MI: Fungal Infections Pt.3

Question 1

List antifungals that target:

• Cell membrane
• DNA/RNA synthesis
• Cell wall

Answer 1

Cell membrane:

• Polyene - amphotericin B, nystatin
• Azole - ketoconazole, itraconazole, fluconazole, clotrimazole

DNA/RNA synthesis:

• Flucytosine (pyrimidine analogue)

Cell wall:

• Echinocandins - caspofungin acetate

Question 2

What is the mechanism of action of azoles?

Answer 2

• Inhibit ergosterol production by inhibiting CYP450 enzyme lanosterol 14a-demethylase
• This inhibition leads to the accumulation of toxic steroids in the cell membrane which cause cell death

Question 3

What are the consequences of cross-reaction of azoles with other CYP450 enzymes?

Answer 3

• Drug interactions
• Impairment of steroidogenesis

Question 4

List examples of the following types of azoles along with their usual indications:

• Water-soluble triazoles
• Lipophilic triazoles

Answer 4

Water-soluble triazoles:

• Fluconazole - active against Candida and Cryptococcus
• Voriconazole - similar to fluconazole but better activity against Aspergillus

Lipophilic triazoles:

• Itraconazole - useful against dermatophytes
• Posaconazole - activity against mucor

Question 5

List some examples of echinocandins.

Answer 5

• Caspofungin
• Micafungin
• Anidulafungin

Question 6

What is the mechanism of action of echinocandins?

Answer 6

• Cyclic lipopeptide antibiotic that inhibits beta-(1,3) D-glucan synthase
• This enzyme is responsible for the production of beta D-glucan which is a component of the fungal cell wall
• This inhibition results in osmotic fragility of the cell

Question 7

Which fungi are echinocandins active against?

Answer 7

• Candida* species
• Aspergillus* species (NOT other moulds)

NOTE: it has NO coverage for Cryptococcus

Question 8

What is the main polyene antifungal?

Answer 8

Amphotericin B

Question 9

How is amphotericin packaged in most formulations?

Answer 9

Put in liposomes to try and reduce toxicity and improve penetration

Question 10

What is ambisome?

Answer 10

Amphotericin within a phospholipid bilayer

Question 11

How is amphotericin B produced?

Answer 11

Fermentation product of Streptomyces nodusus

Question 12

Describe the mechanism of action of amphotericin B.

Answer 12

• Binds to ergosterol in the fungal cell membrane and creates transmembrane channels leading to electroyte leakage
• This leads to fungal cell death

Question 13

Amphotericin B is active against most fungi except…

Answer 13

• Aspergillus terreus
• Scedosporium spp.

Question 14

What is the main side-effect of amphotericin B? Describe the mechanism of this toxicity.

Answer 14

• Nephrotoxicity
• Renovascular - decrease in renal blood flow leads to reduced GFR (azotaemia)
• Tubular - distal tubular ischaemia, wasting of sodium, potassium and magnesium

Question 15

Describe the mechanism of action of flucytosine.

Answer 15

Inhibits DNA synthesis (pyrimidine analogue)

Question 16

What are some mechanisms of resistance to flucytosine?

Answer 16

• Decreased uptake (permease activity)
• Altered 5-FC metabolism

Question 17

Which fungi are flucytosine active against?

Answer 17

Candidiasis

Cryptococcus

Question 18

List some side-effects of flucytosine.

Answer 18

• D&V
• LFT changes
• Blood disorders

NOTE: blood concentrations should be monitored if used with amphotericin B

Question 19

Types of superficial Candida infections?

Answer 19

• Oral candidiasis
• Oesophageal candidiasis
• Vulvovaginitis
• Cutaneous (local/ generalised)

Question 20

What are dermatophytes?

Answer 20

group of fungi capable of invading dead keratin of skin, hair and nails