Candidemia is a serious medical concern and its incidence has increased over the past 3 decades (3,26,27,50,61), with reported mortality rates as high as 60%-80% (8,21,64). Some years ago, the diagnosis of invasive opportunistic fungal infections was rare, and the isolation of Candida species from human tissue or body fluids was considered to be either a contamination or of minor importance. Fungemia was seen predominantly in patients with burns, severe trauma, neutropenia, or advanced malignancies (9,21,30,33,55,63,68). Despite these observations, fungal infections were not believed to increase the risk of mortality.
Over the last 20 years, the increased severity of hospitalized patients, more intensive use of invasive devices and procedures, and wide use of broadspectrum antimicrobial agents have resulted in an increased incidence of nosocomial fungal infections (17,27,37). The invasive potential of Candida species was first documented by Krause and coworkers in 1969 (28), but it was only during the last 2 decades that several clinical studies identified Candida species as important pathogens that can affect the outcome of critically ill patients (5,17,18,21,25). According to the National Nosocomial Infections Surveillance system of the Centers for Disease Control and Prevention, fungi accounted for 30,477 identified nosocomial pathogens (3) with Candida species identified in 8%-15% of all nosocomial bloodstream infection episodes in major United States hospitals in 1993 (63). Furthermore, Candida species were ranked as the fourth most commonly isolated pathogens from patients with bloodstream infections (14,38,50).
Candida species are the most common nosocomial fungal pathogens, of which Candida albicans represents the majority (22). Recently, non-albicans Candida species have emerged as significant pathogens in critically ill and immunosuppressed patients with malignancy; the most commonly isolated species were Candida tropicalis, Candida glabrata and Candida parapsilosis (16,36,60).
Risk factors for candidemia include multiple invasive procedures such as indwelling vascular catheters, parenteral feeding, immunosuppressive therapy, hemodialysis, neutropenia, severe burns, and broad-spectrum antibiotic selective pressure (4,19,22,23,44,56). Bladder catheterization, candiduria, azotemia, and diarrhea constitute additional risk factors (2,10,11,35). Colonization precedes candidemia and several studies have identified Candida colonization as an independent risk factor for infection (18,46,58,64). Genotyping methods have demonstrated the similarity between colonizing and infecting strains, suggesting the existence of an endogenous origin, although exogenous sources are known (43,47,48,52).
We conducted this 12-year retrospective cohort study to describe the local epidemiology of fungemia at a tertiary care hospital, with an emphasis on trends and predisposing factors for mortality among patients with candidemia.
Patients and Methods
The University of Geneva Hospitals (UGH) is a 1,500-bed, referral tertiary care center serving Geneva and the surrounding area. Adult patients with fungemia hospitalized at UGH from January 1989 to December 2000 were identified retrospectively through the microbiology computer system, UNILAB. Of the 328 patients with blood cultures revealing at least 1 fungal species, 315 (96%) medical records were available for review. Demographic information and overall risk factors before the onset of candidemia were analyzed.
Definitions and study variables
Fungemia was defined as at least 1 positive blood culture yielding a yeast or fungus specimen. Study variables included preceding surgery, underlying illness, intravascular device use, cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease, chronic renal failure, hemodialysis or parenteral nutrition, antimicrobial treatment 7 days before fungemia, and intensive care unit (ICU) admission. Immunosuppressive conditions included cancer, hematologic malignancies, acquired immunodeficiency syndrome (AIDS), neutropenia (neutrophil count below 500 cells/mm3), and immunosuppressive therapy: antineoplastic agents and/or steroids administered within 30 days before infection.
Comorbidities present at the time of candidemia were also analyzed in relation to mortality within 30 days after candidemia. Each patient was assessed for the presence of the following underlying conditions: cardiac disease (coronary heart disease resulting in permanent alteration of the cardiac function [New York Heart Association classes II or IV]; angina pectoris; acute myocardial infarction; arterial hypertension [diastolic blood pressure measurements ≥90 mmHg]; or valvular heart disease); chronic renal disease defined as irreversible decline in glomerular filtration rate; diabetes mellitus (requiring either oral therapy or insulin treatment); pulmonary disease (resulting in functional disability and/or requiring chronic bronchodilator therapy and/or chronic obstructive pulmonary disease); and neurologic disease (stroke or other active neurologic conditions with permanent disability).
The search for other specimens culture-positive with the same species of Candida before and during candidemia was done retrospectively for each patient to establish the existence of colonization. Information on hospital-wide fluconazole use was obtained from the Pharmacy Department.
As previously reported (13), ward staff were instructed to draw about 20 mL of blood at least twice from patients with symptoms of sepsis. The available sample was distributed in equal parts into a Septi-Chek Release bottle (Becton Dickinson, Cockeysville, MD) and an Oxoid Signal bottle (Oxoid, Basingstoke, UK). Whenever fungemia was suspected, the inoculation of an Isolator 10 tube (Wampole Laboratories, Cranbury, NJ) based on lysis centrifugation was recommended (12). With the introduction of an automated fluorometric BACTEC 9000 system in the clinical microbiology bacteriology laboratory (August 1994), the Septi-Chek Release and Signal vials were replaced by the BACTEC Plus aerobic/F and the Lytic anaerobic/F vials (Becton Dickinson, Sparks, MD) (57). The Isolator, recommended for patients with suspected fungemia, was replaced when the BACTEC Myco/F Lytic medium for the BACTEC 9000 system became available (November 1997). Yeasts growing in all blood cultures were identified with API C32 (BioMérieux, Lyon, France) in conjunction with microscopic morphology of the fungi subcultured on rice agar. Fungus names in current use proposed by McGinnis et al (31) have been applied.
Antifungal susceptibility tests were performed on all isolates from mid-1999 when the microdilution kit Sensititre YeastOne (AccuMed International Ltd, East Grinstead, UK) became commercially available. According to the manufacturer’s instructions, the test panels were incubated at 35 °C, and the minimum inhibitory concentrations (MICs) were read after 24 h if the growth control well was red; otherwise, they were read after 48 h (6).
The sum of all surgical procedures, blood cultures performed, fungemia and candidemia episodes, or all fungal/yeast isolates documented in each year were considered in the statistical analysis. Rates per 100 admissions or per 10,000 patient-days were calculated. Linear trends were analyzed using the simple linear regression analysis (least-square method) with years considered as an independent variable, and number of procedures, cultures, use of fluconazole (g or g per 10,000 patient-days) and fungemia/candidemia episodes or rates as dependent variables.
Univariate analysis was performed for each of the variables and odds ratios (OR) and their corresponding 95% confidence intervals (95% CI) were calculated and interpreted according to Cornfield (7). Differences in proportions were compared with the chi-square test, using Yates correction when necessary. A p value < 0.05 was considered statistically significant.
The risk of death within 30 days of candidemia was also evaluated by multivariate analysis. The model includes those variables that were of statistical significance in the differentiation between patients who died and those who survived by univariate analysis. Results were analyzed using a commercially available software package (SPSS, version 4.0, SPSS Inc, Chicago, IL).
During the study period, UGH delivered 9,881,021 patient-days of care (mean, 823,418 per year). As the number of hospitalization-days per year decreased (r = −0.8; p = 0.002), despite increased patient admissions (r = 0.57; p = 0.05), the annual incidence of candidemia decreased significantly (r = −0.66; p = 0.02) (Table 1). The number of surgical procedures tended to increase over the study period (r = 0.55; p = 0.06). The number of kidney (r = 0.62; p = 0.03), liver (r = 0.59; p = 0.04), and Langerhans cell (r = 0.91; p = 0.01) transplants per 1,000 admissions/year increased. The annual number of bone marrow and lung transplants remained stable.
Overall, the number of patients with human immunodeficiency virus (HIV) admitted annually at UGH remained stable over the study period. Those admitted in internal medicine ranged from 212 in 1997 to 300 in 1994 for a total of 30,712 patient-days between 1990 and 2000 (mean, 2,792; range, 1,691 to 4,025) with no significant trend over time.
The number of blood cultures analyzed per year tended to increase between 1989 and 2000 (r = 0.85; p = 0.06). The yearly incidence of fungemia ranged between 0.21 (in 1997) and 0.54 (in 1993) episodes per 10,000 patient-days (see Table 1). Of 328 patients with positive fungal blood cultures, 315 (96%) medical records of 104 female (33%) and 211 male (67%) patients were available for review. The mean age was 61 years old. The overall mortality of patients with candidemia was 44%.
The overall distribution of fungal isolates recovered during the study period is shown in Table 2. Candida species were responsible for 93% (308/330) of fungemic episodes, Cryptococcus neoformans for 15 episodes, and other fungal species for 7 additional episodes. Only limited antifungal susceptibility results were obtained during the study period. However, all C. albicans strains tested (n = 20) were susceptible to amphotericin B (MIC ≤ 0.5 μg/mL) and fluconazole (MIC ≤ 2 μg/mL); 18 (90%) were susceptible (MIC ≤ 0.06 μg/mL) and 2 were intermediately susceptible (MIC = 0.25) to itraconazole. Only 5 strains of C. glabrata were tested; all were amphotericin B susceptible, but either resistant or intermediately susceptible to fluconazole (MIC ≥ 16 μg/mL) and itraconazole (MIC ≥ 1 μg/mL).
The annual incidence of candidemia ranged between 0.2 and 0.46 episodes per 10,000 patient-days (see Table 1). C. albicans remained the most frequent species isolated over the study period, followed by C. glabrata (see Table 2). The incidence of C. albicans candidemia tended to decrease overall, particularly since 1996, whereas that of non-albicans Candida strains remained relatively stable during the study period. The species distribution did not shift from C. albicans to non-albicans Candida species (Figure 1). Thirteen episodes of candidemia grew mixed Candida species according to the following distribution:C. albicans with C. glabrata (n = 8);C. glabrata with C. krusei (n = 3);C. albicans with C. parapsilosis (n = 1);C. glabrata with C. tropicalis (n = 1); 1 episode yielded 3 species:C. albicans, C. parapsilosis, and C. tropicalis.
Patients were hospitalized in the following wards at time of candidemia: ICU (38%); internal medicine (25%); surgery (21%); emergency (6%); geriatrics (4%); and others (5%). Common predisposing factors for candidemia included antibiotic therapy for more than 7 days before candidemia (69% of all patients with candidemia); exposure to central venous catheterization (80%); underlying illnesses such as cardiovascular disease (42%), cancer (38%), and diabetes (14%). Six percent of patients had neutropenia at the onset of candidemia. Candida colonization was documented in 122 patients (41%) before candidemia occurred.
Factors associated with mortality among patients with candidemia
Of 294 patients with candidemia, 130 died within 30 days, which resulted in a 30-day crude mortality of 44%. Of the 130 patients who died, 83 (59%) were admitted to the ICU before or at the time of candidemia. Variables associated with candidemia and mortality are listed in Table 3. In the univariate analysis, statistically significant factors were ICU admission, age greater than 65 years, and abdominal cavity colonization with the same Candida species before the occurrence of candidemia. Other predisposing factors, together with corresponding numbers of patients and mortality rate, are listed in Table 3.
Exposure to central venous catheter was high (80% of patients with candidemia) in the study population, but was not associated with increased mortality. The overall number of HIV patients with candidemia was low; only 14 patients (21%) with candidemia suffered from AIDS-related conditions. By multivariate analysis, factors that independently predicted death from candidemia were ICU admission (OR 5.01, 95% CI 2.60–9.68), age greater than 65 years (OR 1.038 per year, 95% CI 1.017–1.059), and the presence of cancer with metastasis (OR 2.64, 95% CI 1.21–5.78).
Secular trends of fluconazole use are presented in Figures 2A and B. As shown, both oral and intravenous use increased significantly and proportionally over the study period (r = 0.92 and 0.82, both p < 0.001, see Figure 2A). Overall fluconazole use increased from 2.68 to 27.14 g per 10,000 patientdays between 1990 and 2000 (r = 0.90, p < 0.001, Figure 2B).
Between 1980 and 1990, there was a reported increase in the incidence of nosocomial Candida infection, with highest rates recorded from burn and trauma services (62). In contrast, the present retrospective study showed that annual candidemia rates varied considerably in our institution. The incidence increased between 1989 and 1996, and then progressively decreased. The epidemiologic hospital data did not differ between 1989–1994 and 1995–2000; however, liver, kidney, and Langerhans cell transplants increased during the latter period (see Table 1). There was no significant increase in the overall number of patients with HIV admitted annually over the study period. The overall distribution of patients with candidemia was higher in the ICU (38%) than in other units, and as reported in other series (34,67). Our institution has reinforced infection control measures considerably since 1994 (15,20,45), so risk factors such as the use of intravascular devices and hand transmission could have played a role before then.
Patients who survive infection have significantly prolonged hospitalization (49,64). Medical costs per candidemia episode have been estimated at US$ 34,123 per Medicare patient and US$ 44,536 per private insurance patient (53). Another study showed that patients with candidemia were more likely to die during hospitalization than patients with bloodstream infections due to nonfungal pathogens (29% versus 17%, p < 0.001) (46).
Approximately one-third of all patients with candidemia die as a direct result of the infection, one-third die due to their underlying disease, and the remainder survive hospitalization and the infection (4,27,62). The global 30-day mortality rate in our patients with candidemia was 44%, similar to other reports (17,18,24,32,60,64). Patient age over 65 years, ICU admission, and metastatic cancer independently predicted death. Mortality due to infections with C. albicans seemed to be higher than those due to non-albicans Candida species, although this difference did not reach statistical significance (see Table 3).
Since colonization was not assessed in a systematic fashion (48), inference about the results of cultures growing Candida species from different body sites before the onset of candidemia cannot be made with certainty. Our findings of a possible relation between abdominal cavity colonization before the occurrence of candidemia and higher mortality was not confirmed by multivariate analysis. It certainly suggests that patients with more serious conditions were cultured more actively; however, such findings require further prospective evaluation.
A changing epidemiology of candidemia and other fungal infections was reported since the introduction of fluconazole prophylaxis and therapy. Several studies have shown an incidence shift from C. albicans toward other Candida species, which could be correlated with the use of fluconazole prophylaxis (1,36,66). Other hospitals have reported increased candidemia due to fluconazole-resistant species such as C. krusei and C. glabrata. Fluconazole use increased significantly at our institution during the period of the study. In our survey, we observed fluctuations in non-albicans Candida species, but no shift toward non-albicans species (see Table 2).
Our study confirmed that C. albicans is the predominant Candida species isolated from blood cultures (39,41,54). In some institutions, the proportion of non-albicans Candida species and C. albicans isolates from blood cultures are equal (59). Other studies reported an increase of non-albicans Candida species such as C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis causing severe infections (29,30,51,65,67). Another publication showed that the proportion of non-albicans Candida species exceeded that of C. albicans (51). The rank order of non-albicans Candida species distribution varied according to the geographic region:C. glabrata was the second most common species observed in Europe and the United States (41,42);C. parapsilosis was the second most common Candida species isolated in Canada and South America (39) (Table 4).
Any relation between the observed increase in fluconazole use at UHG and the somewhat parallel decrease in the incidence of candidemia remains purely speculative and would require further testing in controlled clinical trials. Because of the retrospective nature of the study, we cannot draw inferences as to the possible causal relationship between the observed parameters.
In conclusion, the incidence of fungemia in adults admitted to our tertiary care teaching hospital has decreased since 1996, which is unlike most published studies. The main cause of fungemia was C. albicans. It is noteworthy that no significant changing trend in the incidence of non-albicans Candida species was observed in our study. The crude mortality rate associated with candidemia was high, especially for patients requiring intensive care.
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