Most frequently found
Invasive candidiasis is a severe infection caused by the yeast of the genus Candida. This highly lethal infection can affect any organs, but it is usually identified by the growth of the yeast in bloodstream samples. Although C. albicans was the most frequently found species, there has been a global trend to the non-albicans isolates. The appearance of C. auris, a newly identified species around the world, is a cause of concern because of resistance to antifungals. In this chapter, the epidemiology and risk factors for the acquisition of candidemia and other forms of invasive candidiasis are reviewed, while showing the current knowledge of worldwide epidemiology.
- Candida albicans
- intensive care units
Candidiasis is the common name for diseases produced by the yeast of the genus
2. Microbiology and environment
|Usually the most frequently found|
|Related to cancer|
|Usually resistant to azoles, seen more frequently in developed scenarios and older patients|
|Potentially resistant to amphotericin|
|Intrinsically resistant to azoles|
|Difficult to differentiate from |
|Responsible for a global outbreak|
They grow in agar as colonies with a smooth, creamy, white appearance. The formal identification can be made by use of biochemical physiological reactions, which can differentiate an important number of isolates. The metabolic reactions include carbohydrate fermentation, nitrate use, and urease production.
Susceptibility testing can be performed by different methods, including broth microdilution (recommended in the USA and Europe), but there are other different commercial methods available in hospitals. Two slightly different standards for susceptibility testing are currently available. One is suggested by the Clinical Laboratory Standards Institute (CLSI, in USA), while the other is proposed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), sponsored by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Basic differences between both methodologies include time and instrument to read the results. Different clinical breakpoints have been established for the most commonly found species, with the intention of differentiating the risk of clinical failure after treatment. The experience with fluconazole has allowed to develop better prediction models, in comparison with newer antifungals . In summary, an isolate of
As mentioned before,
4.1 Risk factors
4.1.1 Candida infection in the intensive care unit
Patients in the ICU have the highest rate of
126.96.36.199 Vascular devices
Patients in the ICU have higher rates of
188.8.131.52 Parenteral nutrition
Another commonly identified risk factor is the use of parenteral nutrition or the length of its use [15, 19]. This group of patients shares several risk factors, but parenteral nutrition has been identified in multivariate analysis . Usually, they have an abdominal procedure (see below) and they require parenteral nutrition for several days. Lack of appropriate measures to handle the nutrition, colonization of the catheter or the ports used to infuse it, and probably the availability of optimal growing conditions are conditions related to its use. But clearly, the use of parenteral nutrition leads to the development of mucosal atrophy and a loss of mucosal epithelial barrier function , which might affect the relationship between microorganisms in the gut and the possibility of gaining access to blood vessels. Total parenteral nutrition has also a profound effect in the gastrointestinal microbiome .
184.108.40.206 Surgical procedures
Several studies have shown the relationship between candidemia and a previous surgical procedure [19, 23], specially an abdominal surgery. There are several explanations to this observation, but gut manipulation, and the effect of resected sections over the gut microbiology, microbiota abundance, and epithelial function might contribute to the possibility of candidemia. Studies have shown that patients with high anastomotic leak, as well as those with recurrent gastrointestinal perforation, or acute necrotizing pancreatitis, have a higher risk of candidemia .
220.127.116.11 Antibiotic use
Almost all studies of candidemia have shown an extremely high use of antibiotics previous to the identification of bloodstream or tissue infection. The proportion of patients with antibiotic use is over 80% . The number and spectrum of the antibiotics used might affect the risk of candidemia. Antimicrobials also have an effect over gut microbiota, and some studies have shown some impact from antibiotics with anti-anaerobic effect, and those with higher gastrointestinal concentration . They contribute to the observed increased colonization over time observed in patients in the ICU. With more antibiotic effect, there is a net decrease in the number of species in the gastrointestinal tract, an increase in the number of patients colonized, and the proportion of them being heavily colonized .
18.104.22.168 Other risk factors
Studies have identified several risk factors that alone, or in combination, might increase the probability of having candidemia. The presence of renal failure, the use of antihistaminic blockers, the severity of illness, and the length of stay in the ICU contribute to colonization and development of candidemia [24, 27]. All these factors contribute to the acquisition of
22.214.171.124 Scores based on risk factors
The identification of risk factors lead to the use of some scores based in the presence of such factors to identify patients with higher risk of
A second score to identify risk factors in patients was developed in Spain by León and his collaborators . They identified colonization (with a different definition from that used by Pittet et al.), surgery at ICU admission, and use of total parenteral nutrition as risk factors independently associated with candidemia. They also identified sepsis as independently related, but this is clearly more a clinical syndrome than a risk factor. A third score was developed by a multicenter collaboration group, in which they again identified the same risk factors : antibiotic use, having an intravascular catheter, in conjunction with at least two additional risk factors such as any surgery, immunosuppressive use, pancreatitis, total parenteral nutrition, dialysis, or steroid use.
Common to these scores has been the presence of the aforementioned risk factors. The problem, however, is that such scores identify a huge number of patients at risk with a final intermediate risk of developing candidemia, in a range from 7 to 30% [29, 30]. The great advantage of the diagnostic scores relies in their high negative predictive value. Patients with a negative score have a low probability of candidemia, below a 1% probability.
4.1.2 Hematological malignancy, solid organ transplantation, and other immunosuppressive states
These disorders share a common factor: immunosuppression. However, different types of immunocompromise entail different risks for the patients. The incidence of candidemia among patients with cancer is higher in comparison with other patients in the hospital. In a multicenter study in Greece, patients with hematological disease had an incidence of candidemia of 1.4 cases per 1000 admissions, while other patients hospitalized had an incidence of 0.83 cases per 1000 admissions . A multicenter European study found an incidence of 1.2% cases of candidemia among patients with bone marrow transplantation (BMT) and leukemia . An Italian multicenter study from a surveillance network showed a diminishing trend for candidemia among patients with cancer, especially among those with acute myeloid leukemia . Whether this trend can be inferred to other European countries or not is not known, and the most likely explanation for this decrease in the number of cases could be related to the use of prophylaxis among those patients with acute leukemia with posaconazole. In general, non-albicans
Neutropenia, a count of leukocytes in peripheral blood below 500 cells per μl, is the common risk factor among patients with hematological disorders (i.e., leukemia, lymphoma, multiple myeloma among others) as well as those with bone marrow transplantation (BMT). Neutropenia might be a consequence of the activity of the hematological disease, an effect of chemotherapeutic strategies or side effect of multiple medications including antimicrobials. It also is a marker of the intensity of chemotherapy. Patients with chemotherapy-induced neutropenia accumulate various risk factors: they usually receive wide spectrum antibiotics for several days, they have serious gastrointestinal epithelial tissue dysfunction, usually with diarrhea and signs of mucosal damage, and the use of vascular catheters for the infusion of chemotherapeutic drugs and antibiotics . Several studies have shown that isolates of
In patients with prolonged neutropenia, a condition called hepatosplenic candidiasis might be seen. In it, seeding of yeasts occurs during the neutropenic phase which might be not clinically evident until neutropenia recovery. In these patients, fever persists and lesions can be seen in the liver, usually known as bull-eye lesions  (Figure 1).
126.96.36.199 Concurrent conditions in patients with cancer
In patients with cancer and candidemia, several factors were identified in comparison with those with cancer and bacterial infections . Total parenteral nutrition over 5 days, urinary catheter for more than 2 days, distant metastasis of cancer, and gastrointestinal cancer were independent risk factors. Patients with solid tumors might accumulate factors as patients in critical care, since they have abdominal surgery (gastrointestinal neoplasm), require vascular catheters for extended periods of time (for chemotherapy or antibiotics), total parenteral nutrition and received antibiotics frequently . A study to identify factors predicting catheter-related infections with
Among patients with leukemia and BMT, the risk factors for occurrence of candidemia included bone marrow or cord blood stem cell source, T-cell depletion, use of total body irradiation, and acute graft versus host disease . These data were derived from a huge multicenter registry of patients with cancer and transplantation, which allowed to identify more precisely the risk factors.
Newborns have no gastrointestinal flora at birth and have to be colonized by enterobacteria and other microorganisms, which is made via maternal breast feeding. Any alteration in the normal process can lead to colonization by pathogenic microorganisms, including yeasts . Neonates in the intensive care unit usually have limited breastfeeding, indwelling vascular catheters, total parenteral nutrition, and antibiotics . Such combination of risk factors put. this group of patients at a higer risk of infection, reaching over 10% of patients in units with extreme prematures and low weight at birth (the group that requires more invasive interventions) . Some studies have illustrated this relationship with proportion of candidemia between 3 and 10% among those with a weight of less than 1000 g while showing an incidence of less than 1% for those weighting over 2500 g . In this scenario, disseminated candidemia can be found and near 10% of those with invasive disease can compromise the central nervous system. Another important risk factor includes the time that the patient has been in the unit ; clearly, patients with low weight, lower gestational age, and more comorbidity tend to spend more time in the neonatal ICU and to accumulate other risk factors (surgery, indwelling catheter, antibiotics, etc.) . There are some high-risk units, in which the incidence of candidemia traditionally has been high, usually over 10% of the admitted cases. In this scenario, prophylaxis has been suggested for the prevention of infection .
As shown, colonization is the preliminary step to infection. Besides, a number of interventions are common to immunosuppressed and critically ill patients including indwelling catheters (urinary and vascular), severity of illness, total parenteral nutrition, etc. These conditions predispose the patients to cross contamination. An outbreak among newborns was demonstrated to be due to poor practices of catheter ports disinfection .
A study in China in a cancer institute showed that 21 out of 36 episodes of candidemia were caused by two endemic genotypes . In this study, gastrointestinal cancer and insertion of a nasogastric tube were related to infection. As mentioned before, cancer patients with solid and hematological tumors share several of the risk factors of colonization and infection.
4.2 Global epidemiology
Since 2013, the Leading International Fungal Education (LIFE) portal has facilitated an important effort to know the epidemiology and burden of fungal infections around the world and allowed a better understanding of their epidemiology in different countries . The real incidence of candidemia is difficult to calculate due to differences in the approach. While studies based on hospitals might overestimate the importance of some groups of high-risk patients, they are difficult to compare. Data from population studies might reflect better the real situation, but this kind of information is scarce. Studies have shown ample differences in the incidence in some regions and at specific times .
4.2.1 Changing trend for non-albicans
Two studies deserve a detailed description. The first one is a multicenter study from the Southeast Asia region, including 25 hospitals from 6 countries: China, Hong Kong, India, Singapore, Taiwan, and Thailand . They found differences between the countries that include the frequency of
4.2.2 Epidemiology in Europe and North America
There are data from some population surveillance surveys in Europe and United States. In general, the incidence might be lower than in some other areas of the world. Table 3 shows the incidence from data from North America and European countries [61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77]. In Europe, the highest incidence has been observed in Hungary, while in North America the highest incidence has been seen in some cities in United States.
|Country/region||Publication Year||Incidence (per 100.000 inhabitants)||References|
4.2.3 Epidemiology in Central and South America and the Caribbean
This region has profound differences in healthcare systems, access to care, and medical technology development. With a transition toward a higher income, a growing number of institutions with capacity to attend cancer patients, and more complex medical needs, the number of candidemia cases seems to be higher than in developed countries.
Ample information exists about the problem in Brazil, where a number of studies have been carried out in high-complexity hospitals in the main cities of the country [78, 79]. These studies show a higher frequency of invasive candidiasis in comparison with developed countries, an increased isolation of
4.2.4 Epidemiology in Africa and Asia
A multicenter in Asia gathered information from various countries, including nine hospitals from China . The incidence rate among patients hospitalized was 0.38 per 1000 admissions, which is lower than that observed in the Latin-American region with 1.08 cases per 1000 admissions . The estimated incidence of candidemia in countries in Asia is shown in Table 5 [90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100]. In Asia, the highest incidence has been observed in Pakistan, followed by Qatar and Israel. In China, geographic variations in the causative species and susceptibilities were noted, with increasing isolates resistant to fluconazole . The numbers for the African countries are lacking and for some countries like Algeria, Burkina Faso, Cameroon, Egypt, Malawi, Mozambique, and Tanzania, the estimated incidence is 5.8 cases per 100,000 inhabitants, a standard calculation based on previously reported incidence in other countries [102, 103, 104, 105, 106, 107, 108].
4.2.5 Azole resistance epidemiology
Among patients with cancer, not only are non-albicans
Candida aurisglobal outbreak
Up to 2009, there was no report on
Patients with candidemia and cancer are considered to have higher mortality, but this issue has not been clearly assessed. Older studies showed an attributable mortality around 40%. Although mortality among patients with candidemia or invasive candidiasis is reported usually around 40–50%, they occur in patients with important comorbidity. A recent multicenter analysis showed a crude mortality for patients with candidemia of 53%, while those without candidemia had a mortality of 26% . After adjusting in a propensity score analysis, the crude mortality was 51% for the candidemic patients and 37% for the others and the difference was not statistically significant. The study shows that an increase in mortality might exist for those patients with candidemia, but it is clear that patients with candidemia also have severe comorbidity and some of them can die with candidemia instead of because of it.
Risk factors for mortality among patients with candidemia include ascites, presence of septic shock, ICU admission, concomitant bacterial infection and catheter-related infections . Studies with diverse population have shown that elderly patients have higher mortality . In these patients, a combination of comorbidity, poor clinical situation, and more pathogenic species might contribute to their mortality . A pooled analysis from patients included in randomized clinical trials comparing micafungin and amphotericin B showed differences among geographic regions, severity of disease (measured with Apache score for patients critically ill), and catheter removal . In those with abdominal candidiasis, the lack of control of the source of infection has been related to increased risk of death . Among patients with cancer, risk factor for mortality includes infection by a
The impact of the antifungal treatment in the mortality of patients with candidemia is not entirely clear. There are several constrains to identify the benefits of the antifungal treatment: An important proportion of patients did not receive antifungal treatment despite the identification of a bloodstream infection; of those that receive the treatment, some of them can receive it as empirical treatment, based on the risk factors, clinical condition, while others have an antifungal started upon detection of candidemia. Besides, some of them are infected with a resistant isolate and some do poorly, and an additional antifungal must be started. Although meta-analysis with patient-level data has showed the benefit of equinocandin use (in contrast to azole treatment) , neither the cohort data , nor the randomized trials have confirmed this finding . There is an additional complication in understanding this relationship; the laboratory breakpoints for identification of susceptible versus resistant isolates have changed over the time, especially for azoles . Among those patients with septic shock, the delay in the administration of the antifungal treatment has been associated with increased mortality.
Candidemia is the most frequently found form of invasive candidiasis. The
Conflict of interest
There is no conflict of interest to declare.