What is the clinical overview of candidiasis, including its pathophysiology, symptoms, diagnosis, management, and differential diagnoses?

Candidiasis: Clinical Overview

Pathophysiology

Candida species are opportunistic fungal pathogens that normally colonize human skin, oral mucosa, gastrointestinal tract, and vaginal mucosa without causing disease, but transition to pathogenic forms when host defenses are compromised or local barriers are disrupted. 1

• Candida albicans remains the most common pathogenic species, but non-albicans species now account for approximately 50% of invasive infections, including C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei 1
• The emergence of Candida auris poses a substantial global health threat due to multidrug resistance and healthcare transmission 1, 2
• Key predisposing factors include broad-spectrum antibiotic use (disrupts normal flora), central venous catheters, parenteral nutrition, renal replacement therapy, neutropenia, immunosuppressive agents (corticosteroids, chemotherapy, IL-17 inhibitors), diabetes, advanced HIV disease (CD4 <50 cells/μL), and poor oral hygiene 1, 3
• Invasive candidiasis is primarily a disease of medical progress, with attributable mortality estimated at 15-25% for adults and 10-15% for neonates 1

Clinical Manifestations

Mucocutaneous Candidiasis

• Oropharyngeal candidiasis presents with white plaques on oral mucosa, erythema, erosions, pain, uncomfortable sensation, and taste abnormalities; affects up to 20% of patients with advanced HIV disease 1, 4
• Esophageal candidiasis causes dysphagia, odynophagia, and retrosternal pain; frequently accompanies oropharyngeal disease in immunocompromised patients 1, 5
• Vulvovaginal candidiasis manifests with pruritus, vaginal discharge, dyspareunia, and vulvar erythema 1
• Cutaneous candidiasis presents as erythematous rash with satellite lesions, typically in intertriginous areas, associated with itching and swelling 1, 6

Invasive Candidiasis

• Candidemia is the most common manifestation, ranking as the third or fourth most common healthcare-associated bloodstream infection; presents with fever, hemodynamic instability, and septic shock in severe cases 1, 7
• Deep-seated infections can involve virtually any organ: intra-abdominal (peritonitis, abscesses), hepatosplenic (chronic disseminated candidiasis), endocarditis, CNS infections, endophthalmitis, osteoarticular infections, and urinary tract infections 1, 2
• Chronic disseminated (hepatosplenic) candidiasis occurs in up to 50% of hematologic malignancy patients with prolonged neutropenia, presenting with persistent fever, elevated alkaline phosphatase, and multiple hepatosplenic lesions on imaging 2

Diagnosis

Mucocutaneous Disease

Conventional direct microscopy and culture remain the mainstay of diagnosis for both superficial and invasive Candida infections. 1

• Clinical diagnosis is often sufficient for typical oropharyngeal or vulvovaginal presentations in immunocompetent hosts 4
• KOH preparation demonstrates budding yeasts and pseudohyphae from oral, vaginal, or skin scrapings 8
• Culture with species identification is essential when disease develops on fluconazole therapy, in refractory cases, or with atypical presentations, as clinical appearance cannot distinguish between species 3
• Antifungal susceptibility testing should guide therapy changes in breakthrough infections, as it is predictive of clinical response 3

Invasive Disease

• Blood cultures remain the gold standard but are positive in only 21-71% of autopsy-proven cases, with median turnaround times of 2-3 days 7, 2
• β-D-glucan detection is helpful in certain clinical settings but lacks specificity for Candida species 1, 2
• Mannan antigen and anti-mannan antibodies can aid diagnosis but have limited sensitivity 2
• T2Candida assay provides rapid species identification directly from blood but is not universally available 2
• PCR-based techniques are increasingly used for earlier diagnosis but lack standardization 7
• Imaging (CT, MRI) is essential for identifying deep-seated infections, particularly hepatosplenic candidiasis 2

Critical pitfall: Do not assume all oral candidiasis is C. albicans in patients with previous azole exposure or refractory disease—species identification and susceptibility testing are mandatory 3

Management

Invasive Candidiasis and Candidemia

Echinocandins (caspofungin, micafungin, anidulafungin, or rezafungin) are the recommended first-line treatment for candidemia and all forms of invasive candidiasis except CNS and ocular infections, due to their broad activity, safety profile, and fungicidal activity. 1

• Dosing: Standard echinocandin doses per institutional protocols; rezafungin offers once-weekly dosing advantage 1
• Duration: Minimum 14 days after documented clearance of Candida from bloodstream and resolution of symptoms 1
• Central venous catheter management: Remove or replace CVCs when feasible, as earlier removal is associated with better outcomes 1
• Alternative agents: Liposomal amphotericin B (3-5 mg/kg/day) combined with flucytosine (25 mg/kg four times daily) for CNS infections; fluconazole (800 mg loading dose, then 400 mg daily) only for fluconazole-susceptible species in hemodynamically stable patients 1
• Step-down therapy: Transition to fluconazole (400-800 mg daily) after clinical improvement if isolate is susceptible and patient is stable 1

Critical consideration: Fluconazole resistance must be considered, particularly with C. glabrata and C. krusei (intrinsically resistant) 1, 3

Breakthrough Candidiasis on Fluconazole

• Obtain cultures for species identification and susceptibility testing before changing therapy 3
• For suspected fluconazole-resistant C. albicans: Switch to itraconazole solution 200 mg daily or posaconazole suspension 400 mg twice daily for 3 days, then 400 mg daily 3
• For suspected C. glabrata or other non-albicans species: Use echinocandins as preferred therapy 3
• For critically ill patients: Strongly prefer echinocandins over azoles regardless of prior exposure 3

Chronic Disseminated (Hepatosplenic) Candidiasis

• Initial therapy: Liposomal amphotericin B (3-5 mg/kg/day) for 2 weeks 2
• Sequential therapy: Transition to fluconazole (400-800 mg daily) for minimum total duration of 8 weeks 2
• Corticosteroids may be considered for persistent inflammation 2

Oropharyngeal Candidiasis

• First-line: Clotrimazole troches (10 mg five times daily) or nystatin suspension (400,000-600,000 units four times daily) for 7-14 days 5, 4
• Alternative: Fluconazole 100-200 mg daily for 7-14 days (14 days associated with lower relapse rates) 5
• Refractory disease (fluconazole-unresponsive): Itraconazole oral solution 200 mg daily demonstrated 55% complete resolution in HIV patients clinically unresponsive to fluconazole 5

Important caveat: Approximately 23% of patients relapse within 4 weeks after successful treatment; optimize antiretroviral therapy in HIV patients as best prophylaxis 3, 5

Esophageal Candidiasis

• First-line: Fluconazole 200-400 mg daily for 14-21 days 5
• Alternative: Itraconazole oral solution 200 mg daily (86% clinical response rate, comparable to fluconazole) 5
• Refractory disease: Echinocandin or liposomal amphotericin B 1

Vulvovaginal Candidiasis

• Uncomplicated: Topical azoles (clotrimazole, miconazole) for 1-7 days or single-dose oral fluconazole 150 mg 1
• Complicated/recurrent: Fluconazole 150 mg every 72 hours for 3 doses, then maintenance therapy 1

Novel Agents

• Ibrexafungerp and oteseconazole now complement the antifungal armamentarium for superficial candidiasis 1

Differential Diagnoses

For Oropharyngeal Lesions

• Oral hairy leukoplakia (Epstein-Barr virus-associated, vertical white corrugations on lateral tongue) 4
• Oral lichen planus (reticular white striae, erosive lesions) 4
• Squamous cell carcinoma (indurated ulcer, particularly in tobacco/alcohol users) 4
• Herpes simplex virus stomatitis (painful vesicles and ulcers) 4
• Aphthous ulcers (painful, well-demarcated ulcers without white plaques) 4

For Esophageal Symptoms

• Herpes simplex esophagitis (discrete ulcers on endoscopy) 5
• Cytomegalovirus esophagitis (large, deep ulcers) 5
• Pill esophagitis (history of medication ingestion) 5
• Reflux esophagitis (distal esophageal involvement, no plaques) 5

For Invasive Disease

• Bacterial sepsis (similar presentation but different culture results) 7
• Other invasive fungal infections (aspergillosis, mucormycosis in appropriate clinical context) 7
• Viral infections (CMV, HSV in immunocompromised) 7

For Cutaneous Lesions

• Dermatophyte infections (tinea corporis, KOH shows septate hyphae) 6
• Bacterial intertrigo (Staphylococcus, Streptococcus) 6
• Psoriasis (well-demarcated plaques with silvery scale) 6
• Seborrheic dermatitis (greasy scale, different distribution) 6

Patient Counseling

For Mucocutaneous Disease

• Hygiene measures: Maintain good oral hygiene, keep intertriginous areas dry, avoid tight-fitting clothing 8, 4
• Medication adherence: Complete full course even if symptoms improve; for oral solutions, swish and swallow, hold in mouth before swallowing 5, 4
• Denture care: Remove and clean dentures nightly, soak in antifungal solution if applicable 4
• Risk factor modification: Control diabetes, avoid unnecessary antibiotics, optimize HIV treatment 3, 8
• Relapse risk: Explain that recurrence is common (23% within 4 weeks for esophageal disease); seek care early if symptoms return 5

For Invasive Disease

• Severity and prognosis: Explain that invasive candidiasis is a serious infection requiring prolonged intravenous therapy and close monitoring 1, 7
• Central line management: Discuss importance of catheter removal when feasible 1
• Duration of therapy: Prepare for minimum 14 days of treatment after blood cultures clear 1
• Follow-up: Emphasize need for ophthalmologic examination to rule out endophthalmitis and imaging for deep-seated infections 1

Infection Control (for C. auris)

• Transmission prevention: Implement contact precautions, dedicated equipment, enhanced environmental cleaning 1
• Screening: Close contacts may require screening in outbreak settings 1

Critical pitfall: Earlier intervention with appropriate antifungal therapy and source control is closely linked to mortality reduction—delays in treatment are associated with worse outcomes 1, 7