Fungi

Question 1

Azole MOA

Answer 1

Interferes with ergosterol synthesis
Inhibits the CYP450 which cataylses 14-methylation of lanosterol
Azole does this by forming a complex with the iron atom of CYP450 preventing substrate from binding
Leads to the accumulation of 14 alpha methyl steroids; additional methyl affects the plannarity of the sterol ring
This affects the steroids interacting with the phospholipids and also alters membrane rigidity

Question 2

Imidazole

Answer 2

Miconazole, clotrimazole
Susceptible to metabolic inactivation, lipophilic (high levels of protein binding), low activity

Question 3

Triazoles

Answer 3

fluconazole, itraconazole, voriconazole, posaconazole,
Better half life in plasma, better activity, less prone to metabolic inactivation and less protein binding

Question 4

Azole resistance

Answer 4

1) mutated active site- loss of enzyme activity or reduced inhibitor activity
2) gene amplification - over expression of genes involved in synthetic sterol pathway
3) decreased accumulation due to increased Efflux pumps

Question 5

Amphotercin B

Answer 5

Amphotercin B molecules are similar length to phospholipid molecules
Molecules aggregate together and form channels in the plasma membrane
Channels allow leakage of protons and K+
This disrupts the internal pH of the cell -> enzymes do not work-> cell dies

Binds with higher affinity to ergosterol than cholesterol

Question 6

5’ Flurocytosine

Answer 6

Activity required deamination by cytosine deaminase

Flurocytosine is converted to flurouracil and interacts with RNA biosynthesis inhibiting protein synthesis

Flurocytosine is also converted to flurodeoxyuridinemonophosphate which inhibits DNA synthesis

Humans have no/ little cytosine deaminase activity

Question 7

what are the different anti fungal classes ?

Answer 7

Azoles
Polyene Antifungal
Griseofulvin
Fluorocytosine
Caspofungin

Question 8

How does resistance to azoles occur?

Answer 8

Resistance to azoles
Fungal resistance to azoles – Azoles are fungistatic rather than fungicidal, C. Albicans lives on mucosal membranes as a biofilm
Can occur to people with HIC and long-term fluconazole treatment
Cross-resistance to other azoles

Question 9

what are the key points to remember about imidazole ?

Answer 9

• IMIDAZOLES
  → Topical use only – susceptible to metabolic inactivation
  → E.g. clotrimazole (ear infections); miconazole (vaginal & vulval candidiasis)
  oVery lipophilic – high levels of plasma protein binding & low systemic bioavailability
  → Ketoconazole (vaginal & vulval candidiasis) – improvement on early azoles
  Less metabolic instability
  Less lipophilic – higher plasma levels
  Still metabolised (<1% unchanged in urine)
  Still bound to plasma proteins (<1% unbound)

Question 10

What are the key points to remember about triazoles?

Answer 10

• TRIAZOLES
  → E.g., fluconazole (vaginal/mucosal candidiasis); itraconazole (systemic infections – aspergillosis, candidiasis
  → Fluconazole – improved t1/2 of 30hr in plasma
  o Improved oral bioavailability – 80% unchanged in urine
  o Low protein binding – approx. 12%
  → Improved properties – triazoles can be taken systemically

Question 11

What are the key points to remember about Voriconazole

Answer 11

• VORICONAZOLE
  → Systemic antifungal treating aspergillosis – before only amphotericin B was available to treat life-threatening fungal infections
  o Active against yeasts & moulds
  o Oral and IV preparations
  o Well-absorbed
  o 96% bioavailability – high
  o Approved for: invasive aspergillosis, Scedosporium spp., Fursarium spp., invasive fluconazole-resistance Candida spp.
  o Extensive hepatic metabolism
  → Survival benefit & superior outcome vs amphotericin B in invasive aspergillosis
  o Acceptable overall safety – SE: visual disturbances, hallucinations
  o Generally better tolerated
  o Manageable DDIs

Question 12

What are the key points to remember about isavuconazole?

Answer 12

• ISAVUCONAZOLE
  → Invasive aspergillosis, mucormycosis
  → Patients where amphotericin B is not appropriate (due to SEs)

Question 13

What are the key points to remember about posaconazole?

Answer 13

• POSACONAZOLE
  → Invasive aspergillosis refractory to/patients intolerant of itraconazole or amphotericin B
  → Fusariosis refractory to/patients intolerant of amphotericin B
  → Chromoblastomycosis & mycetoma refractory to/patients intolerant of itraconazole
  → Coccidioidomycoses refractory to/patients intolerant or itraconazole, amphotericin B or fluconazole

Question 14

what are the Key things to remember about Amphotericin B & Nystatin

Answer 14

AMPHOTERICIN B & NYSTATIN
- Amphotericin B – only polyene for systemic treatment
→ Not absorbed orally – IV admin
→ Liposomal preparations
- Nystatin too toxic for systemic – can be used topically & for intestinal infections (not absorbed)
- Specific structures – crucial for MoA
- Amphotericin is also toxic (less than nystatin) so isn’t not tolerated in some patients – azole alternatives
→ Method to reduce toxicity, but is expensive

Question 15

What is the SELECTIVITY & TOXICITY

Answer 15

SELECTIVITY & TOXICITY
- Amphotericin B has stronger binding constant with ergosterol than cholesterol
- Still has some quite severe SEs – nausea, fever, vomiting, diarrhoea etc
- Voriconazole (alternative) has fewer SEs, which are often better tolerated