What is Candida glabrata, particularly in patients with weakened immune systems, such as those with diabetes, cancer, or Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS)?

What is Candida glabrata?

Candida glabrata is an opportunistic fungal pathogen that ranks as the second or third most common cause of invasive candidiasis and represents a particularly concerning threat due to its intrinsic reduced susceptibility to azole antifungals and ability to evade immune detection. 1, 2

Organism Characteristics

• C. glabrata is a haploid, nondimorphic yeast that reproduces primarily through budding and clonal reproduction, distinguishing it from other Candida species like C. albicans that exhibit morphological switching 3, 4
• Phylogenetically, C. glabrata is more closely related to Saccharomyces cerevisiae than to C. albicans, with recent analyses suggesting reclassification as Nakaseomyces glabratus 5, 4
• The organism possesses a 12.3 Mb genome with a stable pangenome structure 5

Clinical Significance in Immunocompromised Populations

High-Risk Patient Groups

• HIV/AIDS patients with CD4+ counts <200 cells/μL face substantially increased risk, with C. glabrata capable of causing refractory mucosal candidiasis particularly in those with advanced immunosuppression 1, 6
• Critically ill ICU patients represent the highest risk population for invasive candidiasis, with C. glabrata accounting for a significant proportion of non-albicans infections 1
• Cancer patients, particularly those with hematological malignancies receiving chemotherapy and experiencing prolonged neutropenia, are at elevated risk 1
• Diabetic patients face increased susceptibility through impaired glycemic control and altered host defenses 7

Epidemiologic Patterns

• C. glabrata accounts for over 90% of invasive candidiasis cases when combined with C. albicans, C. tropicalis, and C. parapsilosis in Taiwan and similar patterns exist globally 1
• The organism has emerged as a leading cause of healthcare-associated bloodstream infections in intensive care units and urinary tract infections 1
• There has been a progressive epidemiologic transition from C. albicans to non-albicans species including C. glabrata over the past decade 1

Critical Antifungal Resistance Profile

Intrinsic Azole Resistance

• C. glabrata exhibits low inherent susceptibility to azole antifungals, with many isolates classified as intermediate (MIC 16-32 mcg/mL) or resistant to fluconazole 8, 2
• The organism demonstrates cross-resistance to multiple azoles through upregulation of CDR genes (ATP-binding cassette efflux transporters), distinguishing it from simple fluconazole resistance 8
• Approximately 10% of clinical C. glabrata isolates display co-resistance to both azole and echinocandin drugs, representing a major therapeutic challenge 2

Resistance Mechanisms

• Resistance arises through multiple mechanisms: mutations in ERG11 (encoding lanosterol 14-α-demethylase), overexpression of efflux pumps (Cdr1, Pdr1), and activation of multidrug transporter proteins 8, 9
• Repeated and prolonged azole exposure, particularly in profoundly immunosuppressed patients, drives emergence of resistant strains 1, 6
• The organism activates specific response pathways such as RIM 101 that contribute to both drug resistance and adhesion capabilities 9

Virulence Strategies and Immune Evasion

• C. glabrata deploys ingenious strategies to disarm macrophages, dampen host inflammatory responses, and replicate intracellularly despite lacking morphological switching or secreted proteolytic activity 4
• The organism expresses cell surface-associated adhesins and aspartyl proteases that contribute to virulence and biofilm formation 4
• Autophagy-related proteins (Atg11, Atg16) and stress response proteins (Sgf11, Alg2) are differentially expressed in virulent isolates 9
• C. glabrata efficiently acquires iron and phosphate from the host environment, supporting its survival in nutrient-limited conditions 4

Clinical Manifestations

Mucosal Infections

• C. glabrata causes oral thrush presenting as erythematous patches or pseudomembranous lesions, particularly in HIV-infected patients with CD4 counts <200 cells/μL 1, 7
• Vulvovaginal candidiasis caused by C. glabrata tends to be more refractory to standard azole therapy compared to C. albicans infections 1
• Esophageal involvement can occur, presenting with retrosternal pain, odynophagia, and altered taste 1

Invasive Disease

• Intraabdominal candidiasis (IAC) caused by C. glabrata carries mortality rates exceeding 50%, with worse outcomes than bacterial intraabdominal infections 1
• Candidemia associated with C. glabrata has mortality rates as high as 45% in European studies 1
• Only 6.9% of IAC patients have concomitant positive blood cultures, making diagnosis challenging in the absence of bloodstream infection 1

Critical Clinical Pitfalls

• The highest fluconazole dose is required for isolates with intermediate susceptibility (MIC 16-32 mcg/mL), and alternative antifungal therapy (amphotericin B, echinocandins) is often necessary 8, 3
• Vaginal pH significantly affects antifungal efficacy, with MICs being >388-fold higher for terconazole against C. glabrata at normal vaginal pH (4.0) compared to laboratory conditions (pH 7.0) 6
• Following HAART introduction in HIV patients, 93% of Candida isolates remain fluconazole-susceptible despite repeated azole exposure, but C. glabrata remains problematic 1, 6
• Failure to identify C. glabrata as the causative organism leads to treatment failure in refractory cases, as this species requires different therapeutic approaches than C. albicans 7, 10
• The World Health Organization has designated C. glabrata as a high-priority fungal pathogen due to increasing antifungal resistance and unmet therapeutic needs 2