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Journal of Perinatology (2012) 32, 621–625 r 2012 Nature America, Inc. All rights reserved. 0743-8346/12 www.nature.com/jp

ORIGINAL ARTICLE

Risk factors for persistent candidemia infection in a neonatal intensive care unit and its effect on mortality and length of hospitalization JA Robinson, HD Pham, BT Bloom and RR Wittler Department of Pediatrics, University of Kansas School of Medicine–Wichita, Wichita, KS, USA

Objective: Candida infections cause substantial morbidity and mortality in neonates. Persistent candidemia has not been associated with increased risk of mortality compared with candidemia of shorter duration. This study sought to determine whether persistent candidemia was associated with increased length of hospitalization or mortality in neonates.

Study Design: A chart review was conducted of neonates with Candida bloodstream infections (n ¼ 37). Demographic, laboratory, pharmacy, nutrition and discharge data were abstracted. Contingency table analysis and logistic regression were used to analyze variables associated with persistent candidemia and mortality. The relationship between length of hospitalization and persistent candidemia was assessed with k-sample equality of medians test. Result: Nine patients (24%) had persistent candidemia. Increased time between blood culture draw and initial antifungal therapy was associated with increased incidence of persistent candidemia (P ¼ 0.03). Five patients (14%) died before hospital discharge; however, no deaths were attributed to persistent candidemia. Length of hospitalization was not increased with persistent candidemia. A decrease in the ratio of enteral feeding days to hyperalimentation days before collection of the first positive blood culture was significantly associated with an increase in all-cause mortality (P ¼ 0.03) and death attributed to candidemia (P ¼ 0.04). The risk of all-cause mortality decreased with a history of receiving any enteral feedings before the first positive blood culture (P ¼ 0.04), as did death attributed to candidemia (P ¼ 0.02). Conclusion: A duration of >1 day between the time of blood culture and the initial dose of systemic antifungal treatment places neonates at increased risk for developing persistent candidemia; however, this is not associated with increased mortality. Journal of Perinatology (2012) 32, 621–625; doi:10.1038/jp.2011.162; published online 10 November 2011 Keywords: Candida; antifungal; enteral feeding; hyperalimentation

Correspondence: Dr RR Wittler, Department of Pediatrics, University of Kansas School of Medicine–Wichita, 3243 East Murdock Suite 402, Wichita, KS 67208, USA. E-mail: [email protected] Received 25 April 2011; revised 5 August 2011; accepted 17 October 2011; published online 10 November 2011

Introduction Candida infections are the third most common cause of late-onset sepsis in very-low-birth weight infants in the neonatal intensive care unit (NICU).1 They are a significant source of infant morbidity and mortality, and may also affect neurodevelopmental outcomes.2,3 Neonatal candidemia can result in disseminated infection and increase the length and cost of hospitalization.4 In a National Institute of Child Health and Human Development Neonatal Research Network Study, antifungal therapy failure (defined as death within 14 days after initiation of antifungal therapy or a positive blood culture for Candida species beyond the 14-day period) was observed in 26% of extremely low-birth weight infants.3 The median number of days of positive blood cultures after systemic antifungal therapy was 3 days for infants who survived, and 10% had candidemia for X14 days. Neurodevelopmental disability and death were associated with delayed catheter removal when controlling for gestational age, gender and center. This study sought to determine whether increased duration of candidemia was associated with increased length of hospitalization and increased mortality in neonates. Furthermore, multiple factors were analyzed to determine association with persistent candidemia.

Methods A retrospective review of Candida bloodstream infections of patients in the NICU at a tertiary care teaching hospital in Wichita, Kansas, USA, from 1 January 2000 to 31 December 2010, was performed. A blood culture that grew any Candida species was defined as a candidemia episode. Recurrent candidemia was defined as two negative peripheral blood cultures in between incidents of Candida-positive blood cultures. For the purposes of this study, a subsequent candidemia episode was not included in the statistical analysis. Based on the study by Levy et al.5 persistent candidemia was defined as a positive culture for >5 days. Two separate sources comprise the database that was interrogated for initial data collection: (1) Meditech, the

Persistent candidemia JA Robinson et al

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Results During the 11-year period of study, 8199 patients were admitted to the NICU. Of these, 37 (0.45%) were found to have at least one positive blood culture for Candida species. There were 710 infants admitted to the NICU during the study period with a birth weight of 5 Days of Positive Blood Cultures) *K−sample equality−of−medians test

Figure 1 Box plot of length of hospitalization in relation to the presence of persistent candidemia.


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were not significantly associated with all-cause mortality or mortality attributed to candidemia.

Discussion Levy et al.5 examined the effect of persistent candidemia (that is, positive blood culture for Candida species for >5 days) versus non-persistent candidemia on morbidity and mortality. They did find an increased incidence of endocarditis with persistent candidemia, but no increase in mortality. We too did not note an Predicted Probability of Death from Candida Infection

The number of days between the first positive culture collection and the initial dose of antifungal therapy was associated with persistent candidemia (P ¼ 0.03) (Table 1). Most patients who developed persistent candidemia (67%, n ¼ 6) had >1 day between first positive culture collection and the start of antifungal therapy compared with only 13% (n ¼ 3) who did not (P ¼ 0.002 by Pearson w2 analysis; risk ratio ¼ 4.33, 95% confidence interval (CI): 1.57–11.94). This relationship was reaffirmed in a multivariate logistic regression model controlling for birth weight, gestational age and the presence of a central venous catheter, as the odds ratio for persistent candidemia when antifungal therapy was started >1 day from culture collection was 21.8 (95th CI: 2.2– 218.7; P ¼ 0.009). No other risk factors were significant (Table 1). All days during which a patient received nutrition by hyperalimentation before the first positive blood culture for Candida were counted, as were the days when the patient was fed enterally. A ratio (all prior enteral feeding days to all prior hyperalimentation days) was calculated for each patient. A decrease in this ratio was significantly associated with an increase in all-cause mortality (P ¼ 0.03) and death attributed to candidemia (P ¼ 0.04) (Figure 2). Likewise, the risk of all-cause mortality was decreased with a history of having received any enteral feedings before the first positive blood culture (P ¼ 0.04; risk ratio ¼ 0.18, 95% CI: 0.04–0.92), as was death attributed to candidemia (P ¼ 0.02; risk ratio ¼ 0.09, 95% CI: 0.01–0.77). By univariate analysis gestational age, birth weight, age at the time of infection, Candida species, presence of a central venous catheter at the time of infection, time to catheter removal and initial antifungal choice

0.5

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0 0

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1

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Ratio of Days Receiving Enteral Feeds to Days Receiving Hyperalimentation

Figure 2 Probability of Candida-related mortality as a function of total days of enteral feedings to total days of hyperalimentation before the first positive blood culture for Candida species.

Table 1 Risk factors and association with the development of persistent candidemia (displaying mean and range in parentheses for continuous values and percentage and number of subjects in parentheses for categorical values) Persistent candidemia Yes (N ¼ 9) Birth weight (kg) Gestational age at birth (weeks) Vaginal delivery Age at infection (days) Central venous catheter present at time of initial positive blood culture Duration of continuation of central venous catheter (days) Candida albicans identified on culture Candida dermatitis in the 7 days preceding the initial positive blood culture Ratio of total enteral feeding days to total hyperalimentation days before the initial positive blood culture History of any enteral feeds Time to initiation of antifungal therapy (days) >1 day to antifungal therapy Number of days previous antibiotics were administered Lowest platelet count in thousands within 1 day of the initial positive blood culture Lowest blood glucose on the day of or the day before the initial positive blood culture Highest blood glucose on the day of or the day before the initial positive blood culture

1.11 27.9 56% 26.3 44% 3.8 78% 44% 0.47 67% 1.6 67% 28 136 101 157

(0.47–2.22) (22–35) (5) (9–60) (4) (2–5) (7) (4) (0–0.88) (6) (0–3) (6) (15–57) (29–298) (80–140) (84–342)

No (N ¼ 25) 1.14 26.7 60% 38.9 48% 4.8 52% 28% 0.62 88% 0.75 13% 29 154 81 133

(0.55–3.79) (23–37) (15) (1–162) (12) (0–28) (13) (7) (0–1.5) (22) (0–2) (3) (3–61) (33–247) (10–133) (36–582)

P-value 0.91 0.47 0.82 0.34 0.86 0.79 0.18 0.37 0.27 0.15 0.03 0.002 0.87 0.66 0.07 0.57



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increase in mortality with persistent candidemia. We did not identify any patients with endocarditis. In contrast, Chapman et al.6 recognized an increased rate of focal complications and death in patients who had a positive repeat culture from a sterile site (urine, cerebrospinal fluid, blood or any other normally sterile site) >24 h after achieving target doses of amphotericin B or fluconazole. Natarajan et al.7 reported greater mortality in infants with refractory candidemia (defined as continuous positive blood cultures for Candida species between 48 and 72 h following treatment with both amphotericin B and fluconazole) compared with those who responded to these initial therapies. These disparate results may reflect a difference in the definition of persistent or prolonged candidiasis and the role of infections outside the bloodstream. In our study, no deaths were attributed to persistent candidemia; all four Candida-related deaths occurred quickly within 5 days of initial positive blood cultures for Candida species. This underscores the importance of prevention, prompt recognition and optimal treatment, including prompt central line removal, of invasive candidiasis.3,6,8,9 The decision to begin empiric therapy (a modifiable risk factor) may have prevented persistent candidemia. In a majority of the cases of persistent candidemia (67%, n ¼ 6), treatment initiation followed initial culture collection by at least 1 day. In a 2009 clinical practice guideline, the Infectious Diseases Society of America supported routine prophylactic treatment for premature infants and extremely low-birth weight infants in hospitals with a high incidence of neonatal candidiasis.8,10 Notably, the site of this study has a low incidence by internal measure (3% for birth weight under 1000 grams); thus, fungal prophylaxis would not be indicated. It has been suggested that empiric therapy, if employed, could be based on systematic risk factor modeling;10 however, a benefit in outcome, specifically mortality, has not been substantiated to date in a prospective randomized study. A single center retrospective study with historical controls did note a reduction in mortality after adopting an institutional guideline for initiating antifungal therapy.9 Benjamin et al.10 identified the following as risk factors for the development of invasive candidiasis: vaginal delivery, lower gestational age at delivery, Candida dermatitis, presence of a central catheter, lack of enteral feeds, increased blood glucose, increased number of antibiotic days and decreased platelet count. From the present study, utilization of a clinical prediction modelFas discussed by Benjamin et al.10Fcould have resulted in five of the six persistent candidemia patients receiving empiric antifungal therapy, as they had at least three of the risk factors above. We believe these findings justify further study of a clinical checklist for initiating empiric antifungal therapy. Two factors distinguished outcome for all of the neonates with candidemia. One, the ratio of total enteral feeding to hyperalimentation days before the first positive culture has not Journal of Perinatology

been previously described in the literature. The ratio was created to describe the balance between the two modes of nutrition. This ratio was not associated with the development of persistent candidemia; the same was true for the history of having received any enteral feedings before candidemia. In contrast, these two variables were independently associated with a decreased risk of both Candida-related death and all-cause mortality. Broadly speaking, the absence of enteral feeds could be reflective of the severity of illness in those patients rather than a predisposing factor itself.2,3,10,11 The limitations of this study include the retrospective design and the size of the study population. Other authors on this topic have cited the constraints of single center study.2 By replicating the work of previous authors,5 this investigation enhances the generalizability of these results and demonstrates that persistent candidemia is not associated with increased duration of hospital stay or increased mortality, as the infants who died from Candidarelated causes did so within 5 days of the first positive blood culture. This study implies that a duration of >1 day between the collection of the first positive blood culture and the initial dose of systemic antifungal treatment places neonates at increased risk for developing persistent candidemia. At a center with a low rate of infection, Candida prophylaxis has not been not recommended; however, empiric treatment utilizing a risk-based clinical checklist may decrease the duration of candidemia for selected high-risk infants with suspected sepsis.

Conflict of interest Dr Bloom was a site investigator and Dr Wittler is a contracted follow-up physician for the Duke Clinical Research Institute’s Prophylactic Fluconazole Study.

Acknowledgments We would like to thank the Wichita Medical Research & Educational Foundation (WMREF) (Wichita, Kansas, USA) for the grant for data collection for this study. WMREF had no role in the study design, data collection, statistical analysis, interpretation of results, manuscript preparation or decision to submit the manuscript for publication. We would also like to thank Jared Shaw and Paula Delmore for assisting with database interrogation and data collection. Thanks to Cari Schmidt for facilitating the IRB and grant applications.

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