INTRODUCTION — Candidemia refers to presence of Candida species in the blood. Candida in a blood culture should never be viewed as a contaminant and should prompt evaluation for metastatic infection [1].
Issues related to the epidemiology and pathogenesis of candidemia will be reviewed here. The clinical manifestations, diagnosis, and treatment of candidemia as well as an overview of Candida infections are presented separately. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Management of candidemia and invasive candidiasis in adults" and "Overview of Candida infections".)
EPIDEMIOLOGY — Candidiasis is an increasingly important nosocomial infection in both adults and children, especially those who are cared for in intensive care units (ICUs) [2-11]. (See "Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology".)
In most cases, the infecting strain is part of the host's endogenous flora; however, nosocomial acquisition of Candida species also occurs [8].
The organism has spread via contaminated solutions in some cases [8], whereas the hands of health care workers were the probable source in others.
Risk factors for candidemia — Patients at highest risk for development of candidemia include those receiving intensive care and those who are immunocompromised. In some areas of the United States, increasing rates of candidemia among people who inject drugs have been observed [12].
Intensive care — Patients in ICUs account for the greatest number of episodes of candidemia in most hospitals. Surgical units, especially those caring for trauma and burn patients, and neonatal units have the highest rates of Candida infections. Besides the risks associated with the extremes of age and trauma or burns, other factors include [3,9]:
●Central venous catheters
●Total parenteral nutrition
●Broad-spectrum antibiotics
●High APACHE scores
●Acute renal failure, particularly if requiring hemodialysis
●Prior surgery, particularly abdominal surgery
●Gastrointestinal tract perforations and anastomotic leaks
●Pancreatitis
In a prospective multicenter study of 300 ICU patients in France with proven invasive candidiasis, C. albicans was the most common species isolated (57 percent), followed by C. glabrata (17 percent), C. parapsilosis (8 percent), C. krusei (5 percent), and C. tropicalis (5 percent) [13]. In a subsequent study among ICU patients in Europe, North America, Latin America, and Asia, C. albicans was more common (70 percent) than non-albicans species; however, this varied by geographic region, with Latin America demonstrating a higher proportion of non-albicans isolates [14].
Risk factors for candidemia with non-albicans Candida species were assessed in a retrospective case-comparator study of patients with candidemia (non-albicans Candida compared with C. albicans) in the medical and surgical ICUs of two tertiary care hospitals in the United States from 1995 to 2005 [15]. Two significant risk factors for candidemia with non-albicans species were identified on multivariate analysis:
●Fluconazole exposure (odds ratio [OR] 11.6, 95% CI 2.3-58.9)
●Central venous catheter exposure (OR 2.0, 95% CI 1.1-3.5)
A subsequent prospective cohort study that included 179 episodes of ICU-acquired candidemia showed that prior gastrointestinal surgery and systemic antifungal exposure were independently significant variables that were associated with bloodstream infection with both non-albicans Candida species and potentially fluconazole-resistant Candida species [4].
In another prospective cohort study that included 154 cases of ICU-acquired candidemia in non-neutropenic patients, independent risk factors for C. glabrata infection included age >60 years, recent abdominal surgery, interval from ICU admission to first positive blood culture ≤7 days, recent cephalosporin use, solid tumor, and absence of diabetes mellitus [16].
A subsequent 2017 CDC surveillance study performed in 9 states reported that the estimated incidence of candidemia was 7 cases per 100,000 people [17]. Among 1122 Candida isolates submitted, C. albicans accounted for 38 percent, followed by C. glabrata (30 percent), C. parapsilosis (14 percent), and C. tropicalis (7 percent). Thus, non-albicans Candida isolates constituted 51 percent of isolates. Only 6 percent of all Candida isolates were resistant to fluconazole; the highest rates were in C. glabrata (7 percent) and C. parapsilosis (9 percent). This study also documented a low rate (2 percent) of resistance to echinocandin antifungals, most of which occurred in C. glabrata.
These findings may help determine initial empiric therapy for candidemia since patients with non-albicans Candida infection are more likely to have a fluconazole-resistant isolate than those with C. albicans infection. (See "Management of candidemia and invasive candidiasis in adults".)
Immunosuppression — Immunocompromised patients are at special risk for candidemia [9,18]. High-risk groups include:
●Those with hematologic malignancies
●Recipients of solid organ or hematopoietic stem cell transplants
●Those given chemotherapeutic agents, especially those associated with extensive gastrointestinal mucosal damage
Neutropenia is common in these settings, and most transplant recipients are also receiving glucocorticoids as well as several immunosuppressants. Other risk factors include broad-spectrum antibiotics and central venous catheters. However, because of the frequent use of azole or echinocandin prophylaxis in patients with chemotherapy-related neutropenia and after hematopoietic stem cell transplant, candidemia has become less common in these populations.
The proportion of Candida infections caused by non-albicans Candida species has been rising at many medical centers that care for patients with hematologic malignancies [18,19]. In a retrospective study of 635 patients with candidemia at a cancer center from 1993 to 2003, C. glabrata and C. krusei were the most common causes of candidemia, accounting for 31 and 24 percent of episodes in patients with hematologic malignancy. However, in solid organ transplant recipients, only 18 and 2 percent were caused by these species, respectively. On multivariate analysis, fluconazole prophylaxis was a risk factor for both C. glabrata and C. krusei candidemia, neutropenia was a risk factor for all candidemias, and central venous catheter–related infection was a risk factor for C. parapsilosis candidemia [18].
A large study from 13 European cancer centers that surveyed 145,030 admissions from 2005 to 2009 documented candidemia in 267 patients who had cancer [20]. An equal proportion of episodes were due to C. albicans and non-albicans Candida species, of which the most common were C. tropicalis, C. glabrata, and C. parapsilosis. The proportion of C. glabrata isolates was highest in patients with solid tumors, whereas C. tropicalis and C. krusei were the most common species isolated from patients who had hematologic malignancies or had received a hematopoietic stem cell transplants, respectively.
These findings have important implications for the empiric treatment of candidemia in patients with hematologic malignancy. (See "Management of candidemia and invasive candidiasis in adults".)
Injection drug use — In patients with candidemia who lack typical candidemia risk factors, especially in those who are 19 to 44 years of age and have community-associated candidemia, injection drug use is an important risk factor [12]. In 2017, the CDC conducted population-based surveillance of candidemia in nine states; an increase in the rate of candidemia associated with injection drug use was observed in some counties [12]. Candida endocarditis, a rare complication of candidemia, is strongly associated with intravenous drug use [21,22].
Host factors — Host-specific polymorphisms in toll-like receptors and cytokine pathways likely play a role in determining development of infection with Candida species [9,23,24].
COVID-19-associated candidemia — Given that patients at highest risk for candidemia include those receiving intensive care, it is not surprising that severe COVID-19 is a risk factor for developing candidemia. In a study of 148 ICU patients with COVID-19, 28 (19 percent) developed candidemia and the likelihood increased as the number of days in the ICU increased (50 percent by day 30 of their ICU stay) [25]. In a population-based candidemia surveillance study, 64 (25 percent) of 251 candidemic patients had COVID-19, and candidemia in these cases was largely attributable to receipt of mechanical ventilation and treatment with corticosteroids, immunomodulatory medications, or renal replacement therapy [26]. Antibiotic treatment prior to the diagnosis of candidemia was common, occurring in over 85 percent of cases [25,26]. All-cause mortality for COVID-19 patients with candidemia has ranged from 62 to 84 percent.
MICROBIOLOGY
Prevalence of Candida species — C. albicans has been the predominant bloodstream isolate; however, over the past decade, non-albicans Candida species have been recovered in as many as half of cases [13,27-30].
In a multicenter surveillance study conducted in the United States between 2004 and 2008, 54 percent of 2019 bloodstream isolates represented non-albicans Candida spp and 46 percent represented C. albicans [29]. C. glabrata was responsible for 26 percent of all cases of candidemia, followed by C. parapsilosis (16 percent), C. tropicalis (8 percent), and C. krusei (3 percent).
In one review of Candida species isolated from patients with invasive candidiasis between 2009 and 2017, there was no increase in non-albicans Candida isolates causing invasive disease; C. albicans remained the most common species, accounting for 48 percent of isolates [31]. C. glabrata remained the second-most common species (24 percent) followed by C. parapsilosis (11 percent) and C. tropicalis (7 percent). Other unusual species constituted only 6 percent of isolates.
The incidence of each species varies in different patient populations and geographic regions [29,32-36]. As an example, in Latin America, the most common species to cause bloodstream infection after C. albicans are C. parapsilosis and C. tropicalis, with C. glabrata being isolated much less frequently [32,34,35].
Knowing the prevalence of the non-albicans Candida species is important because susceptibility to antifungal agents varies among the species. As an example, all isolates of C. krusei are fluconazole resistant, and an increasing proportion of C. glabrata are both fluconazole and voriconazole resistant. Additionally, resistance to fluconazole has been found in a small proportion of isolates of C. albicans, C. parapsilosis, and C. tropicalis [37]. Echinocandin resistance among C. glabrata isolates has been reported with increasing frequency from some medical centers, but has not been universally observed [38-40]. (See "Management of candidemia and invasive candidiasis in adults".)
It is postulated that isolation of non-albicans Candida species is related to the selective pressure associated with fluconazole use [41], and some studies provide strong evidence for this association [41-43]. In addition to azole use, there are other factors, such as echinocandin use [43], geography [30,42], age [33], and perhaps other issues [44], that contribute to these trends.
C. auris emergence
●Epidemiology − In 2016, the United States Centers for Disease Control and Prevention (CDC) and Public Health England issued warnings about the emergence of a multidrug-resistant Candida species, C. auris [45,46]. This pathogen has caused invasive health care-associated infections, and it has been associated with high mortality rates [45]. This species was first described in 2009 in Japan [47], but, based upon retrospective testing of isolate collections, the earliest known infections occurred in 1996 in South Korea [48]. It has been detected in >30 countries and has been associated with outbreaks at health care facilities [49-56]. New cases continue to be detected.
Molecular typing suggests that the isolates are highly related within each country or region but distinct between continents [57-60]. In the United States, epidemiologic links have been found among most cases [61,62]. Whole-genome sequencing analysis suggests that there have been multiple introductions of C. auris into the United States from other continents (South Asia, South America), followed by local transmission.
In the United States, cases have been reported from multiple states, with most cases occurring in New York City, New Jersey, and Chicago, Illinois [54,63]. Information about reported cases can be found on the CDC's website.
●Risk factors – Risk factors for C. auris infection include underlying medical conditions and extensive exposure to health care facilities (particularly high-acuity skilled nursing facilities such as facilities providing mechanical ventilation) [61].
●Outbreaks – A number of C. auris outbreaks have been described.
•In September 2018, public health authorities in southern California initiated a proactive C. auris surveillance program by pursuing species identification for Candida isolates recovered from urine isolates in patients hospitalized in long-term acute care facilities [64]. The first case of C. auris was identified in February 2019; subsequently, point prevalence surveys at 17 facilities identified a total of 182 cases. Gaps in hand hygiene, transmission-based precautions, and environmental cleaning were identified and addressed; the outbreak was contained to two facilities by October 2019. These findings demonstrate the utility of enhanced laboratory surveillance as well as the importance of public health oversight to reduce the risk for nosocomial C. auris transmission.
•An outbreak of C. auris (including candidemia and central nervous system device-associated infection) in a neurologic ICU in the United Kingdom between 2015 and 2017 was associated with reusable skin-surface axillary temperature probes that had been cleaned with wipes containing quaternary ammonium compound (which has poor activity against Candida species) [65]. The incidence of new cases was reduced after removal of the temperature probes.
●Sites of involvement – C. auris has been cultured from the following sites: blood, urine, respiratory tract, bile, wounds, and central venous catheter tips [61].
●Diagnosis – C. auris requires specialized methods for identification; it could be misidentified as another yeast (most commonly C. haemulonii, but also C. famata, C. sake, C. catenulata, unspecified Candida species, Rhodotorula glutinis, and Saccharomyces cerevisiae) when using traditional biochemical methods [49,50]. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults".)
●Treatment – Antifungal susceptibility patterns and treatment recommendations are discussed separately. (See "Management of candidemia and invasive candidiasis in adults".)
●Infection control and prevention – Given concerns about resistance and transmission of C. auris in health care facilities, there are special screening recommendations and infection control precautions for patients who are colonized or infected with C. auris [66,67]. These can be found on the CDC's website.
PATHOGENESIS — There are three major routes by which Candida gain access to the bloodstream:
●Through the gastrointestinal tract mucosal barrier
●Via an intravascular catheter
●From a localized focus of infection, such as pyelonephritis
Gastrointestinal tract — Translocation through the gastrointestinal tract mucosa is probably the most common mechanism for Candida species to enter the bloodstream in both neutropenic patients and in intensive care unit patients. Candida species are part of the normal bowel microbiota; many of the factors noted above lead to overgrowth of yeasts and subsequent egress out of the bowel into the blood. Chemotherapeutic agents that disrupt the intestinal mucosa (mucositis) play a major role in allowing Candida to escape from the bowel in patients with hematologic malignancies [68]. (See "Neutropenic enterocolitis (typhlitis)".)
Intravascular catheters — Intravascular catheters, especially central venous catheters, continue to be an important source for Candida bloodstream infection [3,4,8]. Candida colonization of indwelling vascular devices, especially central catheters, can occur at either the insertion site or the hub and lead to subsequent candidemia. (See "Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology".)
Total parenteral nutrition (TPN) is an important risk factor for candidemia. Although the mechanism by which TPN increases the risk of candidemia is not well understood, one in vitro study suggested that the lipid emulsion present in TPN solutions may increase the biofilm formation on the silicone-elastomer catheters and supports growth of C. albicans.
Localized focus — Bloodstream invasion is relatively uncommon from a localized focus of infection but has been well described with ascending Candida urinary tract infection associated with either intrinsic obstruction (eg, from a fungus ball) or extrinsic compression preventing the flow of infected urine. (See "Candida infections of the bladder and kidneys".)
Colonization — Colonization with Candida species is almost always a necessary prerequisite for candidemia and invasive candidiasis. However, colonization alone does not predict which patients will develop fungemia. Other risk factors, as noted above, are needed in addition to colonization. Most patients with Candida colonization and known risk factors do not develop candidemia or invasive candidiasis. (See 'Risk factors for candidemia' above.)
SUMMARY
●Candida in a blood culture should never be viewed as a contaminant and should always prompt a search for the source of the fungemia. For many patients, candidemia is a manifestation of disseminated candidiasis, whereas for others it reflects colonization of an indwelling intravenous catheter and subsequent introduction into the bloodstream. (See 'Introduction' above.)
●Candidiasis is an increasingly important nosocomial infection in both adults and children, especially those who are cared for in intensive care units (ICUs). (See 'Epidemiology' above.)
●Although the infecting strain is most often part of the host's endogenous flora, nosocomial acquisition of Candida species has been described. (See 'Epidemiology' above.)
●Non-albicans species of Candida account for approximately half of all bloodstream and invasive candidiasis infections. Most prominent have been C. glabrata and C. parapsilosis, followed by C. tropicalis and C. krusei. All C. krusei are fluconazole resistant, and an increasing proportion of C. glabrata are both fluconazole and voriconazole resistant. In addition, echinocandin resistance among C. glabrata isolates is being reported with increasing frequency from certain medical centers. (See 'Prevalence of Candida species' above.)
●In 2016, the United States Centers for Disease Control and Prevention and Public Health England issued warnings about the emergence of a multidrug-resistant Candida species, C. auris. It has been detected in >30 countries and has been associated with outbreaks at health care facilities. New cases continue to be detected. (See 'C. auris emergence' above.)
●Patients in the ICU and those who are immunocompromised (eg, patients with hematologic malignancies, patients with coronavirus disease 2019 [COVID-19], solid organ and hematopoietic stem cell transplant recipients) are at greatest risk for the development of candidemia. Host-specific polymorphisms in toll-like receptors and cytokine pathways likely play a role in determining development of infection with Candida species. (See 'Risk factors for candidemia' above.)
●There are three major routes by which Candida gain access to the bloodstream: through the gastrointestinal tract mucosal barrier, via an intravascular catheter, and from a localized focus of infection, such as pyelonephritis. (See 'Pathogenesis' above.)
●Translocation via the lymphatics through the gastrointestinal tract mucosa is probably the most common mechanism for Candida species to enter the bloodstream in both immunocompromised patients (eg, those receiving chemotherapy who are neutropenic) and in ICU patients. Candida species are part of the normal bowel microbiota; many factors lead to overgrowth of yeasts and subsequent egress out of the bowel into the blood. Chemotherapeutic agents that disrupt the intestinal mucosa play a major role in allowing Candida to escape from the bowel in patients with hematologic malignancies. (See 'Gastrointestinal tract' above.)
●Intravascular catheters, especially central venous catheters, continue to be an important source for Candida bloodstream infection. Candida colonization of indwelling vascular devices, especially central catheters, can occur at either the insertion site or the hub and lead to subsequent candidemia. (See 'Intravascular catheters' above.)
●Colonization with Candida species is almost always a necessary prerequisite for candidemia and invasive candidiasis. However, colonization alone does not predict which patients will develop fungemia. Other risk factors are needed in addition to colonization. Even with risk factors and colonization with Candida species, most patients do not become candidemic. (See 'Colonization' above.)
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