: DOC for invasive aspergillois; Posaconazole: prophylaxis of aspergillosis/candidiasis in immunocompromised. These are relatively safe – liver enzyme abnormalities (LFT monitoring warranted if long-term tx). GI. Voriconazole: visual disturbances. ALL ARE INHIBITORS OF P450.
MOA of Amphotericin B? Is this fungicidal? What is the spectrum? Adverse effects? How are adverse effects minimized? What’s the catch?
MOA: A polyene macrolid that inhibits ergosterol, generating pores int he fungal cell membrane and kills existing fungi – Fungicidal! Spectrum: BROAD – Cadida, Aspergillus, Zygomycoses, Histoplasma, Crytptococcus…This drug has good efficacy but poor tolerability – Adverse Effects: Nephrotoxicity!! (essential to monitor serum creatinine), acute infusion rxn, electrolyte abnormalities. Lipid formulations reduce adverse effects – there is equal efficacy with better tolerability. The catch is that toxicity risks still exist, and that these lipid forms are extremely expensive.
What is the newest class of antifungals? What are the agents and what are the differences between them? MOA? Approved for? Are these safe? How are they administered? (As review, how are azoles and amphotericin B administered?)
Echinocandins: Caspofungin, Anidulafungin, Micafungin (CAM). These are are “me too” drugs and are similar in terms of efficacy and toxicity. MOA: Inhibit B-D-Glucan Synthase – an enzyme needed for cell wall synthesis. Because we don’t have a cell wall, these drugs have very few side effects and few drug interactions. Approved and excellent for azole-resistant candida! Also: refractory aspergillus, other candida (incl. esophageal), empiric for febrile neutropenic pts. These are only given IV (azoles can be oral or IV, Amphotericin B is only IV).
MOA of action of flucytosine? Spectrum? How is this given? Adverse effects?
MOA: Considered an antineoplastic drug – This is a prodrug that is converted to 5-fluorouracil (5-FU) by fungal enzymes and is a pyrimidine analogue that inhibits DNA & RNA synthesis. Spectrum: very narrow, but this is the DOC for Cryptococcal meningitis!! This is only given orally, and it is only ever given in COMBINATION because of resistance (fungal enzymes that activate the prodrug will mutate). Adverse effects: Remember, consider this a chemotherapeutic drug! Bone marrow toxicity, liver dysfunction, GI intolerances. These adverse effects are concentration dependent and blood levels must be measured.
