Candidiasis¶
Part 5 | Infectious Diseases: Fungal · Part 5 – Infectious Diseases: Fungal · Chapter 222
Key Clinical Points¶
- C. auris is an emerging multidrug-resistant pathogen designated an urgent threat by CDC (2019) and critical priority by WHO (2022).
- Echinocandins are the first choice of treatment for disseminated candidiasis.
- C. auris exhibits unique tolerance to high temperature (up to 42°C) and saline concentrations (10%).
- Candidemia treatment duration is 2 weeks beyond the last positive blood culture and resolution of signs and symptoms.
- CMC is associated with monogenic disorders of IL-17 receptor signaling (e.g., STAT1, IL-17RA/RC mutations).
- C. auris strains can be resistant to all three major antifungal classes (azoles, echinocandins, polyenes).
- Recovery of Candida from sputum, urine, or peritoneal catheters may indicate mere colonization rather than deep-seated infection.
- The presence of ocular or macronodular skin lesions is highly suggestive of widespread infection of multiple deep organs.
- For C. auris, echinocandin treatment continues until sensitivities are determined.
- C. auris was first identified in 2009 from the ear drainage of a patient with an ear infection in Japan.
1. DEFINITION & OVERVIEW¶
• Overview: The genus Candida encompasses >150 species, only a few of which cause disease in humans. ◦ Pathogenic species include: C. albicans, C. guilliermondii (Meyerozyma guilliermondii), C. krusei (Pichia kudriavzevii), C. parapsilosis, C. tropicalis, C. lusitaniae (Clavispora lusitaniae), C. dubliniensis, C. glabrata (Nakaseomyces glabratus), and C. auris. ◦ Morphology: Small, thin-walled yeast; reproduces by budding; exists as blastospores, pseudohyphae, and hyphae. ◦ Identification: Via biochemical testing or special agar (e.g., CHROMagar).
• C. auris Status: Designed an urgent threat by CDC (2019) and critical priority by WHO (2022). ◦ Reasons: Multidrug resistance, persistence on surfaces, and association with high mortality.
1.1 Species Classification¶
• Identified Pathogens: - C. albicans - C. guilliermondii (Meyerozyma guilliermondii) - C. krusei (Pichia kudriavzevii) - C. parapsilosis - C. tropicalis - C. lusitaniae (Clavispora lusitaniae) - C. dubliniensis - C. glabrata (Nakaseomyces glabratus) - C. auris
2. EPIDEMIOLOGY¶
• Clinical Context: Common commensals that have become leading nosocomial pathogens in developed countries. ◦ U.S. Status: One of the four most common bloodstream pathogens in hospitalized patients.
• C. auris Profile: First identified in 2009 (Japan); spread to >50 countries. ◦ Risk factors for high mortality (30–60% crude rate): Multidrug resistance, persistence on surfaces.
• Risk Factors for Disseminated Candidiasis: (See Table 222-1) - Antibacterial agents - Indwelling intravenous catheters - Hyperalimentation fluids - Indwelling urinary catheters - Parenteral glucocorticoids - Severe burns - CARD9 deficiency (central nervous system) - Abdominal and thoracic surgery - Cytotoxic chemotherapy - Immunosuppressive agents for organ transplantation - Respirators - Myeloperoxidase deficiency - Neutropenia - Low birth weight (neonates) - Diabetes
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Infection Mechanism: Occurs via hematogenous dissemination from mucosal surfaces or catheter sites. ◦ Tissue Invasion: Facilitated by pseudohyphae/hyphae formation (Note: C. glabrata and C. auris can cause infection without this morphology).
• Virulence Factors: - Adhesins (e.g., candidalysin) - Biofilm formation
• C. auris Unique Traits: - Tolerance to 42°C and 10% saline - Abiotic surface affinity (plastics, medical devices) - Persistent colonization capabilities - SCF1 adhesin (biofilm formation, virulence) - Aggregate-forming properties (immune evasion)
4. CLINICAL FEATURES¶
• Mucocutaneous Infections: - Oral thrush: White adherent patches - Vulvovaginal candidiasis: Pruritus, curd-like discharge - Skin infections: Paronychia, intertrigo
• Deeply Invasive Candidiasis: May involve the brain, heart, kidneys, or joints.
• High-Suspicion Signs: - Ocular involvement (chorioretinitis) - Macronodular skin lesions (highly suggestive of hematogenously disseminated candidiasis; see Figure 222-2).
• Chronic Mucocutaneous Candidiasis (CMC): Definition: A heterogeneous infection of the hair, nails, skin, and mucous membranes that persists despite intermittent antifungal therapy. - Onset: Infancy or first two decades of life - Immunologic dysfunction: IL-17 signaling defects (STAT1, IL-17RA/RC mutations) - Associated endocrine abnormalities: Hypoparathyroidism, adrenal insufficiency, autoimmune thyroiditis, alopecia, pernicious anemia
5. DIFFERENTIAL DIAGNOSIS¶
• Colonization vs. Infection: Distinguishing these is critical for management. - Sputum/urine/peritoneal catheters: Presence of Candida likely indicates colonization rather than deep infection. - Blood cultures from patients with indwelling catheters: May reflect seeding, not dissemination.
• C. auris Identification Challenges: May be misdiagnosed as other species due to atypical morphology (budding yeast, no germ tubes) and growth at 42°C on CHROMagar.
6. DIAGNOSTIC APPROACH¶
• Microscopic Identification: - Identify pseudohyphae/hyphae on Gram stain or PAS stain.
• Molecular & Specialized Methods: - MALDI-TOF MS and molecular techniques confirm C. auris (Table 222-2).
• Decision-Making Steps for C. auris (Table 222-2): 1. Bruker Biotyper MALDI-TOF: - RUO libraries → C. auris confirmed - CA System library → C. auris confirmed 2. bioMérieux VITEK MS MALDI-TOF: - RUO library → C. auris - IVD library (v3.2) → C. auris - Older IVD libraries → C. haemulonii, C. lusitaniae, or No identification3. VITEK 2 YST: - Software version 8.01: - C. auris → C. auris confirmed - C. haemulonii / C. duobushaemulonii / Not identified → C. auris possible; Needs further workup - Older versions → C. auris possible; Needs further workup 4. API 20C: - Rhodotorula glutinis (if characteristic red color absent), C. sake, or Not identified 5. API ID 32C: - C. intermedia, C. sake, S. kluyveri → C. auris possible; Needs further workup 6. BD Phoenix: - C. catenulata, C. haemulonii, or Not identified 7. MicroScan: - No hyphal growth present + (C. lusitaniae/guilliermondii/parapsilosis) → Rule out those 3; C. auris possible; Needs further workup - Hyphal growth present → Possibly C. lusitaniae, C. guilliermondii, C. parapsilosis, or C. auris; Needs further workup - C. famata → C. auris possible; Needs further workup 8. RapID Yeast Plus: - C. parapsilosis → Test on corneal agar 9. GenMark ePlex BCID-FP Panel: - C. auris → C. auris confirmed
7. MANAGEMENT & TREATMENT¶
• First-Line Therapy: Echinocandins are the first choice for disseminated candidiasis.
• Treatment Duration: 1. Standard: 2 weeks beyond last positive blood culture and resolution of symptoms. 2. C. auris specific: Echinocandin treatment continues until sensitivities are determined.
• Antifungal Selection by Species: - Non-auris strains → Azoles. - Auris strains → Echinocandins (monitor for resistance).
• Mucocutaneous Treatment (Table 223): 1. Cutaneous: - Preferred: Topical azole. - Alternatives: Topical nystatin; Oral fluconazole (150 mg) or ibrexafungerp (300 mg twice daily for 1 day). 2. Oral (thrush): - Preferred: Fluconazole tablets (100–200 mg/d). - Alternatives: Clotrimazole troches, nystatin; or itraconazole solution (200 mg/d).
• Systemic Agents for Disseminated Candidiasis (Table 224): 1. Amphotericin B deoxycholate: - Route: IV only. - Dose: 0.5–1.0 mg/kg daily (mostly replaced by lipid formulations) or 3.0–5.0 mg/kg daily. 2. Posaconazole: - Route: IV and oral. - Dose: 300 mg/d (IV); 200 mg tid (oral). Approved for prophylaxis. 3. Fluconazole: - Route: IV and oral. - Dose: 400 mg/d. Most commonly used. 4. Voriconazole: - Route: IV and oral. - Dose: 400 mg/d. (Note: multiple drug interactions, visual hallucinations, fluorosis, phototoxicity; approved for candidemia in nonneutropenic patients). 5. Isavuconazole: - Route: IV only. - Dose: 50 mg/d. 6. [Additional Agent]: - Route: IV only. - Dose: 100 mg/d.
• Echinocandin Doses for C. auris (Table 226): 1. Caspofungin: - Adults: Loading dose 70 mg IV, then 50 mg IV daily. - Children (>2 months): Loading dose 70 mg/m² per day IV, then 50 mg/m² per day IV. - Infants (<2 months): 25 mg/m² per day IV. 2. Micafungin: - Adults: 100 mg IV daily. - Children (>2 months): 2 mg/kg per day IV (option to increase to 4 mg/kg per day in children ≥ 40 kg). - Infants (<2 months): 10 mg/kg per day IV.
8. PROGNOSIS & COMPLICATIONS¶
• C. auris Mortality: 30–60% crude mortality rate.
• Urgent Interventions: - Endophthalmitis: Requires prompt intervention (vitrectomy, intraocular antifungals).
• Prognostic Factors: - Timely diagnosis. - Appropriate antifungal therapy. - Effective infection control measures.
9. SPECIAL CONSIDERATIONS¶
• Neonates: - Risk factors: Low birth weight, prolonged hospitalization. - Clinical features: Generalized cutaneous eruptions, candidemia.
10. KEY PEARLS & CLINICAL TRAPS¶
• C. auris Identification: May be misidentified as other species due to atypical morphology (budding yeast, no hyphal growth). • Clinical Red Flags: Ocular or macronodular skin lesions strongly suggest hematogenously disseminated candidiasis. • Colonization Trap: Candida in sputum, urine, or peritoneal catheters may reflect colonization, not infection. • First-line Choice: Echinocandins are preferred for C. auris despite potential resistance. • Treatment Duration: Standard is 2 weeks post-clearance; however, C. auris requires continued echinocandin until sensitivities are known.
Reference Tables¶
TABLE 222-1 Well-Recognized Factors and Conditions Predisposing to Hematogenously Disseminated Candidiasis…¶
Harrison's 22e, p.1707
| Antibacterial agents Indwelling intravenous catheters Hyperalimentation fluids Indwelling urinary catheters Parenteral glucocorticoids Severe burns CARD9 deficiency (central nervous system) |
Abdominal and thoracic surgery Cytotoxic chemotherapy Immunosuppressive agents for organ transplantation Respirators Myeloperoxidase deficiency Neutropenia Low birth weight (neonates) Diabetes |
|---|---|
TABLE 222-2 Typical Decision-Making Steps in the Diagnosis of C. auris NO. 1. 2.¶
Harrison's 22e, p.1710
| NO. | METHOD | DATABASE/SOFTWARE | INITIAL FINDING | CONFIRMATION | |
|---|---|---|---|---|---|
| 1. | Bruker Biotyper MALDI-TOF |
RUO libraries | C. auris | C. auris | |
| CA System library | C. auris | C. auris | |||
| bioMérieux VITEK MS MALDI-TOF |
RUO library | C. auris | |||
| IVD library (v3.2) | C. auris | ||||
| Older IVD libraries | C. haemulonii | ||||
| C. lusitaniae | |||||
| No identification | |||||
| 3. | VITEK 2 YST | Software version 8.01 | C. auris | C. auris confirmed | |
| C. haemulonii | C. auris possible: Needs further workup | ||||
| C. duobushaemulonii | C. auris possible: Needs further workup | ||||
| Candida spp. not identified | C. auris possible: Needs further workup | ||||
| Older versions | C. haemulonii | C. auris possible: Needs further workup | |||
| C. duobushaemulonii | C. auris possible: Needs further workup | ||||
| Candida spp. not identified | C. auris possible: Needs further workup | ||||
| API 20C | Rhodotorula glutinis, if characteristic red color absent | ||||
| C. sake | |||||
| Candida spp. not identified | |||||
| 5. | API ID 32C | C. intermedia | C. auris possible: Needs further workup | ||
| C. sake | C. auris possible: Needs further workup | ||||
| Saccharomyces kluyveri | C. auris possible: Needs further workup | ||||
| BD Phoenix | C. catenulata | ||||
| C. haemulonii | |||||
| Candida spp. not identified | |||||
| 7. | MicroScan | C. lusitaniae | No hyphal growth present | Can rule out C. lusitaniae, C. guilliermondii, and C. parapsilosis. C. auris possible: Needs further workup |
|
| C. guilliermondii | |||||
| C. parapsilosis | |||||
| C. lusitaniae | Hyphal growth present | Possibly C. lusitaniae, C. guilliermondii, C. parapsilosis, or C. auris: Needs further workup |
|||
| C. guilliermondii | |||||
| C. parapsilosis | |||||
| C. famata | C. auris possible: Needs further workup | ||||
| Candida spp. not identified | C. auris possible: Needs further workup | ||||
| RapID Yeast Plus | C. parapsilosis → Test on corneal agar |
No hyphal growth present | |||
| Hyphal growth present | |||||
| Candida spp. not identified | |||||
| 9. | GenMark ePlex BCID-FP Panel |
C. auris | C. auris confirmed |
TABLE 222-3 Treatment of Mucocutaneous Candidal Infections DISEASE Cutaneous Vulvovaginal¶
Harrison's 22e, p.1710
| DISEASE | PREFERRED TREATMENT | ALTERNATIVES |
|---|---|---|
| Cutaneous | Topical azole | Topical nystatin |
| Oral fluconazole (150 mg) or ibrexafungerp (300 mg twice daily for 1 day) or azole cream or suppository |
||
| Oral (thrush) | Fluconazole tablets (100–200 mg/d) | Clotrimazole trashes, nystatin |
| Fluconazole tablets (100–200 mg/d) or itraconazole solution (200 mg/d) |
TABLE 222-4 Agents for the Treatment of Disseminated Candidiasis AGENT Amphotericin B deoxycholate Amphotericin B lipid…¶
Harrison's 22e, p.1711
| AGENT | ROUTE OF ADMINISTRATION |
DOSEa | COMMENT |
|---|---|---|---|
| Amphotericin B deoxycholate | IV only | 0.5–1.0 mg/kg daily | Mostly replaced by lipid formulations |
| IV only IV only IV only |
3.0–5.0 mg/kg daily 3.0–5.0 mg/kg daily 3.0–5.0 mg/kg daily |
||
| Azolesb | |||
| Posaconazole | IV and oral | 300 mg/d (IV) 200 mg tid (oral) |
Approved for prophylaxis |
| Fluconazole | IV and oral | 400 mg/d | Most commonly used |
| Voriconazole | IV and oral | 400 mg/d | Multiple drug interactions, visual hallucinations, fluorosis, phototoxicity Approved for candidemia in nonneutropenic patients |
| IV only IV only IV only IV only |
50 mg/d 100 mg/d 100 mg/d 400 mg loading dose, 200 mg once weekly thereafter |
TABLE 222-5 Typical MICs of Available Antifungal Drugs for C. auris DRUG Amphotericin B Fluconazole Itraconazole…¶
Harrison's 22e, p.1711
| DRUG | TENTATIVE RESISTANCE BREAKPOINTSa |
MIC RANGE, μg/mL | ||
|---|---|---|---|---|
| MIC | MIC 50 |
MIC 90 |
||
| Amphotericin B | ≥2 | 0.06–8 | 0.5–1 | 2–4 |
| ≥32 | 0.12–≥64 | ≥64 | ||
| Itraconazole | N/A | 0.032–2 | 0.06–0.5 | 0.25–1 |
| N/A | 0.032–16 | 0.5–2 | ||
| Posaconazole | N/A | 0.015–16 | 0.016–0.5 | 0.125–2 |
| N/A | 0.015–4 | 0.125–0.25 | ||
| Caspofungin | ≥2 | 0.03–16 | 0.25–1 | 1–2 |
| ≥4 | 0.015–16 | 0.125–0.5 | ||
| Micafungin | ≥4 | 0.015–8 | 0.125–0.25 | 0.25–2 |
TABLE 222-6 List of CDC-Recommended Echinocandin Doses for the Treatment of C. auris Infections DRUG Caspofungin¶
Harrison's 22e, p.1712
| DRUG | ADULTS | CHILDREN (>2 MONTHS) |
INFANTS (<2 MONTHS) |
|---|---|---|---|
| Caspofungin | Loading dose 70 mg IV, then 50 mg IV daily |
Loading dose 70 mg/m2 per day IV, then 50 mg/m2 per day IV |
25 mg/m2 per day IV |
| Loading dose 200 mg IV, then 100 mg IV daily |
Not approved for use in children |
||
| Micafungin | 100 mg IV daily | 2 mg/kg per day IV with option to increase to 4 mg/ kg per day IV in children at least 40 kg |
10 mg/kg per day IV |