Anti-Fungal Therapy Flashcards by Grace Lee

3 Types of Fungal Infections

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

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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]

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3 Anti-fungal Drug Classifications

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

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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

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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)

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Anti-fungal cell wall targeting drug

Echinocandins (C,A,M)

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Anti-fungal DNA synthesis targeting drug

Flucytosine

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

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

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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

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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

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Which fungal species display intrinsic amphotericin B resistance?

Candida lusitaniae

Pseudallescheria boydii

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

Amphotericin B

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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

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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)

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Preparation for reducing amphotericin B’s high toxicity

LIPOSOMAL PREPARATION - drug formulated in a lipid package

Enables higher doses with reduced nephrotoxicity

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Most common problematic toxicity of Amphotericin B

RENAL DAMAGE (slower toxicity)

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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

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Slower toxicity of Amphotericin B

Renal Damage
Anemia
Occasional impaired liver function

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Main precautionary element of drug interactions regarding Amphotericin B

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

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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

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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

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Resistance mechanisms of flucytosine

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

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

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Limited spectrum - ONLY Candida and Cryptococcus

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

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Synergistic Effect with AMPHOTERICIN B + ITRACONAZOLE

Administration of flucytosine

ORAL - rapid absorption from GI

Mechanism of flucytosine toxicity

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

Flucytosine Toxicity Effects

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

Main precautionary element of adminstering FLUCYTOSINE regarding drug interactions

Avoid administering flucytosine with drugs that suppress bone marrow

2 Subcategories within Anti-fungal azoles

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

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

Which azole sub-class of drugs CAN be used for systemic fungal infections?

TRIAZOLE | Not imidazole - due to high toxicity

Mechanism of AZOLES

NON-COMPETITIVE Inhibition of p450 enzyme lanosterol demethylase (ERG11) -> BLOCKS ergosterol biosynthesis -> RESULT 1: Limit important fungal membrane component -> Weaken membrane structure RESULT 2: Accumulation of TOXIC methylsterols -> Bind and Inhibit membrane Enz

Mechanisms of AZOLE drug resistance:

1) PUMP overexpression - increased drug efflux 2) Target alteration/overexpression - e.g. reduced drug binding capacity 3) Downstream enzyme of ergosterol biosynthesis (ERG3) LOF

Selectivity of AZOLE drugs for targeting fungi rather than humans

Azoles bind specifically to fungal p450 enzymes (ERG) rather than mammalian p450s -> target egolesterol biosynthesis

Are azole drugs Broad spectrum (like amphotericin B) or Limited spectrum (like flucytosine)

BROAD

Precautionary element with administering AZOLE drugs regarding drug interactions

Avoid administering azole drugs with other drugs that get metabolized through p450 (cyclosporine, warfarin, buspirone, dihydropyridine)

3 IMIDAZOLE DRUGS

Ketoconazole - first ORAL but has been replaced by triazoles Miconazole - ONLY TOPICAL Clotrimazole - ONLY TOPICAL "KETO, MICO, CLOT"

What is the most potent azole drug (Triazole)?

Itraconazole "IT"

Administration of Itraconazole | Toxicity of Itraconazole

ORAL | GI distress + TERATOGEN

Precautionary elements when administering itraconazole regarding drug interactions

1) Avoid with H2 and proton pump inhibitors that would DECREASE gastric acidity -> since this drug's oral absorption is INCREASED by gastric acidity 2) Avoid with other drugs that require liver p450 enzymes for metabolism (cyclosporine, warfarin, etc)

3 TRIAZOLE DRUGS

Itraconazole Fluconazole Voriconazole Posaconazole - BROADEST SPECTRUM

Main advantages of FLUCONAZOLE

Oral adminstration with NO problem of gastric acidity | LEAST effects with p450 microsomal enzymes (less drug interactions)

Which triazole drug has the broadest spectrum?

Posaconazole

3 Echinocandin Drugs

Capsofungin Anidulafungin Micafungin

Structure of echinocandins

Water-soluble Lipopeptide derivative of Pneumocandin B

Mechanism of CAPSOFUNGIN (echinocandin)

BINDS and INHIBITS beta (1,3) - glucan synthase (FKS1) - | Membrane enz used to make carbohydrate component of fungal cell wall necessary for viability

What fungal infections (2) is CAPSOFUNGIN primarily used for?

1) CANDIDA | 2) Invasive ASPERGILLOSIS when amphotericin B did not work

Mechanism of resistance for CAPSOFUNGIN (although it's highly selective)

Mutation in FKS1

Synthetic ALLYLAMINE (anti-fungal cell membrane targeting) for MUCOCUTANEOUS infections

Terbinafine

Mechanism of TERBINAFINE (allylamine)

Inhibits SQUALENE EPOXIDASE (ERG1) -> Blocks FIRST STEP of ergosterol biosynthesis Similar mechanism to azole's inhibition of downstream ERG11 -> Blocks ergosterol biosynthesis -> Accumulate toxic methylsterols + weaken fungal cell membrane

What class of drugs is TERBINAFINE (alyllamine) synergistic with?

TRIAZOLE drugs (block a different ERG enzyme of the same biosynthetic pathway for ergosterol synthesis)

TOPICAL anti-fungal drugs

1) Nystatin - mainly used for Candida infections 2) Terbinafine - mainly used against dermatophyte-caused tinea 3) Clotrimazole + Miconazole - mainly for dermatophyte infections

Fungi that are known to cause diseases in humans

Mycoses

Anti-Fungal Therapy Flashcards

(53 cards)