Risk factors for fatal candidemia caused by Candida albicans and non-albicans Candida species

Background Invasive fungal infections, such as candidemia, caused by Candida species have been increasing. Candidemia is not only associated with a high mortality (30% to 40%) but also extends the length of hospital stay and increases the costs of medical care. Sepsis caused by Candida species is clinically indistinguishable from bacterial infections. Although, the clinical presentations of the patients with candidemia caused by Candida albicans and non-albicans Candida species (NAC) are indistinguishable, the susceptibilities to antifungal agents of these species are different. In this study, we attempted to identify the risk factors for candidemia caused by C. albicans and NAC in the hope that this may guide initial empiric therapy. Methods A retrospective chart review was conducted during 1996 to 1999 at the Veterans General Hospital-Taipei. Results There were 130 fatal cases of candidemia, including 68 patients with C. albicans and 62 with NAC. Candidemia was the most likely cause of death in 55 of the 130 patients (42.3 %). There was no significant difference in the distribution of Candida species between those died of candidemia and those died of underlying conditions. Patients who had one of the following conditions were more likely to have C. albicans, age ≧ 65 years, immunosuppression accounted to prior use of steroids, leukocytosis, in the intensive care unit (ICU), and intravascular and urinary catheters. Patients who had undergone cancer chemotherapy often appeared less critically ill and were more likely to have NAC. Conclusion Clinical and epidemiological differences in the risk factors between candidemia caused by C. albicans and NAC may provide helpful clues to initiate empiric therapy for patients infected with C. albicans versus NAC.


Background
Invasive fungal infections caused by Candida species have increased significantly. They now rank fourth as the most common cause of nosocomial bloodstream infections in the United Stated [1] and the most common one at one major hospital in Taiwan [2]. Candidemia is not only associated with a mortality of about 30% to 40% but also extends the duration of hospital stay [3,4] and increases the cost for medical care [5]. In recent years, Candida species associated with candidemia have shifted from Candida albicans to non-albicans Candida species (NAC) [6]. Approximately half of the reported cases of candidemia are now caused by NAC [7][8][9][10].
Patients with candidemia usually present an acute septic syndrome that is indistinguishable from bacteremia, but they may also exhibit a more indolent course manifested by fever of unknown origin. Major risk factors for candidemia include intravascular catheters, parenteral hyperalimentation, and broad-spectrum antibiotics. Empirical antifungal agents may be administrated to patients manifested with fever of unknown origin and have above mentioned risk factors, particularly those who have been treated with broad-spectrum antibiotics. The clinical presentation of the patients with sepsis caused by C. albicans and NAC are indistinguishable. However, NAC are often less susceptible to fluconazole than C. albicans is [7,11,12] and may require greater dosage to cure clinically [13,14].
We have conducted a retrospective chart review of patients whose death was associated with candidemia. The goal was to assist decisions to select the most appropriate empirical therapy for patients suspected to have candidemia. The objective was to determine whether specific risk factors could be identified to help selecting those patients who are more likely infected with C. albicans versus NAC.

Methods
This study was conducted at the Veterans General Hospital-Taipei. This is a 2800-bed teaching hospital with about 69,000 admissions annually [7]. A total of 415 blood isolates of Candida species (one strain per species per patient) were collected from April 1996 to December 1999. During this period 130 patients met the inclusion criteria of having at least one positive blood culture for Candida species within one month prior to the fatal outcome. There were 68 patients infected with C. albicans and 62 with NAC.

Clinical data
Clinical data of 130 patients were recorded on standardized forms and analyzed according to age at the time of diagnosis, gender and underlying illnesses. These included cancer, diabetes, immunosuppression accounted to prior use of steroids, systemic antifungal agents, cancer chemotherapy, parenteral nutrition, the presence of central or arterial line, endotracheal tube, and urinary catheter, admission to an intensive care unit (ICU), history of infection or gastrointestinal surgery, hemogram, antifungal management, and cause of death. The predisposing events within one month prior to diagnosis and the laboratory data within seven days prior to obtaining the first positive blood culture were analyzed. To decide that a patient died directly of candidemia or underlying illness, we recoded the causes of death according to the death certificate of the patients.

Statistical analysis
The statistical significance of association between categorical variables was assessed using the Fisher's Exact Test. The risk factors with p values < 0.1 in the univariate analysis were placed in a multivariate analysis using the multiple logistic regression package in the SAS System for Windows V8. Confidence limit of 95% means that the confidence limit contains the true value of odds ratio with probability of 0.95. The narrower the confidence limit is, the more accurate the estimate is.

Results
The population consisted of 130 patients whose death was associated with candidemia. Fifty-five (42.3 %) of these deaths were considered to be directly caused by Candida species. The remaining died of complications of their underlying illness. The distribution of species of the total deaths and those causally related to candidemia is shown in Table 1. There were no significant differences in causation of death according to species. Interestingly, of the four major species related to candidemia, 61.5% of the isolated Candida glabrata contributed to mortality, followed by 50% of Candida parapsilosis, 41.2% of C. albicans, and 31.3% of Candida tropicalis.
The demographic and clinical characteristics of the study population categorized according to the presence of C. albicans or NAC in the blood are summarized in Table 2. The significant (p ≤ 0.05) risk factors on univariate analysis for C. albicans candidemia were age м 65 years, prior bacterial urinary tract infection, central venous catheter, parenteral nutrition and leucocytosis with white blood cell counts (WBC) м 15000/mm 3 , without significant neutropenia with absolute neutrophil counts (ANC) м 100000/mm 3 . The significant risk factors for NAC were age < 65 years, cancer chemotherapy, neutropenia (WBC < 3000/mm 3 ) and severe thrombocytopenia (platelet count Ϲ 20000 /mm 3 ). NAC patients were more likely to have cancers and to be located on the medical wards (p = 0.08). When multivariate analysis was employed, the significant risk factors for C. albicans were age м 65 years, immunosuppressive therapy, and leucocytosis. Signifi-cant risk factors for NAC were age < 65 years and location on medical wards, which are shown in Table 3.

Discussion
Candida albicans remains the most common species causing candidemia, but the proportion caused by NAC is   [7][8][9][10]. Patients with NAC are more likely to require greater dosage of fluconazole to cure clinically [13,14]. Thus there is a need to identify patients at risk of NAC candidemia to initiate empirical amphotericin B therapy or high-dose fluconazole.
Krcmery and Barnes have identified the following risk factors for NAC [15]. These include prophylaxis with azole compounds as a risk factor for C. krusei and C. glabrata, neutropenia and bone marrow transplantation for C. tropicalis, and insertion of foreign bodies, neonates, and hyperalimentation for C. parapsilosis [15][16][17][18]. In this study we have identified additional risk factors that help distinguish candidemia caused by C. albicans and NAC. The most important risk factors for C. albicans are the old age, procedures associated with intensive care, and an acute sepsis. The most important risk factors for NAC are cancer chemotherapy in association with leukopenia and thrombocytopenia.
It has been reported that Candida species exhibit a spectrum in the extent of adherence to tissues, which correlates with the pathogenicity in humans and animals [19]. Candida albicans exhibit the greatest capacity to adhere to gingival epithelial cells, followed by C. tropicalis and C. glabrata [19]. The capacity of yeasts to attach to a wide range inanimate surfaces appears to protect them from immune responses and antimicrobial agents [20]. This may explain why C. albicans is more likely to be associated with central venous catheters in this study.
Conventional methods to eradicate C. albicans rely upon the use of antifungal drugs designed to kill the yeast or arrest its growth. However, removal of intravascular catheters is in fact the most simple and effective method [21,22]. Another approach is to design new agents that disrupt adherence of the yeasts to host tissues and catheters.

Conclusion
It is customary to administer amphotericin B for critically ill patients suspected of having candidemia. More often than not, azoles are used for relatively stable patients. NAC tend to be less susceptible to fluconazole than C. albicans is [7,11,23]. Thus, greater dosage is needed till the causative microorganism is isolated and identified, particularly with patients at high risk for NAC candidemia. Though, a large, prospective study is needed to validate this concept, the risk factors identified in this study may help, in clinical practice, to differentiate fatal candidemia caused by C. albicans versus NAC.