Invasive Candidiasis/Candidemia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has invasive candidiasis/candidemia? What should you expect to find?

Symptoms mimic the clinical picture seen with bacterial infections/bacteremia:

• Candidemia: fever, chills, hypotension, confusion

• Localized invasive candidiasis: depends on the organ involved; examples include:

  Abdominal abscesses: fever, chills, abdominal pain

  Urinary tract infection: dysuria, frequency, pneumaturia, suprapubic or flank pain

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  Hepatosplenic candidiasis: right upper quadrant discomfort, high fevers, anorexia

Physical findings:

• Candidemia: fever, hypotension, altered mental status

  Sudden appearance of pustular skin lesions on an erythematous base an important clue to candidemia; these can occur anywhere and often appear in clusters and are non-painful

• Localized invasive candidiasis:

  Abdominal abscesses: abdominal tenderness, rigidity, rebound tenderness

  Urinary tract infection: suprapubic or costovertebral angle tenderness

  Hepatosplenic candidiasis: right upper quadrant tenderness

How did the patient develop invasive candidiasis/candidemia? What was the primary source from which the infection spread?

• Candidaspecies are part of the normal human microbiota, and infections are usually due to Candidastrains that colonize the gastrointestinal tract, genitourinary tract or skin. In almost all cases, Candidacolonization is a prerequisite for subsequent infection. Disruption of the gastrointestinal mucosa occurs during surgery and can occur after treatment with certain chemotherapeutic agents that cause mucosal ulcerations. An additional risk factor is the use of broad-spectrum antimicrobial agents that allow overgrowth of Candidain the gut. All of the above lead to subsequent egress of Candidainto the bloodstream.

• Another mechanism by which Candida can enter the bloodstream is by ingress along an indwelling intravenous catheter that becomes colonized from the skin at the entrance site.

• Much less commonly, Candidainfections have been linked to transmission from healthcare workers who are colonized with Candida species, especially Candidaparapsilosis, the predominant species that colonizes hands.

Which individuals are of greater risk of developing invasive candidiasis/candidemia ?

• Risk factors for development of invasive candidiasis/candidemia include: low birth weight premature neonates, trauma/burns, high APACHE II score, recent abdominal surgery, gastrointestinal tract perforation, pancreatitis, mechanical ventilation, central venous catheters, parenteral nutrition, dialysis, and broad-spectrum antibiotic therapy. A large prospective multi-center U.S. study that took place in surgical intensive care units (ICUs) found that prior surgery, acute renal failure, parenteral nutrition, and central venous catheters were independently associated with increased risk for developing candidemia. Another multi-center study in Spain noted that independent risk factors for development of candidemia were sepsis, prior surgery, parenteral nutrition, and Candidacolonization at multiple sites.

• The risks for development of infection due to specific Candida species have been studied:

  For C. glabrata, risk factors include older age, recent abdominal surgery, use of multiple antibiotics, and receipt of parenteral nutrition.

  Patients with C. parapsilosis candidemia are less likely to have neutropenia or to have received steroids or other immunosuppressive drugs, and more likely to have a central venous catheter in place.

  Patients with C. krusei candidemia are more likely to have a hematologic malignancy, a stem cell transplantor neutropenia, and have had prior treatment with corticosteroids or antifungal agents.

Beware: there are other diseases that can mimic invasive candidiasis/candidemia:

• Candidemia frequently presents with clinical manifestations that are similar to those seen with bacteremia due to a variety of different Gram-negative and Gram-positive pathogens.

• In a similar fashion, localized Candida infections, such as meningitis, endocarditis, osteoarticular infection, and urinary tract infections mimic bacterial infections in these same organs.

• A unique syndrome caused by Candida species is hepatosplenic candidiasis, also known as chronic disseminated candidiasis. Other fungi uncommonly can mimic this form of candidiasis, but bacteria do not cause a similar type of disease.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

• Invasive candidiasis in a patient in the ICU setting usually leads to an increased white blood cell (WBC) count and increased neutrophils. However, a major risk factor for invasive candidiasis/candidemia is neutropenia, and obviously these patients cannot mount a WBC response.

• Depending on the organ involved, the presence of WBC may indicate Candida infection; for example, WBC appear in urine or cerebrospinal fluid in patients with urinary tract infection or meningitis, respectively.

• In the specific case of chronic disseminated candidiasis, the alkaline phosphatase is almost always elevated and transaminases are mildly increased.

Results that confirm the diagnosis

• Candidemia is confirmed when blood cultures yield Candida species. However, it should be noted that blood cultures are not sensitive and many patients who have invasive candidiasis documented at post-mortem had negative blood cultures.

• Invasive candidiasis is confirmed when culture of other normally sterile body fluids, besides blood, yield Candida species. This includes abdominal fluid obtained at the time of surgery or cultures obtained at the time of initial insertion of a drainage tube.

• It is important to note that a positive culture from sputum or bronchoalveolar lavage (BAL) fluid is not adequate for a diagnosis of invasive candidiasis, and almost always reflects colonization of the airways.

• A positive culture from an indwelling drain or tube likely reflects colonization of the tube and cannot be used as evidence for invasive candidiasis.

• The growth of Candida species from urine can be seen with contamination from the perineum as the sample was collected, colonization of the bladder or an indwelling urinary catheter, lower tract infection, or upper tract infection. Colony counts in the urine, unfortunately, cannot differentiate the above possibilities.

• Gram stain of a skin pustule showing Gram-positive budding yeasts confirms the diagnosis of candidemia

• Histopathological examination is not used frequently for the diagnosis of candidiasis, but if tissue is obtained by biopsy or at post-mortem and shows either budding yeasts or a mixture of budding yeasts and hyphae, invasive candidiasis is the most likely diagnosis.

What imaging studies will be helpful in making or excluding the diagnosis of invasive candidiasis/candidemia?

• Imaging studies are not very important for the diagnosis of most cases of candidemia.

• For invasive candidiasis involving specific organs, it may be helpful to perform a computed tomography (CT) scan or a magnetic resonance imaging (MRI) scan, but this depends on the specific organ involved. For example, an MRI would be used if it was thought a patient had Candida meningitis or brain abscess. A CT scan helps localize an abdominal abscess that might be caused by Candida species, as well as bacteria. With one exception, imaging findings are not specific for Candida infections, but help define the extent of disease.

• The one case in which imaging is extremely helpful is hepatosplenic (chronic disseminated) candidiasis. In this specific syndrome, CT scans show multiple round, well-demarcated lesions in liver, spleen and sometimes in kidneys. With the appropriate clinical scenario, this finding is almost diagnostic of candidiasis. MRI scans are also helpful but more expensive and no more sensitive than CT scans for this syndrome.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has invasive candidiasis/candidemia, what therapies should you initiate immediately?

An Infectious Diseases specialist should be consulted for help with treatment for patients who have invasive candidiasis/candidemia.

Key principles of therapy

• All patients with candidemia require treatment with an antifungal agent

• Starting treatment with an antifungal agent should begin as soon as possible after the blood cultures are obtained if there is a high suspicion that the illness is due to Candida.

• Source control (i.e., finding the source of the Candida, such as an abdominal abscess or an intravenous catheter, and eliminating it as soon as feasible) is associated with decreased mortality.

• All patients who have candidemia should have follow-up blood cultures to establish when the yeast has been cleared from the bloodstream.

• Treatment should continue for 2 weeks from the date of the first negative blood culture

• All patients who have candidemia should undergo a dilated ophthalmic examination, preferably by an ophthalmologist, to assess whether endophthalmitis is present as a result of candidemia.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Empiric therapy should begin when it is likely that the patient has invasive candidiasis/candidemia. The major options for empiric therapy are fluconazole or an echinocandin (Table I).