SCENARIO-BASED QUESTIONS / PROBLEM-SOLVING EXERCISES

Question 1 - 50-year-old diabetic woman with oesophageal candidiasis

• Amphotericin B has no licensed oral formulation - it must be given IV, making it unsuitable for outpatient oesophageal candidiasis.
• It has significant nephrotoxicity (decreased renal blood flow, tubular damage) and infusion-related toxicity (fever, chills, thrombophlebitis).
• Fluconazole is equally efficacious for Candida albicans infections and is far safer and more convenient.
• AmB is reserved for severe, refractory, or life-threatening disseminated fungal infections. (Harrison's 22E, p.1735)

Question 2 - 40-year-old HIV patient with cryptococcal meningitis (CD4 70/µL)

1. Binding to ergosterol in the fungal cell membrane, forming pore-like aggregates (extramembranous sponge-like structures) that extract ergosterol from the lipid bilayer.
2. This creates membrane channels, increasing permeability - essential ions and cellular contents leak out, causing fungal cell death (fungicidal).
3. At higher concentrations, AmB also binds cholesterol in mammalian cell membranes (accounting for its toxicity, especially renal).

• AmB (fungicidal) rapidly reduces fungal burden in the CSF.
• Fluconazole then maintains suppression during consolidation/maintenance.
• This sequential strategy achieves both rapid clearance and long-term suppression, reducing relapse risk. (Some studies combine AmB + fluconazole for induction in resource-limited settings.)

1. Nephrotoxicity (most important) - azotemia, electrolyte wasting (hypokalemia, hypomagnesemia), decreased GFR. Monitor renal function, potassium, and magnesium regularly.
2. Infusion-related reactions - fever, rigors/chills, headache, nausea, hypotension during infusion.
3. Anaemia (normochromic, normocytic) due to reduced erythropoietin production.
4. Thrombophlebitis at IV site.
5. Hepatotoxicity (less common). Pre-medications (paracetamol, antihistamines, hydrocortisone) and saline pre-loading reduce infusion reactions and nephrotoxicity. (Red Book 2021; Harrison's 22E)

REASONING TYPE QUESTIONS

• Griseofulvin is fungistatic and acts by inhibiting microtubule function, disrupting the mitotic spindle assembly in fungi (interferes with fungal nuclear division).
• Crucially, it has high affinity for keratin - it deposits selectively in newly forming keratin-containing tissues (skin, nails, hair). Because dermatophytes (ringworm fungi like Trichophyton, Microsporum) infect and survive in keratinized tissues, griseofulvin concentrates exactly where the infection is. The drug renders newly formed keratin resistant to dermatophyte invasion.
• It is taken orally and slowly incorporated into growing keratin as skin turns over, effectively making new skin/hair/nail fungus-resistant.

• Conventional AmB deoxycholate causes severe nephrotoxicity - it binds cholesterol in renal tubular cell membranes causing direct tubular damage plus renal vasoconstriction.
• Liposomal formulation encapsulates AmB in lipid vesicles. This:
  • Preferentially delivers drug to fungal cell membranes (which avidly take up liposomes) rather than mammalian tissues.
  • Significantly reduces nephrotoxicity and infusion-related reactions (fever, chills, rigors).
  • Maintains equivalent antifungal efficacy.
• The lipid formulations are therefore preferred in patients at risk for renal impairment or when infusion reactions are unacceptable, though the higher cost limits use in resource-limited settings.

• Ketoconazole is a potent inhibitor of CYP450 enzymes, including those involved in steroid hormone biosynthesis (e.g., CYP17A1/17α-hydroxylase and other steroidogenic enzymes).
• It inhibits testosterone and corticosteroid synthesis in the adrenal glands and gonads.
• In males: reduced testosterone + mild estrogen activity produces gynecomastia (breast tissue enlargement).
• In females: disruption of the normal estrogen/progesterone biosynthesis leads to menstrual irregularities.
• It also causes hepatotoxicity, which is why it is rarely used systemically now.