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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
Amphotericin B solubilizer necessary?
Yes, nearly insoluble in water
26
Conventional formulation of Amphotericin B
amphotericin B deoxycholate. Not used any more because of toxicity.
27
Why lipid-associated delivery system of Amphotericin B
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
Mechanism of Amphotericin B
(1) Binds to ergosterol in fungal cell membrane. (2) Facilitates pore formation --> leaking of intracellular ions and macromolecules --> cell death.
29
Amphotericin B is drug of choice for treatment of
1. Cryptococcal meningitis (intrathecally) 2. Zygomycetes 3. Induction therapy for disseminated histoplasmosis Is also a good option for invasive aspergillosis
30
Adjustment of amphotericin B dose
NO dose adjustments for hepatic or renal impairment or hemodialysis
31
Adverse effects of amphotericin B
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
Avoid co-administration of amphotericin B with?
nephrotoxic agents (cyclosporine, foscarnet-antiviral drug, aminoglycosides)
33
Caspofungin mechanism
IV non-competitive inhibitor of beta (1,3)-D-glucan synthase | Loss of cell wall glucan results in osmotic fragility and cell death
34
Caspofungin fungistatic vs fungicidal
Fungistatic against Aspergillus (blockade of cell wall synthesis) Fungicidal against Candida (destruction of cell due to compromised cell wall)
35
Caspofungin coverage
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
Caspofungin drug of choice for
Refractory Aspergillus infections Alternative for Candida infections May be option as empiric therapy in febrile neutropenic patients that cannot take Amphotericin B
37
Caspofungin adverse effects
- 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
Dose adjustment caspofungin
- need to adjust dose in patients with severe hepatic insufficiency - NOT metabolized by CYP450
39
Flucytosine oral or IV
Both
40
Flucytosine mechanism
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
Flucytosine adverse effects
- metabolized to 5-FU (toxic antineoplastic agent) - risk of bone marrow toxicity, elevated liver enzymes - need to monitor drug levels
42
indications for Flucytosine
Cryptococcus neoformans –synergy with Amphotericin B/ especially for Cryptococcus meningitis (HIV patients)
43
Systemic Antifungal Agents for Mucocutaneous Infections
Terbinafine (oral)
44
treatment of onychomycosis (fungal nail infection)
Terbinafine (oral)
45
Terbinafine oral or iv
Oral
46
Main indication for terbinafine
treatment of onychomycosis (fungal nail infection)
47
Terbinafine mechanism
Interferes with ergosterol synthesis – inhibits squalene epoxidase (unlike Azoles)
48
Terbinafines drug interactions, adverse effects
none
49
Nystatin mechanism
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
Nystatin formulation
Topical
51
Nystatin indication
polyene for treatment of mucocutaneous candidiasis – “Swish and Swallow”
52
Nystatin toxicity
none, very little systemic absorption
53
Clotrimazole, Miconazole (belong in Azoles category) mechanism
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
Clotrimazole, Miconazole formulation
topical
55
Clotrimazole, Miconazole indications
For treatment of mucocutaneous candidiasis and dermatophytic infections
56
Clotrimazole, Miconazole toxicity
No significant systemic absorption; little toxicity
57
Flucytosine penetration
-penetrates into all body fluid compartments
58
flucytosine elimination
-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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