Candidiasis, invasive

Author: Fred F. Ferri, MD

Definition

Severe and invasive diseases are caused by Candida infection. More than 15 different Candida spp. cause disease in humans, but at least 95% of invasive disease is caused by C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei. These organisms cause serious disease referred to as invasive candidiasis. 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. Further, invasive candidiasis is a very common fungus in patients with COVID-19. This coinfection can be associated with severe illness and death.

Synonym

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 is an important nosocomial infection. It affects over 250,000 people worldwide each year and causes more than 50,000 deaths.
•In the U.S., Candida spp. 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 spp. 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 per 100,000 persons.
•Candida auris cases and transmission have seen a dramatic increase in the U.S. since it was first reported in 2016. The rise in echinocandin-resistant cases and evidence of transmission is significant because echinocandins are first-line therapy for invasive Candida infections, including C. auris.¹

Predominant Sex & Age:

Equal between males and females; all ages are susceptible.

Risk Factors:

Prolonged hospitalization and intensive care unit (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

•History
1. 1.Fever unresponsive to broad-spectrum antibiotics
2. 2.History of prolonged indwelling intravenous (IV) catheter
3. 3.A personal history of any of the risk factors listed earlier
•Physical findings (general)
1. 1.Fever
2. 2.Hypotension
3. 3.Generalized malaise
4. 4.Tachycardia
5. 5.Change in mental status
6. 6.Signs of multiorgan system failure
•Specific diseases
1. 1.Candidemia
  1. a.A positive blood culture is the gold standard for the diagnosis of candidemia. Obtain blood cultures in patients suspected to have candidemia. Candida spp. must be isolated from at least one blood culture. A positive culture for Candida should be investigated thoroughly because of the increased risk of morbidity and mortality. Attributable mortality to candidemia in adults is 15% to 20%.
  2. b.Most common manifestation of invasive candidiasis.
  3. c.Physical examination may include fever, macronodular skin lesions, septic shock, Candida endophthalmitis.
2. 2.Disseminated candidiasis
  1. a.Seen in patients with neutropenia who have undergone cytotoxic chemotherapy for a hematologic malignancy
  2. b.Associated with multiple deep-organ infections or failure
  3. c.Blood culture positive
  4. d.Fever not responding to broad-spectrum antibiotics
  5. e.Physical examination: Discrete erythematous or palpable rash, sepsis/septic shock
3. 3.Endophthalmitis
  1. a.Iatrogenic/accidental or traumatic fungal infection of the eye (exogenous) or hematogenous seeding of the eye (endogenous); C. albicans accounts for about 90% of cases of endogenous endophthalmitis.
  2. b.Starts as choroidal lesion, progresses to vitreitis and endophthalmitis and eventually blindness.
  3. c.Physical examination shows fever. An early funduscopic examination by an ophthalmologist should be performed in all patients with candidemia. Funduscopic examination may show large and off-white cotton ball-like lesions with indistinct borders. Patients usually present with decreased visual acuity and occasional pain.
4. 4.Candida infection of the central nervous system
  1. a.Meningitis: Candida can spread hematogenously to the meninges during craniotomy or through ventriculoatrial/peritoneal shunts. Culture cerebrovascular fluid to establish diagnosis.
  2. b.Commonly found in long-term ICU patients.
  3. c.May manifest as meningitis, mycotic aneurysms, change in mental status.
  4. d.Physical examination reveals fever, neck rigidity, confusion, headache, and coma.
5. 5.Candidal musculoskeletal infections
  1. a.Candida infects the skeletal system, especially the joints as a result of trauma, joint injections, and other surgical interventions, such as IV drug use (hematogenous seeding).
  2. b.Previously uncommon; now relatively common probably because of increased frequency of candidemia and disseminated candidiasis.
  3. c.Knee and vertebral column (especially lumbosacral vertebral disks and vertebral bodies, which can lead to vertebral osteomyelitis, with or without diskitis) are involved.
  4. d.Physical examination is usually unremarkable but may show tenderness over involved area, fever, erythema, bone deformity, weight loss, and sometimes a draining fistulous tract.
6. 6.Candidal infections of the heart
  1. a.Usually found in patients with artificial heart valves, IV drug users, and patients with an indwelling central venous catheter
  2. b.May manifest as infective endocarditis, myocarditis, or pericarditis
  3. c.Physical examination reveals fever, hypotension, tachycardia, new or changing murmur, and signs and symptoms of heart failure
7. 7.Hepatosplenic candidiasis (chronic systemic candidiasis)
  1. a.Seen in patients with hematologic malignancy and neutropenia; usually develops during recovery from a neutropenic state (normally after undergoing myeloablative chemotherapy).
  2. b.On examination, patients have low-grade fever, right upper quadrant pain, palpable/tender liver, splenomegaly, and rarely jaundice.
  3. c.MRI/ultrasound (US)/computed tomography (CT) may reveal multiple focal abnormalities in the liver, spleen, and kidneys.
8. 8.Candida peritonitis
  1. a.Associated with GI surgery: Perforations, acute necrotizing pancreatitis, peritoneal dialysis. Pancreatic abscess, gangrenous cholecystitis, and common bile duct obstruction are other GI manifestations of Candida infection. C. albicans is the commonly isolated species in intraabdominal Candida infection.
  2. b.Clinical manifestations include fever, chills, abdominal pain; nausea, vomiting, constipation.
  3. c.Physical examination reveals abdominal distention, abdominal pain, absent bowel sounds.
9. 9.Other forms of invasive candidiasis
  1. a.Candida splenic abscess
  2. b.Candida cholecystitis
  3. c.Renal candidiasis
  4. d.Mediastinitis: Usually occurs after thoracic surgery. Clinical manifestations include chest wall erythema, sternal instability, and fever
  5. e.Empyema: Common in patients with malignancies
  6. f.Pneumonia (rare)
  7. g.Septic arthritis

Etiology

•Fig. 1 illustrates the pathogenesis of invasive candidiasis.
•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

Figure 1 Pathogenesis of invasive candidiasis.

BSI, Bloodstream infection; UTI, urinary tract infection.

(From Cherry JD: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.)

•To successfully treat invasive Candida infection, it is important to start antifungal medication as early as possible. A small delay (;12 to 24 h) 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.
5. 5.Recently the FDA granted orphan drug designation approval of miltefosine for the treatment of invasive candidiasis.
6. 6.The FDA has approved rezafungin (Rezzayo), a unit/week IV echinocandin antifungal, for treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options. Efficacy appears to be similar to once daily caspofungin for treatment of candidemia and invasive candidiasis. Treatment should be continued for 2 wk after blood cultures become negative and symptoms have resolved.²

Treatment Plans (Tables 1 2

Candidemia:

General principles:

•For documented candidemia, 2 wk of antifungal treatment after the first negative blood culture is recommended.
•In nonneutropenic patients, a dilated funduscopic examination in the first week of treatment is recommended.
•In neutropenic patients, delay above until neutrophil recovery because characteristic ocular findings may be delayed.
•Treatment depends on whether the patient is neutropenic or not.
1. 1.Nonneutropenic adult patients: The initial treatment is with an echinocandin (e.g., caspofungin 70 mg loading dose, then 50 mg/day IV or micafungin 100 mg/day IV). Alternatives include 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. An alternative is fluconazole.
3. 3.Preferred oral step-down therapy: Neutropenic and nonneutropenic clinically stable patients can be transitioned to oral fluconazole (400 mg [6 mg/kg] daily) after about 5 to 7 days if they have:
  1. a.Candida-susceptible fluconazole and
  2. b.Negative blood cultures

TABLE 1 Candida Treatment Strategies

Indications	Primary Treatment	Alternative	Comments
Candidemia
Nonneutropenic patients	An echinocandin ^a	Fluconazole: 800-mg (12-mg/kg) loading dose, then 400 mg (6 mg/kg) daily or LFAMB ^b or Voriconazole: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily	Fluconazole for patients who are clinically stable and have no prior azole exposure. Fluconazole can also be step-down therapy for patients who have susceptible isolates and blood cultures converted to negative.
Neutropenic patients	An echinocandin ^a or LFAMB ^b	Fluconazole: 800-mg (12-mg/kg) loading dose, then 400 (6 mg/kg) daily or Voriconazole: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily	An echinocandin is preferred. Fluconazole is step-down therapy for clinically stable patients with susceptible isolates and negative blood cultures. Voriconazole is used when additional coverage for mold is preferred.
Cardiovascular endocarditis	LFAMB ^b with or without 5-FC, 25 mg/kg qid or An echinocandin ^c	Step-down to fluconazole 400-800 mg (6-12 mg) daily for susceptible organism, patient clinically stable, negative blood cultures	Valve replacement is strongly recommended.
Central nervous system	LFAMB ^b with or without 5-FC, 25 mg/kg qid for several weeks	Fluconazole: 400-800 mg (6-12 mg) daily for susceptible organism after clinical improvement	Removal of prosthetic devices is strongly recommended.
Urinary tract
Asymptomatic candiduria	Not indicated except in neonates and instrumentation of infected urinary tract
Symptomatic cystitis	Fluconazole: 200 mg (3 mg/kg) daily for 2 wk	AMB-D: 0.3-0.6 mg/kg for 1-7 days or 5-FC: 25 mg/kg qid	Bladder irrigation with AMB-D, 50 mg/L, can be used for fluconazole-resistant species.
Renal parenchymal candidiasis	Fluconazole: 200-400 mg (3-6 mg/kg) daily for 2 wk or An echinocandin ^a	LFAMB ^b or AMB-D: 0.5-0.7 mg/kg daily with or without 5-FC 25 mg/kg qid ^d or 5-FC alone for 2 wk
Ocular: Chorioretinitis with or without vitritis	Fluconazole: 400-800 mg (6-12 mg/kg) daily or Voriconazole: 6 mg/kg IV q12h for 2 doses, then 4 mg/kg IV q12h	LFAMB: 3-5 mg/kg IV daily, with or without 5-FC, 25 mg/kg qid	Intravitreal AMB-D, 5-10 μg, or voriconazole, 100 μg. Often vitrectomy is used if 3-4+ vitritis or macular involvement is present.

AMB-D,Amphotericin B deoxycholate; 5-FC, 5-fluorocytosine; LFAMB, lipid formulation of amphotericin B.

^aOnce-daily micafungin, 100 mg; caspofungin, 70-mg loading, then 50 mg; or anidulafungin, 200-mg loading, then 100 mg.

^bLiposomal amphotericin B (AmBisome), 3-5 mg/kg daily, or amphotericin B lipid complex (Ablecet), 5 mg/kg daily.

^cFor initial therapy of Candida endocarditis, the 2016 guidelines recommend caspofungin, 150 mg; micafungin, 150 mg; or anidulafungin, 200 mg once daily.

^dStrength of recommendations for 5-FC is weak.

From Bennett JE et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 9, Philadelphia, 2020, Elsevier.

TABLE 2 Candida Treatment: Other Indications

Indication	Primary Treatment	Alternative	Comment
Peritonitis	An echinocandin ^a or Fluconazole: 400-800 (6-12 mg/kg) daily or Voriconazole: 6 mg/kg q12h IV or PO, then 4 mg/kg q12h	LFAMB: 3-5 mg/kg daily	Candida recovered from an existing drain does not necessarily indicate peritonitis. Drains may become colonized. Candida from "freshly placed" drains usually requires treatment. Infected peritoneal dialysis catheters must be removed.
Chronic mucocutaneous candidiasis	Fluconazole or Itraconazole or Posaconazole	LFAMB: 3-5 mg/kg daily or An echinocandin (standard doses)	In severe cases, LFAMB may be necessary. After induction with a systemic antifungal for at least 4 wk, step-down suppressive therapy can be used with topical polyenes.
Oral thrush (mucocutaneous candidiasis)	Clotrimazole troches: 10 mg, dissolved slowly in mouth 5 times daily or Miconazole mucoadhesive buccal tablet: 50 mg placed on gum near canine tooth once daily for 7-14 days or Nystatin suspension: 100,000 U/ml, swish and swallow 4-6 ml 4 times daily; or 1-2 nystatin pastilles: 200,000 U each, dissolved slowly in mouth qid for 14 days or Fluconazole: 100-200 mg daily	Itraconazole solution: 200 mg daily or Posaconazole oral suspension: 100 mg bid on day 1, then 100 mg daily or Voriconazole: 200 mg bid or IV echinocandin ^a or AMB-D: 0.3 mg/kg daily	IV agents are reserved for refractory cases.
Candida esophagitis	Fluconazole: 200-400 mg IV or PO (3-6 mg/kg) daily for 14-21 days or An echinocandin ^a for 14-21 days	Itraconazole oral solution: 200 mg daily for 14-21 days or Posaconazole suspension: 400 mg bid for 14-21 days or Voriconazole: 200 mg bid or AMB-D: 0.3-0.7 mg/kg daily	IV agents are for refractory patients.
Candida vulvovaginitis	Multiple topical agents are available or Fluconazole: 150-mg single dose for mild disease; for severe acute vulvovaginitis, repeat 150 mg q72h for 2-3 doses	Candida glabrata unresponsive to azoles; boric acid gel capsule: 600 mg daily for 14 days	Fluconazole, 150-mg single dose weekly, has been used for recurrent disease.

AMB-D, Amphotericin B deoxycholate; LFAMB, lipid formulation of amphotericin B.

^aOnce-daily micafungin, 100 mg; caspofungin, 70-mg loading dose, then 50 mg; or anidulafungin, 200-mg loading dose, then 100 mg.

From Bennett JE et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 9, Philadelphia, 2020, Elsevier.

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
•Caspofungin 50 mg/day IV or
•Micafungin 100 mg/day IV

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/day or
•Caspofungin 150 mg/day or micafungin 100 mg/day

Esophagitis:

•Caspofungin 50 mg/day IV
•Fluconazole 200 to 400 mg/day

Pericarditis:

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

Surgical Care:

Includes:

•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.

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

Reference(s) ⬆