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Class: Immuno Block > Anti-Fungal Therapy > Flashcards

Flashcards in Anti-Fungal Therapy Deck (53)
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1

3 Types of Fungal Infections

1) SUPERFICIAL - skin/hair/nails
2) SUBCUTANEOUS - dermis/subcutaneous tissue/adjacent structures
3) SYSTEMIC - internal organs

2

What is the difference between superficial/subcutaneous and systemic fungal infections?

Superficial/subcutaneous - Can occur in healthy individuals
Systemic - Opportunistic fungal infections that occur in diseased/immunocompromised conditions
[HIV epidemic, cancer chemotherapy usage, organ Tx immunosuppressive therapy, autoimmune, widespread usage of antibiotics]

3

3 Anti-fungal Drug Classifications

1) SYSTEMIC (oral/IV)
2) SYSTEMIC drugs for MUCOCUTANEOUS infections
3) TOPICAL drugs

4

Anti-fungal Drug Targets (unique to fungi and absent in humans)

1) CELL WALL
2) CELL MEMBRANE (fungi use ERGOSTEROL instead of cholesterol in human cells)
3) DNA SYNTHESIS

5

Anti-fungal cell membrane targeting drugs:

Amphotericin B (used for systemic fungal infections)
Azoles (Imidazoles [K,C,M] + Triazoles [I,F,V,P])
Allylamines
Nystatin (NOT used for systemic fungal infections)

6

Anti-fungal cell wall targeting drug

Echinocandins (C,A,M)

7

Anti-fungal DNA synthesis targeting drug

Flucytosine

8

What is the structure of amphotericin B (most commonly used anti-fungal drug) AND nystatin?

Macrolide with an AMPHIPATHIC ring structure (hydrophilic + hydrophobic components)

9

What is the difference in medication usage between amphotericin B and nystatin?

Amphotericin B - used for systemic (opportunistic) infections
Nystatin - NOT used for systemic (opportunistic) infections

10

Mechanism of AMPHOTERICIN B + NYSTATIN

Amphipathic molecule:
NONPOLAR side: Binds SELECTIVELY to ergosterol (fungal cell membrane) and not cholesterol
POLAR side: Forms pores for ion efflux leakage -> Kills fungi

11

Which fungal species display intrinsic amphotericin B resistance?

Candida lusitaniae
Pseudallescheria boydii

12

What is the drug of choice for nearly ALL life-threatening systemic fungal infections?

Amphotericin B

13

Amphotericin B Clinical Usages

1) Life-threatening systemic infections - Often used as INITIAL treatment in critical cases -> TRIAZOLES (CHRONIC therapy/Relapse preventions)
2) Topical drops for mycotic corneal ulcer/keratitis
3) Local injection for fungal arthritis

14

Amphotericin B Administration

1) Suspension by IV (in deoxycholate lipophilic soln) - Since amphotericin B is INSOLUBLE in water
2) Oral - Only if it is a GI infection (poor drug absorption)

15

Preparation for reducing amphotericin B's high toxicity

LIPOSOMAL PREPARATION - drug formulated in a lipid package
Enables higher doses with reduced nephrotoxicity

16

Most common problematic toxicity of Amphotericin B

RENAL DAMAGE (slower toxicity)

17

Acute (infusion-related) Toxicity of Amphotericin B __
How can this be managed?

Fever/chills/vomiting/headache/hypotension
Managed by:
1) Decreasing dose
2) Premedication with antipyretics (oral acetaminophen), antihistamins, meperidine, hydrocortisone

18

Slower toxicity of Amphotericin B

Renal Damage
Anemia
Occasional impaired liver function

19

Main precautionary element of drug interactions regarding Amphotericin B

Avoid administration if other nephrotoxic drugs are being administered as well (cyclosporine + aminoglycosides)

20

Mechanism of FLUCYTOSINE

1) Uptake by fungal cytosine permease
2) Conversion to 5-FU by cytosine deaminase
3) INHIBIT RNA synthesis: 5-FU converted to 5-FUTP
4) INHIBIT DNA synthesis: 5-FU converted to 5-FdUMP -> Inhibits thymidylate synthase

21

Selectivity of flucytosine: What can flucytosine target that human cells do not have?

CYTOSINE DEAMINASE: 5-flucytosine (5-FC)'s conversion to 5-FU by this enzyme
Mammalian cells poorly convert 5-FC to 5-FU

22

Resistance mechanisms of flucytosine

1) Loss of 5-FC permease
2) Loss of 5-FC conversion to 5-FU
3) Loss of 5-FU to 5-FdUMP conversion

23

Does flucytosine have broad spectrum (like amphotericin B) or limited spectrum

Limited spectrum - ONLY Candida and Cryptococcus

24

Due to the high resistance against flucytosine (5-FC), how is it often administered to patients? (i.e. what combination therapy is prescribed)

Synergistic Effect with AMPHOTERICIN B + ITRACONAZOLE

25

Administration of flucytosine

ORAL - rapid absorption from GI

26

Mechanism of flucytosine toxicity

Gut bacteria actually convert 5-FC to 5-FU in the intestinal tract

27

Flucytosine Toxicity Effects

Decrease in bone marrow function (Leukopenia/thrombocytopenia)
Rash/GI effects

28

Main precautionary element of adminstering FLUCYTOSINE regarding drug interactions

Avoid administering flucytosine with drugs that suppress bone marrow

29

2 Subcategories within Anti-fungal azoles

1) IMIDAZOLE (2 N's in 5-member rings)
2) TRIAZOLE (3 N's in 5-member rings)

30

Diff between Imidazole and Triazole compound AZOLE anti-fungal drugs

IMIDAZOLES - first generation, ONLY used topically
(Systemic infn usage is DISCONTINUED due to toxicity)
TRIAZOLE - Later generation, Broader spectrum, Less side effects
Mainly used for systemic infections