PEDIATRICS Vol. 116 No. 1 July 2005, pp. 61-67 (doi:10.1542/peds.2004-1605)
Frequency of Fungemia in Hospitalized Pediatric Inpatients Over 11 Years at a Tertiary Care Institution
* David Geffen School of Medicine
Department of Pediatrics, Mattel Children's Hospital
Department of Microbiology, University of California, Los Angeles, California
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Objectives. To determine the frequency of bloodstream fungal infections in children who were admitted to our tertiary institution over an 11-year period.
Methods. We conducted a retrospective cohort study of patients who were aged 0 to 21 years, had bloodstream fungal infections, and were admitted to the University of California, Los Angeles from 1991 through 2001. Patients were identified through the microbiology laboratory database. All positive fungal cultures for pediatric inpatients were reviewed. For each fungemic patient, a review of clinical course, cause, and outcome was performed.
Results. Over 11 years, 1124 pediatric inpatients with 3633 positive cultures had evidence of fungal colonization or infection. The mean incidence of positive fungal cultures increased from 105 between 1991 and 1996 to 129 patients per year between 1997 and 2001. Fungal isolates were mainly Candida species (85%) obtained primarily from respiratory (41%) and urine (27%) cultures. Only 7.5% of positive fungal cultures were from blood, although 24490 pediatric admissions prompted 72960 bacterial and fungal blood cultures, at charges of $2.52 million. Of 14592 fungal blood cultures, <2% (n = 272) were positive, involving <1% (n = 97) of patients. The mean rise in number of children with fungemia was significant, from 6.8 between 1991 and 1996 to 13.0 patients per year between 1997 and 2001. Fungemia was associated with a high all-cause mortality rate (46%), particularly in immunocompromised patients (57%). Organisms recovered were primarily Candida species (91%). There was a decline in C albicans and C glabrata fungemia and an increase in C parapsilosis organisms. In 84% of patients, fungal organisms were isolated from both bacterial and fungal blood cultures, and in 74%, the same organism was isolated from additional body sites.
Conclusions. Episodes of fungemia increased significantly over 11 years as compared with a moderate increase in positive fungal cultures and were associated with high all-cause mortality rates. More sensitive assays for early identification of fungal bloodstream infections are warranted.
Key Words: fungal infections children • fungemia pediatrics • nosocomial infections • immunocompromised patients
Abbreviations: UCLA, University of California, Los Angeles
Fungal organisms are uncommon causes of bloodstream infections in pediatric patients who are admitted to tertiary care institutions; however, they result in significant morbidity and mortality.1–4 A steady rise in the incidence of fungemia among hospitalized patients over the past 2 decades has been reported through the National Nosocomial Infections Surveillance System Hospitals, the National Center of Health Statistics, epidemiologic reports from individual and multiple institutions, and population surveillance.1,5–11 The incidence of bloodstream infections as a result of fungal species is rising at a faster pace than that for other pathogens.12,13 In this study, we characterize the incidence, nature, and outcomes of fungal infections in our patient population.
Advances in prevention and treatment of fungal infections have not led to significant improvements in mortality rates over time in adults or in the pediatric population described.1,14–16 With limited improvement in outcomes and an increase in patients with fungemia, the number of deaths as a result of fungemia has increased significantly.1 According to a study by McNeil et al,1 over 17 years (1980–1997), fungemia rose from the 10th leading cause of death as a result of infectious diseases to the 7th leading cause.
Although fungal infections in healthy hosts remain relatively rare events, the risk for such infections rises significantly in immunodeficient patients, who undergo invasive life-saving procedures, such as cancer treatments and organ transplantation.1,3,5,16,17 Baseline characteristics of hospitalized patients changed over the past decade, with greater disease acuity and more immunocompromised patients. Additional risk factors for fungemia include duration of hospital stay; identification of fungal isolates from other body sites; number, type, and duration of antimicrobial treatments; presence of central venous catheters; and underlying disease status, among others.4,5,17,18
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We conducted a retrospective cohort study of children who were admitted to the Mattel Children's Hospital at the University of California, Los Angeles (UCLA) during an 11-year period from January 1991 through December 2001. Our institutional review board approved an exemption for this retrospective study.
Case Review and Data Collection
We retrieved data from the UCLA Clinical Laboratory Microbiology section database for pediatric inpatients (aged 0–21) who were admitted to UCLA Mattel Children's Hospital. Information obtained on all positive fungal cultures from all body sites included date and site of culture, demographics, and fungal etiology. Medical records of patients with fungemia were reviewed in detail (in compliance with Health Insurance Portability and Accountability Act of 1996 requirements), and data were obtained on the clinical significance of positive cultures, underlying illness, hospital course, outcome, and antimicrobial treatment and/or prophylaxis.
Definitions
Patient-days was defined as the number of days of hospitalization between the date of most recent admission and the date of collection of the first positive blood culture. For patients whose first positive culture was obtained within the first 48 hours of hospital admission, fungemia was classified as outpatient acquired. All other cases of fungemia were classified as inpatient acquired. Antimicrobial-days were calculated as the number of days on systemic antimicrobial agents (prophylactic, empiric, and therapeutic) in the 21 days before the first positive blood culture for fungus, irrespective of intermittent hospital admissions and discharges. Immune status was classified according to underlying diagnoses, which encompassed either exogenous immune suppression or inherent immunodeficiencies, including age. Patients who received solid organ or bone marrow transplants or chemotherapy and those with symptomatic, acquired, or congenital immunodeficiencies or prematurity were classified as immunodeficient. Patients who did not receive immune suppression or were not constitutionally immunosuppressed because of age or congenital or acquired immunodeficiencies were classified as immunocompetent. Mortality was defined as death irrespective of inpatient status at any time after the episode of fungemia and included all causes. Bloodstream fungal infections were classified as with or without multiorgan involvement on the basis of medical record review.
Culture Methods
Bacterial presence in blood culture bottles was detected by the Bact/ALERT Blood Culture System (bioMerieux, Inc, Durham, NC). When a bottle was signaled positive, a Gram stain was made and the medium was subcultured to aerobic and anaerobic blood agar plates, chocolate agar, and brain heart infusion broth for sensitivity testing. All cultures were incubated at 37°C. Fungal blood cultures were performed using the Isolator system (Wamploe, Cranbury, NJ). Sediment from the Isolator was plated onto Inhibitory Mold and Sabouraud Dextrose agar and incubated for 4 weeks at 30°C. Fungal isolates were identified using germ tube, cornmeal agar, wet mounts, slide cultures, and API 20C tests (bioMerieux, Inc).
Statistical Methods
P values were calculated by using 2-sided Student's t test and 
2 methods.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Positive Fungal Cultures From Any Body Site for All Pediatric Inpatients Who Were Admitted From 1991 to 2001
Frequency of Positive Fungal Cultures in Pediatric Inpatients
Between January 1991 and December 2001, 24490 pediatric inpatients were admitted to our tertiary institution. Nearly 5% (n = 1124) of patients had evidence of fungal colonization and/or infection with 3633 positive cultures obtained from any body site. The number of individual pediatric inpatient admissions increased from a mean of 2082 patients per year between 1991 and 1996 to 2400 patients per year between 1997 and 2001 (15% increase), whereas the number of positive fungal cultures rose from a mean of 105 patients per year between 1991 and 1996 to a mean of 129 patients per year between 1997 and 2001 (23% increase).
Patients who were younger than 3 years represented 38% (n = 9265) of the overall patient population and were represented proportionally within the population of children who had positive fungal cultures (39% of patients with fungal infections; n = 438). Across the age groups, the number of positive fungal cultures from any body site paralleled the age distribution of the patient population (Fig 1).
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Fungal Species
Candida species were the most frequently isolated organisms from any body site and comprised 85% (n = 3321) of the total number of cultures. Candida isolates were primarily C albicans (63%), whereas C parapsilosis was 12%, C glabrata was 10%, C tropicalis was 8%, C lusitaniae was 3%, C krusei was 2%, and other Candida species were 1%. Respiratory cultures accounted for 34% (n = 1137) and urine specimens accounted for 25% (n = 827) of Candida cultures, both of which likely reflect colonization. Only 3% (n = 34) of Candida respiratory cultures were obtained through bronchoalveolar lavage, pleural fluid, or direct sinus culture. Blood cultures accounted for 7.7% (n = 257) of Candida isolates. The remaining Candida isolates were from other sites, including skin, stool, wound, abscess, tissue, catheter, and body fluids. Aspergillus species accounted for 6% (n = 153) of cultures, with 88% (n = 135) of those isolated from respiratory cultures. One A fumigatus culture was isolated from bone marrow, and 1 A flavus-oryzae was responsible for septic arthritis. The remaining Aspergillus cultures were a mixture of isolates obtained from abdominal, urine, wound, skin, and muscle cultures. Other organisms accounted for 9% of positive cultures.
Colonization Versus Infection
Of the 3633 total fungal cultures obtained, 38% were from respiratory cultures that did not include bronchoalveolar lavage, pleural fluid, or sinus culture. Urine specimens (27%), skin (9%), and stool (4%) were other commonly cultured sources. At least 78% of total positive fungal cultures potentially reflect colonization as opposed to infection.
Fungemia in Pediatric Inpatients Who Were Admitted From 1991 to 2001
Frequency of Fungemia in Pediatric Inpatients
During the study period, 272 blood cultures were positive for fungus in 97 patients. Although the number of pediatric inpatients with positive fungal blood cultures was small, there was a marked increase in the number of fungemic patients over time. This increase exceeded the inpatient population growth and the modest increase observed in fungal infections from other body sites. The mean number of blood cultures that were positive for fungus increased from 6.8 patients per year between 1991 and 1996 to 13.0 patients per year between 1997 and 2001 (91% increase). This was in sharp contrast to the increase in mean patient admissions from 2082 to 2400 for the 2 periods (15% increase). The difference between the rise in positive blood cultures (91%) versus the increase in patient admissions (15%) was statistically significant (P = .001). The increase in fungemia (91%) far exceeded the increase in the number of positive blood cultures from any body site (105–129; 23% increase) during the same time period (P = .02). The rise in incidence of fungemia was also statistically significant: there were 1.8 cases of fungemia per 1000 inpatients in 1991 compared with 6.4 cases per 1000 inpatients in 2001 (P = .01; Fig 2).
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The age distribution of fungemic patients was different from that of other admitted inpatients. Overall, 38% of admitted children were younger than 3 years, whereas a significantly greater proportion of patients, 54%, with fungemia were younger than 3 years (P = .001; Fig 1).
Diagnosis of Infection
Identification of fungal organisms was performed via fungal blood culture, bacterial blood culture, or both. Fungus blood cultures identified mycotic organisms in 98% (95 of 97) of cases. Bacterial blood cultures provided a positive fungemia diagnosis in 84% (81 of 97) of cases. In 81% (79 of 97) of patients, both fungal and bacterial blood cultures were positive for mycotic organisms on the same day, whereas in 2% (2 of 97), bacterial blood cultures were diagnostic in the presence of negative fungal blood cultures. Corroborative tests were common; 60% (58 of 97) of patients had >1 positive fungal blood culture, and the same percentage of patients, 60%, had >1 positive bacterial blood culture. Most fungemic patients (74%; 72 of 97) grew the same fungal organism from other body sites, most commonly urine (43%), respiratory (42%), and catheter tip (34%).
Fourteen percent (14 of 97) of patients with fungemia had a negative bacterial blood culture for fungus on the same day as the positive fungal blood culture for fungus. Note that 2 additional patients did not have a bacterial blood culture drawn on the same day. Therefore, 16 of 97 patients had no growth of fungus in bacterial blood cultures (Table 1). Of the 14 patients with negative bacterial blood cultures for fungus, 8 showed evidence of concurrent fungal infection at other body sites, and 5 of those 8 had >1 positive culture from another body site, most commonly from respiratory and urine samples. Among the same 14 patients, only 1 fungal blood culture was positive per patient. Furthermore, only 14% (2 of 14) of these patients had clinical evidence of multiorgan involvement fungal infections, a significantly lower rate than the 52% (44 of 85) patients identified by bacterial culture (P = .01).
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Fungal Species
Among fungemic patients, Candida species were also the most common fungal isolates, present in 91% (88 of 97) of cases. There was no evidence of Aspergillus fungemia. Candida subspecies identified in the blood changed over time. Overall, C albicans constituted 60% of the fungal pathogens isolated from blood between 1991 and 1996 and 48% of the isolates between 1997 and 2001 (P = .28); this was consistent across age groups. C parapsilosis increased from 6% to 25% of fungal isolates during the same period (P = .03). Notably, this increase was more pronounced in the <3 age group, in which the rate increased from 5% (1 of 19) to 36% (12 of 33; P = .01). Of 4 neonates with fungal infections between 1997 and 2001, all 4 grew C albicans. However, 1 of 2 neonates between 1997 and 2001 grew C parapsilosis, whereas the other grew C albicans. The rate of C glabrata fungemia fell from 9% to 2% during the 2 periods (P = .07), whereas the rates of C lusitaniae and C tropicalis remained fairly constant for the duration of the study. C krusei fungemia was noted only in the second half of the study in children >3, and, conversely, C guilliermondi was present only in the first 5 years (Fig 3).
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Underlying Illness
Immunocompromised patients constituted 63% (61 of 97) of all patients with positive fungal blood cultures. Fungemic immunocompromised patients had the following conditions: malignancy/bone marrow transplantation (n = 17); hepatic failure/liver transplantation (n = 25), congenital malformation/premature infant with or without cerebral palsy (n = 16), and other immune deficiencies (n = 3). Fungemic immunocompetent patients had the following conditions: short bowel syndrome (n = 13), congenital heart disease/cardiac surgery (n = 19), and other conditions (n = 4).
Inpatient Course
The average number of patient-days for inpatients with fungemia was 28.7, although nearly half (47%) were hospitalized for 
2 weeks before a positive fungal culture. Of 97 fungemic patients, 24% were classified as having outpatient-acquired fungemia, whereas 13% had 7 or fewer patient-days, 9% had between 8 and 14 days, 17% had between 15 and 21 days, and 37% had >21 days of admission.
The average number of antimicrobial-days was 9.9. More than half (55%) of the patients had >1 week of previous broad-spectrum antibiotic therapy. Of 97 fungemic patients, 22% had 7 or fewer antimicrobial-days, 23% had between 8 and 14 days, and 32% had >15 days of previous treatment, whereas 23% did not have previous antimicrobial treatment.
Multiorgan Involvement
Nearly half (46 of 97) of patients demonstrated evidence of fungal infection with multiorgan involvement. A higher number of positive blood cultures per patient were associated with a higher frequency of fungal infections with multiorgan involvement, regardless of whether fungal growth occurred in bacterial or fungal cultures. Fungal infection with multiorgan involvement was present in 32% of patients with 1, 48% with 2, 64% with 3 to 6, and 75% with >6 positive fungal blood cultures.
Outcome
Mortality from all causes improved only modestly over time: 50% (16 of 32) of patients with fungemia died between 1991 and 1996, whereas 45% (29 of 65) died between 1997 and 2001 (P = .62). All-cause mortality for immunocompromised patients, 57% (35 of 61), was significantly higher than for immunocompetent patients, 28% (10 of 36), throughout the entire study period (P = .005). Outcomes for different immunocompromised conditions were as follows: among patients with malignancy/bone marrow transplantation, 12 (71%) of 17 died, among which 5 of 8 with acute lymphoblastic leukemia died. For hepatic failure/liver transplantation patients, 14 (56%) of 25 died. For congenital malformation/premature infant conditions, 6 (38%) of 16 patients died. Of patients with other immune deficiencies, including AIDS, 3 (100%) of 3 died.
All-cause mortality for fungemia with multiorgan involvement, 59% (27 of 46), was significantly higher than for fungemia without multiorgan involvement, 35% (18 of 51; P = .02). The all-cause mortality rate was lower among patients with Candidemia than among those with fungemia caused by other organisms in more recent years (from 1997 to 2001). Noncandida fungemia, although a rare event, carried an extremely high mortality rate, as 6 of 9 patients died. All patients with Scedosporium (n = 1), Coccidioides (n = 1), Aureobasidium (n = 2), and Acremonium (n = 1) fungemia died. One of 3 patients with Malassezia fungemia died, whereas the only patient with Rhodotorula fungemia survived (Table 2).
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Cost-Effectiveness
Approximately $39 per fungal blood culture and $34 per bacterial blood culture were charged during the study period, with $2.52 million charged for 72960 blood cultures performed, including bacterial and fungal cultures. The 14592 fungal blood cultures composed 20% of the total number of blood cultures obtained, accounting for charges in excess of $560000. However, 1.9% (272 of 14592) of fungal blood cultures were positive for fungal isolates, with 0.7% (97 of 24490) of the pediatric inpatient population having evidence of fungemia. Given that fungal blood cultures identified 14 patients independent of bacterial blood cultures, at a total cost of $560000, on average $40000 per uniquely identified patient was spent on screening fungal blood cultures.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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At our tertiary institution over 11 years, a moderate but significant increase in the incidence of fungal colonization or infection in pediatric inpatients was observed. Of 3663 total positive fungal cultures, it is likely that
78% reflected colonization as opposed to infection, on the basis of the source of the specimens. Nonetheless, in fungemic patients, evidence of colonization of other body sites correlated with disease severity. Particularly in children who were younger than 3 years, the rise in positive fungal cultures exceeded the rise in inpatient admissions. The number of immunocompromised pediatric patients who were admitted to our hospital steadily increased during the study period. Cases of pediatric fungemia, particularly in immunocompromised patients, increased significantly, confirming trends found at other institutions.12,13 The vast majority of patients with fungemia, regardless of immune status, had a chronic disease process that required prolonged and multiple hospitalizations and the presence of indwelling catheters. Morbidity and mortality rates did not improve appreciably over 11 years despite significant improvements in supportive care, a finding consistent with studies conducted in adult fungemic patients.1,14
Among 14592 fungal blood cultures that were drawn during the study period, <2% (272) were positive, with <1% (97) of admitted pediatric patients having evidence of fungemia. Cultures captured only a subset of patients with more advanced, disseminated disease. In cases of fungemia without multiorgan involvement, the numbers of positive cultures were significantly less than among patients with invasive bloodstream infections. At our institution, there was significant use of empiric antifungal therapy among pediatric inpatients with clinical findings suggestive of fungemia, with favorable clinical responses overall. These patients, however, generally failed to demonstrate fungal growth in blood cultures.19
The addition of fungal blood cultures to bacterial blood cultures as part of routine assessments of febrile patients yielded limited clinical information at a high cost. In the absence of alternative diagnostic methods and the high morbidity and mortality of fungemia, the performance of expensive blood cultures is the only available option. Of 97 patients with fungemia, fungal blood assays identified an additional 14% (14 of 97) not also identified by bacterial blood culture drawn on the same day. Eight of 14 patients had the same pathogen identified concurrently from other body sites. Given that fungal blood cultures identified only 14 patients independent of bacterial blood cultures, at a total charge of $560000, on average $40000 per uniquely identified patient was spent on screening fungal blood cultures. Therefore, the routine, widespread use of fungal blood cultures for assessment of fungemia in febrile patients should be revisited, with specific risk factors also taken into consideration, such as the presence of central venous catheters, prematurity, or prolonged use of antibiotics.
The yield of a positive fungal blood culture was highest for selected patients for whom there was a strong suspicion or evidence of fungal infection in other body sites. As expected, the number of positive cultures correlated with disease severity, as described in other studies.17 In this case, all 14 patients with fungemia identified only with positive fungal blood culture had no more than 1 positive fungal blood culture as well as no more than 1 positive culture from any body site, suggesting a lower fungal burden. A significantly lower percentage of these patients (14%; 2 of 14), compared with those with concurrent positive bacterial cultures for fungus (52%; 44 of 85), had clinical evidence of fungal infections with multiorgan involvement.
This study corroborates the serious threat posed by fungal infections to immunocompromised individuals, as these patients had a significantly higher frequency of fungal infections with multiorgan involvement and death. All-cause mortality rates were higher in immunocompromised (57%) children than in less immunodeficient patients (28%). In particular, mortality rates for malignancy/bone marrow transplantation (71%) and for hepatic failure/liver transplantation patients (56%) were high. All-cause mortality rates were related to disease severity: 59% for fungemia with multiorgan involvement compared with 35% for fungemia without multiorgan involvement. The use of broad-spectrum antibacterial agents steadily increased the colonization of patients with fungal organisms, predisposing them to infection.4,5,17 More than half of our patients had used antibiotics for at least 1 week immediately before the diagnosis of fungemia, whereas fewer than one fourth did not have previous antimicrobial treatment.
More than 90% of the fungemia cases were attributable to Candida species. The Candida organisms identified in the blood changed significantly over time, although C albicans remained the most common pathogen. The significant rise in C parapsilosis in this study corroborates previous studies in children and neonates in particular.20–22 The changes in Candida flora are potentially attributable to increasing use of specific antifungal agents, such as a higher rate of fluconazole use in the second half of the study period, as well as more widespread use of empirical amphotericin B in later years.23
This study identified the need for improved diagnostic markers of fungemia, given the low yield and cost-ineffectiveness of fungal blood cultures. Improved diagnostic methods with improved performance in early detection and identification of fungal infections, such as polymerase chain reaction-based assays, are in high demand. Coupled with a broadened antifungal therapeutic arsenal, such tests could significantly reduce adverse morbidity and mortality outcomes for the expanding population of hospitalized pediatric patients who are immunocompromised or experience chronic underlying illnesses.
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ACKNOWLEDGMENTS |
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We thank Enzon Pharmaceuticals for travel support.
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FOOTNOTES |
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Accepted Oct 27, 2004.
Address correspondence to Karin Nielsen, MD, MPH, Department of Pediatrics, University of California, MDCC 22-442, 10833 Le Conte Ave, Los Angeles, CA 90095. E-mail: knielsen{at}mednet.ucla.edu
Results from this study were presented at the Fifth International Conference of the Hospital Infection Society; September 15–18, 2002; Edinburgh, Scotland; and the Western regional meetings of the Society for Pediatric Research; February 1–3, 2003; Carmel, CA.
No conflict of interest declared.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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