A 52-year-old man with acute leukemia undergoing chemotherapy presents with fever (38.8°C), dysphagia, and retrosternal chest pain for 3 days. Endoscopy reveals multiple white plaques and ulcerations in the esophagus. Blood cultures and esophageal brushings are sent. The patient is started on empiric fluconazole 400 mg daily IV. After 5 days of therapy, repeat endoscopy shows worsening ulcerations and new areas of necrosis. Esophageal biopsy culture grows a Candida species that is resistant to fluconazole. Which of the following organisms is most likely, and what is the most appropriate next step in management?

Explanation

## Clinical Context: Esophageal Candidiasis in Immunocompromised Host **Key Point:** Esophageal candidiasis (EC) in neutropenic patients is a serious opportunistic infection. While C. albicans causes ~80% of EC, fluconazole-resistant non-albicans Candida species (particularly C. glabrata and C. auris) are increasingly encountered in patients with prolonged azole exposure or severe immunosuppression. **High-Yield:** Fluconazole resistance in Candida is categorized as: - **Intrinsic:** C. glabrata and C. auris have inherent reduced susceptibility to fluconazole due to altered lanosterol 14α-demethylase expression and efflux pump upregulation. - **Acquired:** C. albicans may develop resistance through prolonged azole exposure via mutations in ERG11 gene or upregulation of efflux pumps (CDR1, MDR1). ## Differential Diagnosis of Fluconazole-Resistant Candida | Species | Intrinsic Resistance | Clinical Setting | Preferred Agent | |---------|---------------------|------------------|------------------| | C. glabrata | Yes (high-level) | Recurrent VVC, esophagitis in immunocompromised | Echinocandin or amphotericin B | | C. auris | Yes (multidrug) | Healthcare-associated, invasive disease | Echinocandin (caspofungin, anidulafungin) | | C. tropicalis | No (usually susceptible) | Disseminated disease, rarely resistant | Fluconazole or echinocandin | | C. albicans | No (but can acquire) | Recurrent/chronic infections on azoles | Voriconazole or echinocandin | ## Why C. glabrata Is Most Likely 1. **Epidemiology:** C. glabrata is the second most common cause of EC in immunocompromised hosts and accounts for ~10–15% of Candida isolates from blood and esophageal sources. 2. **Intrinsic Resistance:** C. glabrata has constitutively high expression of efflux pumps and altered sterol composition, making it inherently resistant to fluconazole (MIC often ≥64 µg/mL). 3. **Clinical Presentation:** Failure to respond to fluconazole after 5 days in an immunocompromised patient strongly suggests a non-albicans species with intrinsic resistance. 4. **Prevalence:** In patients with prolonged hospitalization and antifungal exposure, C. glabrata is more common than C. auris in most regions outside nosocomial outbreak settings. ## Management of Fluconazole-Resistant EC **Mnemonic:** **ERICA** = **E**chinocandin (first-line for resistant Candida), **R**esistance pattern (intrinsic vs. acquired), **I**nvasive disease (esophagitis is invasive), **C**andida species (identify), **A**mphotericin B (alternative). ### First-Line Options 1. **Echinocandins (Preferred)** - Caspofungin 50 mg IV daily (after 70 mg loading dose) - Anidulafungin 100 mg IV daily (after 200 mg loading dose) - Micafungin 100 mg IV daily - **Mechanism:** Inhibit β-1,3-glucan synthase; fungicidal against Candida. - **Advantage:** Excellent esophageal penetration, no hepatic metabolism interactions, active against C. glabrata and C. auris. 2. **Amphotericin B Deoxycholate** - 0.6–1 mg/kg IV daily - **Advantage:** Broad-spectrum, fungicidal. - **Disadvantage:** Nephrotoxicity, infusion reactions; reserved if echinocandin unavailable. 3. **Liposomal Amphotericin B** - 3–5 mg/kg IV daily - **Advantage:** Reduced nephrotoxicity vs. deoxycholate. - **Disadvantage:** Expensive; reserved for renal impairment. ### Why NOT Voriconazole or Increased Fluconazole - **Voriconazole** is effective for C. albicans with acquired resistance but has variable activity against C. glabrata and poor activity against C. auris. - **Increased fluconazole dosing** is ineffective against intrinsically resistant species; higher doses do not overcome the resistance mechanism. **Clinical Pearl:** Echinocandins are the preferred agents for invasive candidiasis (including esophagitis) caused by non-albicans species in the 2016 IDSA guidelines and are superior to azoles in immunocompromised hosts.