Candidiasis, Invasive

Daniel K. Asiedu, M.D., PH.D.

Basic Information

Definition

Severe and invasive diseases are caused by Candida infection. The most common pathogen is C. albicans. Invasive candidiasis embodies a variety of diseases caused by hematogenous spread of Candida to multiple viscera (e.g., kidney, brain, heart). These diseases include candidemia, disseminated candidiasis, meningitis, and endophthalmitis. Invasive candidiasis is a significant cause of morbidity and mortality for certain groups of patients.

Synonyms

Systemic candidiasis

ICD-10CM CODES
B37.89	Other sites of candidiasis
B37.1	Pulmonary candidiasis
B37.2	Candidiasis of skin and nail
B37.5	Candidal meningitis
B37.6	Candidal endocarditis
B37.7	Candidal sepsis
B37.9	Candidiasis unspecified

Epidemiology & Demographics

Incidence

Invasive candidiasis is the most common fungal disease among hospitalized patients in the developed world. It affects over 250,000 people worldwide each year and causes more than 50,000 deaths.

In the U.S., Candida species cause 8% to 10% of nosocomial bloodstream infections (fourth most common bloodstream infection). C. albicans is the most common cause of candidemia, but other non-albicans species have been implicated in recent years. These include C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei. Incidence rates of candidemia are between 2 and 14 cases/100,000 persons.

Prevalence

No data available

Predominant Sex and Age

Equal between males and females; all ages are susceptible.

Risk Factors

Prolonged hospitalization and ICU stay, use of broad-spectrum antibiotics, prolonged indwelling of catheters (especially central venous catheters), acute and chronic renal failure, surgery requiring general anesthesia, cancer (e.g., solid neoplasms), transplantation (bone marrow or solid organ), recent chemotherapy/radiation therapy, use of immunosuppressive drugs, parenteral alimentation, use of internal prosthetic devices, organ transplant, hemodialysis, mechanical, surgical procedures

Physical Findings & Clinical Presentation

1.
History
1. ○
  
  Fever unresponsive to broad-spectrum antibiotics
2. ○
  
  History of prolonged indwelling IV catheter
3. ○
  
  A personal history of any of the risk factors listed earlier
2.
Physical findings (general)
1. ○
  
  Fever
2. ○
  
  Hypotension
3. ○
  
  Generalized malaise
4. ○
  
  Tachycardia
5. ○
  
  Change in mental status
3.
Specific diseases
1. ○
  Candidemia
  1. 1.
    
    A positive blood culture is the gold standard for the diagnosis of candidemia. Obtain blood cultures in patients suspected to have candidemia. Candida species must be isolated from at least one blood culture.
  2. 2.
    
    Most common manifestation of invasive candidiasis
  3. 3.
    
    Physical exam may include fever, macronodular skin lesions, septic shock, Candida endophthalmitis.
2. ○
  Disseminated candidiasis
  1. 1.
    
    Seen in patients with neutropenia
  2. 2.
    
    Associated with multiple deep-organ infections or failure
  3. 3.
    
    Blood culture negative
  4. 4.
    
    Fever not responding to broad-spectrum antibiotics
  5. 5.
    
    Physical exam: discrete erythematous or palpable rash, sepsis/septic shock
3. ○
  Endophthalmitis
  1. 1.
    
    Iatrogenic/accidental fungal infection of the eye (exogenous) or hematogenous seeding of the eye (endogenous)
  2. 2.
    
    Starts as choroidal lesion, progresses to vitreitis and endophthalmitis and eventually blindness
  3. 3.
    
    Physical exam shows fever. Funduscopic examination shows large and off-white cotton ball–like lesions with indistinct borders.
4. ○
  Candida infection of the CNS
  1. 1.
    
    Exogenous and endogenous forms
  2. 2.
    
    Commonly found in long-term ICU patients
  3. 3.
    
    May present as meningitis, mycotic aneurysms, change in mental status
  4. 4.
    
    Physical examination reveals fever, neck rigidity, confusion, and coma.
5. ○
  Candidal musculoskeletal infections
  1. 1.
    
    Previously uncommon; now relatively common probably due to increased frequency of candidemia and disseminated candidiasis
  2. 2.
    
    Knee and vertebral column (especially lumbosacral vertebral disks and vertebral bodies) are involved.
  3. 3.
    
    Physical exam is usually unremarkable but may show tenderness over involved area, fever, erythema, bone deformity, weight loss, and sometimes a draining fistulous tract.
6. ○
  Candidal infections of the heart
  1. 1.
    
    May present as infective endocarditis, myocarditis, or pericarditis.
  2. 2.
    
    Physical examination reveals fever, hypotension, tachycardia, new or changing murmur.
7. ○
  Hepatosplenic candidiasis (chronic systemic candidiasis)
  1. 1.
    
    Seen in patients with hematologic malignancy and neutropenia; usually develops during recovery from a neutropenic state (normally after undergoing myeloablative chemotherapy)
  2. 2.
    
    On examination, patients have low-grade fever, right upper quadrant pain, palpable/tender liver, splenomegaly, and rarely jaundice.
8. ○
  Candida peritonitis
  1. 1.
    
    Associated with GI surgery, peritoneal dialysis
  2. 2.
    
    Clinical manifestations include fever, chills, abdominal pain; nausea, vomiting, constipation.
  3. 3.
    
    Physical examination reveals abdominal distention, abdominal pain, absent bowel sounds.
9. ○
  Other forms of invasive candidiasis
  1. 1.
    
    Candida splenic abscess
  2. 2.
    
    Candida cholecystitis
  3. 3.
    
    Renal candidiasis

Etiology

•

Several species of Candida exist in nature
•
Medically significant include:
1. 1.
  
  C. albicans: together with C. glabrata, they account for 70% to 80% of Candida in invasive candidiasis.
2. 2.
  
  C. glabrata: together with C. albicans, they account for 70% to 80% of Candida in invasive candidiasis.
3. 3.
  
  C. parapsilosis: associated with indwelling vascular catheters and prosthetic devices
4. 4.
  
  C. tropicalis: especially in leukemic patients
5. 5.
  
  C. krusei: resistant to fluconazole and ketoconazole

Diagnosis

Differential Diagnosis

•

Sepsis (bacterial)
•

Septic shock
•

Cryptococcosis
•

Aspergillosis

Workup

Laboratory Tests

•

Laboratory studies are nonspecific. It is often necessary to perform several diagnostic tests to achieve maximum accuracy.
•

High index of suspicion is needed.
•
Candidemia/disseminated candidiasis: Candidemia represents the tip of the iceberg with respect to the more invasive forms of candidiasis. Central lines often contribute to the propagation of candidemia. From the blood, infection can spread to almost any organ.
1. 1.
  
  Blood cultures are the mainstay of diagnosis. They are helpful but have low positive yield.
2. 2.
  
  Diagnosis can also be made from normally sterile sites.
3. 3.
  
  Serum (1,3) beta-D-glucan detection assay: high specificity and high positive predictive value but it is relatively difficult to perform.
•

Two commercial PCR tests are available (Septifast, Multiplex T2 candida panel) and have shown promising results.
•
Hepatosplenic candidiasis (focal)
1. 1.
  
  Elevated serum alkaline phosphatase

Imaging Studies

•

Imaging studies are generally not required or useful.
•

Ultrasound is useful for diagnosing hepatosplenic abscess. “Bull’s eye or target lesions” are observed in the liver and spleen.
•

CT scanning may be used to diagnose hepatosplenic candidiasis, as well as intraabdominal/renal abscesses.
•

ECHO is useful to rule in or rule out Candida endocarditis.

Treatment

•
To successfully treat invasive Candida infection, it is important to start antifungal medication as early as possible. A small delay (approximately 12-24 hr) in starting treatment may result in a significantly excessive mortality rate.
1. 1.
  
  Do not dismiss Candida spp. as a contaminant when it is isolated in blood cultures or other sterile sites.
2. 2.
  
  Before treatment, also consider removal of an intravenous catheter.
•
Antifungals available include:
1. 1.
  
  Azoles (e.g., fluconazole, posaconazole, itraconazole, voriconazole). They inhibit the synthesis of ergosterol, a fungal cell component.
2. 2.
  
  Echinocandins (e.g., caspofungin, micafungin, anidulafungin). These are glucan synthesis inhibitors. Glucan is an important component of fungal cell walls. Most studies have provided reasonable support for echinocandins as treatment of choice for the majority of patients with invasive candidiasis.
3. 3.
  
  Polyenes (e.g., amphotericin B, lipid formulation of amphotericin, nystatin). Broad spectrum. Their mechanism of action is to increase cytoplasmic permeability.
4. 4.
  
  Antimetabolites (e.g., flucytosine). Flucytosine is deaminated to 5-fluorouracil in fungal cell. 5-Fluorouracil inhibits RNA and protein synthesis.

Treatment Plans

Candidemia

•
Treatment depends on whether the patient is neutropenic or not.
1. 1.
  
  Nonneutropenic adult patients: drug of choice is fluconazole; 800 mg as loading dose then 400 mg/day for at least 2 wk after clinical improvement or negative blood culture. Amphotericin B is equally efficacious.
2. 2.
  
  Neutropenic adult patients: an echinocandin is the drug of choice (e.g., caspofungin 70 mg IV loading dose then 50 mg/day IV or micafungin 100 mg/day IV or anidulafungin 200 mg IV loading dose then 100 mg IV all for at least 2 wk after clear blood culture and after clinical improvement.

Disseminated Candidiasis

Fluconazole is the drug of choice.

Disseminated Candidiasis with End-Organ Infection

•

Treatment is the same as for candidemia of nonneutropenic patients. In most cases, therapy is prolonged for at least 4 to 6 wk.
•

The echinocandins are the first-line therapy.

Osteomyelitis or Septic Arthritis

•

Fluconazole 400 mg IV or PO or
•

Lipid-based amphotericin B 3 to 5 mg/kg qd

Endocarditis

•

Caspofungin 50 to 150 mg/day or
•

Micafungin 100 to 150 mg/day or
•

Anidulafungin 100 to 200 mg/day

Myocarditis

•

Lipid-based amphotericin B 3 to 5 mg/kg daily or
•

Fluconazole 400 to 800 mg daily IV or PO

Esophagitis

•

Fluconazole 200 to 400 mg/day or
•

Caspofungin 50 mg IV daily

Pericarditis

•

Lipid-based amphotericin B 3 to 5 mg/kg daily or
•

Fluconazole 400 to 800 mg PO qd IV or PO

Surgical Care

Include:

•

Drainage
•

Removal of any foreign bodies
•

Surgical debridement
•

Organ-specific care (e.g., valve replacement for endocarditis, splenectomy for splenic abscess, or vitrectomy for fungal endophthalmitis)

Disposition

•

Several factors affect prognosis: infection site, degree of immune suppression, and how quickly diagnosis and therapy are initiated
•

Overall mortality rate: 30% to 40%

Referral

•

Always involve an infectious disease specialist.
•
Referral to specialist will depend on the organ involved. For example:
1. 1.
  
  Endocarditis will require a cardiothoracic surgeon.
2. 2.
  
  Endophthalmitis will require an ophthalmologist.

Follow-Up Care

•

Prolonged periods, mainly in the hospital, of antifungal treatment may be necessary.
•

Closely monitor patients on amphotericin B because of the high incidence of side effects. Check basic metabolic panel, magnesium, and CBC at least twice a week.

Pearls & Considerations

Prevention

Basic preventive measures are similar to those used for nosocomial infections. This includes:

•
Maximizing hand hygiene recommendations:
1. 1.
  
  Hand washing
2. 2.
  
  Using alcohol/chlorhexidine solution
•

Adhering strictly to recommendations for placement and care of central lines and catheters.
•
Judicious use of antimicrobials
1. 1.
  Notes on C. auris:
  1. •
    
    CDC issued warnings in 2016 about the emergence of C. auris, a multidrug-resistant Candida species.
  2. •
    
    It has caused invasive healthcare-associated infections in many countries and has high mortality rates.
  3. •
    
    Initial treatment is with echinocandin. Patient should be closely followed with cultures.
  4. •
    
    Special infection control precautions should be followed for patients infected with or colonized by C. auris.

Prophylaxis

Antifungal prophylaxis should be limited to patients in whom it has proved beneficial: patients with gastrointestinal anastomotic leakage, patients undergoing transplantation of the pancreas or small bowel, selected patients undergoing liver transplantation who are at high risk for candidiasis and extremely low-birth-weight neonates in settings with a high incidence of neonatal candidiasis. (Kullberg BJ, Arendrup MC: NJEM 373:1445-1456, 2015.)

Patient/Family Education

•

Inform them about the risk factors for invasive candidiasis.
•

Inform them of the seriousness of the disease and the associated high morbidity/mortality rates, thus requiring aggressive treatment.
•

Side effects and toxicities associated with treatment

Ferri – Candidiasis, Invasive