Candidiasis

Etiology and PathogenesisTop

1. Etiologic agent: Candida albicans is the most frequently isolated species of Candida; however, non–C albicans species are increasing in frequency and include C glabrata, C parapsilosis, C tropicalis, C krusei, C guilliermondii, C lusitaniae, and C dubliniensis. In some geographic areas C albicans accounts for <50% of invasive infections. C auris is an emerging fungal pathogen that has now been found worldwide, with many strains displaying decreased susceptibility to azoles and echinocandins and some to all classes of antifungals.

2. Reservoir and transmission: C albicans is widely present in the environment and can be found in soil, in hospitals, on animals, on objects, and in food. Candida spp are saprophytes that reside in the human body and are present on the skin, in the gastrointestinal tract, and in the female genital tract. The majority of Candida infections are endogenous from translocation through gut mucosa or breaches of the skin, but transmission can occur between humans and also from the environment. C auris can persist in the environment and the clonal nature of spread within clades supports hospital acquisition.

3. Risk factors for infection: Risk factors for systemic candidiasis: Antibacterial treatment, chemotherapy, mechanical ventilation, immunosuppressive treatment (including glucocorticoids), malignancy (particularly hematologic), neutropenia or neutrophil function disorders, abdominal surgery, thoracic surgery, central vascular lines, hemodialysis, parenteral nutrition, extensive burns, prematurity or low birth weight in neonates, HIV infection with low CD4+ cell counts, IV drug use, cirrhosis.

4. Incubation and contagious period: The duration of incubation and contagious periods varies and depends on a number of parameters, including the immunologic status of the patient, risk factors, and environment.

Clinical Features and Natural HistoryTop

Patients may develop candidemia (presence of Candida spp in blood) without internal organ involvement, candidemia with internal organ involvement, or systemic candidiasis without candidemia.

1. Candidemia: Presence of Candida spp in blood cultures.

2. Cardiovascular candidiasis: Endocarditis (see Infective Endocarditis) and myocarditis, pericarditis, vascular bed infection (usually associated with catheters or prosthetic grafts).

3. Urinary tract candidiasis.

4. Candidiasis of joints, bones, and bone marrow.

5. Central nervous system candidiasis.

6. Respiratory candidiasis: Candida pneumonia is a very rare and poorly defined condition, as differentiation between a true infection and colonization is difficult. Contamination of respiratory tract specimens by oropharyngeal candida also complicates diagnosis.

7. Candidiasis of other organs: The peritoneum, liver, spleen, pancreas, gallbladder, thyroid, and eye may be involved.

8. Systemic candidiasis: Various organs may be affected (with formation of microabscesses), most frequently the kidney, brain, heart, or eye, and less frequently the lungs, gastrointestinal tract, skin, and endocrine glands.

DiagnosisTop

Diagnostic Tests

1. Identification of the etiologic agent:

1) Blood cultures: In patients with systemic candidiasis blood cultures can be negative in ~50% due to the absence of viable organism, insufficient concentration in blood, or intermittent release. If Candida spp are isolated from blood, repeat blood cultures should be performed every day or every other day until clearance is documented, as this will impact the duration of treatment.

2) Serologic studies: Tests for detection of Candida spp antigen and antibodies are not widely available and their results should be interpreted with caution, as they do not allow for definite differentiation between systemic infection and contamination. An antigen test based on detection of beta-D-glucan, found in the cell wall of Candida spp, has a sensitivity of 75%. Specificity is lower, as it is also found in other fungal pathogens such as Aspergillus, Trichosporon, Saccharomyces, Fusarium, and Pneumocystis jiroveci. False-positive results can occur in patients with bacteremia in the intensive care unit, in lung transplant recipients, in individuals who have received human blood products, and following the receipt of piperacillin with tazobactam. Some consider testing for this antigen helpful in making the decision to start empiric antifungal therapy or for predicting blood culture–negative invasive candidiasis.

3) Histologic examination with fungal stains (Gomori methenamine silver [GMS] or periodic acid–Schiff [PAS] stain): This is the most reliable method for identifying systemic candidiasis in internal organs.

4) Molecular studies: Polymerase chain reaction [PCR] and sequencing are additional methods to detect Candida species. Direct molecular detection methods from blood may increase sensitivity; however, they require further clinical evaluation and are not widely available.

5) Identification of Candida species: Identification from culture is usually performed by automatic methods (eg, Vitek 2, MicroScan) or manual strips (analytical profile index [API] strips) based on enzymatic and assimilation reactions. Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) is an accurate identification method with rapid results in <30 minutes. Misidentification of C auris as C haemulonii, C duobushaemulonii, or C famata can occur depending on the identification method. Recent updates in the database libraries for MALDI-TOF have improved the accuracy of identification of C auris.

6) Antifungal susceptibility testing: Species-specific clinical breakpoints are available for multiple antifungal agents. In patients with candidemia or severe systemic candidiasis consider performing antifungal susceptibility for azole antifungals. C krusei is intrinsically resistant to fluconazole and should always be reported as resistant. Susceptibility testing for echinocandins should be considered in patients with a history of treatment with these drugs as well as and in the case of C glabrata or C parapsilosis infection and for other species where local antibiogram data suggest increasing resistance. Antifungal susceptibility testing to all 3 classes of antifungals should be performed with C auris. Interpretive breakpoints from the Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) are not available for C auris; however, recommendations have recently been published by the Centers for Disease Control and Prevention (CDC).

2. Other tests:

1) Imaging studies and endoscopy: These are performed depending on the location of infection.

2) Ophthalmoscopy: Candidiasis can cause chorioretinitis (inflammation of the choroid and the retina) or endophthalmitis (inflammation of the vitreous body). These lesions are detected by dilated fundoscopic examination. In the case of ophthalmitis of unknown etiology, it is recommended to perform diagnostic vitreous aspiration. In all patients with confirmed candidemia dilated ophthalmologic examination should be performed in the first week of treatment. However, a recent meta-analysis has suggested the need to review guideline recommendations for universal screening.

3) Echocardiography: Limited studies support routine consideration of echocardiography to evaluate for endocarditis.

TreatmentTop

Treatment should take into account risk factors, clinical manifestations, coexisting neutropenia, and the strain of Candida causing the infection. If candidiasis is suspected in a patient with risk factors, start empiric treatment and continue until the diagnosis is confirmed or excluded. If the isolated species is other than C albicans, patient has a history of fluconazole treatment, or infection is severe, the recommended agents include an echinocandin or amphotericin B. Amphotericin B (AmB) includes 1 conventional preparation (AmB deoxycholate) and 3 lipid formulations of AmB (LFAmB): AmB lipid complex, liposomal AmB, and AmB colloidal dispersion. LFAmB is less nephrotoxic than conventional AmB.

Candidemia in Patients Without Neutropenia

1. Preferred treatment: Echinocandins: Caspofungin every 24 hours, first dose 70 mg, subsequent doses 50 mg; micafungin 100 mg every 24 hours; or anidulafungin, first dose 200 mg, subsequent doses 100 mg every 12 hours.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and heterogeneity. Of note, the IDSA guidelines judge the Quality of Evidence as high and the ESICM/ESCMID as low. Martin-Loeches I, Antonelli M, Cuenca-Estrella M, et al. ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients. Intensive Care Med. 2019 Jun;45(6):789-805. doi: 10.1007/s00134-019-05599-w. Epub 2019 Mar 25. PubMed PMID: 30911804. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Feb 15;62(4):e1-50. doi: 10.1093/cid/civ933. Epub 2015 Dec 16. PubMed PMID: 26679628; PubMed Central PMCID: PMC4725385.

2. Alternative treatment:

1) Fluconazole 800 mg (12 mg/kg of body weight) followed by a maintenance dose of 400 mg (6 mg/kg) per day. Fluconazole should be considered in patients without severe infection with a Candida strain of confirmed susceptibility to fluconazole.

2) LFAmB 3 to 5 mg/kg/d. This regimen should be used in case of intolerance or unavailability of echinocandins or resistance to other classes of antifungal agents.

3. Treatment duration: Treatment should be continued for 14 days from obtaining negative blood culture results provided the infection has not spread to other organs. In clinically stable patients infected by a Candida strain susceptible to fluconazole, after 5 to 7 days of treatment with echinocandins or LFAmB switch to fluconazole. In the case of infection with C glabrata, if testing indicates dose-dependent susceptibility to fluconazole, maintenance therapy with fluconazole 800 mg (12 mg/kg) per day is recommended. For maintenance treatment in patients with candidemia caused by C krusei, use voriconazole in standard doses if susceptible.

4. Removal of intravascular catheters should be performed unless this may cause severe consequences for the patient.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Janum S, Afshari A. Central venous catheter (CVC) removal for patients of all ages with candidaemia. Cochrane Database Syst Rev. 2016 Jul 11;7:CD011195. doi: 10.1002/14651858.CD011195.pub2. Review. PubMed PMID: 27398809; PubMed Central PMCID: PMC6457908.

Candidemia in Patients With Neutropenia

1. Preferred treatment: Echinocandins: Caspofungin every 24 hours, first dose 70 mg, subsequent doses 50 mg; micafungin 100 mg every 24 hours; or anidulafungin, first dose 200 mg, subsequent doses 100 mg every 12 hours.

2. Alternative treatment:

1) LFAmB 3 to 5 mg/kg/d.

2) Fluconazole (in patients who not previously treated with this agent) 800 mg (12 mg/kg) followed by 400 mg (6 mg/kg) per day or voriconazole 400 mg (6 mg/kg) every 12 hours for one day followed by 200 mg (3 mg/kg) every 12 hours. In the case of C krusei infection the preferred agents are echinocandins, LFAmB, or voriconazole.

3. Pharmacotherapy duration: 14 days from obtaining a negative blood culture result and clinical improvement provided the infection has not spread to other organs.

4. Supportive treatment: Granulocyte colony-stimulating factor (G-CSF) in patients with chronic candidemia.

5. Removal of intravascular catheters: Should be considered on an individual basis (in patients with neutropenia sources other than intravascular catheters are more frequent).

6. Patients with candidemia and endophthalmitis: Echinocandins should not be used as these drugs do not penetrate into the affected tissue. Management should involve an ophthalmologist as the patient may require intravitreal injection of deoxycholate AmB or voriconazole.

Suspected Candidiasis in Patients Without Neutropenia: Empiric Treatment

Empiric treatment in such cases should be considered in critically ill patients with risk factors for systemic candidiasis and with fever of unknown origin.

1. Preferred treatment: Echinocandins: Caspofungin every 24 hours, first dose 70 mg, subsequent doses 50 mg; micafungin 100 mg every 24 hours; or anidulafungin, first dose 200 mg, subsequent doses 100 mg every 12 hours.

2. Alternative treatment:

1) Fluconazole 800 mg (12 mg/kg) followed by 400 mg (6 mg/kg) per day. This should be used in patients who have not been previously treated with imidazole antifungals; do not use fluconazole in patients colonized with strains resistant to imidazole antifungals.

2) LFAmB 3 to 5 mg/kg/d.

3. Pharmacotherapy duration: 2 weeks. In patients without confirmed fungal infection and no clinical improvement in 4 to 5 days, consider discontinuation of treatment.

Suspected Candidiasis in Patients with Neutropenia: Empiric Treatment

Treatment should be started in patients with persistent fever after 4 days of antimicrobial treatment.

1. Preferred treatment: LFAmB 3 to 5 mg/kg/d, caspofungin at a loading dose of 70 mg followed by 50 mg/d, or voriconazole 400 mg (6 mg/kg) every 12 hours followed by 200 mg (3 mg/kg) every 12 hours.

2. Alternative treatment: Fluconazole 800 mg (12 mg/kg) followed by 400 mg (6 mg/kg) per day or itraconazole 200 mg (3 mg/kg) every 12 hours.

Chronic Systemic Candidiasis, Hepatosplenic Candidiasis

1. Preferred treatment: Start with LFAmB 3 to 5 mg/kg/d or echinocandins (caspofungin every 24 hours, first dose 70 mg followed by 50 mg; micafungin 100 mg every 24 hours; or anidulafungin, first dose 200 mg followed by 100 mg every 12 hours) administered for a few weeks. Then continue treatment with oral fluconazole 400 mg (6 mg/kg) in patients with no resistance to fluconazole.

2. Pharmacotherapy duration: The duration is not determined. Usually treatment lasts a few months until regression of lesions; it should be continued for the whole duration of immunosuppression, including chemotherapy and hematopoietic stem cell transplant (HSCT).

3. Supportive treatment: In patients with persistent fever consider nonsteroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids for 1 to 2 weeks.

Fungal Endocarditis

1. Preferred treatment: LFAmB 3 to 5 mg/kg/d (with or without flucytosine 25 mg/kg every 6 hours) or echinocandins (caspofungin 150 mg/d, micafungin 150 mg/d, or anidulafungin 200 mg/d). Treatment may be continued with fluconazole 400 to 800 mg (6-12 mg/kg) per day provided that susceptibility to fluconazole has been confirmed. In clinically stable patients in whom candidemia has resolved as well as in those infected with a fluconazole-resistant strain, it is recommended to use oral voriconazole 200 to 300 mg (3-4 mg/kg) every 12 hours or oral posaconazole 300 mg every 24 hours provided that susceptibility to these agents has been confirmed.

2. Surgical treatment: Assessment by a cardiac surgeon required (for valve replacement).

3. Duration of pharmacologic treatment: At least 6 weeks following surgery or longer in the case of a perivalvular abscess or other complications. In patients with contraindications to valve replacement and infection with fluconazole-susceptible Candida strains, start long-term treatment with fluconazole 400 to 800 mg/d. In patients with prosthetic valve infection, treatment is the same as in those with native valve infection; continue treatment with fluconazole 400 to 800 mg/d to prevent recurrences.

Fungal Myocarditis or Pericarditis

1. Pharmacologic treatment: LFAmB 3 to 5 mg/kg/d, fluconazole 400 to 800 mg/d (6-12 mg/kg/d), or an echinocandin.

2. Surgical treatment: Pericardiectomy may be considered.

3. Pharmacotherapy duration: Usually a few months.

Fungal Thrombophlebitis

1. Pharmacologic treatment: LFAmB 3 to 5 mg/kg/d, fluconazole 400 to 800 mg/d (6-12 mg/kg/d), or an echinocandin (caspofungin 150 mg/d, micafungin 150 mg/d, or anidulafungin 200 mg/d). In the case of infections with strains susceptible to imidazole antifungals, once response to primary treatment is achieved consider continuing treatment with fluconazole 400 to 800 mg/d (6-12 mg/kg).

2. Surgical treatment: Surgical treatment is recommended whenever possible.

3. Pharmacotherapy duration: Treatment should be continued for 14 days from obtaining negative blood culture results.

Fungal Infections of a Cardiac Pacemaker, ICD, or VAD

1. Preferred treatment: LFAmB 3 to 5 mg/kg/d (with or without flucytosine 25 mg/kg every 6 hours) or echinocandins (caspofungin 150 mg/d, micafungin 150 mg/d, or anidulafungin 200 mg/d). Treatment may be continued with fluconazole 400 to 800 mg (6-12 mg/kg) per day provided that susceptibility to fluconazole has been confirmed. In clinically stable patients in whom candidemia has resolved as well as in those infected with a fluconazole-resistant strain, it is recommended to use oral voriconazole 200 to 300 mg (3-4 mg/kg) every 12 hours or oral posaconazole 300 mg every 24 hours provided that susceptibility to these agents has been confirmed.

2. Pharmacotherapy duration: 4 weeks following removal of the device in patients with pocket infection, ≥6 weeks in patients after electrode replacement. In patients with a ventricular assist device (VAD), use long-term treatment with fluconazole for the whole duration of VAD treatment.

3. Surgical treatment: Removal of the pacemaker or implantable cardioverter-defibrillator (ICD). Reinsertion is based on the presence/absence of concomitant valvular endocarditis and clearance of fungemia.

Candida Lung Infections

Isolation of Candida strains from lower respiratory tract specimens usually indicates colonization as opposed to primary pulmonary infection, and treatment is rarely required.

Asymptomatic Candiduria

See Candiduria.

Symptomatic Fungal Cystitis

Removal of the urinary catheter is a starting point.

1. Preferred treatment: In the case of infections with Candida strains susceptible to fluconazole, use fluconazole 200 mg (3 mg/kg) per day for 14 days. In the case of infections with C glabrata strains resistant to fluconazole, use AmB deoxycholate 0.3 to 0.6 mg/kg for 1 to 7 days or flucytosine 25 mg/kg every 6 hours for 7 to 10 days. In the case of infections with C krusei, use AmB deoxycholate 0.3 to 0.6 mg/kg for 1 to 7 days.

2. Alternative treatment: Intravesical administration of AmB deoxycholate (50 mg/L of sterile water per day) is used only in the case of infection with strains with primary resistance to fluconazole (eg, C glabrata, C krusei). Treatment duration is 5 days.

Fungal Pyelonephritis

1. Preferred treatment: In the case of infections with strains susceptible to fluconazole, use fluconazole 200 to 400 mg (3-6 mg/kg) per day for 14 days. In the case of infections with C glabrata strains resistant to fluconazole, use AmB deoxycholate 0.3 to 0.6 mg/kg for 1 to 7 days as monotherapy, AmB deoxycholate in combination with flucytosine 25 mg/kg every 6 hours, or flucytosine as monotherapy for 14 days. In the case of infections with C krusei, use AmB deoxycholate 0.3 to 0.6 mg/kg for 1 to 7 days.

2. Surgical treatment: Removal of urinary tract obstruction. In patients with nephroureteral stents or nephrostomy catheters, consider their replacement.

Urinary Tract Candidiasis With Fungus Balls

1. Pharmacologic treatment: As in pyelonephritis. Additionally perform irrigation with a nephrostomy catheter using AmB deoxycholate 25 to 50 mg dissolved in 200 to 500 mL of sterile water.

2. Surgical treatment: Mechanical removal of the fungus balls.

Fungal Osteomyelitis

1. Preferred treatment:

1) Fluconazole 400 mg (6 mg/kg) per day for 6 to 12 months.

2) Echinocandins (caspofungin 50-70 mg/d, micafungin 100 mg every 24 hours, or anidulafungin 100 mg/d) for ≥2 weeks followed by fluconazole 400 mg (6 mg/kg) per day for 6 to 12 months.

2. Alternative treatment: LFAmB 3 to 5 mg/kg/d for ≥2 weeks followed by fluconazole for up to 6 to 12 months.

3. Surgical treatment: Debridement and/or removal of the lesion are frequently necessary.

Fungal Arthritis

See Infectious Arthritis.

Central Nervous System Candidiasis

See Meningitis.

C auris Infection 

1. Pharmacologic treatment: Anidulafungin, first dose 200 mg IV followed by 100 mg IV every 24 hours; caspofungin, first dose 70 mg/d IV followed by 50 mg/d IV; or micafungin 100 mg/d IV. In case of lack of response or fungemia persisting >5 days, use LFAmB 5 mg/kg/d.

2. Pharmacotherapy duration and surgical treatment: As recommended for the specific type of infection. Specialist consultation is required.

PrognosisTop

In patients with systemic candidiasis the prognosis is poor. Patients with hepatosplenic candidiasis are at a very high risk of death.

PreventionTop

Prophylactic use of antifungal agents to prevent invasive candidiasis is controversial. It may be considered in:

1) Recipients of allogeneic HSCT (fluconazole, posaconazole, micafungin).

2) Patients treated in intensive care units, particularly those after surgery (fluconazole).

3) Patients with chemotherapy-induced neutropenia until granulocyte counts increase.

4) Patients with HIV infection, recurrent candidiasis, and low CD4+ counts.

Candida auris has been associated with clonal spread and nosocomial transmission causing hospital outbreaks. Due to the persistence of C auris in the environment, consider surveillance for carriage of C auris in high-risk patients. Contact precautions are recommended to limit nosocomial transmission.