Antifungals I & II Flashcards by Joanne Song

Amphotericin B spectrum of activity

) Candida spp. (except C. lusitinae)
) Cryptococcus neoformans
) Aspergillus spp. (less activity against aspergillus terreus)
) Histoplasma
) Blastomyces dermatiditis
) Coccidioides immitis
) Mucor spp. (ex: zygomycetes)

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What is amphotericin B the drug of choice for?

Cryptococcus (in combo)

Histoplasma

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Ketoconazole MOA

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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Ketoconazole spectrum of activity?

) Candida albicans
) Cryptococcus neoformans
) Histoplasma
) Dermatophytes (tinea)

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Ketoconazole bioavailability/absoprption?

Has good bioavialability

Absorption is INVERSELY related to gastric pH

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How is ketoconazole metabolized?

By liver

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

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Ketoconazole toxicities?

) GI –> N/V/D; abdominal pain
) Hepatoxicity
) 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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Fluconazole spectrum of activity

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

(opportunistic pathogens)

( but no activity against aspergillus or filamentous fungi)

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What is fluconazole the drug of choice for?

Cryptococcus neoformans fungal infections

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Fluconazole absorption?

Has good oral absorption!

Is INDEPENDENT of gastric acidity (unlike ketoconazole)

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What is Itraconazole spectrum of activity?

) Candida albicans and some other candida spp.
) Cryptococcus neoformans
) Histoplasma, blastomyces, sporothrix
) Aspergillus

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What is itraconazole the DOC for?

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

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Itraconazole bioavailability/absorption?

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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Itraconazole Metabolism

Metabolized by CYP450 3A4 enzyme

active metabolite = hydroxyitraconazole

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

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Itraconazole dose/indication?

Histoplasmosis (FIRST LINE):

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

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Itraconazole toxicities?

) Heptaotxicity (not as bad a ketoconazole)
) congestive heart failure (BOXED WARNING) –> CI in pts with CHF
) QTc prolongation
) CI in pregnancy and nursing moms

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Voriconazole spectrum of activity?

) Aspergillus spp.
) Fusarium spp.
) Candida species (including some fluconazole resistant strains)
) Aspergillus (may be more effective for this than amphotericin B)
) Cryptococcus

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Can voriconazole cross the BBB?

Yes

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Voriconazole toxicities?

) May be teratogenic (thus CI in pregnancy)

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

Posaconazole spectrum of activity?

Broadest spectrum azole to date

Similar to voriconazole

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

Isavuconazole spectrum of activity

Similar to voriconazole

) Candida species
) Cryptococcus
) yeast and molds
) aspergillus

What are the echinocandin drugs?

Are lipopeptides

) caspofungin
) micafungin
) anidulafungin

Spectrum of activity for casofungin?

Candida spp

Aspergillus fumigatus

Spectrum of activity for micafungin?

Candida spp

Aspergillus fumigatus

Spectrum of activity for anidulafungin?

Candida spp Aspergillus fumigatus

Echinocandins MOA?

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

How does echinocandins have selectivity for fungi?

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

Echinocandins cross resistance?

None

Echinocandin toxicities?

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

Flucytosine MOA?

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)

How is flucysotine selective for fungi infected cells?

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

Flucytosine spectrum of activity?

1. ) Candida 2. ) Cryptococcus neoformans These are YEASTS!

How is flucytosine given?

Oral (good oral bioavailability) Usually always given with amphotericin B or fluconazole

Dosing of flucytosine?

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

What are thing you want to monitor with flucytosine?

1. ) Baseline CBC, platelets, Scr, BUN | 2. ) Reduce dose in pts with bone marrow or GI toxicity

Does flucytosine enter the CSF?

YES

Flucytosine toxicities?

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

Flucytosine excretion?

Removed by HD and PD

Griseofulvin MOA?

Disrupts fungal microtubules (thus preventing cell division)

Griseofulvin spectrum of activity?

Used for dermatophytes (epidermophyton, trichopyton, microsporum)

HOW is griseofulvin given?

Must be given orally Becomes incorporated into keratin precursor cells (thus good for nail infections)

Tavaborale MOA?

Inhibits leucyl transfer RNA synthase (leuRS) --> which inhibits protein synthesis (needs boron in structure which is essential for its activity)

Tavaborole use?

Topical treatment of onchomycosis (nail bed infections)

What drugs are resistant to candida krusei?

Fluconazole (intrisically) | Flucytosine and amphotericin B (reduced susceptibility)

What drugs are resistant to candida glabrata?

Multiazole 2. ) Echinocandin 3. ) multidrug resistance naturally occuring resistance

What drugs are resistant to aspergillus terreus

Amphotericin (intrinsic)