How to differentiate between Candida glabrata colonization and infection?

Distinguishing Candida glabrata Colonization from Infection

The key to differentiating C. glabrata colonization from infection is combining clinical evidence of tissue invasion (fever, leukocytosis, organ dysfunction) with microbiological confirmation from sterile sites or tissue biopsy showing >10^5 organisms/gram or yeasts on microscopy. 1

Critical Diagnostic Principles

Sterile Site Isolation = Infection

• Any C. glabrata isolated from blood, cerebrospinal fluid, or other normally sterile sites must be considered true infection, not colonization 1
• Blood cultures are definitive but insensitive—only 50% of patients with disseminated candidiasis have positive blood cultures 1
• Lysis centrifugation increases blood culture yield by 30-40% 1

Tissue Biopsy: The Gold Standard

• Tissue biopsy definitively distinguishes infection from colonization through either:
  • Quantitative culture showing >10^5 organisms per gram of tissue, OR
  • Direct visualization of yeasts on microscopy (pending culture) 1
• Immunohistochemistry with genus-specific antibodies confirms infection when yeasts are seen in tissue but blood cultures are negative 1
• This is particularly important for oropharyngeal/esophageal disease where biopsy "might discriminate between infection and colonization" 1

Clinical Context Assessment

Signs of Invasive Infection

• Fever unresponsive to antibacterial antibiotics (>4 days suggests empiric antifungal therapy) 1
• Leukocytosis or other signs of systemic inflammatory response 2
• Organ dysfunction consistent with sepsis 2
• Candidal chorioretinitis (occurs in <15% but is pathognomonic when present) 1

Colonization Risk Stratification

• Colonization at ≥2 body sites significantly increases risk of invasive infection 1, 2
• Sites to sample: urine, rectum, gastric aspirate, vascular access sites, sputum/throat, wounds, surgical drains 1, 2
• The "corrected Candida colonization index" using semi-quantitative cultures achieved 100% sensitivity and specificity in one study 1
• Surveillance cultures every 5 days in high-risk patients helps monitor progression 2

Site-Specific Considerations

Candiduria

• In non-catheterized patients: candiduria strongly suggests renal involvement in disseminated disease 1, 2
• In catheterized ICU patients: candiduria is no more significant than isolation from any other single site and often represents colonization 1, 2
• Up to 50% of patients with disseminated candidiasis do NOT have candiduria 1

Non-Sterile Sites

• The greatest diagnostic challenge is distinguishing infection from colonization at non-sterile sites 1
• Quantitative culture thresholds are less well-established for Candida than bacteria 1
• Clinical correlation is mandatory—positive cultures without symptoms likely represent colonization 2

Biomarker Testing

Beta-D-Glucan (BDG)

• Recommended for detection of invasive candidiasis and chronic disseminated candidiasis 1
• Strongly associated with clinical findings 1
• Useful when blood cultures are negative 1

Mannan and Anti-Mannan Antibodies

• Particularly useful for chronic disseminated candidiasis with 86% sensitivity 1
• Positive results appear an average of 16 days before cultures 1

C. glabrata-Specific Challenges

Microscopic Limitations

• C. glabrata does NOT form pseudohyphae or filaments during infection—only yeast cells are visible 1
• Yeasts are 3-5 microns in size, difficult to visualize on H&E staining 3
• Grocott methenamine silver (GMS) staining improves detection 3
• Can be confused with Histoplasma capsulatum due to similar yeast-only morphology 3

Culture Confirmation Required

• Mycology culture is the definitive method for C. glabrata identification 3
• Species identification and susceptibility testing are mandatory for isolates from blood and deep sites 1
• Also indicated for recurrent/complicated superficial cases and patients with prior azole exposure 1

Common Pitfalls to Avoid

• Do not rely on blood cultures alone—negative cultures do not exclude invasive disease 1
• Do not assume all positive cultures represent infection—clinical correlation is essential 2
• Do not overlook the need for speciation—C. glabrata has reduced azole susceptibility compared to C. albicans 1, 4
• Do not expect pseudohyphae on microscopy—their absence does not exclude C. glabrata infection 1
• Cultures from existing drains may represent colonization; new symptoms (fever, abdominal pain) and imaging changes are required for infection diagnosis 2