PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1680-1687 (doi:10.1542/peds.2005-1996)
Changing Incidence of Candida Bloodstream Infections Among NICU Patients in the United States: 1995–2004
a Mycotic Diseases Branch, Division of Bacterial and Mycotic Diseases
c Health Outcomes Branch, Division of Healthcare Quality Promotion, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, US Department of Health and Human Services, Atlanta, Georgia
b Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVES. Recent reports suggest that candidemia caused by fluconazole-resistant strains is increasing in certain adult populations. We evaluated the annual incidence of neonatal candidemia and the frequency of disease caused by different species of Candida among neonates in the United States.
PATIENTS. The study included neonates admitted to 128 NICUs participating in the National Nosocomial Infections Surveillance system from January 1, 1995, to December 31, 2004 (study period).
METHODS. Reports of bloodstream infection (BSI) with Candida spp.; Candida BSIs, patient admissions, patient-days, and central venous catheter days were pooled by birth weight category. The number of Candida BSIs per 100 patients (attack rate) and per 1000 patient-days (incidence density) was determined. Both overall and species-specific rates were calculated; data were pooled over time to determine the differences by birth weight category and by year to determine trends over time.
RESULTS. From the 130523 patients admitted to NICUs during the study period, there were 1997 Candida spp. BSIs reported. Overall, 1472 occurred in the <1000-g birth weight group. Candida albicans BSIs were most common, followed by Candida parapsilosis, Candida tropicalis, Candida lusitaniae, Candida glabrata, and only 3 Candida krusei. Among neonates <1000 g, incidence per 1000 patient-days decreased from 3.51 during 1995–1999 to 2.68 during 2000–2004 but remained stable among heavier neonates. No increase in infections by species that tend to demonstrate resistance to fluconazole (C glabrata or C krusei) was observed.
CONCLUSIONS. Although Candida BSI is a serous problem among neonates <1000 g, incidence has declined over the past decade, and disease with species commonly resistant to azoles was extremely rare.
Key Words: Candida • intensive care units • hospital-acquired infection • fungemia • candidiasis • bloodstream infection • high-risk nursery • extremely low birth weight infant • neonatal
Abbreviations: BSI—bloodstream infection • NNIS—National Nosocomial Infections Surveillance • CVC—central venous catheter
Candida bloodstream infections (BSIs) are a common cause of late-onset sepsis in the NICU and are associated with significant mortality and neurodevelopmental impairment.1–5 The incidence of fungal BSIs and causative species are important measures in the NICU and aid in analyzing the effects of new therapies and preventive strategies. The introduction of triazoles, such as fluconazole in the early 1990s, provided a new option for therapy against systemic fungal infections. The efficacy of fluconazole in specialized adult populations has been documented for both the treatment and prevention of Candida infections.6–8 Because certain isolates have a propensity for decreased susceptibility to fluconazole (eg, Candida krusei or Candida glabrata), the increased use of fluconazole may be a factor in the emergence of C glabrata infections reported from adults in hospitalized settings in both the United States and other countries.9–11
In the NICU in the 1990s, the overall incidence of candidemia increased because of the increased survival and intensive care of extremely preterm infants. During that time period, the proportion of candidemia because of Candida albicans decreased, whereas that of Candida parapsilosis increased; few data reported from single-center studies include other Candida species.12, 13 Following trends in causative species may yield important outcome information. In the NICU, mortality varies greatly by species causing candidemia. In preterm infants <1500 g, mortality in patients with C albicans sepsis is as high as 44% compared with only 16% with C parapsilosis.1–3, 5, 14
Amphotericin B deoxycholate has remained the primary antifungal agent in the NICU during this time period, but as studies involving fluconazole use in neonates have been published, its use has increased in critically ill infants.1, 15 The use of antifungals is much higher than the percentage of patients with candidemia. The National Institute of Child Health and Human Development neonatal network reported that, whereas the incidence of candidemia in infants <1500 g was 3.1%, antifungals were used in 9% of the patients and 
30% of infants <750 g.1 In that study, amphotericin B was used for 85% of doses compared with fluconazole administered for 10% of doses. Recently, in a single center study, fluconazole prophylaxis has been shown to be beneficial in preventing candidemia.16 In the past few years, echinocandins, a new class of antifungals, have emerged in the treatment of fungal infections in adults; some use in neonates has been reported, with more studies underway.17 The expanded use of antifungals is likely to influence the temporal trends of candidemia in neonates of various birth weight rates, as well as the species causing candidemia. Although the trends of antifungal use and their effect on Candida species have been intensively studied in adults, multicenter reports on Candida species in neonates have not had such examination.
To evaluate the trend over the past decade in incidence of BSI with different Candida species, we analyzed data from the NICUs reporting to the National Nosocomial Infections Surveillance (NNIS) system from 1995–2004.
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METHODS |
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Description of NNIS System
Begun in 1970, the NNIS system is the oldest ongoing surveillance system for hospital-associated infections in the United States. Hospitals are not systematically selected, and participation is voluntary. Compared with other US hospitals, NNIS system hospitals tend to have more hospital beds, and the majority have academic affiliations.18 We analyzed data reported to the high-risk nursery (NICU) component.
Surveillance Methodology
All of the participating centers submitted 
1 month of data from January 1995 to December 2004 (the study period). Centers choose the month for which they will report data before the first day of the month and prospectively follow all of the patients during the month(s) (ie, surveillance month) chosen for study; therefore, some months for which data were reported include no infections. During each month for which data were submitted, infection control personnel monitored all of the neonates in level III or II/III NICUs for exposure to central venous catheter (CVC) and the occurrence of BSIs, regardless of pathogen or birth weight. A BSI was reported if it occurred while a patient was in the NICU during a surveillance month or within 48 hours after the patient was discharged from the NICU. Only BSIs, patient admissions, patient-days, and CVC-days that occurred during the month of study are reported for that month. NICU patients were categorized according to birth weight (<1000, 1001–1500, 1501–2500, and >2501 g). Summary data for patient admissions, patient-days, and CVC-days were reported for each month according to birth weight category.
Definitions
Standardized NNIS definitions of BSI were used; a Candida BSI was defined as isolation of Candida spp. from 1 blood culture. Infection control personnel further classified BSIs as either secondary (primary infection was present at a distant site) or primary according to NNIS criteria.19 Patients were only eligible to be reported as having >1 Candida BSI only if the patient has fully responded to initial therapy, usually >30 days after the last positive blood culture for Candida spp., and the patient's subsequent infection occurred in the NICU during a surveillance month. Furthermore, mortality was categorized as attributable to the candidemia if it occurred during the NICU stay and the reviewing infection control practitioner considered the infection as causal or contributory to the death. This assessment was based on notations in the patient's medical chart or through consultation with the clinical team.
Measures of Incidence
Data, including BSIs detected, total patients, patient-days, and device-days, were pooled according to birth weight category within each NICU. We calculated 3 separate measures of incidence: the CVC-associated candidemia rate (number of primary BSIs with Candida spp. per 1000 CVC-days), the attack rate (number of primary or secondary Candida BSIs per 100 patients), and the Candida BSI rate (number of primary or secondary BSIs with Candida spp. per 1000 patient-days).
Statistical Analysis
NICU-specific incidence and percentile distributions were determined by pooling all of the data within a specific NICU over the study period by birth weight category. Birth weight-specific incidence was determined by aggregating data across NICUs, for each birth weight category, both for each year of the study period and pooled across the entire study period. Furthermore, Candida spp.-specific rates were determined for each of the more common species (ie, C albicans, C glabrata, C parapsilosis, Candida tropicalis, and C krusei, among those in the <1000-g birth weight category).
Because only 85% of Candida BSIs were classified as primary, and the likelihood of developing Candida BSI increases with stay in the NICU, we focused the trend analyses on the Candida BSI rate (number of Candida BSIs per 1000 patient-days) to best account for any changes in patients' lengths of stay over time. Because trends did not demonstrate a definitive linear decline, we evaluated differences statistically by comparing the incidence between the 2 time periods in which the decline was most clear: incidence up through 1999 compared with after 1999 by the Poisson regression. Pairwise comparisons of patient characteristics and outcome were made between groups based on species of Candida associated with the BSI. Differences between birth weight groups were also compared by Poisson regression, whereas comparisons of nonincidence density categorical variables were made using 
2. All of the analyses were performed using SAS 6.12 software (SAS Institute, Cary, NC).
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RESULTS |
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Reporting Hospitals
From January 1, 1995, through December 31, 2004, 128 NICUs submitted 1632 months of data (median: 10 months; range: 1–48 months per NICU) covering 130523 patients, 1348945 patient-days, and 480536 CVC-days (Table 1). NICUs reported 1997 cases of candidemia, for an overall attack rate of 1.53% among NICU patients.
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Candida Species and Classification of Candidemia
Among all of the candidemia reported, C albicans BSIs were most common (57.9%), followed by C parapsilosis (33.7%), C tropicalis (3.8%), Candida lusitaniae (2.3%), C glabrata (2%), and only 3 C krusei (0.2%; Table 2). Of note, C parapsilosis BSIs were significantly more likely to be classified as primary BSI compared with C albicans (91% vs 82%; P < .01; Table 2). Time from birth to infection was similar between species, except neonates with C parapsilosis BSI were significantly older than neonates with C albicans BSI (median: 26 vs 19 days; P < .001). Mortality was 13%, where 259 of all neonates with candidemia died for reasons believed to be associated with infection during the hospital stay; this mortality rate did not significantly differ by Candida species (Table 2).
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Overall, 288 (14.4%) cases of candidemia were classified as secondary; this proportion remained constant during each year of the study period (data not shown). Among these secondary BSIs, the primary site of infection was reported as urinary tract in 101 (35%), gastrointestinal in 50 (18%), skin or soft tissue infection in 43 (15%), pneumonia in 39 (13%), central nervous system in 23 (8%), cardiovascular in 16 (5%), and other sites in 16 (5%). Extremely low birth weight infants (<1000 g) were also significantly less likely to be classified as having primary candidemia (1427 of 1235 [84%]) compared with other infants (474 of 525 [90%]; P < .01).
Trends in Candida Spp. Associated With BSI
During the study period, there were 60 to 70 NICUs reporting data during each year, except in 2004, where only 35 nurseries had already reported data at time of this analysis (Fig 1). When accounting for the number of months each NICU reported data, the number of neonates <1000 g cared for in these NICUs per month increased over the study period; the number of neonates <1000 g reported on from each NICU increased from 13.8 patients per month in 1995 to 17.0 patient per month in 2004 (Fig 1).
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During the study period, there was a significant decrease in the incidence of candidemia among the <1000-g birth weight group but not among the other birth weight categories (Fig 2). This decrease was also present when examining attack rates and the risk-adjusted CVC-associated BSI rate, as well (data not shown). This decrease began around the year 2000; there was a 24% reduction in the number of infections per 1000 patient-days, from 3.51 during 1995–1999 to 2.68 during 2000–2004 (P < .01) When examining incidence by species of Candida within the <1000-g birth weight group, significant decreases occurred among both C albicans BSI (P < .01) and C parapsilosis BSI (P < .01); the incidence of C glabrata species BSI remained extremely low and stable (P = .53; Fig 3).
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Incidence by Birth Weight
Overall, among infants <1000 g, the pooled mean attack rate for candidemia in the more recent time period (2000–2004) was 5.07%, the Candida BSI incidence was 2.68 per 1000 patient-days, and the risk-adjusted incidence of CVC-associated primary Candida BSI was 5.55 per 1000 CVC-days (Table 3). All of the incidence measures were significantly higher among infants <1000 g and among those 1001 to 1500 g compared with heavier infants (Table 3). However, the NICU-specific rates varied greatly; among neonates <1000 g, the median attack rate was 7.5%, but 25% of the NICUs reported rates >13.5% (Table 4). The other incidence measures were also extremely high (more than double the median rate) among the 75th percentile of NICUs reporting, regardless of birth weight category (Table 4).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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During 1995 through 2004 there was a significant decrease in the incidence of hospital-acquired candidemia among neonates weighing <1000 g in NNIS hospitals. This decrease was because of a decrease in both C albicans and C parapsilosis BSIs with no increase in the incidence of C glabrata BSIs. However, there was great variation in the rates of candidemia across NICUs, regardless of which incidence measurement we evaluated, suggesting that significant differences exist between neonates cared for in these different NICUs that are not adjusted for when evaluating incidence based on birth weight category. This wide variation is similar to that from the smaller National Institute of Child Health and Human Development Neonatal Network data where institutional rates of candidemia range from 2.4% to 20.4%. Importantly, from the NNIS data, although the overall rate among infants <1000 g was 5.07%, more than one quarter of the NICUs reported attack rates >13.5%. Additional study of institutional differences between low- and high-incidence NICUs may be helpful in identifying risk factors, infection control measures, or prophylaxis practices in extremely low birth weight infants.
These data represent the largest number of NICUs evaluated in a standardized way for candidemia among neonates published in the last decade, providing a more representative assessment of the burden of disease than previous studies have reported. The data also demonstrate the higher incidence in neonates compared with adults. The incidence of CVC-associated primary candidemia in these NICUs (4.15 per 1000 CVC-days) is nearly ninefold greater compared with NNIS adult ICU data (4.8 per 10000 CVC-days).20 However, the data among neonates <1000 g suggest that the incidence of 5.07% during 2000–2004 is at the lower end of the spectrum described in these studies published previously (5.5–16%).1, 16, 21, 22 Differences between NNIS hospitals compared with non-NNIS hospitals are likely minimal, because these single and multicenter institution reports were also from predominantly academic centers.18
In this article, we reported on attributable mortality. This has been an area of great interest in studies of neonatal sepsis, and this is the first article from multiple centers using this definition in this patient population. However, it is at times difficult to define, because these infants often have overlapping respiratory, intracranial, gastrointestinal, and infectious illness, all with high associated mortality. Several articles have examined overall mortality and further delineated causal mortality by defining early death as 3-day, 4- to 7-day, 7-day, and 30-day mortality.1–5, 13 Attributable mortality for all of the species in our study was 13%, which compares with multicenter studies of preterm infants of 7.2% and 15.2% for 3-day mortality and 12% and 23.2% for 7-day mortality.1, 3, 5 Mortality is inversely proportional to gestational age, and continued research and advances in intensive care, treatment, and prevention of fungal sepsis should focus on extremely low birth weight infants and survival.
Several factors may have contributed to the decreased incidence of candidemia. BSI rates associated with all bacterial and fungal pathogens in adult ICUs have decreased over the past decade23; it may be that a similar phenomenon is occurring in the NICUs as well. However, this would not explain the stable rate of infections among the heavier infants and only a decline among <1000-g neonates. Exposure to the neonate occurs via horizontal and vertical transmission, so important factors may include changes in the incidence and treatment of vaginal candidiasis in pregnant mothers and hand colonization of NICU care givers.21 Choice of broad spectrum antibiotics (third-generation cephalosporins and carbapenems), histamine type 2 antagonists, systemic steroids, and topical petrolatum use may have decreased during the time period, because there were concerns for increased fungal sepsis with their use.14, 24–26 Empiric antifungal therapy may also be contributory to this observation. Empiric antifungal use has been reported to be high in this population: 34% among infants with birth weight between 401 and 500 g, 28% among infants weighing 501 to 750 g, and 10% among infants weighing 751 to 1000 g.1, 14 Finally, prophylactic fluconazole use may have increased in preterm infants <1000 g as a result of the publication of a single-center trial on its efficacy in preventing neonatal candidemia.16
If the decrease is a result of fluconazole use, we may expect an increased incidence of C glabrata BSI, as was reported in adult ICUs.6–8, 20 The lack of any increase in C glabrata is encouraging. If the use of fluconazole prophylaxis increases in this patient population, it will be important to continue to monitor the pathogen profiles of Candida BSIs, but for now it seems that essentially all (>97%) of the infecting species are those that historically remain susceptible to fluconazole.27
One major limitation of this study is the voluntary nature of the surveillance program. Over the study period, a single NICU may have contributed as little as 1 month of data, whereas others contributed more; the maximum number of months any 1 NICU contributed was 48 months, far less than the 120 months covered in this analysis. For this reason, evaluating unit-specific infection rates may be misleading, because reporting <6 months of data will unlikely represent the true infection rate of the NICU. However, the large variation in infection rates between NICUs remained despite limiting analysis to only NICUs reporting 12 months of data (data not shown), suggesting that the differences between NICUs, despite adjusting for birth weight, is likely real. Furthermore, the use of a pooled mean incidence among birth weight categories for each year by aggregating the data across NICUs essentially weights the data according to the number of months data were submitted, controlling for the impact of outlier rates in NICUs reporting less data. Therefore, this incidence should be reflective of the nation's NICUs as a whole. Second, there was not uniform methodology in the microbiologic methods used to identify Candida spp. in blood cultures. Some centers may routinely use less blood in blood culture bottles compared with other centers, and this may explain some variation in observed rates. Additional limitations to this study include the lack of detailed individual patient clinical information. Some of our findings may be attributable to patient risk factors not routinely collected by NNIS hospitals. The wide variability in infection rates among infants <1000 g suggests that there are unmeasured factors that differ between NICUs that may explain the wide variation in rates. Such factors may include a larger proportion of neonates weighing <750 g, extremely young gestational age, more neonates with abdominal disease, and differences in infection control practices. All of these factors have been shown to increase neonates' risk for developing candidemia and, if not equally distributed among neonates <1000 g, may explain some of the observed variability. Also, changes in the frequency of established risk factors for candidemia would explain the decreasing rate; however, there is little evidence that these factors have decreased over the past decade.1, 28 However, we evaluated disease rates by 3 methods, accounting for patient-days and CVC-days to best adjust for the most important predictors of BSI. The observed trends were present with each of the 3 methods. Finally, we do not have NICU-specific fluconazole-use data. These data would have enabled us to perform analyses comparing antifungal prophylaxis use between NICUs and correlating fluconazole use and changing rates of disease. Because of these limitations, we could only speculate about the factors contributing to the changing incidence of candidemia.
Among NICU patients, the incidence of candidemia significantly decreased among neonates <1000 g during 1995–2004. However, this disease remains a significant problem in this vulnerable population, and extremely high rates of disease were observed among many NICUs. Although additional efficacy studies to justify fluconazole prophylaxis in this population are needed, as clinician practice changes, ongoing surveillance is warranted to detect species-specific changes in the incidence of candidemia.
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ACKNOWLEDGMENTS |
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We acknowledge the exceptional work of the infection control and hospital epidemiology staff performing surveillance as part of the National Health Care Safety Network (formerly known as the National Nosocomial Infection Surveillance18 system).
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FOOTNOTES |
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Accepted Oct 31, 2005.
Address correspondence to Scott Fridkin, MD, MS C-09, Mycotic Diseases Branch, Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333. E-mail: sfridkin{at}cdc.gov
The authors have indicated they have no financial relationships relevant to this article to disclose.
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