A 58-year-old man with poorly controlled diabetes mellitus (HbA1c 10.2%) presents with a 3-week history of progressive dysphagia and retrosternal chest pain. Endoscopy reveals white plaques in the oesophagus that do not scrape off easily. KOH mount of the biopsy specimen shows pseudohyphae and budding yeast. He is started on fluconazole 200 mg daily. After 5 days of therapy, he develops severe hepatotoxicity with ALT 1200 U/L and bilirubin 4.2 mg/dL. What is the most appropriate next step in management?

Explanation

## Clinical Context This patient has oesophageal candidiasis (confirmed by KOH mount showing pseudohyphae and budding yeast) complicating poorly controlled diabetes. Fluconazole is the first-line agent, but he has developed severe hepatotoxicity—a known but uncommon adverse effect of azole antifungals. ## Mechanism of Fluconazole Hepatotoxicity **Key Point:** Fluconazole inhibits hepatic cytochrome P450 enzymes and can cause idiosyncratic hepatotoxicity, particularly in patients with underlying liver disease or those receiving concurrent hepatotoxic drugs. Once hepatotoxicity manifests with ALT >1000 U/L and hyperbilirubinaemia, the azole must be discontinued. ## Why Amphotericin B? **High-Yield:** Amphotericin B deoxycholate is the alternative polyene antifungal for oesophageal candidiasis when azoles are contraindicated (hepatotoxicity, resistance, or intolerance). Although amphotericin B carries nephrotoxicity risk, it does not undergo hepatic metabolism and is safe in liver disease. The dose 0.7–1 mg/kg/day IV is standard for invasive candidiasis. **Clinical Pearl:** Liposomal amphotericin B (3–5 mg/kg/day) is preferred if renal function is borderline, but deoxycholate is acceptable if creatinine clearance is adequate. ## Why Not the Other Options? | Option | Problem | |--------|----------| | Continue fluconazole (reduced dose) | Hepatotoxicity at this severity mandates discontinuation, not dose reduction. The liver is already injured. | | Itraconazole | Also an azole; carries same hepatotoxicity risk. Contraindicated when fluconazole causes LFT derangement. | | Topical clotrimazole only | Insufficient for oesophageal candidiasis; systemic therapy is mandatory. Topical agents do not reach the oesophagus adequately. | ## Management Algorithm ```mermaid flowchart TD A["Oesophageal candidiasis diagnosed"]:::outcome --> B["Start fluconazole 200 mg/day"]:::action B --> C{"LFTs normal at day 5?"}:::decision C -->|"Yes"| D["Continue fluconazole, review at 2 weeks"]:::action C -->|"No: ALT >1000, bili >3"|E["STOP fluconazole immediately"]:::urgent E --> F{"Renal function normal?"}:::decision F -->|"Yes"| G["Switch to Amphotericin B deoxycholate 0.7–1 mg/kg/day IV"]:::action F -->|"Impaired"| H["Switch to Liposomal Amphotericin B 3–5 mg/kg/day IV"]:::action G --> I["Monitor renal function, electrolytes, LFTs"]:::action H --> I ``` **Key Point:** Azole hepatotoxicity is idiosyncratic and unpredictable; once detected, the drug must be stopped and replaced with a non-hepatically metabolized alternative.