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PHRM 865 > Antifungals I & II > Flashcards

Antifungals I & II Flashcards

1
Q

Amphotericin B spectrum of activity

A
  1. ) Candida spp. (except C. lusitinae)
  2. ) Cryptococcus neoformans
  3. ) Aspergillus spp. (less activity against aspergillus terreus)
  4. ) Histoplasma
  5. ) Blastomyces dermatiditis
  6. ) Coccidioides immitis
  7. ) Mucor spp. (ex: zygomycetes)
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2
Q

What is amphotericin B the drug of choice for?

A

Cryptococcus (in combo)

Histoplasma

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3
Q

Ketoconazole MOA

A

Is a azole

Binds to and blocks the fungi 14-alpha-demethylase (a CYP450 enzyme) inhibiting conversion of lanosterol to ergosterol –> disruption of fungal cell membrane –> leakage of cytoplasm –> inhibition of growth

FUNGISTATIC

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4
Q

Ketoconazole spectrum of activity?

A
  1. ) Candida albicans
  2. ) Cryptococcus neoformans
  3. ) Histoplasma
  4. ) Dermatophytes (tinea)
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5
Q

Ketoconazole bioavailability/absoprption?

A

Has good bioavialability

Absorption is INVERSELY related to gastric pH

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6
Q

How is ketoconazole metabolized?

A

By liver

Dose adjustments are not needed in renal failure; Not removed by HD or PD

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7
Q

Ketoconazole toxicities?

A
  1. ) GI –> N/V/D; abdominal pain
  2. ) Hepatoxicity
  3. ) Endocrine (dose-dependent inhibition of adrenal steroid and testosterone synthesis –> leading to gynecomastia, decreased libido, loss of hair, menstural irregularities, etc.)
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8
Q

Fluconazole spectrum of activity

A
  1. ) Candida albicans (and many other candida spp.)
  2. ) Cryptococcus neoformans (DOC)
  3. ) Cryptococcus meningitis (prophylaxis) –> CNS penetration
  4. ) Histoplasma, blastomyces, sporothrix –> but NOT therapeutically useful against these

(opportunistic pathogens)

( but no activity against aspergillus or filamentous fungi)

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9
Q

What is fluconazole the drug of choice for?

A

Cryptococcus neoformans fungal infections

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10
Q

Fluconazole absorption?

A

Has good oral absorption!

Is INDEPENDENT of gastric acidity (unlike ketoconazole)

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11
Q

What is Itraconazole spectrum of activity?

A
  1. ) Candida albicans and some other candida spp.
  2. ) Cryptococcus neoformans
  3. ) Histoplasma, blastomyces, sporothrix
  4. ) Aspergillus
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12
Q

What is itraconazole the DOC for?

A

Histoplasma, blastomyces, sporothrix (system infections & yeast –> sporothrix)

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13
Q

Itraconazole bioavailability/absorption?

A

Good oral bioavailability –> is dependent on gastric acidity

Oral solution –> not affected by gastric acidity ( is better absorbed than capsules)

Capsules better absorbed when taken with meal or acidic cola soda

SUBA-itraconazole –> absorption NOT affected by gastric acidity (recommend to give with food)

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14
Q

Itraconazole Metabolism

A

Metabolized by CYP450 3A4 enzyme

active metabolite = hydroxyitraconazole

no dosage adjustment for renal dysfunction (not removed by HD or PD)

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15
Q

Itraconazole dose/indication?

A

Histoplasmosis (FIRST LINE):

200 mg PO TID X 3 days, then 200 mg PO BID

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16
Q

Itraconazole toxicities?

A
  1. ) Heptaotxicity (not as bad a ketoconazole)
  2. ) congestive heart failure (BOXED WARNING) –> CI in pts with CHF
  3. ) QTc prolongation
  4. ) CI in pregnancy and nursing moms
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17
Q

Voriconazole spectrum of activity?

A
  1. ) Aspergillus spp.
  2. ) Fusarium spp.
  3. ) Candida species (including some fluconazole resistant strains)
  4. ) Aspergillus (may be more effective for this than amphotericin B)
  5. ) Cryptococcus
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18
Q

Can voriconazole cross the BBB?

A

Yes

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19
Q

Voriconazole toxicities?

A
  1. ) May be teratogenic (thus CI in pregnancy)

2. ) Visual disturbances (flickering lights or zigzag lines)

20
Q

Posaconazole spectrum of activity?

A

Broadest spectrum azole to date

Similar to voriconazole

Better activity against filamentous fungi such as zygomycetes (and aspergillus is also one)

21
Q

Isavuconazole spectrum of activity

A

Similar to voriconazole

  1. ) Candida species
  2. ) Cryptococcus
  3. ) yeast and molds
  4. ) aspergillus
22
Q

What are the echinocandin drugs?

A

Are lipopeptides

  1. ) caspofungin
  2. ) micafungin
  3. ) anidulafungin
23
Q

Spectrum of activity for casofungin?

A

Candida spp

Aspergillus fumigatus

24
Q

Spectrum of activity for micafungin?

A

Candida spp

Aspergillus fumigatus

25
Q

Spectrum of activity for anidulafungin?

A

Candida spp

Aspergillus fumigatus

26
Q

Echinocandins MOA?

A

Inhibit synthesis of beta(1-3)glucan (target enzyme) which is a cell wall component

27
Q

How does echinocandins have selectivity for fungi?

A

Mammalian cells lack the beta(1-3) glucan synthase

28
Q

Echinocandins cross resistance?

A

None

29
Q

Echinocandin toxicities?

A
  1. ) Hepatic toxicity
  2. ) Infusion toxicities
  3. ) rash (all antifungal agents)
30
Q

Flucytosine MOA?

A

Is a pyrimidine analog

  1. ) COMPETITIVE INHIBITOR and suicide inhibitor of thymidylate synthase –> traps this enzyme in an inactive form and thus can’t react with dUMP (endogenous) –> inhibiting DNA synthesis
  2. ) Interferes protein synthesis (deaminated to 5-FU –> this get incorporated into fungal RNA –> interference with protein synthesis)
31
Q

How is flucysotine selective for fungi infected cells?

A

Mammalian cells aren’t able to convert flucyotsine into its active form

32
Q

Flucytosine spectrum of activity?

A
  1. ) Candida
  2. ) Cryptococcus neoformans

These are YEASTS!

33
Q

How is flucytosine given?

A

Oral (good oral bioavailability)

Usually always given with amphotericin B or fluconazole

34
Q

Dosing of flucytosine?

A

Renal dysfunction needs dose adjustments!

Normal renal function:
- 100-150 mg/kg/DAY in 4 divided doses

Renal dysfunction:

  • CrCl > 40 — 25-37.5 mg/kg q6h
  • CrCl 20-40 — 25-37.5 mg/kg q12h
  • CrCL 10-19 — 25-37.5 mg/kg q24h
  • CrCl < 10 — 25-37.5 mg/kg & follow conc. q24-48h
  • HD — 37.5 mg/kg after HD

Dose based on IBW if non severe or adjusted BW if severe

35
Q

What are thing you want to monitor with flucytosine?

A
  1. ) Baseline CBC, platelets, Scr, BUN

2. ) Reduce dose in pts with bone marrow or GI toxicity

36
Q

Does flucytosine enter the CSF?

A

YES

37
Q

Flucytosine toxicities?

A
  1. ) Intestinal flora can metabolize to 5-FU which is a anti cancer drug
  2. ) When given with amphotericin B –> monitor b/c can worsen kidney toxicity
38
Q

Flucytosine excretion?

A

Removed by HD and PD

39
Q

Griseofulvin MOA?

A

Disrupts fungal microtubules (thus preventing cell division)

40
Q

Griseofulvin spectrum of activity?

A

Used for dermatophytes (epidermophyton, trichopyton, microsporum)

41
Q

HOW is griseofulvin given?

A

Must be given orally

Becomes incorporated into keratin precursor cells (thus good for nail infections)

42
Q

Tavaborale MOA?

A

Inhibits leucyl transfer RNA synthase (leuRS) –> which inhibits protein synthesis

(needs boron in structure which is essential for its activity)

43
Q

Tavaborole use?

A

Topical treatment of onchomycosis (nail bed infections)

44
Q

What drugs are resistant to candida krusei?

A

Fluconazole (intrisically)

Flucytosine and amphotericin B (reduced susceptibility)

45
Q

What drugs are resistant to candida glabrata?

A

Multiazole

  1. ) Echinocandin
  2. ) multidrug resistance

naturally occuring resistance

46
Q

What drugs are resistant to aspergillus terreus

A

Amphotericin (intrinsic)

PHRM 865 (6 decks)

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