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M1 - Microbiology > Anti-Fungal Therapy (Zheng) - 5/12/16 > Flashcards

Anti-Fungal Therapy (Zheng) - 5/12/16 Flashcards

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1
Q

Where are the three locations that fungal infections can occur?

A

Superficial - localized to the skin, hair, and nails

Subcutaneous - infection confined to dermis, subcutaneous tissue or adjacent structures

Systemic - infections of the internal organs

  • HIV epidemic
  • Cancer patients
  • Organ transplantation patients
  • Autoimmune patients
  • Widespread use of antibiotics
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2
Q

Drug Classifications? (3)

A
  1. Systemic (oral and IV)
  2. Systemic drugs for mucocutaneous infections
  3. Topical drugs
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3
Q

Antifungal drug targets in the cell?

A

Cell membrane (Fungi use ergosterol instead of cholesterol in human cells) [amphotericin B, nystatin, azoles, allylamines]

Cell Wall [Cell wall inhibitor - echinocandins]

DNA Synthesis [Nucleic acid inhibitor - flucytosine]

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4
Q

Drugs for Systemic Infections:

Mode of action?
Amphotericin B

(Nystatin)

A

Macrolide w/ an amphipathic ring structure

Mode of Action:

  • Polar side forms pores for ions to leak out of cells
  • Non-polar side binds tightly to ergosterol (lipid) in fungal cell membrane
  • Selective for ergosterol containing fungal membrane but not the cholesterol containing human or bacterial cell membrane
  • Mycosamine sugar unit = crucial link between amphotericin and ergosterol that enables the formation of ion channel pores
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5
Q

Amphotericin B

Broad anti-fungal spectrum?

Resistance?

A

Broad anti-fungal spectrum:

  • Yeast: Candida albicans, Cryptococcus neoformans
  • Endemic fungi: Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitis
  • Pathogenic molds: Aspergillus fumigatus, mucor

Resistance:

  • Candida lusitaniae and Pseudallescheria boydii (display intrinsic amphotericin B resistance)
  • Acquired drug resistance can occur in vitro but clinically not significant (decreased ergosterol, modified ergosterol, drug cannot penetrate cell wall)
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6
Q

Amphotericin B

Clinical uses?

A
  • Drug of choice for nearly all life-threatening systemic infections
  • Often used as the initial treatment in critical cases, then followed by triazoles for chronic therapy or prevention of relpase
  • Topical drops for mycotic corneal ulcer/keratitis
  • Local injection for fungal arthritis
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7
Q

Amphotericin B

Administration and Pharmacokinetics?

Liposomal Preparations?

A
  • Drug is nearly insoluble in water
  • Administration by IV as suspension in deoxycholate (50:41 colloid)
  • Drug poorly absorbed by GI - oral administration is only for GI infections
  • Excreted slowly in urine w/ half life 15 days
  • Widely distributed, except for CSF
  • Drug levels = insensitive to renal or hepatic dysfunction

Liposomal Preparations:

  • Improved drug formulation with package in lipid
  • Enables higher doses w/ reduced nephrotoxicity
  • Expensive/commonly used when normal amphotericin B colloid causes problems
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8
Q

Amphotericin B

Adverse Effects:

  • Infused related toxicity?
  • Slower toxicity?
  • Drug Interactions?
A

Infused related toxicity:

  • Fever, chills, vomiting, headache, hypotension
  • Decreasing dose
  • Premedication with antipyretics (oral acetaminophin), antihistamines, meperidine, hydrocortisone may help

Slower toxicity

  • RENAL DAMAGE IS THE MOST COMMON PROBLEM
  • Variable anemia
  • Occasional impaired liver function

Drug Interactions
- Nephrotoxic drugs (e.g. cyclosporine and aminoglycosides)

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9
Q

Drugs for Systemic Infections:

Mode of action?
Flucytosine

A

Pro drug

Taken up by fungal cytosine permase –> converted to 5-fluorouracil (5-FU) by cytosine deaminase –> 5-FU converted to 5-FUTP that inhibits RNA synthesis –> 5-FU converted to 5-FdUMP that inhibits DNA synthesis

*Cytosine deaminase is only found in fungal cells, not human cells so prodrug can be converted into cytotoxic drug

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10
Q

Flucytosine

Selectivity?

Resistance?

A

Selectivity?
Mammalian cells poorly convert 5-FC to 5-FU

Resistance?
Loss of 5FC to 5FU conversion, or 5FU to 5FUMP conversion, or loss of 5-FC permease

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11
Q

Flucytosine

Administration?

Clinical Uses?

A

Administration:

  • Oral- absorbed rapidly from GI
  • Well distributed (including CSF and aqueous humor)
  • Removed by kidney - half life 3-6 hours
  • Drug can rise to toxic levels with renal impairment
  • Synergy with amphotericin B and itraconazole

ClinicalUses:

  • Limited spectrum of actin, limited to Candida and Cryptococcus
  • Usually given in combination therapy to avoid drug resistance: used in combo with amphotericin B or azoles
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12
Q

Flucytosine

Toxic Effects?

Drug Interactions?

A

Toxic Effects:

  • Decrease function of bone marrow (leukopenia, thrombocytopenia)
  • Rash and GI effects
  • Side effects: due to conversion to 5FU by bacteria in intestinal tract

Drug Interactions
- Drugs that suppress bone marrow

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13
Q

Drugs for Systemic Infections:

Anti-fungal azoles
Classification?

A

Imidazole compounds (2 Ns in five member rings): Ketoconazole, clotrimazole, Miconazole

Triazole compounds (3 Ns in five member rings): Itraconazole, Fluconazole, Voriconazole

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14
Q

Drugs for Systemic Infections:

Anti-fungal azoles
Mode of action?

A

Inhibit ergosterol synthesis: target third step (binds to active site)

cause accumulation of toxic methylsterols that inhibit membrane enzymes

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15
Q

Drugs for Systemic Infections:

Anti-fungal azoles
Selectivity?

Adverse effects?

A

Bind less efficiently to mammalian p450s, offering some specificity toward fungal cells

Minor effect:

  • Minor GI distress
  • Liver enzyme abnormality, causing rare drug-induced hepatitis
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16
Q

Drugs for Systemic Infections:

Anti-fungal azoles
Broad Spectrum?

A

Candida spp., Cryptococcus neoformans, endemic mycosis, dermatophytes, aspergillus, pseudollescheria boydii (amphotericin B resistant strain)

17
Q

Drugs for Systemic Infections:

Anti-fungal azoles
Drug Interactions?

A

Affect many drugs metabolism through P450 (cyclosporine, warfarin, buspirone, dihydropyridine)

18
Q

Imidazoles?

Ketoconzole:

Miconazole and clotrimazole:

A

Ketoconzole: first oral azole but has generally been replaced by newer triazole compounds, though this drug is much cheaper

Miconazole and clotrimazole: only used topically

19
Q

Triazoles: Itraconazole

Description?

Administration?

Metabolism?

Toxicity?

Drug Interaction?

A

Description:

  • Most potent azole
  • Itraconzole is favored over ketoconazole because: wider spectrum of action, fewer side effects (more specific than imidazoles)
  • Used on when infection is severe

Administration:

  • Oral-absorption is increased by gastric acid and food
  • Widely distributed, except for CSF
  • Limited bioavailability, but improved with cyclodextrin formulations

Metabolism:
- Lipid soluble
- Metabolism in liver through the cytochrome CYP3A4 isoenzyme
- Primary metabolite, hydroxyitraconazole, also has anti-fungal activity
Half life = 30-40 hrs

Toxicity:
- GI distress, teratogenic

Drug Interaction:

  • H2 and proton pump blockers that decrease gastric acidity
  • Drugs metabolized by P450 enzymes
20
Q

Triazoles: Fluconazole

(Voriconazole, Posaconazole)

Description?

Administration?

Metabolism?

Toxicity?

Drug Interaction?

A

Fluconazole:

  • Oral and well absorbed, no problem with gastric acidity
  • Widely distributed, including CSF
  • Least affects hepatic microsomal enzymes (fewer drug interactions)
  • Wide therapeutic index
  • Long half life (25-30 hrs)

Voriconazole, Posaconazole:

  • Newest triazoles with improved bioavailability
  • Posaconazole has the broadest spectrum
21
Q

Echinocandins?

A
  • Newest anti-fungal agents
  • Water soluble semi-synthetic lipopeptide derivative of pneumocandin B
  • Include caspofungin, micafungin, and anidulafungin
  • Caspofungin = first candin to market
22
Q

How do caspofungins work?

A

Disrupt cell wall

Caspofungin inhibits beta (1,3)-glucan synthase (FKS1)

Context:
Cell wall has 3 layers made up of mannoproteins, beta (1,6)-glucan/beta (1,3)-glucan, and chitin

23
Q

Clinical uses

A
  • Candida infections
  • For invasive aspergillosis that fails amphotericin B
  • Is taken parenterally
  • Minor adverse effects include-fever, nausea, flushing, and vomiting
  • Resistance due to mutation in FKS1
24
Q

Systemic drugs for mucocutaneous infections:

Terbinafine?

A
  • Synthetic allylamine
  • Inhibits squalene epoxidase to block ergosterol biosynthesis (step 1) and thus ergosterol biosynthesis
  • Inhibition leads to tox accumulation of sterol squalene
  • Drug accumulates in skin, nail, and fat to prevent nail beds and skin infections
  • Must be used continuously until infection is cleared
  • Synergistic with triazole compounds
  • No significant drug interactions to date and minimal side effects-GI distress and headache
25
Q

Topicals

Administered as creams or ointments, suppositories, or lozenges

Nystatin?

  • Mode of action
  • Administration
  • Clinical uses
A

Topical amphotericin derivative

Mode of action: ergosterol binder; pore former

Administration: Creams and ointments

Clinical uses: local suppression of candidal infections

26
Q

Topicals

Administered as creams or ointments, suppositories, or lozenges

Terbinafine?

Clotrimazole and Miconazole?

A

Terbinafine:

  • Squalene epoxidase inhibitors
  • Targets dermatophyte-caused tinea

Clotrimazole and Miconazole:
- Oral and vulvovaginal candidiasis; dermatophyte infections

27
Q

Summary: Mode of action of anti-fungal drugs

A
  1. Membrane distrupting agents amphotericin B, nystatin, azoles, allylamines
  2. Cell wall disruptors echinocandins
  3. Nucleic acid inhibitor flucytosine

M1 - Microbiology (23 decks)

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