Candida species (spp.) are important nosocomial pathogens in critically ill patients and are associated with substantial mortality and prolonged hospitalization in the intensive care unit (ICU).1,2Candida albicans accounts for the majority of cases with candidemia, but an increasing number of infections due to non-albicans spp. have been reported.3,4 According to the Surveillance and Control of Pathogens of Epidemiologic importance program, the most commonly isolated Candida non-albicans was C. glabrata (causing 3%–35% of all candidemias), followed by C. tropicalis, C. parapsilosis, C. krusei, and other Candida spp.5 The SENTRY Antimicrobial Resistance Surveillance program reported that the rank order of the various Candida non-albicans spp. differed among patients in various geographic locations, but the reason for such differences remains unclear.6
Several retrospective studies have identified a number of predisposing factors for development of candidemia in patients in the ICU, such as the use of multiple antibiotics, total parenteral nutrition administration, central venous catheter (CVC) placement, major surgeries, renal failure, glucocorticosteroid treatment, mechanical ventilation, persistent neutropenia, candiduria, or multiple sites of colonization, burns, and hemodialysis.7 Other studies also reported epidemiological data and risk factors regarding the development of nosocomial infection with certain Candida non-albicans spp.8–10
However, there is a relative scarcity of data regarding differences between Candida albicans and non-albicans bloodstream infections (BSI) in critically ill patients. We conducted this prospective study to identify potential risk factors associated with BSI due to Candida non-albicans spp. among critically ill patients.
Study Design and Patient Selection
The study was conducted prospectively from January 2001 to December 2005 in the 14-bed medical-surgical adult ICU of Sotiria Hospital in Athens, Greece. The unit has about 200 admissions yearly. Sotiria Hospital is a tertiary hospital in Athens specializing mainly in respiratory diseases.
All patients with Candida BSI were evaluated for possible inclusion in the study. In cases where a patient had more than one episode of candidemia, the first episode was used in the risk factor analysis. The cases were classified according to the responsible Candida spp. in the C. albicans and non-albicans candidemia groups. The IRB of the hospital approved the conduct of the study. No informed consent was obtained from the individual patients whose data were analyzed in this observational, noninterventional study. All decisions regarding diagnostic testing and treatment were made by the attending physicians and were irrelevant to the study collection data and analysis.
Patients were eligible for inclusion in the study if they had Candida ICU-acquired BSI according to the Centers for Disease Control and Prevention-National Nosocomial Infection Surveillance criteria, and if they had a length of stay (LOS) >48 h after ICU admission. Since this was an observational study, all decisions regarding patient management, including the need to obtain blood cultures when fever was present or sepsis was clinically suspected, were left to the discretion of the attending physicians. Immunosuppressed patients [including those with neutropenia (neutrophil count <1000/mm3) and/or those who had received chemotherapy in the last 30 days] and patients with a diagnosed candidemia before ICU admission were not studied. Patients were excluded from the analysis if they had a single positive blood culture for Candida spp. but were without signs of infection, if they were treated with an antifungal drug before ICU admission, or if they were candidemic before their admission to the ICU.
Definitions of Infections
Candidemia was defined as at least one positive blood culture for Candida spp. in patients hospitalized for more than 48 h with signs or symptoms of infection. Candiduria (as there is no actual definition) was defined as the presence of more than 100,000 cfu/mL of the same Candida spp. in two distinct urine samples obtained within 1 wk. Candidemia was considered catheter-related in patients with a catheter-positive culture for the same yeast species isolated in blood, as well as in patients with positive blood cultures and intravascular catheters in place without other confirmed sites of infection.
Patients with candidemia were followed-up clinically and microbiologically until their discharge from the ICU or until the time of death. Candida spp. were isolated from blood using the BACTEC 860 system (Becton Dickinson, Sparks, MD) and were identified using the API-32C system (BioMerieux Vitek, St. Louis, MO). No identification of Candida strains isolated from urine was made.
Demographic, clinical, laboratory, and microbiological data were collected upon the confirmation of candidemia. Study population characteristics and data extracted included age and sex of the patients, reason for ICU admission (medical or surgical), LOS in ICU, APACHE (Acute Physiology and Chronic Health Evaluation) II score at admission, duration of mechanical ventilation, predisposing risk factors for candidemia such as diabetes mellitus (defined as blood glucose >180 mg/dl), broad spectrum antibiotic treatment (for >3 days) during the ICU stay, candiduria, systematic administration of glucocorticosteroids for any reason in the last 30 days before ICU admission (regardless of dose), total parenteral nutrition administration, CVC placement (for >2 days), acute or chronic renal failure at the onset of candidemia, and antifungal administration (as prophylaxis before the onset of candidemia), the day of candidemia occurrence, and outcome (i.e., dead or alive at ICU discharge). Antifungal prophylaxis administration with fluconazole (400 mg/daily) was added when patients met the criteria of intense colonization (persistent candiduria after urinary catheter removal or more than three sites colonized with Candida). At the time of the study, guidelines suggesting that antifungal prophylaxis with fluconazole in high-risk patients may include a daily dose of 800 mg were not yet available.
The χ2 test or Fisher’s exact test was used to evaluate categorical variables and the t-test to evaluate continuous variables. Multivariable, backwards stepwise, logistic regression analyses were performed to identify independent variables associated with candidemia due to Candida non-albicans as well as mortality. Potential risk factors were included in these models if they were associated with the dependent variables in the univariable analyses at a statistical level P < 0.1. A P < 0.05 was considered statistically significant in the multivariable models to show association between various potential risk factors and the dependent variables.
During the study period, 60 patients with candidemia were identified among 1037 patients admitted to the ICU (5.4%). Four patients were excluded from the study according to the specified inclusion/exclusion criteria because they had a single positive blood culture for Candida spp. without signs of infection, thus leaving 56 cases of candidemia for analysis. The incidence of candidemia in ICU patients during the study period was 3.8 per 1000 patient days/year. C. albicans and non-albicans spp. were responsible for 36/56 (64.3%) and 20/56 (35.7%) candidemia cases, respectively. In all patients a single Candida blood pathogen was identified. The distribution of C. non-albicans spp. was 8/56 (14.3%) C. glabrata, 6/56 (10.7%) C. tropicalis, 3/56 (5.4%) C. parapsilosis, 1/56 (1.8%) C. lusitaniae, 1/56 (1.8%) C. krusei, and 1/56 (1.8%) C. dubliniensis. As shown in Table 1, during the study period (2001–2005) an upward trend was observed in the number of cases per year, with the overall number doubling between 2001 (n = 7) and 2005 (n = 14). The most obvious spp. contributing to this increase was C. albicans. On the other hand, non-albicans spp. demonstrated a stable temporal distribution, although no safe conclusions can be drawn with regard to the contribution of non-albicans spp., as numbers are low.
The results of the univariable and multivariable analysis (respectively) regarding the comparison of the distribution of different variables between critically ill patients with C. albicans and C. non-albicans BSI indicated that variables independently associated with candidemia due to C. non-albicans spp. (in the multivariable logistic regression analysis) were administration of glucocorticosteroids, CVC placement, and preexisting candiduria (Odds ratio [OR]: 45.1, 95% confidence interval [CI]: 3.0–669.9; OR: 26.2, 95% CI: 2.1–334.8; and OR: 16.5, 95% CI: 1.6–173.9, respectively) (Tables 2 and 3).
Antifungal prophylaxis was not statistically significantly associated with the albicans versus the non-albicans Candida spp. However, it should be mentioned that in 8 of 20 patients who received antifungal prophylaxis for C. non-albicans BSI, C. glabrata was the responsible pathogen in 3/8 (37.5%), C. parapsilosis in 3/8 (37.5%), C. tropicalis in 1/8 (12.5%) and C. krusei in 1/8 (12.5%). Sixteen of 36 patients (44.4%) with C. albicans BSI had received antifungal prophylaxis with fluconazole (400 mg/daily), whereas 8/20 (40%) of patients with C. non-albicans BSI had received fluconazole prophylactically.
Antifungal treatment was administered as follows: 4/16 (25%) and 12/16 (75%) patients with C. albicans BSI who received fluconazole as prophylaxis were treated with caspofungin and amphotericin B, respectively; 8/20 (40%) and 12/20 (60%) patients with C. albicans BSI who did not receive fluconazole as prophylaxis were treated with caspofungin and amphotericin B, respectively; and all (20/20, 100%) patients with C. non-albicans BSI received amphotericin B as antifungal treatment, regardless of whether they received fluconazole as prophylaxis. Twenty-nine of 36 patients (80.6%) with C. albicans BSI responded to the administered antifungal treatment. On the other hand, 9/20 (45%) patients with C. non-albicans BSI responded to the administered antifungal treatment. The difference in the response rate between patients with C. albicans BSI and patients with C. non-albicans BSI was statistically significant (29/36 [80.6%] vs 9/20 [45%], P = 0.006).
Among the studied critically ill patients with candidemia, mortality was more frequent in those with non-albicans spp. than C. albicans BSI (18/20 [90%] vs 19/36 [52.8%], P = 0.005). No mixed infections were observed. Of the 20 patients with C. non-albicans BSI, the two patients who survived were infected with C. tropicalis (one patient) and C. parapsilosis (one patient). However, we did not attempt to evaluate a possible association between different Candida spp. and mortality, since it has been considered rather difficult to attribute a death of a patient with candidemia to a specific cause. Preexisting candiduria (3/19 [15.8%] vs 18/37 [48.6%], P = 0.02) and candidemia due to C. non-albicans spp. (18/20 [90%] vs 19/36 [52.8%], P = 0.005) were associated with mortality in the univariable analysis (Table 4). Multivariable logistic regression analysis, however, revealed that only candidemia due to C. non-albicans spp. was independently associated with death (OR: 6.7, 95% CI: 1.2–37.7, P = 0.03).
The main findings of this study were the statistically significant difference in risk factors and outcome between critically ill patients with candidemia due to Candida albicans and non-albicans spp. Steroid administration, CVC placement, and preexisting candiduria were the independent risk factors for candidemia due to C. non-albicans spp. On the other hand, C. non-albicans candidemia was associated with increased mortality compared with C. albicans BSI.
There are several specific risk factors identified for particular C. non-albicans spp. fungeamia (azoles prophylaxis, foreign body insertion, hyperlimentation in neonates, neutropenia, bone marrow transplantation, etc.) in noncritically ill patients, and mortality is similar to that of C. albicans, varying from 15% to 35%.11 However, there are very few data regarding the differences in risk factors and outcome between ICU-acquired Candida albicans and non-albicans BSIs.
The fact that in our study CVC placement was more likely in patients with non-albicans infection could reflect an increased LOS before ICU admission and, in turn, greater exposure to azole administration (a common practice in medical wards, especially if candiduria is present). However, in our study patients, despite the prior hospitalization in clinical wards, CVC placement (new catheter or removal and exchange of an existing catheter) was performed immediately after ICU admission to avoid time-dependent catheter-related infection. The exposure to azole prophylaxis was not statistically different in the groups compared (44.4% vs 40%, P = 0.75). Candiduria was more frequent in the Candida non-albicans group, although a Foley catheter was in place in all the patients and exposure to broad spectrum antibiotic administration (probably the major risk factor for candiduria development) was similar in both groups. Steroid administration was more frequent in the Candida non-albicans group (22.2% vs 60%, P = 0.005), although it is not considered a particular risk factor for C. non-albicans candidemia development.11
Our results are in accordance with the conclusions of previously published studies in mixed hospital populations.12–15 Overall, Candida albicans accounted for the majority of candidemias (64.2%), followed by C. glabrata (14.4%), C. tropicalis (10.7%), and C. parapsilosis (5.4%). The epidemiology of the isolated pathogens may well be influenced by the inclusion and exclusion criteria of our study, for example, patients with immunosuppression were excluded from our analysis. In contrast to several reports involving patients with cancer or large populations of patients from multinational studies, we did not find a very high incidence of non-albicans spp. or an increasing prevalence during the study period.16–21 Moreover, although a significant increase in non-albicans spp. of Candida has been reported, especially regarding C. parapsilosis, our results from the limited available data suggest that most of the non-albicans spp. reported at Sotiria Hospital in Athens, Greece, had an almost unchanged comparative incidence (statistically non significant) during the 5-yr study period.22
Studies from Europe or America report a constant increase in C. non-albicans infections, especially among adult patients with cancer, but the underlying mechanism causing the marked increase in infections due to strains of these species remains uncertain.23–26 The increased use of invasive medical procedures as well as the widespread use of azoles has been implicated in the emergence of C. non-albicans spp. Certain Candida spp., such as C. glabrata, have a tendency toward decreased susceptibility to fluconazole, and others, such as C. krusei, are resistant to fluconazole.6,27 Therefore, the availability and increased use of fluconazole may be a factor in the emergence of C. glabrata infections reported from different hospitals worldwide.28 Other species, such as C. parapsilosis, show a propensity to colonize and infect implantable or semi-implantable synthetic materials, including indwelling CVCs.29–31 A near-universal use of indwelling intravascular catheters in patients undergoing treatment for various diseases, especially in patients admitted to the ICU, may have played a central role in promoting candidemias. On the other hand, the above-mentioned increase in non-albicans spp. may, at least in part, reflect changes in the detection and isolation techniques applied during the last years.
Mortality was more frequent in patients with non-albicans spp. than with C. albicans BSI in our study (90% vs 52.8%, P = 0.005). In part, this could be associated with the statistically significant difference in the response rate to the administered treatment between patients with C. albicans BSI and patients with C. non-albicans BSI (80.6% vs 45%, P = 0.006). Non-albicans BSI can therefore comprise an independent predictor of mortality in ICU patients with candidemia. In previous publications, mortality in patients with candidemia has been reported to be up to 80%.32 Other studies in candidemic patients have also reported a considerable attributable mortality in patients with candidemia.33,34Candida infection is not solely related to the pathogenicity of the Candida spp., but also to a failure of host-defense mechanisms and to complications associated with the patient’s underlying disease.35 The more severely ill patients are at higher risk for Candida infection and have a worse prognosis. This is particularly evident in ICU patients who require indwelling catheters and broad-spectrum antibiotic therapy, which place them at risk for Candida colonization and subsequent infection.36–38 However, the excess mortality observed in the non-albicans group could be attributed to inappropriate treatment or a delayed therapy caused by a slower growth of non-albicans spp.. Moreover, patients with non-albicans infections may be more critically ill than those with C. albicans, as reflected by a higher rate of candiduria, which could also be considered as a marker of a higher Candida spp colonization density and in turn play a role in the severity of the fungal disease.
Many studies have reported the role of early treatment or “prophylactic” intervention with antifungal drugs in reducing the risk for subsequent candidemias in various populations.39–42 It seems that the growing use of these drugs may be associated with unintended clinical consequences. As with the widespread use of antibiotics, the selective pressure exerted by the frequent use of antifungals may encourage the proliferation of treatment-resistant Candida spp., posing a new challenge in the effective management of nosocomial candidemia. The epidemiology of Candida spp. may also be influenced, as the more susceptible spp. such as C. albicans will be more easily eradicated, promoting the proliferation of less susceptible spp. such as C. glabrata.43
The establishment of colonization of Candida spp. on epithelial and plastic surfaces before invasion is dependent on a variety of adhesion factors. Candida adhesins are mannoproteins associated with the surface fibrillar layer of the cell. These adhesions bind to the epithelial cell surfaces via glucoside receptors, which may be blood group antigens or glycosphingolipids. Hydrophobicity may play a role in this process, and seems to be an important factor in the adhesion of the organism to plastic surfaces (host-defense mechanisms as a cell-mediated immunity appear to play an important role in the Candida invasion). The presence and function of neutrophils is an important factor. A number of factors affect neutrophil function. Administration of glucoglucocorticosteroids reduces chemotaxis, phagocytosis, and phagosomal function. Major surgeries, extensive burns or the use of certain broad-spectrum antibiotics are also incriminating factors.7
Our study is not without limitations. The small number of patients (56) over a long period of time (5 yr) in only one center (Sotiria Hospital) is an important limitation that could compromise the statistical power of the study. The relatively small number of patients with each of the studied spp. does not allow meaningful analysis of possible associations between the outcomes (response rate, mortality) within individual spp. However, Sotiria Hospital is a representative general public hospital of Greece. Second, we did not perform in vitro susceptibility studies of the Candida isolates. Third, we did not examine the effect of specific antifungal drugs on the possibility of development of candidemia due to C. albicans and non-albicans spp.. Fourth, we relied on the discretion of the attending physicians to order blood cultures when clinically indicated, i.e., we did not include routine cultures at specified times during the study design. Fifth, the Candida strains isolated from the urine were not identified to the species level to perform an analysis of a possible association between urine and blood isolates. Sixth, no data for the various types and doses of glucocorticosteroids administered were collected to allow an in-depth analysis of the association of this risk factor with non-albicans spp. candidemia. Finally, and of greatest importance, we did not analyze the effect of the various administered therapeutic regimens on the outcome of candidemia.
In conclusion, among critically ill patients with candidemia, administration of glucocorticosteroids, CVC placement, and preexisting candiduria were found to be independent risk factors for BSI due to non-albicans spp. Also, in the ICU population studied, candidemia due to non-albicans spp. was associated with higher mortality compared with candidemia due to C. albicans, although this finding should be interpreted with caution because we did not analyze the effect of the various antifungal therapeutic regimens administered to our patients.
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