Continuing Education Activity

Candidemia describes the presence of the yeast species Candida in the bloodstream. It is the most common fungal bloodstream infection, and the fourth most common bloodstream infection seen in the ICU. This activity reviews the diagnosis and management of candidemia, and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Describe the etiology of candidema.
• Describe the most common risk factors for candidemia.
• Explain the management and treatment options for patients with candidemia.
• Outline the importance of interprofessional team collaboration in the diagnosis and management of candidemia.

Introduction

Candidemia is defined as the presence of Candida species in the blood. It is the most common fungal bloodstream infection in hospitalized patients[1]. Mortality is very high. It reaches almost 50% in some studies[2]. Although Candida albicans is still the most common Candida species causing candidemia, in recent years there has been an increase in nonalbicans Candida species, which may represent a therapeutic challenge given the different antibiotic susceptibility profile of different Candida species[1]. This new trend is likely caused by the process of natural selection of resistant species to the most common antifungals used.

Etiology

Candida albicans is the most common cause of candidemia, representing 35% to 60% of isolates. Candida parapsilosis, Candida tropicalis, Candida glabrata and Candida krusei, are the most common nonalbicans Candida species identified in cultures[3][4][5]. C. glabrata and C. krusei are frequently resistant to the azole antifungals.[6]

C. albicans, C. tropicalis, and C. glabrata are the more virulent species, and infections with them represent a higher risk of mortality.

Epidemiology

Candidemia is the most common fungal bloodstream infection, and possibly the fourth most common all-type bloodstream infection seen in the intensive care unit setting[1].

The incidence of Candida bloodstream infection is bimodal, with the elderly and very young having the highest risk of any population for suffering from this disease[1].

Most common risk factors include critical illness and prolonged intensive care unit stay. The presence of a central venous catheter, antibiotic exposure, abdominal surgery (especially if repeated laparotomies or anastomotic leakage is present), malignancy (solid organ and hematologic), acute necrotizing pancreatitis, organ transplant recipients, and total parenteral nutrition are other major risk factors.[3][4][7]

Pathophysiology

Candida species are part of the normal gastrointestinal microbiome. The most common mechanism causing Candida bloodstream infection is thought to be by translocation through the intestinal mucosa after some insult. This is the reason that abdominal surgeries, anastomotic leakage, antibiotic exposure, and pancreatitis increase the risk of infection. Access via an intravenous catheter, especially in patients with central venous lines, is also a common mechanism of infection. This is especially true in the case of patients receiving total parenteral nutrition (TPN) as lipid emulsions have been shown to increase Candida biofilm production and morphology, possibly increasing its virulence. It is also hypothesized that recipients of TPN have altered the gut function to Candida, making it easier for translocation to occur.[8][9]

Another less frequent mechanism of infection is the direct introduction of Candida from a sterile site, such as in ascending renal candidiasis. Although candidemia is the most common manifestation of invasive candidiasis, culture-negative deep-tissue infection after hematogenous seeding can occur[1]. It is likely that some genetic factors are linked to susceptibility for developing candidemia. This is currently an avid area of research.

History and Physical

Clinical manifestations of candidemia are nonspecific. It presents like any other bloodstream infection with a clinical spectrum that goes from chills, shivering, and fever to severe sepsis and septic shock with signs of end-organ damage. Physical findings can vary from a normal exam to findings specific to localized deep-seated tissue infections, for example, endophthalmitis skin lesions, candiduria, and central nervous system findings.[10]

Evaluation

The gold standard for diagnosis of candidemia is based on direct fungal detection in blood cultures. The advantage of cultures is the ability to do susceptibility testing. However, sensitivity is low, reaching only 21% to 71% in some studies. Cultures have the further disadvantage of taking a long time to grow and being negative in cases where candidemia has subsided but has caused a persistent deep-seated tissue infection without bloodstream infection.

• In patients with localized findings, a biopsy should be done and sent for culture and gram staining.
• Other markers of infection like Candida mannan antigen and anti-mannan antibodies and B-d-glucan have the advantage of resulting faster but can have a high false-positive rate.[11]
• New polymerase chain reaction tests are being developed and evaluated in clinical trials. They show promising results. Currently available is the T2Candida test.
• When evaluating a patient with suspicion for invasive candidiasis, consideration should be made to order blood both cultures and one non-culture method like B-d-glucan.[12]

Treatment / Management

Early empiric antifungal therapy should be strongly considered in critically ill patients with risk factors for invasive candidiasis in whom the disease is suspected, as some studies have shown reduced mortality with this strategy. The decision to start therapy should be based on clinical suspicion, risk factors, and surrogate markers of candidemia (e.g., B-d-glucan). Empiric therapy should start with an echinocandin (caspofungin, micafungin, anidulafungin) as first choice therapy. Fluconazole may be considered in certain patients who are not critically ill and in whom susceptibility to fluconazole is likely. Amphotericin B can be given to patients with intolerance or contraindications to other treatments.[12]

When blood cultures have confirmed candidemia, treatment with an echinocandin and central venous catheter removal should be the first step to take[2][12][1]. Transition to fluconazole is recommended for stable patients in whom cultures have resulted in sensitive Candida species, such as C. albicans. Repeated blood cultures should show clearance of the bloodstream infection. Amphotericin B is given in the case of azole- and echinocandin-resistant fungi.

Initial treatment with an azole should be considered in a patient with concomitant meningitis, endophthalmitis, urinary tract infections (due to low penetrance of echinocandins to this areas), as well as in patients with prior exposure to echinocandins.[12]

Recommended duration of therapy is at least two weeks after documented clearance of the infection and longer (i.e., four weeks) for complicated infections, such as endophthalmitis, endocarditis or osteomyelitis.[12][1]

Some species of Candida have particular susceptibility profiles. For example, C. parapsilosis is less susceptible to echinocandins. This should be taken into consideration when starting therapy and when titrating to culture results. Emergent resistance to different antifungals is more commonly caused by selection of species with intrinsic resistance when using certain drugs as opposed to developing resistance in a previously susceptible isolate (although this too has been reported).

Differential Diagnosis

• Ascending cholangitis

• Acalculous cholecystitis

• Bacterial meningitis

• Bacterial sepsis

• Bacterial endocarditis

• Chronic granulomatous disease

• Cholecystitis

• Graft-versus-host disease

• Granulomatous hepatitis

• HIV seropositive state

• Hepatic abscess

• Relapsed malignancy

• Tuberculosis

Pearls and Other Issues

There is no role for routine prophylaxis for candidemia. Prophylaxis should be considered in the ICU for selected patients at high risk of candidemia as in those individuals with recurrent gastrointestinal perforations, anastomotic leakage, and small bowel or pancreas transplant. Prophylaxis, when indicated, is done with fluconazole.

All patients with candidemia should undergo an ophthalmologic evaluation to rule out endophthalmitis.

Enhancing Healthcare Team Outcomes

Candidemia is a life threatening infection with very high mortality. The infection is best managed by an interprofessional team that includes an infectious disease expert, intensivist, microbiologist, laboratory specialist and an internist. These patients should be monitored by ICU nurses. The key is to reverse the state of immunosuppression. Most patients have involvement of multiple organs and the prognosis is poor, despite optimal treatment.[13][14]