1
Q
Amphotericin B Class Mechanism Spectrum Toxicity Use
A
- Class - polyene
- Mechansim – binds w/ ergosterol → membrane disruption / porosity → loss of membrane potential / death. AmB also oxidaized by lipoxygenases → free radical damage. Fungicidal.
- Spectrum – Everything except Candida lusitaniae and Aspergillus terreus. Great for Cryptococcus, Endemic fungi (Histo, Blasto, Coccidiomycosis), and Zygomycetes.
- Toxicity – Main problem is renal toxicity (distal tubular acidosis / electrolyte wasting). Must monitor kidney function.
- Infusion fever, rigors, and SOB. Must pre-treat w/ Tylenol or acetaminophin and benedryl.
- Use – 1st line for cryptococcal meningitis, severe endemic disease, and zygomycosis.
2
Q
Are triazoles fungistatic or fungicidal?
A
Fungistatic against yeast
Fungicidal against molds
3
Q
Mechanism of azoles
A
Inhibition of fungal p450 enzyme 14-alpha-demethylase, interrupting conversion of lanosterol to ergosterol
4
Q
General side effects of azoles (3)
A
Liver toxicity
Endocrine effects such as low testosterone and glucocorticoids → gynecomastia and adrenal insufficiency.
Teratogens.
5
Q
Fluconazole Spectrum Distribution Elimination Toxicity Use Resistance mechanism
A
- Spectrum – Most Candida (not C glabrata or C krusei), Cryptococcus, and Coccidioidomycosis. NOT aspergillus or zygomycetes.
- Good distribution to CNS (cryptococcal meningitis) and urine (Candida cystitis).
- Renal elimination
- Toxicity – Overall very safe. Teratogen, QT prolongation w/ risk of Torsades (do ECG before and during use), and drug interactions (CYP450 inhibitor)
- Use – 1st line for mucosal Candidiasis (oral, esophageal, vaginal), Candida cystitis, and Coccidioidomycosis meningitis. 1st line step down therapy for invasive candidiasis (not glabrata or krusei) and cyrptococcal meningitis (start w/ Amphotericin B which is bactericidal).
- Resistance – due to alteration of target enzymes (14 demethylase) and efflux.
6
Q
Itraconazole Spectrum Absorption (2 forms) Distribution Toxicity Use
A
- Spectrum – same as Fluconazole (Candida and Cryptococcus) + ENDEMICS, ASPERGILLUS, DERMATOPHYTES (tinea), sporothrix shenckii, penicillium, and pheohyphomycetes. NOT Zygomycetes.
- Absorption – liquid form is better than capsule form. Need acid and food for capsule. Do drug monitoring to make sure they’re actually absorbing enough of the drug.
- Poor CNS and urine distribution. Not good for meningitis.
- Toxicity – Drug interactions due to CYP450 inhibition. Need to do drug monitoring. QT prolongation and teratogenicity.
- Use – 1st line for dermatophytes (tinea). Step down for endemics.
7
Q
Voriconazole Spectrum Distribution Metabolism Toxicity Use
A
- Spectrum – Itraconizole (CANDIDA, Cryptococcus, endemics, ASPERGILLUS, dermatophytes) + C GLABRATA and C KRUSEI. NOT zygomycetes.
- Good CNS distribution. Not urine.
- Variable metabolism speed due to CYP19 polymorphism. CYP450 inhibitor. Need to do drug monitoring.
- Toxicity – More issues than other azoles.
- Photopsia – see bright / blue lights. Benign and reversible, but should not drive at night.
- Hepatotoxicity
- Common photosensitivity w/ prolonged tx. Avoid sun exposure.
- Teratogen
- QT prolongation
- Rare hallucinations, mainly in elderly.
- Use – 1st line for invasive aspergillosis, Fusarium, and Scedosporium.
8
Q
Posaconazole Spectrum Absorption (2 types) Distribution Toxicity Use
A
- Spectrum – Voraconazole (Candida, Cryptococcus, ENDEMICS, ASPERGILLUS, dermatophytes) + ZYGOMYCETES (rhizapus and mucor).
- Absorption
- Solution absorption is poor and saturable. Need acid and food. Avoid PPI’s and H2 inhibitors.
- Tablet absorption is much better. Best with food, especially fat.
- Poor CNS and urine distribution
- Toxicity – Drug interactions. Need drug monitoring.
- Use – 1st line prophylaxis for leukemia and bone marrow transplant. 2nd line zygomycetes (amphotericin B first).
9
Q
Isavuconazole Spectrum Absorption Toxicity Use
A
- Spectrum – Identical to posaconazole. Candida, Cryptococcus, Endemics, Aspergillus, Zygomycetes, and Dermatophytes. Good for empiric therapy.
- Great absorption. Do not need acid or food.
- No toxicity. Only azole that drug monitoring is NOT needed.
- Use – 1st line aspergillus (along w/ voriconazole) and zygomycetes. Also Fusarium and Scedosporium.
10
Q
Terbinafine Class Mechanism Spectrum Limitations Toxicity Use
A
- Class - Allylamine
- Mechanism – Inhibit ergosterol synthesis at level of squalene epoxidase. Fungicidal.
- Spectrum – DERMATOPHYTES, Aspergillus, endemics, and PCP
- Nonsatruable protein binding limits utility. Concentrates in stratum corneum, persisting long after drug is discontinued.
- No toxicity
- Use – Skin and anail dermatophyte infections.
11
Q
Flucytosine Class Abbreviation Mechanism Spectrum Distribution Elimination Toxicity Use
A
- Class - Pyrimidine
- Abbreviation - 5FC
- Mechanism – Enters cells via cytosine permease, converted to 5FU via cytosine deaminase, phosphorylated to FUMP → inhibits thymidylate and DNA synthesis. Fungistatic.
- Spectrum – Candida and CRYPTOCOCCUS.
- Great CNS and urine distribution
- Renal elimination. Dose adjust for renal insufficiency.
- Toxicity – High concentrations can be lethal. Nephrotoxicity, especially when combined w/ amphotericin B. Bone marrow suppression. Need drug monitoring.
- Use – 1st line combo w/ amphotericin for induction Cryptococcal meningitis. 2nd line for Candida glabrata cystitis.
- Combo w/ Amphotericin B is better than Amphotericin B alone.
12
Q
Echinocandins 3 drugs Mechanism Spectrum Distribution Toxicity Use
A
- Caspofungin, Micafungin, and Anidulafungin
- Mechanism – noncompetitive inhibition of beta-(1,3)-glucan synthetase in cell memberane, depleting glucan → osmotic instability / lysis.
- Spectrum – Cidal for Candida (except C parapsilosis). Static for aspergillus.
- Poor CNS, eye, and urine distribution
- No toxicity or drug interactions
- Use – 1st line for invasive candidiasis (not C parapsilosis or CNS / eye infections). Combine w/ mold-active triazole for invasive aspergillosis.
13
Q
Tx for invasive Candidiasis
Non C parapsilosis or CNS / eye infection?
C parapsilosis?
Step down?
A
- Use echinocandin unless C parapsilois or CNS / eye infection
- Use Flucoonazole or LAmB for C parapsilosis
- Fluconazole is good step down for all except glabrata or krusei
- Voriconazole is good step down for krusei
14
Q
Tx for oral / esophageal Candidiasis
A
Fluconazole. Voriconazle for glabrata or krusei. Echinocandins for triazole refractory disease.
15
Q
Tx for vaginal Candidiasis
A
Fluconazole. Systemic azoles are not allowed during pregnancy.
16
Q
Tx for Aspergillosis
A
Voriconazole (1st line), Isavuconazole, and Azole / Echinocandin combo
17
Q
Tx for Zygomycetes
A
LamB. Step down posaconazole and isavuconazole.
18
Q
Tx for endemic fungi
Initial tx
Step down
A
Start w/ LAmB. Step down itraconazole for 3-12 months. If CNS, step down w/ voriconazole or fluconazole.
19
Q
Tx for Cryptococcal meningitis
A
LAmB + 5FC. Step down w/ Fluconazole.
20
Q
Tx for Dermatophytes
A
Terbinafine (1st line) or Itraconazole
Microbio Gram Neg
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