Fungal Infections/Anti-Fungals

Question 1

Notes on azoles:

Answer 1

• Inhibits 14-alpha demethylase which produces ergosterol
• As a class associated with P450 inhibition and liver toxicity

Fluconazole

• High oral bioavailability
• Appropriate for candidaemia in non-neutropenic patients or known sensitive Candida
• Prophylaxis in SCT

Itraconazole

• Broader spectrum that fluconazole, issues with oral absorption, GI side effects and drug-drug interactions

Voriconazole

• Drug interactions
• Can cause visual changes, hallucinations, prolonged QTC, neuropathy, memory loss, difficulty concentrating, alopecia, photosensitive rash
• Up to 30% → deranged LFTs
• Broader coverage including to fluconazole resistant Candida
• Recommend drug level monitoring

Question 2

Mechanism of action amphoteracin B (polyenes)

Answer 2

• Binds with ergosterol forming a transmembrane channel → ion leakage
• Conventional Amphoteracin
  
  • A/W nephrotoxicity, flu-like symptoms (infusion related)
• Liposomal amphoteracin
  
  • Less nephrotoxicity and infusion reaction, better CSF penetration
• Often reserved for treatment of resistant Candidaemia

Question 3

Mechanism of action flucytosine

Answer 3

• Converted to 5-Flurouracil by cytosine deaminase → inhibits thymidylate synthase and disrupts fungal protein synthesis
• Can be associated with vomiting

Question 4

Mechanism of action caspofungin (class → Echinocandins)

Answer 4

• Inhibits synthesis of beta-glucan → major fungal cell wall component
• 97% protein bound
• Metabolised slowly by hydrolysis and N-acetylation
• Drug interactions: Cyclosporin A, tacrolimus, ART, phenytoin, carbamazepine, rifampicin
• Broad spectrum of action - not active against C. parapsilosis
• Can be associated with flushing
• Indications → treatment of candidaemia in neutropenic patients/unstable patients, resistant Candidaemia

Question 5

Mechanism of action nystatin (class → polyenes)

Answer 5

• Binds with ergosterol forming a transmembrane channel that → iron loss (same as Amphoteracin B)
• Toxic - only used topically

Question 6

Mechanism of action terbinafine:

Answer 6

• Inhibits squalene epoxidase
• Commonly used to treat fungal nail infections
• Belongs to allylamines class of antifungals

Question 7

Candida - mycology and epidemiology of candidaemia

Answer 7

• Yeast - unicellular, >40 species
• Large round white colonies on agar
• Universal commensal of skin, mouth, respiratory, GI, and female genital tract
• Candidaemia → common nosocomial infection, incidence rising (4th most common bloodstream infection in USA)
• C.albicans most common species, incidence of non-albicans rising:
  
  • C. parapsilosis, C. glabrata followed by C.tropicalis, C. krusei

Question 8

Risk factors for Candidaemia

Answer 8

• Co-morbidities:
  
  • Cancer (32%) - solid organ > haematological >post transplant
  • GI conditions (19%)
  • Chronic CVS disease
  • Diabetes
  • Pancreatitis and HIV rare (2.5%, 0.6% respectively)
• Iatrogenic risk factors:
  
  • Indwelling venous access (72%)
  • Antibiotic usage (77%)
  • Major surgery (37%)
  • TPN feeding (33%)
• Risk factors for non-albicans candidaemia
  
  • Widespread fluoconazole use
    
    • Personal level - prolonged fluconazole prophylaxis
    • Institutional level → bulk fluconazole use → change in ecology of Candida species

Question 9

Notes on Candida auris

Answer 9

• Emerging, drug resistant yeast responsible for hospital outbreaks
• Bloodstream infections most frequently reported - mortality 30-60%
• Resistance to caspofungin and amphoteracin seen (first line treatment still echinocandins → caspofungin)
• Strict infection control, single room isolation