2. HDS Pulmonary > Antifungals > Flashcards

Antifungals Flashcards

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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

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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

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A

Time-dependent

Fungicidal against molds

Fungistatic against yeasts

23
Q

Fluconazole

Indications

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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

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A
  • Hepatotoxicity
    • Least toxic d/t renal elimination
  • Rash
  • Drug interactions
    • Fewest b/c it does not ⊗ CYP450-3A4
25
Itraconazole Indications
**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
Itraconazole Adverse Effects
* 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
Voriconazole Indications
**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
Voriconazole Pharmacokinetics
* 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
Voriconazole Adverse Effects
* **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
Posaconazole Indications
**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
Posaconazole Formulations & Pharmacokinetics
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
Posaconazole Adverse Effects
Better than Voriconazole. Worse than Fluconazole. * Hepatotoxicity * Rash * Drug interactions
33
Isavuconazole Indications
* 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
Isavuconazole Pharmacokinetics
* **Given as prodrug isavuconazonium sulfate** * **Long half-life ~ 130 hrs** * Give loading dose to get to therapeutic level
35
Isavuconazole Adverse Effects
* **Hepatotoxicity** * Less than voriconazole * Rash * **Drug interactions** * Less than other mold-active azoles
36
Ketoconazole
* Poor oral absorption * **Used topically** * Oral formulation exists but don't use it systemically
37
Topical Azoles
* Medications: * Clotrimazole * Econazole * Miconazole * Oxiconazole * Sulconazole * Terconazole * Tioconazole * Adverse effects ⇒ dermatologic
38
5-Flucytosine (5-FC) MOA
**Antimetabolite** * Deaminated within fungals cells ⇒ 5-fluorouracil * **5-fluorouracil replaces uracil ⇒ ⊗ RNA production & DNA synthesis** "5-FU for fungi"
39
5-Flucytosine Pharmacokinetics
* 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
5-Flucytosine Indications
* 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
5-Flucytosine Adverse Effects
* **Bone marrow suppression** * Peak dose-related * **GI intolerance** * Hepatotoxicity * Rash
42
Systemic Antifungals Spectrum
43
Terbinafine MOA
Allyamine antifungal ## Footnote **⊗ squalene epoxidase ⇒ ⊗ ergosterol synthesis**
44
Terbinafine Indications
Available PO and topically. * Activity: * **Mainly for dermatophytes** * e.g. Trychophyton * Active against Candida & Aspergillus * Not used clinically * Utility: * **Onychomycosis**
45
Terbinafine Pharmacokinetics
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
Terbinafine Adverse Effects
* Hepatotoxicity * Neutropenia * Steven-Johnson syndrome
47
Griseofulvin MOA
⊗ fungal mitosis via interaction w/ microtubules
48
Griseofulvin Pharmacokinetics
Given PO Prolonged half-life
49
Griseofulvin Indications & Adverse Effects
* Active against dermatophytes * Used in treatment of onychomycosis * Not preferred * Adverse effects * CNS * Mainly headaches
50
Candida Susceptibility
Antifungal activity is species dependent.
2. HDS Pulmonary
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