Infectious Diseases

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

    • 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).

Table I.

Therapy Options
Disease Drug Dose Alternative
Candidemia Fluconazole in a setting in which C. glabrata is not commonly seen and in a patient who has not had prior azole therapy 12mg/kg (800mg) IV loading dose, followed by 6mg/kg (400mg) IV daily; oral dosing can be used if patient can take oral meds Echinocandins (Micafungin, anidulafungin, caspofungin)ORlipid formulation amphotericin B (AmBisome, Abelcet)
Candidemia Echinocandin in a setting in which C. glabrata is common and for patients who have had prior azole therapy. Preferred for seriously ill patients Micafungin 100mg IV daily; Anidulafungin 200mg loading dose, then 100mg IV daily;Caspofungin 70mg loading dose, then 50mg IV daily FluconazoleORlipid formulation amphotericin B (AmBisome, Abelcet)
Urinary tract infection Fluconazole 200mg oral daily for cystitis; 400mg oral daily for pyelonephritis Amphotericin B deoxycholate
Abdominal abscess Fluconazole in a setting in which C. glabrata is not commonly seen and in a patient who has not had prior azole therapy;Echinocandin in a setting in which C. glabrata is common and for patients who have had prior azole therapy. Preferred for seriously ill patients 12mg/kg (800mg) IV loading dose, followed by 6mg/kg (400mg) IV daily; oral dosing can be used if patient can take oral meds Micafungin 100mg IV daily; Anidulafungin 200mg loading dose, then 100mg IV daily;Caspofungin 70mg loading dose, then 50mg IV daily Lipid formulation amphotericin B (AmBisome, Abelcet)
Hepatosplenic candidiasis Fluconazole for stable patientsLipid amphotericin B for severe disease, then fluconazole when stable 6mg/kg (400mg) oral daily 3-5mg/kg IV daily Echinocandins (Micafungin, anidulafungin, caspofungin)

2. Next list other key therapeutic modalities.

  • For patients who have candidemia and have an indwelling central catheter, the catheter should be removed and the tip sent for culture. Another central catheter should not be placed until the blood cultures have been documented to no longer yield Candida.

  • Abscesses should be drained by an interventional radiological or surgical procedure.

  • In immunosuppressed hosts who have invasive candidiasis, if possible, a decrease in immune suppression may be helpful.

How do you contract invasive candidiasis/candidemia and how frequent is this disease?

Epidemiology

Candida species are part of the normal human microbiotia, 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.

In a nationwide survey performed in U.S. hospitals (now almost a decade ago), Candida species were the fourth most common cause of bloodstream infections in hospitalized patients, accounting for approximately 10% of all bloodstream infections. It is likely that these rates are lower now with increased early use of empiric treatment for candidiasis. Historically, among immunosuppressed patients and in cancer hospitals, rates of candidemia were high. However, because of routine prophylaxis for those at highest risk, including patients with hematological malignancies, especially when neutropenic, hematopoietic cell transplant recipients, and liver, pancreas and small bowel transplant recipients, the rates of candidemia in these settings is now about 1-2%.

What pathogens are responsible for this disease?

Any species of Candida can cause invasive candidiasis/candidemia, but several species are most common. These include C. albicans, C. glabrata, C. parapsilosis, C. tropicalis,and C. krusei.

C. albicans is the most common species that causes invasive disease and bloodstream infection. It is the most common colonizing species in humans.

C. glabrata is an increasing cause of invasive candidiasis/candidemia. Because of reduced susceptibility to fluconazole, it is seen in patients who have received prophylaxis or prior treatment with fluconazole; thus, patients with hematological malignancies, transplant recipients, and patients in the ICU setting are more likely to be colonized and subsequently infected with C. glabrata.

Older adults make up a disproportionate percentage of patients who have C. glabrata infection, whereas infants and neonates rarely are infected with this species. There are conflicting data as to whether the mortality rate is higher or lower with this species when compared to that noted with C. albicans. C. glabrata is susceptible to the echinocandin antifungal agents.

C. parapsilosis is a common infecting species in neonates and infants. It is also commonly associated with central venous catheter associated bloodstream infections. This may be related to its enhanced ability to form biofilms on catheter material. Outbreaks with this species have been reported related to parental nutrition and to healthcare workers' hands. The overall mortality of C. parapsilosis candidemia is less than that due to other species of Candida in most studies. C. parapsilosis remains susceptible to fluconazole and other azole agents, but is less susceptibe to the echinocandins.

C. tropicalis is less commonly isolated than the previous species, and is more common in patients who have cancer, including hematological malignancies. It is more virulent than C. albicans in experimental animal studies, and that appears to be true in humans as well. C. tropicalis remains susceptible to fluconazole and the other azoles, as well as the echinocandins.

C. kruseiis uncommon, accounting for less than 5% of all blood culture Candidaisolates. It is seen primarily in patients who have hematological malignancies or have received a hematopoietic cell transplant (HCT). Prior exposure to fluconazole, to which this species is innately resistant, is a risk factor for colonization and infection with this species. This species is susceptible to echinocandins.

How do these pathogens cause invasive candidiasis/candidemia?

Candida species normally colonize the mucosal surfaces, including the bowel, of humans. A breach in this surface allows the organism to enter the deeper tissues and bloodstream. The first response to this invasion is phagocytosis by neutrophils and monocytes/macrophages. These cells have receptors for fungal cell wall components termed pathogen-associated molecular patterns (PAMPs) that lead to activation of intracellular signaling pathways. This activation triggers the inflammatory response, increasing neutrophil accumulation and macrophage cytokine production. Ingested yeasts are killed by oxidative and non-oxidative mechanisms.

Mucosal control of Candida is mediated by cellular immunity. Patients with low CD4 cells and those on corticosteroids which inhibit cellular immunity, are thus at risk for localized mucosal infections with Candida species, but not at risk for invasive candidiasis/candidemia.

Neutropenia is a major risk factor for invasive candidiasis. Another is use of corticosteroids, which inhibit the chemotaxis of and phagocytosis by neutrophils.

What other additional laboratory findings may be ordered?

PCR has been investigated as a diagnostic test for candidiasis, and appears promising. However, the assays are not standardized and there are no commercially available tests at this time.

The beta-D-glucan (BDG) assay detects a component of the cell wall of Candida species. One problem is that many fungi have BDG in their cell walls, and thus, this assay is not specific for candidiasis. However, in the correct setting, for example, an ICU setting, this test has been shown in some centers to be useful in earlier diagnosis of candidemia.

A recent study compared the sensitivity and specificity of PCR and BDG for patients who were known to have invasive candidiasis or candidemia and found that both assays enhanced the sensitivity of the diagnosis of invasive candidiasis, when combined with blood cultures. PCR, in particular, was more sensitive than blood cultures and BDG for the diagnosis of invasive candidiasis. In this setting, when comparing patients known to have invasive candidiasis with hospitalized control patients, both BDG and PCR had the same specificity (about 70%).

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

De Pauw, B, Walsh, TJ, Donnelly, JP. "Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group". Clin Infect Dis. vol. 46. 2008. pp. 1813-1821.

(This paper has become the standard for defining invasive fungal diseases, including candidiasis)

Wisplinghoff, H, Bischoff, T, Tallent, SM, Seifert, H, Wenzel, RP, Edmond, MB. "Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study". Clin Infect Dis. vol. 39. 2004. pp. 309-317.

(For many years, this paper has been quoted regarding rates of candidemia in hospitalized patients in the U.S.)

Nguyen, MH, Wissel, MC, Shields, RK, Salomoni, MA, Hao, B, Press, EG. "Performance of Candida Real-time Polymerase Chain Reaction, beta-D-Glucan Assay, and Blood Cultures in the Diagnosis of Invasive Candidiasis". Clin Infect Dis. vol. 54. 2012. pp. 1240-1248.

(Excellent study comparing PCR and beta-D-glucan assays for the rapid diagnosis of invasive candidiasis and noting that PCR is more sensitive, but not standardized or commercially available, and beta-D-glucan is not as sensitive).

Kollef, M, Micek, S, Hampton, N, Doherty, JA, Kumar, A. "Septic shock attributed to Candida infection: importance of empiric therapy and source control". Clin Infect Dis. vol. 54. 2012. pp. 1739-1746.

(An important study showing a shockingly high mortality rate for candidemia associated with shock when appropriate antifungal therapy is not given promptly and the source of the infection - most often abdominal abscesses or intravenous catheters - is not drained or removed.)

Andes, DR, Safdar, N, Baddley, JW, Playford, G, Reboli, AC, Rex, JH. "Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials". Clin Infect Dis. vol. 54. 2012. pp. 1110-1122.

(Retrospective review of 7 controlled clinical trials for the treatment of candidemia that found better outcomes in patients with candidemia when central catheters were removed and when echinocandins were used rather than fluconazole.)

Pappas, PG, Kauffman, CA, Andes, D, Benjamin, DK, Calandra, TF, Edwards, JE. "Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America". Clin Infect Dis. vol. 48. 2009. pp. 503-535.

(IDSA treatment guidelines that are the standard for management of various types of Candida infections.)
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