PEDIATRICS Vol. 121 No. 4 April 2008, pp. 831-832 (doi:10.1542/peds.2008-0068)
COMMENTARY |
First, Do No Harm
Department of Pediatrics, Duke University, Duke Clinical Research Institute, Durham, North Carolina
Healy et al1 are to be commended for their continued study of fluconazole resistance, one of the potential negative effects of systemic antifungal prophylaxis. In this issue of Pediatrics, the authors provide modest new evidence to support fluconazole use, provided that we first correctly investigate the risks and benefits of fluconazole prophylaxis.
All drugs cause harm to at least a small proportion of children who receive them. Some drugs reduce or cure disease in children, and very few drugs benefit more children than are harmed by their use. The pressing public health concern regarding the adoption of fluconazole prophylaxis hinges on this risk/benefit ratio. Although antifungal prophylaxis has reduced candidiasis in the high-incidence setting, some questions remain unanswered by investigators (1) Does prophylaxis reduce neonatal mortality?, (2) Is prophylaxis beneficial in nurseries with low-moderate incidence of candidiasis?, and (3) What are the effects of prophylaxis on subsequent neurodevelopment?
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ALL CAUSE MORTALITY |
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 TOP ALL CAUSE MORTALITY BENEFIT TO THE MAINSTREAMNEURODEVELOPMENTAL CONSEQUENCESREFERENCES |
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Mortality and candidiasis are competing outcomes and although incorporating competing outcomes into trial design seems obvious (infants who die at age 12 days cannot develop candidiasis at age 15 days), it is often ignored. The composite end point of death and invasive candidiasis is virtually identical in the preprophylaxis era compared with the prophylaxis era in Healy et al2 Prevention should either document improved mortality, or improvement in a composite end point that includes mortality (eg, death or candidiasis), or improvement in a validated measure of morbidity relevant to function (eg, neurodevelopmental outcome). No trial completed to date has documented fluconazole prophylaxis results in any 1 of these 3 areas.
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BENEFIT TO THE MAINSTREAM |
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TOPALL CAUSE MORTALITYBENEFIT TO THE MAINSTREAMNEURODEVELOPMENTAL CONSEQUENCESREFERENCES |
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The concerns of long-term risk/benefit are crucial to the majority of us who work in nurseries where the incidence of invasive candidiasis in neonates born weighing 750 to 1000 g is 1% to 4% because we must expose so many infants to help so few. Unfortunately, large differences in neonatal infection rates by center have resulted in what can be called a "prophylaxis paradox." Specifically, prophylaxis studies have been conducted in a few nurseries with extremely high incidence of disease (those with infection rates 3- to 10-fold higher than the national median).3,4 The observed reductions in positive cultures have led several authors to conclude that those of us in the mainstream (lower-incidence settings) should adopt widespread use. Those of us with low incidence of disease (attributable to effective infection control, antimicrobial stewardship, or other factors), are wise to be less than enthusiastic because we must expose 100 infants to prophylaxis for every prevented case.
The prophylaxis paradox (not unique to invasive fungal infections) is the phenomenon that although prophylaxis may be effective where it is studied (the high-incidence setting), it should not necessarily be adopted by all (low-incidence and moderate-incidence) units. The cause of the prophylaxis paradox is an example of sample selection bias. Sites that participate and often lead enrollment in prophylaxis studies are high-incidence sites that naturally view the infection under study as a public health threat. Resolution of the paradox is the conduct of simple trials with a large number of centers whose median incidence of disease reflects the broader community.
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NEURODEVELOPMENTAL CONSEQUENCES |
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TOPALL CAUSE MORTALITYBENEFIT TO THE MAINSTREAMNEURODEVELOPMENTAL CONSEQUENCESREFERENCES |
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Healy et al1,4 correctly note that most infants at <1000 g birth weight who develop candidiasis suffer death or disability; however, no group has provided even a modest amount of neurodevelopmental follow-up after prophylaxis.
Neurodevelopmental follow-up is the key question that must be answered before routinely exposing tens of thousands of extremely premature infants with a rapidly developing brain to a pharmacologic agent for 6 weeks every year for the foreseeable future. This question should be answered in the form of a well-powered blinded trial that compares neurologic outcomes between exposed and unexposed infants before advocating the widespread adoption of fluconazole prophylaxis.
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FOOTNOTES |
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Accepted Jan 8, 2008.
Address correspondence to Daniel K. Benjamin, Jr, MD, PhD, MPH, Department of Pediatrics, Duke University, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715. E-mail: danny.benjamin{at}duke.edu
The author has indicated that he has no financial relationships relevant to this article to disclose.
Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.
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REFERENCES |
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TOPALL CAUSE MORTALITYBENEFIT TO THE MAINSTREAMNEURODEVELOPMENTAL CONSEQUENCESREFERENCES |
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- Healy CM, Campbell JR, Zaccaria E, Baker CJ. Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality without emergence of fluconazole-resistant candida species.
Pediatrics. 2008:121
(4):703
–710
[Abstract/Free Full Text] - Healy CM, Baker CJ, Zaccaria E, Campbell JR. Impact of fluconazole prophylaxis on incidence and outcome of invasive candidiasis in a neonatal intensive care unit. J Pediatr. 2005;147 (2):166 –171[CrossRef][Web of Science][Medline]
- Cotten CM, McDonald S, Stoll B, Goldberg RN, Poole K, Benjamin DK Jr. The association of third generation cephalosporin use and invasive candidiasis in extremely low birth weight infants.
Pediatrics. 2006;118
(2):717
–722
[Abstract/Free Full Text] - Benjamin DK Jr, Stoll BJ, Fanaroff AA, et al. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality, and neurodevelopmental outcomes at 18–22 months.
Pediatrics. 2006;117
(1):84
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[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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