Published online October 31, 2008
PEDIATRICS Vol. 122 No. 5 November 2008, pp. 1158-1159 (doi:10.1542/peds.2008-1837)

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kaufman, D. Search for Related Content PubMed PubMed Citation Articles by Kaufman, D. Related Collections Infectious Disease & Immunity Social Bookmarking                         What's this?

LETTER TO THE EDITOR

Fluconazole Prophylaxis Decreases the Combined Outcome of Invasive Candida Infections or Mortality in Preterm Infants

David Kaufman, MD
Department of Pediatrics,
University of Virginia School of Medicine,
Charlottesville, VA 22908

To the Editor.—

In a recent issue of Pediatrics, Healy et al¹ described the continued benefit and safety of fluconazole prophylaxis in infants weighing <1000 g in preventing invasive Candida infections and eliminating these infections as a cause of mortality in their NICU. The efficacy and safety of preventing these invasive Candida infections with fluconazole prophylaxis has been proven in single and multicenter randomized trials in preterm infants without the development of resistance.^2,3 In addition, retrospective studies have added safety and efficacy data from >2000 additional preterm infants.³ The evidence significantly outweighs the risks; 73% of infected infants <1000 g die or develop neurodevelopmental impairment (NDI).⁴

In the accompanying commentary,⁵ Benjamin discussed the desire for studies demonstrating a decrease in the combined outcome of invasive Candida infections and mortality and for neurodevelopmental data. Analysis of all the randomized, controlled trials demonstrates a significant decrease in this combined outcome of invasive Candida infection or mortality (odds ratio: 0.36 [95% confidence interval: 0.23–0.58]; P < .0001) (Table 1). Including mortality with infection in the primary outcome actually overestimates the effect of a therapy and is controlled for in randomized, placebo-controlled trials. It is important to note that fluconazole does not have any mechanism that would increase NDI. What does increase NDI are invasive Candida infections, having the highest rate of impairment of 57% compared with other infections.⁶

View this table: [in this window] [in a new window]   TABLE 1 Fluconazole Prophylaxis and the Combined Outcome of Invasive Candida Infection or Mortality

 
Recommending to wait with the efficacy and safety data we have is actually recommending for more patients to be harmed or die as a result of Candida-related NDI and mortality.⁷ We finally have an evidence-based prevention for one of the major infections in our preterm infants. On the basis of data from the Centers for Disease Control and Prevention,⁸ nearly 30000 patients are born at <1000 g each year in the United States, which translates into 3000 invasive Candida infections, 400 Candida-related deaths, and 1500 infants developing NDI.⁹ The 2006 Red Book supports the use of fluconazole prophylaxis in high-risk preterm infants born at <1000 g, and a recent Cochrane analysis demonstrated efficacy and safety.^10,11 Each NICU should explore its incidence of infection and institute prevention in those preterm infants at high risk of infection.³ Because of the high mortality and NDI, prophylaxis should be considered for infants born at <1000 g.

In striving for better outcomes for our most extremely preterm infants, infection prevention is critical. At this time, the benefits of antifungal prophylaxis significantly outweigh any risks. Everyday we wait, we place our most vulnerable infants at risk of harm from invasive Candida infections.

REFERENCES

1. Healy CM, Campbell JR, Zaccaria E, Baker CJ. Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality rates without emergence of fluconazole-resistant Candida species. Pediatrics. 2008;121 (4):703 –710[Abstract/Free Full Text]
2. Clerihew L, Austin N, McGuire W. Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants. Cochrane Database Syst Rev. 2007;(4):CD003850
3. Kaufman DA. Fluconazole prophylaxis: can we eliminate invasive Candida infections in the neonatal ICU? Curr Opin Pediatr. 2008;20 (3):332 –340[CrossRef][Web of Science][Medline]
4. Benjamin DK Jr, Stoll BJ, Fanaroff AA, et al. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics. 2006;117 (1):84 –92[Abstract/Free Full Text]
5. Benjamin DK Jr. First, do no harm. Pediatrics. 2008;121 (4):831 –832[Free Full Text]
6. Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 2004;292 (19):2357 –2365[Abstract/Free Full Text]
7. Emanuel EJ, Miller FB. The ethics of placebo-controlled trials: a middle ground. N Engl J Med. 2001;345 (12):915 –919[Free Full Text]
8. Centers for Disease Control and Prevention, National Center for Health Statistics. VitalStats. Available at: www.cdc.gov/nchs/datawh/vitalstats/VitalStatsbirths.htm. Accessed September 4, 2008
9. Fridkin SK, Kaufman D, Edwards JR, Shetty S, Horan T. Changing incidence of Candida bloodstream infections among NICU patients in the United States: 1995–2004. Pediatrics. 2006;117 (5):1680 –1687[Abstract/Free Full Text]
10. American Academy of Pediatrics. Candidiasis. In: Pickering L, Baker CJ, Long SS, McMillian JA, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2006:246
11. Clerihew L, Austin N, McGuire W. Systemic antifungal prophylaxis for very-low-birth-weight infants: systematic review. Arch Dis Child Fetal Neonatal Ed. 2008;93 (3):F198 –F200[Abstract/Free Full Text]
12. Kicklighter SD, Springer SC, Cox T, Hulsey TC, Turner RB. Fluconazole for prophylaxis against candidal rectal colonization in the very low birth weight infant. Pediatrics. 2001;107 (2):293 –298[Abstract/Free Full Text]
13. Kaufman D, Boyle R, Hazen KC, et al. Fluconazole prophylaxis against fungal colonization and infection in preterm infants. N Engl J Med. 2001;345 (23):1660 –1666[Abstract/Free Full Text]
14. Manzoni P, Stolfi I, Pugni L, et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007;356 (24):2483 –2495[Abstract/Free Full Text]

---

PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

CiteULike    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kaufman, D. Search for Related Content PubMed PubMed Citation Articles by Kaufman, D. Related Collections Infectious Disease & Immunity Social Bookmarking                         What's this?