A 58-year-old man with acute leukaemia undergoing intensive chemotherapy develops persistent oral candidiasis unresponsive to fluconazole 400 mg daily for 10 days. Oral examination reveals white plaques on the tongue and palate that cannot be scraped off easily. Culture from oral swab grows a yeast that is germ tube negative, does not ferment glucose, and shows resistance to azoles. The isolate is identified as *Candida glabrata*. Which of the following mechanisms best explains the azole resistance in this organism?

Explanation

## Azole Resistance in Candida glabrata ### Clinical Context The patient presents with fluconazole-refractory oral candidiasis caused by *C. glabrata*, a species with intrinsically lower azole susceptibility and a propensity for developing resistance during prolonged antifungal exposure. **Key Point:** *Candida glabrata* is an emerging cause of invasive candidiasis in immunocompromised hosts and is notorious for azole resistance, making it a significant clinical challenge. ### Mechanisms of Azole Resistance in C. glabrata | Mechanism | C. glabrata | C. albicans | Clinical Significance | |-----------|-------------|------------|----------------------| | **Efflux pump upregulation** | Primary mechanism | Secondary | Most common in *C. glabrata* | | **CYP51 mutations** | Rare | Common | Develops with prolonged azole exposure | | **Reduced ergosterol** | Uncommon | Rare | Leads to polyene resistance | | **Cell wall changes** | Possible | Uncommon | Contributes to reduced permeability | ### Efflux Pump-Mediated Resistance (Correct Answer) **High-Yield:** *Candida glabrata* has constitutively high expression of ATP-binding cassette (ABC) transporters (CDR1, CDR2) and major facilitator superfamily (MFS) transporters (MDR1). These pumps actively extrude azole drugs from the fungal cell, reducing intracellular drug concentration below therapeutic levels. 1. Azole drugs (fluconazole, itraconazole) enter the fungal cell 2. Efflux pumps recognize and actively transport azoles out of the cell 3. Intracellular azole concentration remains subtherapeutic 4. Lanosterol 14α-demethylase (CYP51) is not sufficiently inhibited 5. Ergosterol synthesis continues → cell membrane remains intact **Clinical Pearl:** *C. glabrata* isolates with upregulated efflux pumps often show cross-resistance to multiple azole classes (fluconazole, itraconazole, voriconazole), making them difficult to treat. ### Why Efflux Pumps Are the Primary Mechanism in C. glabrata - *C. glabrata* has fewer CYP51 genes (one copy) compared to *C. albicans* (two copies), making CYP51 mutations less likely - The organism has a naturally thicker cell wall with higher chitin content, which may reduce azole permeability as a secondary mechanism - Efflux pump overexpression is the most frequently detected resistance mechanism in clinical isolates ### Management of Azole-Resistant C. glabrata **Mnemonic: AFVE** — Alternative agents for *C. glabrata* resistance: - **A**mphotericin B (liposomal formulation preferred) - **F**lucytosine (5-FC) combined with amphotericin B - **V**oriconazole (higher doses, variable efficacy) - **E**chinocandins (caspofungin, micafungin, anidulafungin) — preferred first-line for invasive disease **Key Point:** Echinocandins are now the preferred agents for invasive *C. glabrata* infections due to consistent efficacy and low resistance rates. [cite:Textbook of Microbiology Baveja 5e Ch 24; Candida glabrata Epidemiology & Resistance Review]