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Epidemiology and outcome of multiple-species candidemia at a tertiary care center between 2004 and 2007
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Diagnostic Microbiology and Infectious Disease 64 (2009) 289 – 294 www.elsevier.com/locate/diagmicrobio
Epidemiology and outcome of multiple-species candidemia at a tertiary care center between 2004 and 2007☆ Heather L. Nacea,b,⁎, David Hornc,1 , Dionissios Neofytosc,d,2 a
Section of Infectious Diseases, Temple University School of Medicine, Philadelphia, PA 19140, USA b Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA c Division of Infectious Diseases, Thomas Jefferson University, Philadelphia, PA 19107, USA d Division of Infectious Disease, School of Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA Received 23 December 2008; accepted 16 March 2009
Abstract The incidence of multiple-species candidemia (MSC) among cases of candidemia ranges between 2.8% and 8.0%. We sought to study the epidemiology and outcome of MSC at a tertiary care center. A retrospective analysis of MSC episodes occurring between 2004 and 2007 was performed. MSC was defined as ≥2 different Candida spp. growing concomitantly within the same blood culture bottle or within 72 h of each other. Information on demographics, comorbidities, antifungal use, and survival was collected. Forty MSC patients with 81 Candida isolates were identified. Non-albicans Candida spp. (54 of 81 isolates, 66.7%) were more frequently identified. The most common combinations observed were Candida albicans/Candida glabrata (15 of 40 patients, 37.5%), C. albicans/Candida parapsilosis (8, 20.0%), and C. glabrata/Candida krusei (5, 12.5%). The overall crude 4- and 12- week mortality, excluding patients lost to follow-up, was 41.9% and 66.7%, respectively. In this contemporary sampling of patients with MSC, the combination of C. albicans/C. glabrata was most frequently observed and mortality was high. © 2009 Elsevier Inc. All rights reserved. Keywords: Multiple species; Candidemia; Fungemia
1. Introduction Candidemia is the 4th most common cause of nosocomial bloodstream infections (BSIs) in the United States, representing 7.6% to 9.0% of all nosocomial bloodstream pathogens (Edmond et al., 1999; Wisplinghoff et al.,
Part of this manuscript was presented at the annual meeting of the Infectious Diseases Society of America, Washington, DC, October 24–27, 2008. Poster session M-721. ☆ Institute where work was performed: Thomas Jefferson University 125 S. 9th St., Ste 403 Philadelphia, PA 19107. ⁎ Corresponding author. Section of Infectious Diseases, Temple University School of Medicine, Philadelphia, PA 19140, USA. Tel.: +1215-707-1982; fax: +1-215-707-4414. E-mail address: [email protected] (H.L. Nace). 1 D.H. has received grant support (research) from Astellas (Deerfield, Illinois), has been a member of a scientific advisory board for Astellas, and has received speaking honoraria from Astellas, Pfizer (New York, NY), and Roche (Nutley, NJ). 2 D.H. has received grant support (research) from Astellas. 0732-8893/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2009.03.010
2004). Candidemia has been associated with the highest crude mortality of all nosocomial BSIs in the United States (Edmond et al., 1999), with rates ranging between 30.0% and 81.0% (Anaissie et al., 1998; Chen et al., 2006; Edmond et al., 1999; Morgan et al., 2005; Nieto-Rodriguez et al., 1996; Poikonen et al., 2003). Although Candida albicans has traditionally been the most commonly identified species in patients with candidemia (Pfaller and Diekema, 2007), nonalbicans Candida spp. are becoming increasingly more prevalent (Nguyen et al., 1996). Less frequently encountered, multiple-species candidemia (MSC) has been reported to have an incidence among cases of candidemia ranging between 2.8% and 8.0% (Boktour et al., 2004; Guerra-Romero et al., 1989; Jensen et al., 2007; Klotz et al., 2007; Pulimood et al., 2002). Bacterial polymicrobial BSIs have been associated with higher mortality rates compared with monomicrobial BSIs (Weinstein et al., 1986). We hypothesized that patients with MSCs would have a worse outcome as opposed to patients with single-species candidemia. We conducted a
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retrospective study of the epidemiology and outcome of MSC at Thomas Jefferson University Hospital (TJUH) in Philadelphia, PA.
2. Materials and methods 2.1. Study design A retrospective analysis of all episodes of MSC between 2004 and 2007 at TJUH was performed. Cases were identified by review of the microbiology and the infectious disease consultation records from January 2004 to December 2007. TJUH is a large tertiary care teaching hospital in innercity Philadelphia with 950 acute care beds. All specialties are represented, including medicine, hematology and oncology, bone marrow and solid organ transplantation, as well as multiple surgical subspecialties. The study was approved by the institutional review board of TJUH. 2.2. Definitions MSC was defined as isolation of greater than or equal to 2 different species of Candida growing concomitantly within the same blood culture bottle or growing within 72 h of each other from separate culture bottles. Candidemia diagnosis was based on published guidelines (Pappas et al., 2004). Briefly, candidemia was defined as identification of Candida spp. in blood cultures with associated clinical symptoms or signs (e.g., fever, etc.). Therapy was defined as empiric (initiation of antifungal treatment at the time of the report of visualization of yeast on Gram stain or a positive yeast culture before species identification), monotherapy (administration of 1 antifungal agent throughout the entire treatment course), combination (concomitant administration of 2 or more antifungal agents), and sequential (administration of more than 1 agent sequentially).
diagnosis). Detailed data collection and assessment was performed on all positive blood cultures for Candida spp., including the number of positive blood culture bottles, duration of culture positivity for each species isolated, concomitant (within 72 h) isolation or not of different Candida spp., and for the latter, the number of days between different species isolation. Information on antifungal therapy administered, including the specific antifungal agent(s) and dose used, combination therapy, sequential versus concomitant administration of antifungal treatment, and duration of treatment was collected. Central line removal and timing of removal based on the day the fungal blood culture was drawn were also assessed. Four- and 12-week mortality rates were assessed. 2.4. Microbiologic methods Blood culture samples were processed using the MicroScan system (Sacramento, CA). Blood was subcultured to Sabouraud and CHROMagar Candida plates (CHROMagar, Paris, France) and incubated at 35 °C for a minimum of 1 week. Susceptibility testing for all Candida spp. was performed using the YeastOne colorimetric antifungal panel (Trek Diagnostics, Westlake, OH). Antifungal agents tested for susceptibility included fluconazole, itraconazole, ketoconazole, amphotericin B, caspofungin, and flucytosine. MIC breakpoints used for the assessment of antifungal susceptibility followed established guidelines by the Clinical and Laboratory Standards Institute (Wayne, PA). 2.5. Analysis Statistical analysis was performed using the SAS system (SAS, Cary, NC, USA). Survival distribution function was estimated using the Kaplan–Meier product-limit method. Categoric variables were analyzed using the χ2 test. A P value of ≤0.05 was considered significant.
2.3. Variables Records were reviewed to determine demographic data, including age, gender, and ethnicity. Comorbidities were assessed, including dialysis dependence, diabetes mellitus, human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), coronary artery disease, and malignancy. Other risk factors assessed included prior antifungal therapy (within 30 days before the diagnosis of candidemia), parenteral nutrition, mechanical ventilation, admission to the intensive care unit, use of central venous catheters (including peripherally inserted central catheters, tunneled and nontunneled central catheters, and arterial lines), previous surgery (within 30 days before the diagnosis of candidemia), corticosteroid use (within 30 days before the diagnosis of candidemia), neutropenia (absolute neutrophil count of ≤500 cells/mm3, within 30 days before diagnosis), immunosuppression, concomitant bacterial infections (culture-confirmed infections diagnosed within 7 days before diagnosis), and antibiotic use (within 7 days before
3. Results During the 4-year study period, 40 (7.6%) of 526 patients with candidemia met the definition for MSC. A total of 81
Fig. 1. Frequency of patients with multiple- versus single-species candidemia between 2004 and 2007 [Results are presented as the absolute number of patients with candidemia per year].
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Candida isolates from 40 patients with MSC were identified: 39 patients had 2 and 1 patient had 3 Candida spp. isolated. A trend toward decreasing incidence of MSC was found: 14 episodes occurred in the 1st year, 11 in the 2nd, 8 in the 3rd, and 7 in the last year. This parallels a significant drop in overall candidemia incidence rates reported in our hospital between 2004 and 2007 (Fig. 1) (Neofytos et al., 2007). 3.1. Baseline patient characteristics The baseline patient characteristics are summarized in Table 1. Most of the patients with MSC were male (n = 22, 55.0%) and Caucasian (n = 23, 57.5%), with a mean age of 60.75 years. A total of 19 (47.5%) patients were treated in the intensive care unit, and 21 (52.5%) patients received
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parenteral nutrition. One patient was neutropenic (2.5%) and 14 (35.0%) received corticosteroids. Nineteen (44.2%), 15 (34.9%), and 9 (20.9%) patients had peripherally inserted, nontunneled, and tunneled central venous catheters, respectively, and 2 patients (5.0%) did not have central venous access. Most of the patients (n = 21, 52.5%) were on the general medical service, and 15 (37.5%) were cared for by surgical services. Median duration of hospital stay was 32 days (range, 4–130 days). Non-albicans Candida spp. (n = 54 isolates, 66.7%) were collectively more commonly identified compared with C. albicans (n = 27, 33.3%). The most common species isolated were C. albicans (n = 27 isolates, 33.3%) and Candida glabrata (n = 27, 33.3%), followed by Candida parapsilosis (n = 14, 17.3%), Candida tropicalis (n = 6, 7.4%), Candida
Table 1 Baseline patient characteristics P valuea
Patient characteristics
All patients, n = 40 (%)
CALB/CGLA, n = 15 (%)
CALB/CPAR, n = 8 (%)
CGLA/CKRU, n = 5 (%)
Age (mean, range) (year) Gender, male Ethnicity Caucasian African American Asian Unknown Prior antifungal therapy (≤30 days prior) Comorbidities/risk factorsb Dialysis dependent Diabetes mellitus Total parenteral nutrition Coronary artery disease Malignancy ICU/mechanical ventilation Previous surgery (≤30 days prior) Corticosteroid therapy (≤30 days prior) HIV/AIDS Central intravenous catheterb,c Peripherally inserted Tunneled Nontunneled Bacterial infection (≤7 days prior)b,d Genitourinary Pulmonary Bacteremia Clostridium difficile colitis Otherd Previous antibiotics (≤7 days prior) 1 agent ≥2 agents Underlying diseaseb General medicine Surgery Solid tumor
60.75 (34–86) 22 (55.0)
64.4 (36–86) 9 (60.0)
59.25 (39–78) 5 (62.5)
54 (36–60) 0
23 (57.5) 13 (32.5) 1 (2.5) 3 (7.5) 11 (27.5)
8 (53.3) 5 (33.3) 0 2 (13.3) 5 (33.3)
5 (62.5) 2 (25.0) 0 1 (12.5) 2 (25.0)
4 (80.0) 1 (20.0) 0 0 2 (40.0)
6 9 21 13 11 19 17 14 2
1 (6.7) 3 (20.0) 10 (66.7) 7 (46.7) 5 (33.3) 8 (53.3) 6 (40.0) 4 (26.7) 1 (6.7)
1 (12.5) 2 (25.0) 4 (50.0) 3 (37.5) 2 (25.0) 3 (37.5) 5 (62.5) 1 (12.5) 0
0 0 3 (60.0) 2 (40.0) 0 2 (40.0) 2 (40.0) 3 (60.0) 0
0.69 0.49 0.74 0.91 0.33 0.73 0.56 0.18
19 (44.2) 9 (20.9) 15 (34.9)
6 (40.0) 3 (20.0) 6 (40.0)
4 (57.1) 2 (28.6) 1 (14.3)
5 (100.0) 0 0
0.06 0.49 0.13
4 10 17 2 9
2 (10.5) 2 (10.5) 9 (47.4) 1 (5.3) 5 (26.3)
0 2 (40.0) 2 (40.0) 0 1 (20.0)
0 2 (40.0) 0 0 3 (60.0)
6 (16.2) 31 (83.8)
2 (13.3) 13 (86.7)
1 (16.7) 5 (83.3)
1 (20.0) 4 (80.0)
0.92 0.40
21 (52.5) 15 (37.5) 5 (12.5)
5 (33.3) 8 (53.3) 2 (13.3)
5 (62.5) 3 (37.5) 1 (12.5)
3 (60.0) 2 (40.0) 0
0.33 0.73 0.69
(15.0) (22.5) (52.5) (32.5) (27.5) (47.5) (42.5) (35.0) (5.0)
(9.5) (23.8) (40.5) (4.8) (21.4)
0.57 0.82
0.84
0.43 0.04
CALB = C. albicans; CGLA = C. glabrata; CPAR = C. parapsilosis; CKRU = C. krusei; ICU = intensive care unit. a P value refers to the statistical analysis results from the comparison of the 3 most commonly identified Candida spp. combinations. b Comorbidities/risk factors, central intravenous catheter, bacterial infections, and underlying disease were not mutually exclusive (patients could have more than 1). c A total of 43 lines were observed in 38 patients; 15, 7, and 5 central lines were noted in patients with CALB/CGLA, CALB/CPAR, and CGLA/CKRU, respectively. d Includes intracranial infections, septic arthritis, osteomyelitis, intra-abdominal, and wound infections.
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krusei (n = 5, 6.2%), Candida dubliniensis (n = 1, 1.2%), and Candida lusitaniae (n = 1, 1.2%). The most frequently encountered combinations were C. albicans and C. glabrata (n = 15 patients, 37.5%), C. albicans and C. parapsilosis (n = 8, 20.0%), and C. glabrata and C. krusei (n = 5, 12.5%). 3.2. Antifungal treatment Median duration of treatment (from the day of the 1st positive culture) was 14 days (range, 0–97). A total of 31 (77.5%) patients received fluconazole, 18 (45.0%) received caspofungin, and 7 (17.5%) received voriconazole. Notably, amphotericin B products were not used in any patient in this series. Empiric treatment with fluconazole was administered in 19 (47.5%), caspofungin in 14 (35.0%), and voriconazole in 4 (10.0%) patients. A total of 18 (45.0%) patients received monotherapy: 14 (35.0%) with fluconazole, 3 (7.5%) with caspofungin, and 1 (2.5%) with voriconazole. Antifungal agents were not administered concomitantly in any of the cases. Nineteen patients received sequential therapy: 11 with caspofungin followed by fluconazole (n = 9) or voriconazole (n = 2), 4 with fluconazole followed by caspofungin, 3 with voriconazole followed by fluconazole, and 1 with fluconazole followed by voriconazole. In some cases, caspofungin was subsequently replaced by fluconazole, when fluconazolesusceptible Candida spp. were identified, such as C. albicans or C. parapsilosis. In cases where fluconazole was administered empirically followed by caspofungin or voriconazole, the growth of intrinsically fluconazole-resistant or potentially fluconazole-resistant Candida spp. such as C. krusei or C. glabrata was observed in 4 (80.0%) of 5 cases. No treatment was administered in 3 (7.5%) patients. One patient was discharged from the hospital before positive culture results. The 2nd patient died before positive cultures. In the 3rd patient, the positive culture for 2 Candida spp. was drawn from a femoral central venous catheter, the line was removed, all subsequent blood cultures were negative, and the patient was not treated. Notably, of the 43 central intravenous catheters observed in 38 patients, 39 (90.7%) were removed, with 29 of them removed within 2 days of the diagnosis of MSC. 3.3. Outcome A total of 9 and 16 patients were lost to follow-up at 4 and 12 weeks, respectively. Of the remaining patients, 13 (of 31, 41.9%) and 16 (of 24, 66.7%) patients had expired at 4- and 12-week follow-up. Notably, 1 patient died before treatment could be initiated. The Kaplan–Meier survival curve for 12 weeks is illustrated in Fig. 2A. Patients with the 3 most common Candida spp. combinations, C. albicans and C. glabrata (n = 15), C. albicans and C. parapsilosis (n = 8), and C. glabrata and C. krusei (n = 5), were compared for baseline characteristics and clinical outcome. There were no significant differences found regarding demographics, comorbidities, prior anti-
Fig. 2. Kaplan–Meier survival curves at 12-week follow-up for patients with MSC (A) overall and (B) based on most commonly observed species combinations.
fungal therapy, or other risk factors among these patient groups (Table 1). Similarly, survival among these patient groups did not appear to significantly differ (log-rank test, P = 0.24; Fig. 2B).
4. Discussion This study represents, to our knowledge, the largest sampling to date of MSC for a 4-year period, reporting an overall incidence among all cases of candidemia between 2004 and 2007 of 7.6%. Prior studies have reported an incidence of MSC of 2.8% to 8.0% (Boktour et al., 2004; Guerra-Romero et al., 1989; Jensen et al., 2007; Klotz et al., 2007; Pulimood et al., 2002). Our findings are in accordance with prior reports and suggest that MSC remains a significant problem among patients at risk for candidemia. A search of the literature found 4 case series specifically addressing MSC. Guerra-Romero et al. (1989) reported 22 patients from 1972 to 1985 and found similar clinical setting, risk factors, and mortality as monomicrobial fungemia. Pulimood et al. (2002) described 16 patients with MSC from 1992 to 2000 and found similar crude mortality rates to monomicrobial candidemia, but polymicrobial candidemia was reported in sicker nononcologic patients with frequent concomitant bacterial infections. Boktour et al. (2004) reported on 33 patients with cancer between 1993 and 2000 with MSC and found MSC patients were more likely to have leukemia, prolonged neutropenia before infection,
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chemotherapy within 1 month, higher Acute Physiology and Chronic Health Evaluation II scores, and previous antifungal prophylaxis versus those patients with C. albicans candidemia, although 30-day overall mortality rates did not significantly differ among the 2 patient populations. Jensen et al. (2007) described 15 patients with mixed fungemia between 1985 and 2006 and found that patients with MSC more frequently experienced organ transplant and surgery but less frequently received parenteral nutrition or intravenous lines. They also had a lower incidence of shock and lower overall mortality compared with monomicrobial fungemia, but no statistically significant difference in related mortality was found. Excluding the patients that were lost to follow-up, we report an overall, crude 4-week mortality of 41.9%, similar to previous reported rates for MSC (Boktour et al., 2004; Pulimood et al., 2002). However, 2 other groups have reported different mortality rates for MSC (Guerra-Romero et al., 1989; Jensen et al., 2007). Mortality as high as 59.0% was reported by Guerra-Romero et al., which may, in part, be explained by the lower incidence of candidemia in the 1970s to 1980s, leading to a lower clinical suspicion and timely initiation of treatment and/or the paucity of effective and safe antifungal therapeutic agents at the time. The lowest mortality (20.0%) among patients with MSC was reported by Jensen et al., but the results may have been biased by the small number of patients included in this study. The fairly high 12-week mortality rate of 66.7% reported in our study may, in part, be explained by the small number of patients included in this series (n = 40) and the significant number of patients (n = 16 of 40, 40.0%) that were lost to follow-up at 12-weeks. In most of the previous series of MSC, C. albicans has been the most common species identified (Boktour et al., 2004; Jensen et al., 2007; Pulimood et al., 2002). In contrast, we observed similar numbers for C. albicans and C. glabrata, whereas collectively, non-albicans Candida spp. were most commonly identified. This is consistent with a reported trend of increasing rates of non-albicans candidemia in North America (Abi-Said et al., 1997; Chang et al., 2008; Horn et al., 2007; Nguyen et al., 1996; Pfaller et al., 1998; Trick et al., 2002). Consistent with prior reports, the most common combination observed was C. albicans and C. glabrata. A total of 5 patients were diagnosed with C. krusei MSC in this series; 2 of them had been prophylactically treated with fluconazole. C. krusei is an intrinsically fluconazole-resistant species and has been increasingly identified as a pathogen in this decade, perhaps as a result of the more frequent use of fluconazole for prophylaxis in high-risk patient populations (Chow et al., 2008). Boktour et al. reported that MSCs occurred with increased frequency in patients with leukemia, prolonged neutropenia, and recent chemotherapy. In this series, only 1 patient was neutropenic and 11 patients had an underlying malignancy, none of which was hematologic. Although solid organ transplantation has been reported as a risk factor for MSC
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(Jensen et al., 2007), none of the cases in this series were observed in a transplant recipient. This may be because of an aggressive antifungal prophylaxis protocol followed by the solid organ and stem cell transplant teams in our institution as well as guidelines for antifungal prophylaxis and empiric treatment for patients with neutropenic fevers. MSC may represent a therapeutic challenge because the treating physician has to administer effective and safe treatment targeting more than 1 species. Fluconazole was the most commonly prescribed therapeutic agent for initial therapy for MSC, with caspofungin being increasingly used as the study period progressed. Sequential therapy was observed in close to half of the cases described. Notably, no patients were treated with amphotericin B products. Although this may represent the treatment policy observed in a single institution, recent data suggest that conventional amphotericin B is less frequently used (Horn and Neofytos, 2007). This may be the result of the advent and validation of highly active, better tolerated, and less toxic antifungal agents. We have already reported decreasing rates of candidemia in our institution during the same study period (Neofytos et al., 2007). This may, in part, be the result of more stringent infection control practices implemented during the study period. However, with the increasing use of central venous catheters, total parenteral nutrition, immunosuppressive and antibacterial agents, and other factors in the recent years that have led to a sicker patient population, vigilance for the timely identification and management of single-species candidemia and MSC should be reinforced. This study has a number of limitations. This is a retrospective, observational, single institution study with a relatively small number of patients. The study design also did not allow for the calculation of attributable mortality because of MSC. In conclusion, we report the largest contemporary sampling of MSC to date. Non-albicans Candida spp. were collectively isolated more frequently than C. albicans. MSC is an entity occasionally observed in the clinical setting with mortality rates remaining high and similar to prior reported results for patients with MSC. Acknowledgments The authors would like to thank Mindy Tokarczyk from the Department of Microbiology, Thomas Jefferson University Hospital (Philadelphia, PA, USA), for her significant help. References Abi-Said D, Anaissie E, Uzun O, Raad I, Pinzcowski H, Vartivarian S (1997) The epidemiology of hematogenous candidiasis caused by different Candida species. Clin Infect Dis 24:1122–1128. Anaissie EJ, Rex JH, Uzun O, Vartivarian S (1998) Predictors of adverse outcome in cancer patients with candidemia. Am J Med 104:238–245. Boktour MR, Kontoyiannis DP, Hanna HA, Hachem RY, Girgawy E, Bodey GP, Raad II (2004) Multiple-species candidemia in patients with cancer. Cancer 101:1860–1865.
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Chang A, Neofytos D, Horn D (2008) Candidemia in the 21st century. Future Microbiol 3:463–472. Chen S, Slavin M, Nguyen Q, Marriott D, Playford EG, Ellis D, Sorrell T (2006) Active surveillance for candidemia, Australia. Emerg Infect Dis 12:1508–1516. Chow JK, Golan Y, Ruthazer R, Karchmer AW, Carmeli Y, Lichtenberg D, Chawla V, Young J, Hadley S (2008) Factors associated with candidemia caused by non-albicans Candida species versus Candida albicans in the intensive care unit. Clin Infect Dis 46:1206–1213. Edmond MB, Wallace SE, McClish DK, Pfaller MA, Jones RN, Wenzel RP (1999) Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis 29:239–244. Guerra-Romero L, Telenti A, Thompson RL, Roberts GD (1989) Polymicrobial fungemia: microbiology, clinical features, and significance. Rev Infect Dis 11:208–212. Horn DL, Fishman JA, Steinbach WJ, Anaissie EJ, Marr KA, Olyaei AJ, Pfaller MA, Weiss MA, Webster KM, Neofytos D (2007) Presentation of the PATH Alliance registry for prospective data collection and analysis of the epidemiology, therapy, and outcomes of invasive fungal infections. Diagn Microbiol Infect Dis 59:407–414. Horn DL, Neofytos D (2007) Contemporary patterns in the use of antifungal agents in the treatment of invasive fungal infections: perspectives from registries and databases. Curr Fungal Infect Rep 1:72–78. Jensen J, Muñoz P, Guinea J, Rodríguez-Créixems M, Peláez T, Bouza E (2007) Mixed fungemia: incidence, risk factors, and mortality in a general hospital. Clin Infect Dis 44:e109–e114. Klotz SA, Chasin BS, Powell B, Gaur NK, Lipke PN (2007) Polymicrobial bloodstream infections involving Candida species: analysis of patients and review of the literature. Diagn Microbiol Infect Dis 59:401–406. Morgan J, Meltzer MI, Plikaytis BD, Sofair AN, Huie-White S, Wilcox S, Harrison LH, Seaberg EC, Hajjeh RA, Teutsch SM (2005) Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-based candidemia surveillance. Infect Control Hosp Epidemiol 26:540–547.
Neofytos D, Katz-Slenker A, Horn D (2007) Candidemia incidence, Candida spp. epidemiology and antifungal use in a tertiary care center. Poster Session, Abstract # 167, IDSA, San Diego CA. Nguyen MH, Peacock Jr JE, Morris AJ, Tanner DC, Nguyen ML, Snydman DR, Wagener MM, Rinaldi MG, Yu VL (1996) The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance. Am J Med 100:617–623. Nieto-Rodriguez JA, Kusne S, Manez R, Irish W, Linden P, Magnone M, Wing EJ, Fung JJ, Starzl TE (1996) Factors associated with the development of candidemia and candidemia-related death among liver transplant recipients. Ann Surg 223:70–76. Pappas PG, Rex JH, Sobel JD, Filler SG, Dismukes WE, Walsh TJ, Edwards JE (2004) Guidelines for treatment of candidiasis. Clin Infect Dis 38:161–189. Pfaller MA, Jones RN, Messer SA, Edmond MB, Wenzel RP, SCOPE Participant Group (1998) National surveillance of nosocomial blood stream infection due to species of Candida other than Candida albicans: frequency of occurrence and antifungal susceptibility in the SCOPE Program. Diagn Microbiol Infect Dis 30:121–129. Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133–163. Poikonen E, Lyytikainen O, Anttila VJ, Ruutu P (2003) Candidemia in Finland, 1995–1999. Emerg Infect Dis 9:985–990. Pulimood S, Ganesan L, Alangaden G, Chandrasekar P (2002) Polymicrobial candidemia. Diagn Microbiol Infect Dis 44:353–357. Trick WE, Fridkin SK, Edwards JR, Hajjeh RA, Gaynes RP (2002) Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989–1999. Clin Infect Dis 35:627–630. Weinstein MP, Reller LB, Murphy JR (1986) Clinical importance of polymicrobial bacteremia. Diagn Microbiol Infect Dis 5:185–196. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39:309–317.
Diagnostic Microbiology and Infectious Disease 64 (2009) 289 – 294 www.elsevier.com/locate/diagmicrobio
Epidemiology and outcome of multiple-species candidemia at a tertiary care center between 2004 and 2007☆ Heather L. Nacea,b,⁎, David Hornc,1 , Dionissios Neofytosc,d,2 a
Section of Infectious Diseases, Temple University School of Medicine, Philadelphia, PA 19140, USA b Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA c Division of Infectious Diseases, Thomas Jefferson University, Philadelphia, PA 19107, USA d Division of Infectious Disease, School of Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA Received 23 December 2008; accepted 16 March 2009
Abstract The incidence of multiple-species candidemia (MSC) among cases of candidemia ranges between 2.8% and 8.0%. We sought to study the epidemiology and outcome of MSC at a tertiary care center. A retrospective analysis of MSC episodes occurring between 2004 and 2007 was performed. MSC was defined as ≥2 different Candida spp. growing concomitantly within the same blood culture bottle or within 72 h of each other. Information on demographics, comorbidities, antifungal use, and survival was collected. Forty MSC patients with 81 Candida isolates were identified. Non-albicans Candida spp. (54 of 81 isolates, 66.7%) were more frequently identified. The most common combinations observed were Candida albicans/Candida glabrata (15 of 40 patients, 37.5%), C. albicans/Candida parapsilosis (8, 20.0%), and C. glabrata/Candida krusei (5, 12.5%). The overall crude 4- and 12- week mortality, excluding patients lost to follow-up, was 41.9% and 66.7%, respectively. In this contemporary sampling of patients with MSC, the combination of C. albicans/C. glabrata was most frequently observed and mortality was high. © 2009 Elsevier Inc. All rights reserved. Keywords: Multiple species; Candidemia; Fungemia
1. Introduction Candidemia is the 4th most common cause of nosocomial bloodstream infections (BSIs) in the United States, representing 7.6% to 9.0% of all nosocomial bloodstream pathogens (Edmond et al., 1999; Wisplinghoff et al.,
Part of this manuscript was presented at the annual meeting of the Infectious Diseases Society of America, Washington, DC, October 24–27, 2008. Poster session M-721. ☆ Institute where work was performed: Thomas Jefferson University 125 S. 9th St., Ste 403 Philadelphia, PA 19107. ⁎ Corresponding author. Section of Infectious Diseases, Temple University School of Medicine, Philadelphia, PA 19140, USA. Tel.: +1215-707-1982; fax: +1-215-707-4414. E-mail address: [email protected] (H.L. Nace). 1 D.H. has received grant support (research) from Astellas (Deerfield, Illinois), has been a member of a scientific advisory board for Astellas, and has received speaking honoraria from Astellas, Pfizer (New York, NY), and Roche (Nutley, NJ). 2 D.H. has received grant support (research) from Astellas. 0732-8893/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2009.03.010
2004). Candidemia has been associated with the highest crude mortality of all nosocomial BSIs in the United States (Edmond et al., 1999), with rates ranging between 30.0% and 81.0% (Anaissie et al., 1998; Chen et al., 2006; Edmond et al., 1999; Morgan et al., 2005; Nieto-Rodriguez et al., 1996; Poikonen et al., 2003). Although Candida albicans has traditionally been the most commonly identified species in patients with candidemia (Pfaller and Diekema, 2007), nonalbicans Candida spp. are becoming increasingly more prevalent (Nguyen et al., 1996). Less frequently encountered, multiple-species candidemia (MSC) has been reported to have an incidence among cases of candidemia ranging between 2.8% and 8.0% (Boktour et al., 2004; Guerra-Romero et al., 1989; Jensen et al., 2007; Klotz et al., 2007; Pulimood et al., 2002). Bacterial polymicrobial BSIs have been associated with higher mortality rates compared with monomicrobial BSIs (Weinstein et al., 1986). We hypothesized that patients with MSCs would have a worse outcome as opposed to patients with single-species candidemia. We conducted a
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retrospective study of the epidemiology and outcome of MSC at Thomas Jefferson University Hospital (TJUH) in Philadelphia, PA.
2. Materials and methods 2.1. Study design A retrospective analysis of all episodes of MSC between 2004 and 2007 at TJUH was performed. Cases were identified by review of the microbiology and the infectious disease consultation records from January 2004 to December 2007. TJUH is a large tertiary care teaching hospital in innercity Philadelphia with 950 acute care beds. All specialties are represented, including medicine, hematology and oncology, bone marrow and solid organ transplantation, as well as multiple surgical subspecialties. The study was approved by the institutional review board of TJUH. 2.2. Definitions MSC was defined as isolation of greater than or equal to 2 different species of Candida growing concomitantly within the same blood culture bottle or growing within 72 h of each other from separate culture bottles. Candidemia diagnosis was based on published guidelines (Pappas et al., 2004). Briefly, candidemia was defined as identification of Candida spp. in blood cultures with associated clinical symptoms or signs (e.g., fever, etc.). Therapy was defined as empiric (initiation of antifungal treatment at the time of the report of visualization of yeast on Gram stain or a positive yeast culture before species identification), monotherapy (administration of 1 antifungal agent throughout the entire treatment course), combination (concomitant administration of 2 or more antifungal agents), and sequential (administration of more than 1 agent sequentially).
diagnosis). Detailed data collection and assessment was performed on all positive blood cultures for Candida spp., including the number of positive blood culture bottles, duration of culture positivity for each species isolated, concomitant (within 72 h) isolation or not of different Candida spp., and for the latter, the number of days between different species isolation. Information on antifungal therapy administered, including the specific antifungal agent(s) and dose used, combination therapy, sequential versus concomitant administration of antifungal treatment, and duration of treatment was collected. Central line removal and timing of removal based on the day the fungal blood culture was drawn were also assessed. Four- and 12-week mortality rates were assessed. 2.4. Microbiologic methods Blood culture samples were processed using the MicroScan system (Sacramento, CA). Blood was subcultured to Sabouraud and CHROMagar Candida plates (CHROMagar, Paris, France) and incubated at 35 °C for a minimum of 1 week. Susceptibility testing for all Candida spp. was performed using the YeastOne colorimetric antifungal panel (Trek Diagnostics, Westlake, OH). Antifungal agents tested for susceptibility included fluconazole, itraconazole, ketoconazole, amphotericin B, caspofungin, and flucytosine. MIC breakpoints used for the assessment of antifungal susceptibility followed established guidelines by the Clinical and Laboratory Standards Institute (Wayne, PA). 2.5. Analysis Statistical analysis was performed using the SAS system (SAS, Cary, NC, USA). Survival distribution function was estimated using the Kaplan–Meier product-limit method. Categoric variables were analyzed using the χ2 test. A P value of ≤0.05 was considered significant.
2.3. Variables Records were reviewed to determine demographic data, including age, gender, and ethnicity. Comorbidities were assessed, including dialysis dependence, diabetes mellitus, human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), coronary artery disease, and malignancy. Other risk factors assessed included prior antifungal therapy (within 30 days before the diagnosis of candidemia), parenteral nutrition, mechanical ventilation, admission to the intensive care unit, use of central venous catheters (including peripherally inserted central catheters, tunneled and nontunneled central catheters, and arterial lines), previous surgery (within 30 days before the diagnosis of candidemia), corticosteroid use (within 30 days before the diagnosis of candidemia), neutropenia (absolute neutrophil count of ≤500 cells/mm3, within 30 days before diagnosis), immunosuppression, concomitant bacterial infections (culture-confirmed infections diagnosed within 7 days before diagnosis), and antibiotic use (within 7 days before
3. Results During the 4-year study period, 40 (7.6%) of 526 patients with candidemia met the definition for MSC. A total of 81
Fig. 1. Frequency of patients with multiple- versus single-species candidemia between 2004 and 2007 [Results are presented as the absolute number of patients with candidemia per year].
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Candida isolates from 40 patients with MSC were identified: 39 patients had 2 and 1 patient had 3 Candida spp. isolated. A trend toward decreasing incidence of MSC was found: 14 episodes occurred in the 1st year, 11 in the 2nd, 8 in the 3rd, and 7 in the last year. This parallels a significant drop in overall candidemia incidence rates reported in our hospital between 2004 and 2007 (Fig. 1) (Neofytos et al., 2007). 3.1. Baseline patient characteristics The baseline patient characteristics are summarized in Table 1. Most of the patients with MSC were male (n = 22, 55.0%) and Caucasian (n = 23, 57.5%), with a mean age of 60.75 years. A total of 19 (47.5%) patients were treated in the intensive care unit, and 21 (52.5%) patients received
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parenteral nutrition. One patient was neutropenic (2.5%) and 14 (35.0%) received corticosteroids. Nineteen (44.2%), 15 (34.9%), and 9 (20.9%) patients had peripherally inserted, nontunneled, and tunneled central venous catheters, respectively, and 2 patients (5.0%) did not have central venous access. Most of the patients (n = 21, 52.5%) were on the general medical service, and 15 (37.5%) were cared for by surgical services. Median duration of hospital stay was 32 days (range, 4–130 days). Non-albicans Candida spp. (n = 54 isolates, 66.7%) were collectively more commonly identified compared with C. albicans (n = 27, 33.3%). The most common species isolated were C. albicans (n = 27 isolates, 33.3%) and Candida glabrata (n = 27, 33.3%), followed by Candida parapsilosis (n = 14, 17.3%), Candida tropicalis (n = 6, 7.4%), Candida
Table 1 Baseline patient characteristics P valuea
Patient characteristics
All patients, n = 40 (%)
CALB/CGLA, n = 15 (%)
CALB/CPAR, n = 8 (%)
CGLA/CKRU, n = 5 (%)
Age (mean, range) (year) Gender, male Ethnicity Caucasian African American Asian Unknown Prior antifungal therapy (≤30 days prior) Comorbidities/risk factorsb Dialysis dependent Diabetes mellitus Total parenteral nutrition Coronary artery disease Malignancy ICU/mechanical ventilation Previous surgery (≤30 days prior) Corticosteroid therapy (≤30 days prior) HIV/AIDS Central intravenous catheterb,c Peripherally inserted Tunneled Nontunneled Bacterial infection (≤7 days prior)b,d Genitourinary Pulmonary Bacteremia Clostridium difficile colitis Otherd Previous antibiotics (≤7 days prior) 1 agent ≥2 agents Underlying diseaseb General medicine Surgery Solid tumor
60.75 (34–86) 22 (55.0)
64.4 (36–86) 9 (60.0)
59.25 (39–78) 5 (62.5)
54 (36–60) 0
23 (57.5) 13 (32.5) 1 (2.5) 3 (7.5) 11 (27.5)
8 (53.3) 5 (33.3) 0 2 (13.3) 5 (33.3)
5 (62.5) 2 (25.0) 0 1 (12.5) 2 (25.0)
4 (80.0) 1 (20.0) 0 0 2 (40.0)
6 9 21 13 11 19 17 14 2
1 (6.7) 3 (20.0) 10 (66.7) 7 (46.7) 5 (33.3) 8 (53.3) 6 (40.0) 4 (26.7) 1 (6.7)
1 (12.5) 2 (25.0) 4 (50.0) 3 (37.5) 2 (25.0) 3 (37.5) 5 (62.5) 1 (12.5) 0
0 0 3 (60.0) 2 (40.0) 0 2 (40.0) 2 (40.0) 3 (60.0) 0
0.69 0.49 0.74 0.91 0.33 0.73 0.56 0.18
19 (44.2) 9 (20.9) 15 (34.9)
6 (40.0) 3 (20.0) 6 (40.0)
4 (57.1) 2 (28.6) 1 (14.3)
5 (100.0) 0 0
0.06 0.49 0.13
4 10 17 2 9
2 (10.5) 2 (10.5) 9 (47.4) 1 (5.3) 5 (26.3)
0 2 (40.0) 2 (40.0) 0 1 (20.0)
0 2 (40.0) 0 0 3 (60.0)
6 (16.2) 31 (83.8)
2 (13.3) 13 (86.7)
1 (16.7) 5 (83.3)
1 (20.0) 4 (80.0)
0.92 0.40
21 (52.5) 15 (37.5) 5 (12.5)
5 (33.3) 8 (53.3) 2 (13.3)
5 (62.5) 3 (37.5) 1 (12.5)
3 (60.0) 2 (40.0) 0
0.33 0.73 0.69
(15.0) (22.5) (52.5) (32.5) (27.5) (47.5) (42.5) (35.0) (5.0)
(9.5) (23.8) (40.5) (4.8) (21.4)
0.57 0.82
0.84
0.43 0.04
CALB = C. albicans; CGLA = C. glabrata; CPAR = C. parapsilosis; CKRU = C. krusei; ICU = intensive care unit. a P value refers to the statistical analysis results from the comparison of the 3 most commonly identified Candida spp. combinations. b Comorbidities/risk factors, central intravenous catheter, bacterial infections, and underlying disease were not mutually exclusive (patients could have more than 1). c A total of 43 lines were observed in 38 patients; 15, 7, and 5 central lines were noted in patients with CALB/CGLA, CALB/CPAR, and CGLA/CKRU, respectively. d Includes intracranial infections, septic arthritis, osteomyelitis, intra-abdominal, and wound infections.
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krusei (n = 5, 6.2%), Candida dubliniensis (n = 1, 1.2%), and Candida lusitaniae (n = 1, 1.2%). The most frequently encountered combinations were C. albicans and C. glabrata (n = 15 patients, 37.5%), C. albicans and C. parapsilosis (n = 8, 20.0%), and C. glabrata and C. krusei (n = 5, 12.5%). 3.2. Antifungal treatment Median duration of treatment (from the day of the 1st positive culture) was 14 days (range, 0–97). A total of 31 (77.5%) patients received fluconazole, 18 (45.0%) received caspofungin, and 7 (17.5%) received voriconazole. Notably, amphotericin B products were not used in any patient in this series. Empiric treatment with fluconazole was administered in 19 (47.5%), caspofungin in 14 (35.0%), and voriconazole in 4 (10.0%) patients. A total of 18 (45.0%) patients received monotherapy: 14 (35.0%) with fluconazole, 3 (7.5%) with caspofungin, and 1 (2.5%) with voriconazole. Antifungal agents were not administered concomitantly in any of the cases. Nineteen patients received sequential therapy: 11 with caspofungin followed by fluconazole (n = 9) or voriconazole (n = 2), 4 with fluconazole followed by caspofungin, 3 with voriconazole followed by fluconazole, and 1 with fluconazole followed by voriconazole. In some cases, caspofungin was subsequently replaced by fluconazole, when fluconazolesusceptible Candida spp. were identified, such as C. albicans or C. parapsilosis. In cases where fluconazole was administered empirically followed by caspofungin or voriconazole, the growth of intrinsically fluconazole-resistant or potentially fluconazole-resistant Candida spp. such as C. krusei or C. glabrata was observed in 4 (80.0%) of 5 cases. No treatment was administered in 3 (7.5%) patients. One patient was discharged from the hospital before positive culture results. The 2nd patient died before positive cultures. In the 3rd patient, the positive culture for 2 Candida spp. was drawn from a femoral central venous catheter, the line was removed, all subsequent blood cultures were negative, and the patient was not treated. Notably, of the 43 central intravenous catheters observed in 38 patients, 39 (90.7%) were removed, with 29 of them removed within 2 days of the diagnosis of MSC. 3.3. Outcome A total of 9 and 16 patients were lost to follow-up at 4 and 12 weeks, respectively. Of the remaining patients, 13 (of 31, 41.9%) and 16 (of 24, 66.7%) patients had expired at 4- and 12-week follow-up. Notably, 1 patient died before treatment could be initiated. The Kaplan–Meier survival curve for 12 weeks is illustrated in Fig. 2A. Patients with the 3 most common Candida spp. combinations, C. albicans and C. glabrata (n = 15), C. albicans and C. parapsilosis (n = 8), and C. glabrata and C. krusei (n = 5), were compared for baseline characteristics and clinical outcome. There were no significant differences found regarding demographics, comorbidities, prior anti-
Fig. 2. Kaplan–Meier survival curves at 12-week follow-up for patients with MSC (A) overall and (B) based on most commonly observed species combinations.
fungal therapy, or other risk factors among these patient groups (Table 1). Similarly, survival among these patient groups did not appear to significantly differ (log-rank test, P = 0.24; Fig. 2B).
4. Discussion This study represents, to our knowledge, the largest sampling to date of MSC for a 4-year period, reporting an overall incidence among all cases of candidemia between 2004 and 2007 of 7.6%. Prior studies have reported an incidence of MSC of 2.8% to 8.0% (Boktour et al., 2004; Guerra-Romero et al., 1989; Jensen et al., 2007; Klotz et al., 2007; Pulimood et al., 2002). Our findings are in accordance with prior reports and suggest that MSC remains a significant problem among patients at risk for candidemia. A search of the literature found 4 case series specifically addressing MSC. Guerra-Romero et al. (1989) reported 22 patients from 1972 to 1985 and found similar clinical setting, risk factors, and mortality as monomicrobial fungemia. Pulimood et al. (2002) described 16 patients with MSC from 1992 to 2000 and found similar crude mortality rates to monomicrobial candidemia, but polymicrobial candidemia was reported in sicker nononcologic patients with frequent concomitant bacterial infections. Boktour et al. (2004) reported on 33 patients with cancer between 1993 and 2000 with MSC and found MSC patients were more likely to have leukemia, prolonged neutropenia before infection,
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chemotherapy within 1 month, higher Acute Physiology and Chronic Health Evaluation II scores, and previous antifungal prophylaxis versus those patients with C. albicans candidemia, although 30-day overall mortality rates did not significantly differ among the 2 patient populations. Jensen et al. (2007) described 15 patients with mixed fungemia between 1985 and 2006 and found that patients with MSC more frequently experienced organ transplant and surgery but less frequently received parenteral nutrition or intravenous lines. They also had a lower incidence of shock and lower overall mortality compared with monomicrobial fungemia, but no statistically significant difference in related mortality was found. Excluding the patients that were lost to follow-up, we report an overall, crude 4-week mortality of 41.9%, similar to previous reported rates for MSC (Boktour et al., 2004; Pulimood et al., 2002). However, 2 other groups have reported different mortality rates for MSC (Guerra-Romero et al., 1989; Jensen et al., 2007). Mortality as high as 59.0% was reported by Guerra-Romero et al., which may, in part, be explained by the lower incidence of candidemia in the 1970s to 1980s, leading to a lower clinical suspicion and timely initiation of treatment and/or the paucity of effective and safe antifungal therapeutic agents at the time. The lowest mortality (20.0%) among patients with MSC was reported by Jensen et al., but the results may have been biased by the small number of patients included in this study. The fairly high 12-week mortality rate of 66.7% reported in our study may, in part, be explained by the small number of patients included in this series (n = 40) and the significant number of patients (n = 16 of 40, 40.0%) that were lost to follow-up at 12-weeks. In most of the previous series of MSC, C. albicans has been the most common species identified (Boktour et al., 2004; Jensen et al., 2007; Pulimood et al., 2002). In contrast, we observed similar numbers for C. albicans and C. glabrata, whereas collectively, non-albicans Candida spp. were most commonly identified. This is consistent with a reported trend of increasing rates of non-albicans candidemia in North America (Abi-Said et al., 1997; Chang et al., 2008; Horn et al., 2007; Nguyen et al., 1996; Pfaller et al., 1998; Trick et al., 2002). Consistent with prior reports, the most common combination observed was C. albicans and C. glabrata. A total of 5 patients were diagnosed with C. krusei MSC in this series; 2 of them had been prophylactically treated with fluconazole. C. krusei is an intrinsically fluconazole-resistant species and has been increasingly identified as a pathogen in this decade, perhaps as a result of the more frequent use of fluconazole for prophylaxis in high-risk patient populations (Chow et al., 2008). Boktour et al. reported that MSCs occurred with increased frequency in patients with leukemia, prolonged neutropenia, and recent chemotherapy. In this series, only 1 patient was neutropenic and 11 patients had an underlying malignancy, none of which was hematologic. Although solid organ transplantation has been reported as a risk factor for MSC
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(Jensen et al., 2007), none of the cases in this series were observed in a transplant recipient. This may be because of an aggressive antifungal prophylaxis protocol followed by the solid organ and stem cell transplant teams in our institution as well as guidelines for antifungal prophylaxis and empiric treatment for patients with neutropenic fevers. MSC may represent a therapeutic challenge because the treating physician has to administer effective and safe treatment targeting more than 1 species. Fluconazole was the most commonly prescribed therapeutic agent for initial therapy for MSC, with caspofungin being increasingly used as the study period progressed. Sequential therapy was observed in close to half of the cases described. Notably, no patients were treated with amphotericin B products. Although this may represent the treatment policy observed in a single institution, recent data suggest that conventional amphotericin B is less frequently used (Horn and Neofytos, 2007). This may be the result of the advent and validation of highly active, better tolerated, and less toxic antifungal agents. We have already reported decreasing rates of candidemia in our institution during the same study period (Neofytos et al., 2007). This may, in part, be the result of more stringent infection control practices implemented during the study period. However, with the increasing use of central venous catheters, total parenteral nutrition, immunosuppressive and antibacterial agents, and other factors in the recent years that have led to a sicker patient population, vigilance for the timely identification and management of single-species candidemia and MSC should be reinforced. This study has a number of limitations. This is a retrospective, observational, single institution study with a relatively small number of patients. The study design also did not allow for the calculation of attributable mortality because of MSC. In conclusion, we report the largest contemporary sampling of MSC to date. Non-albicans Candida spp. were collectively isolated more frequently than C. albicans. MSC is an entity occasionally observed in the clinical setting with mortality rates remaining high and similar to prior reported results for patients with MSC. Acknowledgments The authors would like to thank Mindy Tokarczyk from the Department of Microbiology, Thomas Jefferson University Hospital (Philadelphia, PA, USA), for her significant help. References Abi-Said D, Anaissie E, Uzun O, Raad I, Pinzcowski H, Vartivarian S (1997) The epidemiology of hematogenous candidiasis caused by different Candida species. Clin Infect Dis 24:1122–1128. Anaissie EJ, Rex JH, Uzun O, Vartivarian S (1998) Predictors of adverse outcome in cancer patients with candidemia. Am J Med 104:238–245. Boktour MR, Kontoyiannis DP, Hanna HA, Hachem RY, Girgawy E, Bodey GP, Raad II (2004) Multiple-species candidemia in patients with cancer. Cancer 101:1860–1865.
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