What is the recommended method for testing for systemic Candida (C.) glabrata infection?

Testing for Systemic C. glabrata Infection

Blood cultures remain the cornerstone for diagnosing systemic C. glabrata infection, supplemented by β-D-glucan (BDG) testing and tissue/fluid cultures from suspected deep-seated sites, with species identification mandatory for all positive isolates. 1

Primary Diagnostic Approach

Blood Cultures

• Obtain blood cultures immediately when systemic C. glabrata infection is suspected, as they detect candidemia in approximately 50% of invasive candidiasis cases 1
• Blood cultures have a detection limit of ≤1 colony-forming unit/mL and should be positive during the vast majority of active bloodstream infections 1
• Expect median time to positivity of 2-3 days, though results may range from 1 to ≥7 days 1
• Species identification to the species level is mandatory for all positive blood cultures, as C. glabrata exhibits inherently low susceptibility to azole antifungals 1, 2

β-D-Glucan (BDG) Testing

• BDG testing is recommended for detecting invasive candidiasis and can identify cases days to weeks before positive blood cultures 1
• The test has pooled sensitivity of 75-80% and specificity of 80% for invasive candidiasis 1
• BDG is particularly useful when blood cultures are negative but clinical suspicion remains high 1
• Note that BDG is not specific for Candida and will be positive with other invasive fungal infections (Aspergillus, Pneumocystis) 1

Deep-Seated Infection Testing

Tissue and Body Fluid Cultures

• Obtain tissue biopsies or fluid samples from suspected infection sites, as these are essential when chronic disseminated candidiasis or deep-seated infection is suspected 1
• Tissue biopsy is highly advisable for chronic disseminated candidiasis since blood cultures are rarely positive in this condition 1
• Cultures from tissues/fluids exhibit poor sensitivity (often <50%) but isolation from normally sterile sites is usually indicative of deep-seated infection 1
• C. glabrata may take 5-14 days to grow in culture, so negative results do not exclude infection 1, 3

Mannan and Anti-Mannan Antibody Testing

• Consider mannan/anti-mannan antibody testing for chronic disseminated candidiasis, which shows 86% sensitivity and can be positive 16 days on average before cultures 1
• The combined assay performs best for C. glabrata infections specifically (along with C. albicans and C. tropicalis) 1
• This test is approved in Europe but not widely available in the United States 1

Critical Diagnostic Considerations for C. glabrata

Microscopy Limitations

• C. glabrata does not form pseudohyphae or hyphal elements, appearing only as yeast cells 3-5 microns in size on microscopy 1, 4, 5, 6
• Yeast cells are difficult to visualize on H&E staining but can be detected on Grocott methenamine silver (GMS) staining 6
• The absence of hyphal forms makes C. glabrata difficult to distinguish from Histoplasma capsulatum on histopathology alone 6

Antifungal Susceptibility Testing

• Perform antifungal susceptibility testing on all C. glabrata isolates from blood and deep sites, as this species has inherent reduced azole susceptibility and approximately 10% of isolates show co-resistance to both azoles and echinocandins 1, 2
• Use reference procedures or validated commercial techniques, noting that discrepant results may occur with commercial methods (Etest, Sensititre YeastOne) for isolates with borderline MIC values 1

When Blood Cultures May Be Negative

Blood cultures can be negative in several scenarios despite active systemic infection 1:

• Extremely low-level or intermittent candidemia
• Deep-seated candidiasis that persists after bloodstream sterilization
• Direct inoculation of Candida without candidemia
• Prior antifungal exposure reducing diagnostic sensitivity 1

Common Pitfalls to Avoid

• Do not rely on microscopy alone for C. glabrata identification, as the absence of pseudohyphae and small yeast size can lead to misidentification as Histoplasma 6
• Do not assume azole susceptibility—C. glabrata requires susceptibility testing due to inherent resistance patterns 1, 2
• Do not stop at negative blood cultures—consider BDG testing and tissue sampling if clinical suspicion remains high 1
• Negative culture results do not exclude infection, particularly in patients receiving antifungal prophylaxis or empiric therapy 1, 3