Published online September 18, 2006
PEDIATRICS Vol. 118 No. 4 October 2006, pp. e1019-e1026 (doi:10.1542/peds.2006-0446)
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ARTICLE

Antifungal Prophylaxis to Prevent Neonatal Candidiasis: A Survey of Perinatal Physician Practices

Lauren A. Burwell, MDa,b, David Kaufman, MDc, Jennifer Blakely, MPHb, Barbara J. Stoll, MDd and Scott K. Fridkin, MDb

a Office of Workforce and Career Development
b Mycotic Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
c Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia
d Department of Pediatrics, Emory University, Atlanta, Georgia


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 APPENDIX: ANTIFUNGAL PROPHYLAXIS...
 REFERENCES
 
BACKGROUND. Bloodstream infections with Candida species have a high mortality rate in very low birth weight infants. Preliminary data suggest that prophylaxis with fluconazole reduces the incidence of colonization and invasive Candida infections in high-risk, very low birth weight neonates. The extent of antifungal prophylaxis use to prevent neonatal candidemia is unknown.

METHODS. We surveyed a 20% random sample of the members of the American Academy of Pediatrics Section on Perinatal Pediatrics. We collected information on prophylactic agents used, indications for use, and rationale for reported practices.

RESULTS. A total of 219 (47%) of 469 members sampled responded; 3 clinicians who did not provide care to very low birth weight infants were excluded. Antifungal prophylaxis use was reported by 73 (34%) respondents. Agents used included intravenous fluconazole (66%), oral nystatin (59%), and intravenous amphotericin B (21%). Decreased birth weight or early gestational age was the most frequent indication to start prophylaxis (57 [78%]). Respondents who did not use antifungal prophylaxis compared with respondents who used fluconazole prophylaxis were significantly more likely to have concerns about (1) the emergence of antifungal resistance, (2) unclear criteria on which to base the decision to start prophylaxis, and (3) the need for clarification of the role of surveillance cultures.

CONCLUSIONS. Although preliminary data suggest that fluconazole is efficacious to prevent candidemia in a subset of neonates, this practice is not used widely by clinicians who care for very low birth weight infants. Additional efficacy studies should address the emergence of antifungal resistance or clarification of criteria to initiate prophylaxis, including the role of surveillance cultures.

Key Words: candidemia • prophylaxis • prevention • sepsis • survey

Abbreviations: VLBW—very low birth weight • ELBW—extremely low birth weight • AAP—American Academy of Pediatrics

Fungal bloodstream infections are the third most common cause of late-onset sepsis in very low birth weight (VLBW; <1500 g) infants, and the mortality rate as a result of Candida albicans bloodstream infection in these infants is as high as 44%.1 Risk factors for candidemia in neonates include lower birth weight, earlier gestational age, use of broad-spectrum antibiotics, central venous catheters, mechanical ventilation, parenteral nutrition, and colonization with Candida species.2–7

Previous colonization with Candida species has been associated with invasive candidiasis in neonates.3,8 Clinicians have used antifungal prophylaxis to prevent colonization and subsequent invasive disease. One randomized, double-blinded trial demonstrated that fluconazole administration during the first 28 days of life decreased the risk for rectal colonization in VLBW infants,9 but the authors of the study reported that it was not designed to evaluate candidemia as an outcome. A second randomized, double-blinded study in preterm, extremely low birth weight (ELBW; <1000 g) infants demonstrated that fluconazole prophylaxis administration for 6 weeks to infants with central venous catheters or endotracheal intubation decreased both the incidence of fungal colonization and invasive infection.10 Although this single-center study documented the efficacy of fluconazole prophylaxis in this subset of patients, the study was limited to 1 medical center, and the findings may not be applicable to other populations of neonates.

The extent of neonatologists' use of antifungal prophylaxis to prevent neonatal candidemia in the United States is unknown. The goals of this study were to describe the frequency of use of antifungal prophylaxis among a sample of clinicians who care for VLBW infants, identify the factors on which clinicians base their decision to use prophylaxis, and identify barriers to the use of prophylaxis.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 APPENDIX: ANTIFUNGAL PROPHYLAXIS...
 REFERENCES
 
Study Participants
We identified 2354 members of the American Academy of Pediatrics (AAP) Section on Perinatal Pediatrics. Although membership on this committee is not limited to board-certified neonatologists, it is considered to be the most inclusive list of practicing neonatologists in the United States. The list of members was purchased from the AAP.

In June 2004, the survey was mailed by the Emory University School of Medicine to a 20% random sample of this membership list. Clinicians who did not respond initially were mailed an additional copy of the survey. A final attempt to contact clinicians who had not responded initially was made by telephone, and clinicians were faxed a copy of the survey when they expressed interest in participating. Participants received a complimentary copy of the 2002–2003 Nelson's Pocket Book of Pediatric Antimicrobial Therapy.11

Survey
The survey assessed demographic information; the use or lack of use of antifungal prophylaxis; the specific antifungal agent or agents used for prophylaxis; and any criteria used in clinicians' decisions to start antifungal prophylaxis, including birth weight, gestational age, presence of a central venous catheter, ventilator use, abdominal surgery or disease, antibiotic use, or Candida colonization. In addition, attitudes regarding the use or lack of use of antifungal prophylaxis were assessed by requesting responses to listed factors that may have influenced any decision to use or not use antifungal prophylaxis. Responses were measured on a 5-point Likert scale (1: least important; 5: most important). Clinicians were excluded from analysis when they did not care for any VLBW infants at their institutions.

The study protocol was approved by the Institutional Review Boards at the Emory University School of Medicine and the University of Virginia. It was exempt from Institutional Review Board review at the Centers for Disease Control and Prevention.

Statistical Analysis
Completed surveys were entered into Microsoft Office Excel (Microsoft Corp, Redmond, WA). Data analysis was performed in SAS 9.0 (SAS Institute, Inc, Cary, NC). Descriptive analysis of the Likert items included calculation of the frequency, the mean of responses, and the 2-sided 95% confidence interval about the sample mean. Most of the mean responses were between values 3 and 4, so the responses were dichotomized. Responses ≥4 were categorized as very important, and those ≤3 were categorized as less important.

Respondents were grouped into those who used any antifungal agent for prophylaxis, those who used fluconazole prophylaxis, and those who did not use any antifungal prophylaxis. Categorical variables were compared by {chi}2 analysis. Reported P values are 2-tailed.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 APPENDIX: ANTIFUNGAL PROPHYLAXIS...
 REFERENCES
 
Characteristics of Respondents
Of 469 surveys distributed, completed surveys were received from 219 clinicians (response rate 47%). Three clinicians responded that they did not take care of or admit any VLBW infants in their nurseries, and their responses were not included in the analysis. Most (69%) of the respondents were board-certified neonatologists and had been in practice for 10 years or greater. The median number of yearly admissions to the respondents' NICUs was 538 (range: 15–3000), and the median number of yearly admissions of VLBW infants to respondents' NICUs was 86 (range: 1–1200).

Antifungal Prophylaxis Practices
Although only 23 (11%) respondents reported that there was a written protocol in place at their NICUs guiding antifungal prophylaxis practice, 73 (34%) reported that they had used antifungal prophylaxis to prevent candidemia. The choice of antifungal agent used for prophylaxis was variable. Of these, 48 (66%) used intravenous fluconazole for prophylaxis, 43 (59%) used oral nystatin, 15 (21%) used amphotericin B, 10 (14%) used other topical agents, and 29 (40%) did not use 1 agent exclusively but used different agents at different times for prophylaxis.

Most respondents (57 [78%]) stated that they based their decision to initiate antifungal prophylaxis on either a decreased birth weight or early gestational age. Of these, 42 (74%) used at least 1 other criterion in their decision to initiate prophylaxis. These included the presence of a central venous catheter (27 [64%]), colonization status (from either clinical cultures or scheduled surveillance cultures [22 (52%)]), previous exposure to antibacterial agents (19 [45%]), and abdominal surgery or disease (14 [33%]). There was no association between respondents' characteristics (academic institution, board certification, level of NICU, or yearly NICU admissions) and use of antifungal prophylaxis (data not shown).

Rationale for Practice
A variety of factors influenced the decision to use or not use antifungal prophylaxis. Factors that were ranked as most important included the need for additional efficacy studies, concern regarding increased antifungal resistance, and the need for clarification of criteria of high-risk patients in whom prophylaxis should be attempted. Cost of the antifungal agent was less important. The mean Likert scale response for each listed factor is shown in Table 1.


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  		TABLE 1 Factors That Influenced Respondents' Decisions to Use or Not Use Antifungal Prophylaxis According to Rank

 
We compared factors that were rated as very important (≥4 on Likert scale) by respondents who did not use antifungal prophylaxis with factors that were rated as very important by respondents who used fluconazole prophylaxis (Table 2). Concern about the emergence of antifungal resistance was rated as very important significantly more often by respondents who did not use antifungal prophylaxis compared with those who used fluconazole prophylaxis (113 [80%] of 142 vs 22 [46%] of 48; P < .01). Other factors that were rated as very important significantly more often by respondents who did not use antifungal prophylaxis included the need for clarification of criteria of high-risk patients in whom prophylaxis should be attempted and the clarification of the role of surveillance cultures in identifying high-risk neonates. When we compared factors that were rated as very important by respondents who did not use antifungal prophylaxis with those who used any antifungal agent for prophylaxis, these same factors were statistically significant.


View this table:
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  		TABLE 2 Comparison of the Frequency of Factors That Were Categorized as Very Important by Respondents Who Did Not Use Any Antifungal Prophylaxis and Those Who Used Fluconazole Prophylaxis

 
The majority of respondents cited that additional efficacy studies of antifungal agents in the perinatal population were needed, regardless of whether they did not use prophylaxis or used fluconazole prophylaxis (74% and 71%, respectively). Safety of antifungal agents in the newborn population was less of a concern; 43% and 33%, respectively, rated safety concerns as very important.


   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 APPENDIX: ANTIFUNGAL PROPHYLAXIS...
 REFERENCES
 
Only one third of the clinicians surveyed reported using antifungal prophylaxis. Among clinicians who did use antifungal prophylaxis, there was variation in the choice of antifungal agent and the criteria on which the decision to use prophylaxis was based. The majority of respondents suggested that additional studies of the efficacy of antifungal prophylaxis were needed.

Among respondents who did not use prophylaxis, the most significant factor that influenced their decision not to use prophylaxis was concern about the emergence of fluconazole-resistant species, such as C krusei and C glabrata, in NICUs. Increased fluconazole resistance has been reported in adult immunosuppressed patient populations who have received fluconazole prophylaxis, but the overall incidence of infection from these organisms has remained low.12–16 Because VLBW neonates become less susceptible to invasive Candida infections as they mature, they may benefit from a shorter duration and decreased total dosage of fluconazole prophylaxis than that given to adult immunosuppressed patients. Such shorter course prophylaxis might decrease the emergence of fluconazole resistance in this population. Kaufman et al10,17 recently demonstrated that a twice-weekly dosing schedule had similar efficacy to the more frequent dosing protocol that was published initially. Furthermore, the fungal isolates from the neonates in that study did not demonstrate fluconazole resistance.17 The emergence of antifungal drug resistance should be studied in larger numbers of treated neonates for better understanding of the true risk of prophylaxis.

Respondents who did not use prophylaxis also were more likely to report that the criteria on which to base the decision to start prophylaxis were unclear. Although several risk factors for neonatal candidemia have been identified, there are no published guidelines that identify specific subsets of neonates in whom prophylaxis should be initiated.

Clarification of the role of surveillance cultures also is needed. Candida colonization can occur via vertical transmission at birth or via horizontal transmission in the NICU, and colonization usually precedes invasive infection. Limiting prophylaxis to those with positive Candida surveillance cultures may minimize unnecessary exposure to fluconazole, but this strategy was unsuccessful in preventing fungal sepsis with nystatin.18–20 It is not clear how frequently surveillance cultures should be performed and the length of time to treat with fluconazole to eliminate colonization. These questions should be addressed by additional studies.

Both respondents who did use prophylaxis and those who did not use prophylaxis reported that additional efficacy studies were warranted. At the time of the survey, there was only 1 randomized, controlled study published of nystatin prophylaxis and 1 of fluconazole prophylaxis for the prevention of invasive fungal disease in preterm infants.10,21 The findings of Kaufman et al10 documented the efficacy of fluconazole prophylaxis to prevent neonatal candidemia in a subset of patients; their study involved 1 site and the subset of ELBW infants with central venous catheters or endotracheal intubation while infants required intravenous access up to 6 weeks. Therefore, the results of this study may not be applicable to other populations of neonates. Healy et al22 instituted fluconazole prophylaxis for all ELBW infants in the NICU beginning in 2002, and ELBW infants who were administered fluconazole prophylaxis had decreased incidence of invasive candidiasis compared with ELBW infants in the baseline period before standardization of prophylaxis. However, this was not a randomized comparison study but relied on historical controls to estimate treatment effect. In addition, 3 similar observational studies have been reported in VLBW infants but have similar limitations.23–25 To date, there is favorable efficacy and safety data in 876 VLBW infants, but dosing and criteria for prophylaxis differed in some of these studies.9,10,17,22–25 Our data suggest that a large, multicenter study is needed to confirm the safety and the efficacy of and to clarify dosing and guidelines for antifungal prophylaxis.

There were several limitations to our study. First, we did not ask respondents to report the incidence rates of neonatal candidemia in their NICUs. We had concerns that the incidence data would not be risk-adjusted adequately to allow comparison among hospitals. Therefore, we were unable to link incidence rates at specific centers to reported responses or practices. Neonatologists who work in NICUs with higher rates of candidemia may be more likely to use antifungal prophylaxis than those who work in NICUs with little or no candidemia. Second, the study may contain selection bias, because respondents who used prophylaxis regularly may have been more inclined to participate in the survey. Therefore, respondents may not represent accurately the entire AAP Section on Perinatal Pediatrics. Last, the survey did not test physicians' knowledge of the current literature regarding antifungal prophylaxis to prevent neonatal candidemia; it merely assessed their practices.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
APPENDIX: ANTIFUNGAL PROPHYLAXIS...
 REFERENCES
 
This is the first survey to describe the use of antifungal prophylaxis to prevent neonatal candidemia. Addressing factors such as the need for additional efficacy studies, the emergence of antifungal resistance, identification of criteria on which to base the decision to initiate prophylaxis, and the role of surveillance cultures will help development of a more standardized approach to antifungal prophylaxis. This survey demonstrates that antifungal prophylaxis to prevent neonatal candidemia is not used by most neonatologists and highlights factors that need additional study.


   APPENDIX: ANTIFUNGAL PROPHYLAXIS SURVEY
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 APPENDIX: ANTIFUNGAL PROPHYLAXIS...
REFERENCES
 

Figure 1Figure 1Figure 1


   FOOTNOTES
 
Accepted May 23, 2006.

Address correspondence to Lauren A. Burwell, MD, Tuberculosis Control Program, Los Angeles County Department of Public Health, 2615 S Grand Ave, Room 507, Los Angeles, CA 90007. E-mail: lburwell{at}ph.lacounty.gov

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 APPENDIX: ANTIFUNGAL PROPHYLAXIS...
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



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