Continuing Education Activity

Candidemia is a life-threatening bloodstream infection associated with substantial mortality, prolonged hospitalization, increased health care costs, and complications such as septic shock, endocarditis, endophthalmitis, and metastatic infection. Diagnosis remains challenging because blood cultures have limited sensitivity and delayed turnaround times, while newer nonculture assays require careful interpretation within the clinical context. Current practice gaps include delayed recognition of patients at risk, inconsistent diagnostic evaluation, suboptimal antifungal selection, and variable implementation of source control and follow-up blood cultures. This educational activity is designed to narrow that gap by reviewing the epidemiology, risk factors, clinical presentation, diagnostic approach, and evidence-based treatment of candidemia. Participants will gain skills in early risk stratification, interpretation of diagnostic test results, prompt initiation of appropriate antifungal therapy, assessment of complications, and coordination of interdisciplinary care to improve timely treatment and patient outcomes.

Objectives:

• Identify clinical and health care–associated risk factors that increase the likelihood of candidemia in neonatal and adult patient populations.
• Assess patients with suspected candidemia for characteristic clinical features, potential metastatic complications, and the need for targeted diagnostic evaluation.
• Select appropriate initial antifungal therapy based on patient characteristics, likely species distribution, and current guideline recommendations.
• Collaborate with infectious diseases, microbiology, pharmacy, and critical care professionals to coordinate evidence-based treatment and complication prevention for patients with candidemia.

Introduction

Candida spp are commensal yeasts normally present on the skin and mucosal surfaces of the mouth, intestine, and vagina in most healthy individuals. These organisms may become opportunistic pathogens under appropriate conditions.[1] The human mycobiome, which constitutes the collective fungal community inhabiting the human body, accounts for less than 0.1% of the intestinal microbiome yet plays an essential role in immune regulation and metabolic balance. Mycobiome composition is highly dynamic, shaped by factors such as age, diet, antimicrobial exposure, and environment, reflecting the intricate interplay between fungi and other microbial domains within the human ecosystem.[2] Candida spp may become pathogenic when the equilibrium between commensal organisms is disturbed, and risk factors for overgrowth or invasion are present, including invasive devices such as central venous catheters, immunosuppression, total parenteral nutrition, and exposure to broad-spectrum antibiotics. Candida spp can cause invasive, deep-seated candidiasis via dissemination of Candida to sterile tissues, a condition termed invasive candidiasis.[3] Candidemia is the most common form of invasive candidiasis. Please see StatPearls' companion reference, "Candidiasis" for further information.

Precise global data on candidemia are limited, although one estimate suggests that more than 1.5 million cases of candidemia or invasive candidiasis occur annually, accounting for almost 1 million deaths.[4] In the United States, an estimated 25,000 cases of candidemia occur every year, with an overall incidence of 7 cases per 100,000 population.[CDC. Data and Statistics on Candidemia][5] Among hospitalized individuals, the incidence is approximately 100 cases per 100,000 admissions overall and up to 550 cases per 100,000 admissions to intensive care units.[6] Candidemia is associated with poor patient outcomes, longer hospital stays, and increased healthcare costs, and carries an attributable mortality rate that varies from 35% to 70%.[1][7][8]

Candidemia is a significant global problem. Candida albicans has historically been the most common species isolated from blood cultures, although non–albicans Candida spp have become increasingly prevalent and have different epidemiology and antifungal susceptibility profiles.[1][9] Additionally, the emergence of Candida auris presents a new challenge because this multidrug-resistant species can cause outbreaks, particularly in health care settings. The epidemiologic shift from Candida albicans to nonalbicans Candida spp complicates the selection of appropriate antifungal agents, necessitating broader-spectrum initial antifungal therapy with targeted therapy once Candida isolates are speciated and antifungal susceptibility testing is complete. Clinicians should also remove indwelling vascular devices when possible, document the clearance of blood cultures, and ensure that the infection has not spread to other sites, which could lead to further complications.[10]

Etiology

Candida is a genus of yeast, a type of fungus, that belongs to the subphylum Saccharomycotina.[11] More than 200 species of Candida exist, including the most common pathogen, Candida albicans. Candida spp are commensal yeasts and part of the normal human flora on the skin and mucosal surfaces, such as the mouth, intestine, and vagina. Up to 60% of healthy individuals are colonized with Candida spp, although rates vary by body site (eg, skin versus intestine) and population (eg, healthy versus hospitalized). Colonization is generally considered a prerequisite for the development of candidemia.[7]

Epidemiology

Certain Candida spp are most commonly isolated in candidemia,[1] although epidemiology may differ by country, healthcare system, and host risk factors.[12] Candida albicans has historically been the most common cause of candidemia worldwide, although over the past 2 decades, non–albicans Candida spp have become more common, causing as many as half of candidemia infections.[13][14] After Candida albicans, other common causes of candidemia include Candida glabrata (renamed Nakaseomyces glabrata), Candida parapsilosis, Candida tropicalis, and Candida krusei (renamed Pichia kudriavzevii). The prevalence of non–albicans Candida spp varies by patient population and geographic region. For example, Candida glabrata is more common in the United States, Australia, and Northern Europe, whereas Candida parapsilosis is less common. Conversely, in Asia (including Japan and China), Brazil, and Spain, Candida parapsilosis is much more common than Candida glabrata, and Candida tropicalis has shown an increased incidence in Brazil and parts of Asia. Candidemia caused by Candida glabrata is more common among older adults and among solid organ and hematopoietic stem cell transplant recipients, whereas Candida parapsilosis is more common among younger individuals, particularly neonates.[3][15]

The increasing incidence of candidemia with non-albicans Candida spp is concerning because these Candida spp have different epidemiologic and antifungal susceptibility profiles compared with Candida albicans and can exhibit varied acquired and inherent antifungal susceptibility.[1][9][16] Resistance to fluconazole, frequently associated with exposure to the drug, has been well documented in Candida albicans but remains low. Although fluconazole resistance rates remain low in regions such as the United States, this pattern may change with increased fluconazole use.[17] Certain non-albicans Candida spp, including Candida glabrata and Candida parapsilosis, may display higher rates of fluconazole resistance than Candida albicans, and Candida krusei is inherently resistant to fluconazole because of an altered cytochrome P450 isoenzyme.[1][9][16][18] This epidemiologic shift may complicate antifungal selection, delay treatment, and contribute to poor patient outcomes and high mortality rates.[1] 

The incidence of candidemia in neonates ranges from 5 to 10 cases per 100,000 births.[19][20][21] Risk factors include prematurity and low birth weight, exposure to broad-spectrum antibiotics, the number of sites colonized with Candida spp, the presence of invasive devices such as central venous catheters, exposure to corticosteroids and drugs that suppress gastric acid, and parenteral nutrition, among others.[22] Clinicians should recognize that the risk of neonatal candidemia increases when multiple risk factors are present.

In adults, risk factors for candidemia include critical illness, prolonged intensive care unit stay, indwelling central venous catheter, hematopoietic stem cell or solid organ transplant, exposure to broad-spectrum antibiotics, prior abdominal surgical procedures, immunosuppression, malignant neoplasm, and total parenteral nutrition, among others.[23][24][25] Injection drug use should also be considered a potential cause in adults who lack these traditional risk factors, particularly in the case of Candida endocarditis complicating candidemia.[26][27] Lastly, severe COVID-19 infection is a risk factor for candidemia, largely because these individuals are often critically ill in the intensive care unit and receiving mechanical ventilation, corticosteroids, and renal replacement therapy, which are all individual risk factors for candidemia.

Pathophysiology

Candida spp are commensal organisms normally present in the gastrointestinal tract, vaginal, oral, and skin microbiomes.[8] Colonization with Candida spp is considered a prerequisite for developing invasive candidiasis and candidemia. Risk factors for candidiasis include conditions that allow Candida spp to cross mucosal or skin barriers, factors that promote organism proliferation and biofilm formation, and conditions that decrease the body's ability to fight infection.[28] These factors include indwelling vascular catheters, immunosuppression, gastrointestinal tract surgical procedures (which allow translocation through the intestinal mucosa), and exposure to broad-spectrum antibiotics. Persons receiving peripheral and total parenteral nutrition and lipid emulsions are also at risk for developing candidemia.[28][29][30]

Histopathology

On Gram stain, gram-positive budding yeast, often with pseudohyphae, can be visualized. Samples are plated on culture media such as Sabouraud dextrose agar or chromogenic media (CHROMagar™ Candida), the latter of which differentiates Candida species by color. On Sabouraud dextrose agar, Candida spp grow within 2 to 3 days and typically form creamy, white-to-yellowish, smooth, shiny colonies, though the appearance can vary by species (see Image. Candida albicans Histology).

Species identification can be made through a germ tube test. Candida albicans forms germ tubes (hyphal outgrowths) in serum, differentiating this organism from most other Candida spp. Candida dubliniensis also forms true germ tubes, and Candida tropicalis forms pseudohyphae that produce a constriction at the point of origin of the yeast cell, resembling true germ tubes. Candida glabrata does not form germ tubes but rapidly ferments trehalose, distinguishing it from other Candida spp. Species identification can also be made using biochemical tests, chromogenic media, matrix-assisted laser desorption/ionization time-of-flight, and polymerase chain reaction (PCR). Species identification can also be made through biochemical tests, chromogenic media, matrix-assisted laser desorption/ionization time-of-flight, and PCR.

History and Physical

A detailed history should be obtained to assess for clinical symptoms that may suggest candidemia or invasive candidiasis, and to identify risk factors for candidemia. A complete physical examination should also be performed in all patients, including a focused examination of potentially affected organ systems, especially in patients with risk factors that increase vulnerability to serious infections such as candidemia.[10] Candidemia may manifest clinically with nonspecific symptoms and physical findings ranging from minimal symptoms such as fever to severe sepsis with symptoms such as rigors, dyspnea, confusion, and hypotension. Therefore, clinicians should maintain a high index of suspicion when evaluating patients with risk factors such as immunosuppression, indwelling vascular catheters, and exposure to broad-spectrum antibiotics.  

Physical examination findings in candidemia are often nonspecific, but clinical clues may suggest hematogenous spread of Candida, which can involve nearly any organ system, including the visceral organs, vasculature (including vessels and heart valves), bones and joints, eyes, and central nervous system.[31] Ocular candidiasis, including chorioretinitis and endophthalmitis, occurs in around 2% of individuals with candidemia, according to results from 1 recent meta-analysis using strict criteria to define Candida endophthalmitis, with up to 11% having ocular abnormalities potentially due to candidemia.[32] Persons with chorioretinitis are often asymptomatic, whereas endophthalmitis can present with visual impairment or vision loss. All persons with candidemia should be screened for ocular involvement with an indirect fundoscopic examination, when feasible.[8][33] The site of the indwelling vascular catheter should always be inspected for erythema or frank purulent discharge coming from the entry site, which may indicate an infected indwelling device. Patients who develop septic shock may develop multiorgan failure, with or without reversibility. Skin lesions may be present from disseminated candidemia, especially in neutropenic patients, most commonly resembling single or multiple erythematous or purpuric 0.5- to 1-cm papulonodules with pale centers on the trunk and proximal extremities.[34] Candida endocarditis is an uncommon but serious complication of candidemia, occurring in 1.5% of individuals hospitalized with candidemia.[35]

Evaluation

Conventional diagnostic methods, such as blood culture, remain the gold standard for diagnosing candidemia, despite limited sensitivity. For adults, 2 to 3 blood culture sets should be collected because the diagnostic yield of blood cultures increases with the volume of blood collected and the number of bottles incubated. If a blood culture is positive for Candida spp, clinicians should always consider this result an actual infection, not a contaminant. When candidemia or another bloodstream infection is suspected, clinicians should always obtain 2 sets of blood cultures, and 1 set should always be drawn through the indwelling vascular catheter, if present.[10] Once the organism is isolated, speciation and antifungal susceptibility testing should always be performed. Unfortunately, blood cultures are limited by low sensitivity, with positive results in only about 50% of cases in 1 study, and by a slow turnaround time. Blood cultures require 1 to 3 days for growth and an additional 1 to 2 days for organism identification, which is suboptimal when timely antifungal initiation is essential.

Because of the low sensitivity of blood cultures for Candida spp and long turnaround times, nonculture methods are increasingly being used to supplement culture. The β-D-glucan assay detects β-D-glucan, which is present in the cell wall of fungi, so the assay is not specific for Candida. The BDG assay has high sensitivity for detecting Candida infections but low specificity. In 1 systematic review and meta-analysis of studies published between 2009 and 2016 of adults admitted to the intensive care unit with candidemia or invasive candidiasis, results showed the pooled sensitivity and specificity were 81% and 61%, respectively.[36] In another systematic review and meta-analysis of neonates with invasive candidiasis, the pooled sensitivity and specificity were 89% and 60%, respectively.[37] Therefore, clinicians should not use the β-D-glucan assay as a standalone test given its low specificity, but the assay can be helpful as an adjunct test along with blood culture, and a negative β-D-glucan test result has a high negative predictive value and can be used to help guide the discontinuation of empiric antifungal therapy in the hospital setting.

The T2Candida® assay is a US Food and Drug Administration-approved molecular test used to diagnose bloodstream infections from the 5 most common causes of candidemia, namely Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, and Candida krusei. Unlike culture-based methods, results are available within 2 to 5 hours, enabling early detection of candidemia. In results from 1 study that led to approval by the US Food and Drug Administration, the sensitivity and specificity were 91% and 99%, respectively.[38] In results from a meta-analysis evaluating the diagnostic accuracy of the T2Candida® assay, the pooled sensitivity and specificity were 91% and 94%, respectively.[39] Therefore, the T2Candida® assay may be a useful adjunct to blood cultures in patient populations with a high prevalence of candidemia, although the assay detects only the 5 Candida species that most commonly cause candidemia.

PCR assays are another option for diagnosing candidemia, but a standardized PCR assay is not yet available, so performance varies with the assay type and patient population. In 1 study of 103 individuals with blood culture-proven candidemia and 46 controls, the sensitivity of real-time PCR compared with β-D-glucan testing was 33% and 57%, respectively, with PCR sensitivity particularly low in patients in the intensive care unit, among Candida albicans candidemia, and when testing was performed earlier than blood culture sampling. The specificity of PCR was 93% compared with 89% for β-D-glucan testing.[40]  In another study comparing a multiplex PCR assay with blood culture for the diagnosis of candidemia in patients in the intensive care unit, PCR had a sensitivity of 100% and a specificity of 94%.[41] Standardization of PCR assays for the diagnosis of candidemia remains necessary.

Treatment / Management

Infectious diseases or clinical microbiology consultation is strongly recommended for all individuals with candidemia. When such expertise is lacking, antifungal stewardship teams can play an invaluable role in ensuring strict adherence to evidence-based treatment guidelines. Furthermore, antifungal stewardship should be embraced as a critical component of broader antimicrobial stewardship and quality improvement initiatives. Both the Infectious Diseases Society of America (IDSA)[10] and the European Confederation for Medical Mycology (ECMM)[33] have guidelines with recommendations on the diagnosis and treatment of candidiasis. Treatment of candidemia consists of early initiation of appropriate antifungal therapy and source control (eg, removal of a central venous catheter). Blood cultures should be obtained daily or every other day once antifungal therapy is initiated to monitor treatment response. If blood cultures have positive results for several days after initiation of appropriate antifungal therapy and adequate source control, clinicians should evaluate for endocarditis, an abscess, or another focus of infection.

First-line initial treatment for candidemia should include an echinocandin, such as anidulafungin, caspofungin, micafungin, or the newest echinocandin, rezafungin. If an echinocandin is unavailable or there is concern for echinocandin resistance (eg, the individual was previously colonized or infected with an echinocandin-resistant Candida strain), liposomal amphotericin B or an azole such as fluconazole or voriconazole is also an option. In neutropenic individuals with candidemia, fluconazole is not a good option for initial therapy given the widespread use of azole prophylaxis and the increasing prevalence of fluconazole-resistant Candida strains.

Targeted and step-down therapy should be guided by the Candida drug-susceptibility testing and response to initial therapy. In clinically stable individuals who have received 5 or more days of an echinocandin or other appropriate initial treatment with negative blood cultures, a Candida isolate susceptible to fluconazole, and the ability to tolerate oral treatment, treatment can typically be transitioned to oral fluconazole. Although the optimal duration of candidemia treatment is unknown, both the IDSA and ECMM recommend a minimum of 2 weeks of antifungal therapy from the first day of persistently negative blood cultures, assuming that clinical symptoms attributed to candidemia have resolved, the individual is no longer neutropenic, and there is no evidence of a deep-seated infection or metastatic foci (eg, endocarditis).

Differential Diagnosis

The differential diagnosis of candidemia includes systemic infections with nonspecific symptoms such as fever, including bacterial bloodstream infections, other fungal infections (eg, Aspergillus or Cryptococcus infection), as well as conditions resulting in inflammatory states such as cholangitis or graft-versus-host disease. Differential diagnostic considerations include the following conditions, although this list is not comprehensive:

• Ascending cholangitis
• Bacterial meningitis
• Bacterial sepsis
• Bacterial endocarditis
• Chronic granulomatous disease
• Cholecystitis
• Graft-versus-host disease
• Granulomatous hepatitis
• Hepatic abscess
• Tuberculosis

Prognosis

Candidemia is a significant public health and medical concern because it is associated with poor patient outcomes, longer hospital stays, increased health care costs, and carries an attributable mortality rate varying from 35% to 70%.[1][1][8] Results from 1 study reported the 30-day overall mortality associated with candidemia to be 64%.[42]

Complications

Candidemia can lead to seeding and infectious foci in almost every organ, including the visceral organs, vasculature (including vessels and heart valves), bones and joints, eyes, and the central nervous system.[31] Infectious foci may result in end-organ damage, depending on the site, and frequently lead to prolonged hospitalization, increased healthcare costs, longer durations of antifungal treatment, and increased mortality. 

Consultations

Infectious diseases or clinical microbiology consultation is strongly recommended for all individuals with candidemia. When such expertise is lacking, antifungal stewardship teams can play an invaluable role in ensuring strict adherence to evidence-based treatment guidelines. Results from studies showed that consultation with infectious disease clinicians decreases patient mortality, is associated with earlier selection of empiric or targeted antifungal therapy, improves identification and control of the infectious source, and supports earlier removal of indwelling central lines compared with patients who do not receive such consultation.[43][44]

Pearls and Other Issues

Antifungal prophylaxis is indicated in a number of situations, including for individuals with acute myeloid leukemia, myelodysplastic syndromes, or those undergoing allogeneic hematopoietic stem cell transplant, particularly during periods of prolonged neutropenia. Some patients with high-risk cancer, including those receiving intensive chemotherapy or with severe immunosuppression, may also benefit, as well as some solid organ transplant recipients. Pediatric patients with conditions such as chronic granulomatous disease also often require antimold prophylaxis. Individuals with recent abdominal surgical procedures and recurrent gastrointestinal tract perforations or anastomotic leakages may benefit from antifungal prophylaxis as well.

Enhancing Healthcare Team Outcomes

Candidemia is a serious infection with a high mortality rate that must be treated promptly. An interdisciplinary team that includes an infectious disease clinician, an intensivist, a microbiologist, intensive care nurses, and a pharmacist is necessary to coordinate all aspects of the patient's care. Patients can become quite ill, with persistent candidemia and complications such as septic shock, and close collaboration among all health care professionals is essential.[45][46]

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Disclosure: Ashwaq Mahdaly declares no relevant financial relationships with ineligible companies.

Disclosure: Jeffrey Jenks declares no relevant financial relationships with ineligible companies.

Disclosure: Ellis Tobin declares no relevant financial relationships with ineligible companies.