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2. HDS Pulmonary > Antifungals > Flashcards

Antifungals Flashcards

1
Q

Infectious Disease

Approach

A
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2
Q

Kingdom Myceteae

A

Yeast ⇒ unicellular, replicate by budding

Mold ⇒ multicellular hyphae

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3
Q

Polyenes

Overview

A

2 common agents:

Nystatin & Amphotericin B

MOA:

Bind ergosterol in fungal cell membrane ⇒ cell death

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4
Q

Polyenes

Adverse Effects

A

Considerable toxicity:

  • Nephrotoxicity
  • Electrolyte wasting
    • ​K+, Mg2+, etc lost in urine
  • Infusion related reactions
    • Common occurance
    • Anything from fevers to rigors
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5
Q

Polyenes

Pharmacokinetics

A
  • Poorly absorbed
  • Highly distributed
    • Minimally detectable in CNS
  • Metabolism and elimination unknown
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6
Q

Polyenes

Pharmacodynamics

A

Concentration-dependent

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7
Q

Amphotericin B (AmB)

Overview

A
  • Polyene antifungal
  • Broad spectrum
    • Candida spp.
      • Except C. lusitaniae
    • Cryptococcus neoformans
    • Dimorphic fungi
    • Many molds
  • Considerable nephrotoxicity
  • Amphotericin B deoxycholate (AmBd)
    • First polyene ⇒ called conventional AmB
    • Worse toxicity
    • Cheapest
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8
Q

Amphotericin B

Nephrotoxicity

A
  1. Damages distal tubule
    • Leads to Na+, K+, and Mg2+ wasting
  2. Damages afferent arterioles
    • Reduces glomerular perfusion and kidney function
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9
Q

Amphotericin B

Lipid Formulations

(LFABs)

A
  • 3 formulations
    • Amphotericin B Colloidal Dispersion (ABCD)
      • No longer made
    • Amphotericin B Lipid Complex (ABLC)
    • Liposomal amphotericin B (LAmB)
      • ​Best option, most protective of host
  • Efficacy differences ⇒ need bigger doses
  • Safety profiles
    • Nephrotoxicity ⇒ ABCD = ABLC > LAmB
    • Infusion reactions ⇒ ACBD >> ABLC > LAmB
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10
Q

Nystatin

A
  • Polyene antifungal
  • Broad spectrum
  • Only given topically due to toxicity
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11
Q

Echinocandins

MOA

A

⊗ β-1,3-glucan synthetase ⇒ ↓ β-1,3-glucan production ⇒ cell wall stability

(Many molds and dimorphic don’t have β-1,3-glucan in their cell walls = not effective)

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12
Q

Echinocandins

Spectrum

A
  • Strong in vitro activity against clinical Candida spp.
    • Weaker against C. parapsilosis
  • Active against Aspergillus spp.
  • Ineffective for Cryptococcus & many molds
  • Efficacy unknown for many mycoses
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13
Q

Echinocandins

Pharmacokinetics

A

All given IV.

  • Poor bioavailability
  • Well distributed
  • Variable metabolism
  • Not eliminated renally
    • Not useful for fungal UTI’s
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14
Q

Echinocandins

Pharmacodynamics

A

Concentration-dependent

All fungicidal against yeast

All pseudo-static against molds (abnormal growth morphology)

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15
Q

Echinocandins

Adverse Effects

A
  • Mild hepatotoxicity
  • Infusion-releated reactions
    • More Vancomycin-like
  • Phlebitis
    • Give through central venous line to minimize
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16
Q

Echinocandins

Medications

A
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17
Q

Azoles

MAO

A

⊗ fungal cytochrome P450 (14α-demethylase) ⇒ ↓ ergosterol formation

(Ergosterol is not present in human cell membranes)

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18
Q

Azoles

Spectrum

A

Drug of choice for many fungal infections.

Variable antifungal spectrum:

  • Flucanazole ineffective against some C. glabrata, C. krusei, Aspergillus spp., molds
  • Itraconazole is effective against Aspergillus
  • New agents have extended spectrum
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19
Q

Azoles

Issues

A

⊗ human cytochrome P450s ⇒ many adverse effects

  • Drug interactions
  • Fluconazole resistance
  • Used for prophylaxis
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20
Q

Azoles

Adverse Reactions

A
  • Hepatotoxicity
    • Worse w/ Voriconazole
    • Best w/ Fluconazole
  • Rash
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21
Q

Azoles

Pharmacokinetics

A

Can be given PO.

  • Absorption variable between agents
  • Widely distributed including CNS
  • All have some hepatic metabolism
  • Flucanzole mostly excreted renally
    • Can be used for UTIs
22
Q

Azoles

Pharmacodynamics

A

Time-dependent

Fungicidal against molds

Fungistatic against yeasts

23
Q

Fluconazole

Indications

A

Available as IV, tablets, and oral suspensions

(100% bioavailability PO ⇒ same dose as IV)

  • Activity
    • Yeasts including many Candida and Cryptococcus
      • Exceptions:
        • C. kruseii ⇒ “cruise past it”
        • C. glabrata ⇒ “glides past it”
    • Some dimorphic fungi
    • No anti-mold activity
  • Uses:
    • Treatment of many forms of candidiasis
    • Prophylaxis of candidiasis
    • Treatment of some dimorphic fungal infections
24
Q

Fluconazole

Adverse Effects

A
  • Hepatotoxicity
    • Least toxic d/t renal elimination
  • Rash
  • Drug interactions
    • Fewest b/c it does not ⊗ CYP450-3A4
25
Q

Itraconazole

Indications

A

Available as capsules and oral solution.

  • Activity:
    • Yeasts including Candida and Cryptococcus
    • Aspergillus
    • Many dematiaceous molds
    • Dimorphic fungi
  • Utility:
    • Dimorphic fungal infections
    • Onychomycosis
    • Some mold and yeast infections
26
Q

Itraconazole

Adverse Effects

A
  • Absorption issues
    • Capsules are very poorly absorbed
    • Oral solution better but suspension agent can cause diarrhea ⇒ poor tolerance/compliance
  • Hepatotoxicity
  • Rash
  • Widening of QT interval
    • Worse of the Azoles
  • ⊖ inotrope ⇒ exacerbate CHF
  • Drug interactions
    • Does ⊗ CYP450-3A4 ⇒ lots of interactions
27
Q

Voriconazole

Indications

A

Available as IV, tablets, and oral suspension.

Muct better absorption than Itraconazole.

  • Activity:
    • Yeasts including Candida and Cryptococcus
    • Molds including Aspergillus, Fusarium, Scedosporium, dematiaceous molds, endemic fungi
  • Utility:
    • Invasive aspergillosis and other mold infections ⇒ drug of choice
    • Invasive candidiasis
      • Equally as effective as Fluconazole but more poorly tolerated, not drug of choice
    • Esophageal candidiasis
    • Febrile neutropenia?
28
Q

Voriconazole

Pharmacokinetics

A
  • Well-absorped
  • Hepatically metabolized
  • Non-linear elimination
    • ​Pharmacokinetics and elimination are not dose proportional
    • ↑ dose ⇒ ↓ clearance
  • SBECD of IV form is renally eliminated
    • Cyclodextrin part of drug
    • Accumulates in renal failure
  • High intra- and inter- patient variability
    • High concentrations ⇒ toxicity
    • Low concentrations ⇒ failure
    • Must monitor dosing
29
Q

Voriconazole

Adverse Effects

A
  • Visual effects ⇒ 40-50% of pts
    • Chromatic aboritions
  • Visual hallucinations
  • Hepatotoxicity
    • Higher than other drugs in the class
    • Usually just see ↑ total bilirubin w/ minimal change in AST/ALT
  • Rash
  • Drug interactions
    • Does ⊗ CYP450-3A4 ⇒ lots of interactions
30
Q

Posaconazole

Indications

A

Available as IV, tablet, or oral suspension.

  • Activity:
    • Yeasts including Candida and Cryptococcus
    • Molds including Aspergillus and Zygomycetes
      • Few antifungals active against Zygomycetes
  • Utility:
    • Approved for prophylaxis of fungal infections
    • Mold infections
31
Q

Posaconazole

Formulations & Pharmacokinetics

A

Available as IV, tablet, or oral suspension.

  • Suspension requires high-fat meal or acidic beverage
    • Largely not used anymore
  • Oral tablet ⇒ delayed release
  • IV form recently approved
32
Q

Posaconazole

Adverse Effects

A

Better than Voriconazole.

Worse than Fluconazole.

  • Hepatotoxicity
  • Rash
  • Drug interactions
33
Q

Isavuconazole

Indications

A
  • Activity:
    • Yeasts including Candida and Cryptococcus
    • Molds including Aspergillus and Mucormycetes
    • Dimorphic fungi
  • Utility:
    • Approved for treatment of aspergillosis and mucormycosis
      • Voriconazole is drug of choice for aspergillosis but is not active against mucormycosis
34
Q

Isavuconazole

Pharmacokinetics

A
  • Given as prodrug isavuconazonium sulfate
  • Long half-life ~ 130 hrs
    • Give loading dose to get to therapeutic level
35
Q

Isavuconazole

Adverse Effects

A
  • Hepatotoxicity
    • Less than voriconazole
  • Rash
  • Drug interactions
    • Less than other mold-active azoles
36
Q

Ketoconazole

A
  • Poor oral absorption
  • Used topically
  • Oral formulation exists but don’t use it systemically
37
Q

Topical Azoles

A
  • Medications:
    • Clotrimazole
    • Econazole
    • Miconazole
    • Oxiconazole
    • Sulconazole
    • Terconazole
    • Tioconazole
  • Adverse effects ⇒ dermatologic
38
Q

5-Flucytosine (5-FC)

MOA

A

Antimetabolite

  • Deaminated within fungals cells ⇒ 5-fluorouracil
  • 5-fluorouracil replaces uracil ⇒ ⊗ RNA production & DNA synthesis

“5-FU for fungi”

39
Q

5-Flucytosine

Pharmacokinetics

A
  • High bioavailability
  • Widely distributed including CNS
  • Renally excreted
    • Dose adjustment in renal dysfunction
  • Pharmacokinetic monitoring available
    • Trough concentrations: 20-25 mcg/mL
  • Dose: 12.5-37.5 mg/kg q6h
40
Q

5-Flucytosine

Indications

A
  • Activity:
    • Candida species
    • Cryptococcus neoformans
    • Less active against C. krusei
    • Some activity against Aspergillus and other molds
  • Utility:
    • Combo therapy for cryptococcal meingitis
      • ​Main use
      • 5-FC w/ AmB is a good combo
    • Rarely used for candidiasis
41
Q

5-Flucytosine

Adverse Effects

A
  • Bone marrow suppression
    • Peak dose-related
  • GI intolerance
  • Hepatotoxicity
  • Rash
42
Q

Systemic Antifungals

Spectrum

A
43
Q

Terbinafine

MOA

A

Allyamine antifungal

⊗ squalene epoxidase ⇒ ⊗ ergosterol synthesis

44
Q

Terbinafine

Indications

A

Available PO and topically.

  • Activity:
    • Mainly for dermatophytes
      • e.g. Trychophyton
    • Active against Candida & Aspergillus
      • Not used clinically
  • Utility:
    • Onychomycosis
45
Q

Terbinafine

Pharmacokinetics

A

Available PO or topically.

  • 40% bioavailability d/t 1st pass effect
  • Concentrates in nails, fat, and skin
  • Metabolized in liver
  • Metabolites renally excreted
  • Non-linear elimination
    • T½ 12 hrs → 200-400 hrs w/ repeated dosing
46
Q

Terbinafine

Adverse Effects

A
  • Hepatotoxicity
  • Neutropenia
  • Steven-Johnson syndrome
47
Q

Griseofulvin

MOA

A

⊗ fungal mitosis via interaction w/ microtubules

48
Q

Griseofulvin

Pharmacokinetics

A

Given PO

Prolonged half-life

49
Q

Griseofulvin

Indications & Adverse Effects

A
  • Active against dermatophytes
  • Used in treatment of onychomycosis
    • Not preferred
  • Adverse effects
    • CNS
    • Mainly headaches
50
Q

Candida Susceptibility

A

Antifungal activity is species dependent.

2. HDS Pulmonary (28 decks)

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