A 52-year-old man with poorly controlled diabetes mellitus (HbA1c 11.2%) presents with a 3-week history of progressive dysphagia and retrosternal chest pain. Endoscopy reveals white plaques on the esophageal mucosa that do not scrape off easily. KOH mount of the biopsy specimen shows pseudohyphae and budding yeast. He has no prior antifungal exposure. Which antifungal agent is the most appropriate first-line therapy for this patient?

## Clinical Diagnosis **Key Point:** The patient has oesophageal candidiasis, confirmed by endoscopy (white plaques) and KOH mount (pseudohyphae and budding yeast). The risk factor is poorly controlled diabetes. ## First-Line Antifungal for Oesophageal Candidiasis **High-Yield:** Fluconazole is the standard first-line agent for oesophageal candidiasis in non-neutropenic, non-severely immunocompromised patients. ### Mechanism & Rationale Fluconazole is an azole antifungal that: - Inhibits fungal lanosterol 14α-demethylase (CYP51), blocking ergosterol synthesis - Achieves excellent oesophageal tissue penetration and saliva levels - Oral bioavailability ~90%, allowing convenient outpatient dosing (200–400 mg daily for 14–21 days) - Has a favourable safety profile with minimal drug interactions in this patient **Clinical Pearl:** Azoles are fungistatic (not fungicidal) but sufficient for immunocompetent hosts with intact cell-mediated immunity. ## Comparative Antifungal Agents | Agent | MOA | Indication | Limitation | | --- | --- | --- | --- | | **Fluconazole** | CYP51 inhibitor (azole) | First-line: oesophageal candidiasis, non-severe | Resistance in *C. glabrata*, *C. auris*; fungistatic | | **Amphotericin B** | Binds ergosterol, pore formation | Severe/disseminated candidiasis, neutropenic patients | Nephrotoxic, IV-only, reserved for severe disease | | **Terbinafine** | Squalene epoxidase inhibitor | Dermatophyte infections, onychomycosis | Ineffective against *Candida*; hepatotoxicity risk | | **Caspofungin** | β-1,3-glucan synthase inhibitor (echinocandin) | Invasive candidiasis, neutropenic fever | IV-only, more expensive; reserved for azole-refractory or severe disease | **Warning:** Do not confuse terbinafine (used for dermatophytes and *Malassezia*) with azoles — it has poor activity against *Candida*. ## Dosing & Duration - **Fluconazole:** 200–400 mg PO daily for 14–21 days - Monitor for clinical response (resolution of dysphagia) by 7–10 days - Repeat endoscopy not routinely needed if symptoms resolve **Tip:** Always optimize glycaemic control (target HbA1c <7%) to prevent recurrence and improve immune function. [cite:Harrison 21e Ch 196]