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Week 5 of Micro TA presentation > Treatments for Fungal Infections > Flashcards

Treatments for Fungal Infections Flashcards

1
Q

List of antifungal targets and corresponding drugs

A

Griseofulvin – disrupts MT synthesis, deposits in keratin

Cell Membrane – Ergosterol biosynthesis inhibitors – Azoles and Allylamines

Cell Wall – Glucan synthesis – Echinocandins.

Direct membrane damage – Polyenes – (like dapto for fungus)

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2
Q

Mechanism of action of azoles?

Fungistatic vs. fungicidal?

A

Inhibit production of ergosterol by binding to lanosterol 14-alpha demethylase, a cytochrome P450 enzyme (has greater affinity for fungal P450 enzymes than for human CYP450 enzymes)
Azoles are fungistatic –> resistance is increasing

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3
Q

List of Azoles

A

Imidazole -Ketoconazole (topical use)
First Gen. Triazoles: Fluconazole, Itraconazle
Second Gen. Trizaoles: Voriconazole, Posaconazole – suspension
Triazoles&raquo_space; Imidazole

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4
Q

Azole for topical use

A

Imidazole: Ketoconazole

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5
Q

Oral drug of choice for prevention of Zygomycetes

A

Posaconazole – suspension (oral)/ No IV form

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6
Q

Drug of choice for invasive Aspergillosis

A

Voriconazole – oral, IV
itraconazole could also be used
Fluconazole has no coverage

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7
Q

Chemoprophylaxis for cancer/neutropenic patients

A

Voriconazole – oral, IV

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8
Q

maintenance therapy for cryptococcal meningitis

A

Fluconazole

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9
Q

Triazoles Spectrum (Candida and Aspergillus coverage)

A

Fluconazole: C. albicans, C. tropicalis +/- C. glabrata, No Aspergillus, No mucor

Itraconazole: Similar Candida coverage as fluconazole, + Aspergillus

Voriconazole: Broad, includes most Candida spp., Aspergillus, Fusarium sp. Not Zygomycoses

Posaconazole: Broad, effective against most Candida spp., Aspergillus, and Zygomycetes
Oral drug of choice for prevention of Zygomycetes

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10
Q

Triazoles oral vs IV

Bioavailability of oral form

A

Fluconazole: both; Tablet (>90%)
Itraconazole: both; Capsule (6-25%), oral Solution (20-60%), IV. Oral bioavailibility poor.
Voriconazole: both; Tablet (>90%)
Posaconazole: only oral suspension, no IV

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11
Q

Triazoles clearance

A

Fluconazole: Renal (80%)
Itraconazole: Hepatic 3A4
Voriconazole: Hepatic 2C19, 3A4

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12
Q

Triazoles serum half life in hours

A

Fluconazole: 24
Itraconazole: 24-30
Voriconazole: 6-24 (shorter)

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13
Q

Triazoles CSF penetration

A

Fluconazole: Excellent
Itraconazole: poor
Voriconazole: excellent
Posaconazole: excellent

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14
Q

Triazoles CYP 3A4 inhibition

A

Fluconazole: weak
Itraconazole: strong
Voriconazole: moderate/strong
Posaconazole: moderate/strong

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15
Q

Triazoles Adverse effects

A

Fluconazole: N&V, hepatic
Itraconazole: N&V, diarrhea (solution), hepatic, CHF
Voriconazole: N&V, visual disturbances, hepatic, rash
Posaconazole: N&V, elevated liver enzymes, rash

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16
Q

Drug of choice for of invasive and mucocutaneous candidiasis

A

Fluconazole

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17
Q

Treatment for coccidiomycoses

A

Fluconazole

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18
Q

Treatment of Dermatophytoses and Onychomycosis (fungal nail infection) if topical drugs do not work

A

Itraconazole

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19
Q

Treatment used for invasive disease caused by Histoplasma, Blastomyces

A

Itraconazole

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20
Q

Voriconazole drug Interactions

A

-mediated mainly by CYP450

contraindicated drugs include: carbamazepine, long acting barbiturates, ergot alkaloids, sirolimus, rifabutin

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21
Q

Posaconazole drug interactions

A

Contraindicated drugs include – quinidine (antiarrhythmic), cisapride, pimozide
-concomitant use –> prolonged QTc

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22
Q

prevention of invasive mold infections

A

Posaconazole

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23
Q

Triazoles solubilizer necessary

A

Fluconazole - no
Itraconazole - cyclodextrin
Voriconazole - cyclodextrin

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24
Q

Amphotericin B oral or IV

A

IV administered cell membrane active antifungal (nearly insoluble in water)

25
Q

Amphotericin B solubilizer necessary?

A

Yes, nearly insoluble in water

26
Q

Conventional formulation of Amphotericin B

A

amphotericin B deoxycholate. Not used any more because of toxicity.

27
Q

Why lipid-associated delivery system of Amphotericin B

A

Lipid-packaged drug does not bind readily to mammalian cell, has less toxicity, and possibly greater drug delivery in tissues; most used is liposomal Amphotericin B

28
Q

Mechanism of Amphotericin B

A

(1) Binds to ergosterol in fungal cell membrane. (2) Facilitates pore formation –> leaking of intracellular ions and macromolecules –> cell death.

29
Q

Amphotericin B is drug of choice for treatment of

A
  1. Cryptococcal meningitis (intrathecally)
  2. Zygomycetes
  3. Induction therapy for disseminated histoplasmosis

Is also a good option for invasive aspergillosis

30
Q

Adjustment of amphotericin B dose

A

NO dose adjustments for hepatic or renal impairment or hemodialysis

31
Q

Adverse effects of amphotericin B

A

Amphoterrible – “shake and bake”, nephrotoxic, IV phlebitis (similar to red man).

  1. Infusion-related Toxicity
    - fever, chills, muscle spasms, vomiting, headache, hypotension
    - can mitigate effects by slowing rate of infusion or by pre-medicating with antipyretics, antihistamines, mepiridine (opioid analgesic), corticosteroids
  2. Slower Toxicity
    a) Renal Toxicity
    - reversible component –decreased renal perfusion/ can be prevented with sodium loading
    - irreversible component –renal tubular injury with prolonged administration and/or renal tubular acidosis (severe potassium and magnesium wasting)
    - Cannot adjust dose to stop this process
32
Q

Avoid co-administration of amphotericin B with?

A

nephrotoxic agents (cyclosporine, foscarnet-antiviral drug, aminoglycosides)

33
Q

Caspofungin mechanism

A

IV non-competitive inhibitor of beta (1,3)-D-glucan synthase

Loss of cell wall glucan results in osmotic fragility and cell death

34
Q

Caspofungin fungistatic vs fungicidal

A

Fungistatic against Aspergillus (blockade of cell wall synthesis)
Fungicidal against Candida (destruction of cell due to compromised cell wall)

35
Q

Caspofungin coverage

A

Active against most Candida spp.
Active against most Aspergillus spp.
Additive or synergistic effect with Amphotericin B
NOT active against Cryptococcus, Fusarium, and Zygomycetes

36
Q

Caspofungin drug of choice for

A

Refractory Aspergillus infections
Alternative for Candida infections
May be option as empiric therapy in febrile neutropenic patients that cannot take Amphotericin B

37
Q

Caspofungin adverse effects

A
  • well tolerated in comparison to Amphotericin B
  • most effects are infusion related (flushing**, headache, fever, erythema, rash) but are much less frequent than with Amphotericin B
  • minor GI side effects**

** most important ones

38
Q

Dose adjustment caspofungin

A
  • need to adjust dose in patients with severe hepatic insufficiency
  • NOT metabolized by CYP450
39
Q

Flucytosine oral or IV

A

Both

40
Q

Flucytosine mechanism

A

synthetic fluorinated pyrimidine
Taken up by fungal cells via cytosine permease –> converted to F-dUMP and FUTP
Inhibits DNA and RNA synthesis – causes bone marrow suppression

-human cells are unable to convert flucytosine to active metabolites (no cytosine deaminase) so are not affected

41
Q

Flucytosine adverse effects

A
  • metabolized to 5-FU (toxic antineoplastic agent)
  • risk of bone marrow toxicity, elevated liver enzymes
  • need to monitor drug levels
42
Q

indications for Flucytosine

A

Cryptococcus neoformans –synergy with Amphotericin B/ especially for Cryptococcus meningitis (HIV patients)

43
Q

Systemic Antifungal Agents for Mucocutaneous Infections

A

Terbinafine (oral)

44
Q

treatment of onychomycosis (fungal nail infection)

A

Terbinafine (oral)

45
Q

Terbinafine oral or iv

A

Oral

46
Q

Main indication for terbinafine

A

treatment of onychomycosis (fungal nail infection)

47
Q

Terbinafine mechanism

A

Interferes with ergosterol synthesis – inhibits squalene epoxidase (unlike Azoles)

48
Q

Terbinafines drug interactions, adverse effects

A

none

49
Q

Nystatin mechanism

A

Mechanism same as amphotericin B
(1) Binds to ergosterol in fungal cell membrane. (2) Facilitates pore formation –> leaking of intracellular ions and macromolecules –> cell death.

50
Q

Nystatin formulation

A

Topical

51
Q

Nystatin indication

A

polyene for treatment of mucocutaneous candidiasis – “Swish and Swallow”

52
Q

Nystatin toxicity

A

none, very little systemic absorption

53
Q

Clotrimazole, Miconazole (belong in Azoles category) mechanism

A

Inhibit production of ergosterol by binding to lanosterol 14-alpha demethylase, a cytochrome P450 enzyme (has greater affinity for fungal P450 enzymes than for human CYP450 enzymes)

54
Q

Clotrimazole, Miconazole formulation

A

topical

55
Q

Clotrimazole, Miconazole indications

A

For treatment of mucocutaneous candidiasis and dermatophytic infections

56
Q

Clotrimazole, Miconazole toxicity

A

No significant systemic absorption; little toxicity

57
Q

Flucytosine penetration

A

-penetrates into all body fluid compartments

58
Q

flucytosine elimination

A

-eliminated by glomerular filtration and removed by hemodialysis/ need to adjust dose for patients with renal failure and hemodialysis

Week 5 of Micro TA presentation (4 decks)

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