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INSIGHTSABSTRACTS FROM THE LITERATURE

CURRENT LITERATUREAND CLINICAL ISSUES

Fluconazole prophylaxis againstfungal colonization and infectionin preterm infants

Kaufman D, Boyle R, Hazen KC,Patrie JT, Robinson M, Goodman-Donowitz L. N Engl J Med2001;345:1660-6

Context: Systemic fungal infections areassociated with high morbidity andmortality in preterm infants.

Objective: To evaluate the efficacy ofprophylactic fluconazole in preventingfungal colonization and invasive infec-tion in extremely-low-birth-weight in-fants.

Design: A prospective, randomized dou-ble-blind clinical trial.

Setting and participants: Pretermneonates (n = 100) with a birth weight<1000 g who were younger than 5 daysold and had no evidence of liver failurewere enrolled at a single institution.

Intervention: The local pharmacy ran-domly assigned infants to receiveeither fluconazole or placebo. Flu-conazole was administered intra-venously for 6 weeks at a dose of 3 mgper kilogram of body weight everythird day for the first 2 weeks, everyother day during the third and fourthweeks, and daily during the fifth andsixth weeks. Infants in the placebogroup were given an equal volume ofnormal saline on the same schedule.

Weekly surveillance cultures from thenasopharynx, skin, and stool or rectumwere obtained from all patients. Theadministration of the study drug andthe obtaining of surveillance cultureswere discontinued before the end ofthe 6-week treatment period if intra-venous access was discontinued, if an-tifungal therapy was initiated for thetreatment of a documented or pre-sumed systemic fungal infection, if theinfant was discharged from the hospi-tal or transferred to another facility, orif the infant died. The primary out-come was invasive fungal infection de-fined by a positive culture of blood,urine, or cerebrospinal fluid.

Results: The demographic and clinicalcharacteristics of the infants were sim-ilar in the 2 groups. The use of surfac-tant was not reported. The meanduration of the administration of thestudy drug and the mean length offollow-up was given for all study par-ticipants, but not by group. Invasivefungal infection developed in 10 in-fants in the placebo group (20%) andin no infant in the fluconazole group(risk difference, –0.20; 95% confidenceinterval [CI] –0.04 to –0.36; P = .008).Fungal colonization was present at oneor more sites in 30 of the infants in theplacebo group (60%) and 11 of thosein the fluconazole group (risk differ-ence, 22%; P = .002). There was no sta-tistically significant difference inmortality or secondary outcomes be-tween the groups. No adverse effects

of fluconazole were documented. Pat-terns of sensitivity to fluconazole didnot change during the 30-monthstudy.

Conclusions: Prophylactic administra-tion of fluconazole during the first 6weeks of life is effective in preventingfungal colonization and invasive fun-gal infection in infants with birthweights of <1000 g.

Comment: This is a well designed andexecuted randomized controlled trial.However, there was not completefollow-up of all patients. Surveillancewas discontinued if intravenous ac-cess was discontinued, if antifungaltherapy was initiated for the treat-ment of a documented or presumedsystemic fungal infection, or if the in-fant was discharged from the hospitalor transferred to another facility. Theintervention was proved efficaciousin a study setting with a very highbaseline risk of fungal invasive dis-ease (20%). On the basis of the re-ported risk difference, one wouldneed to treat only 5 infants with flu-conazole to prevent one invasive fun-gal infection during their first 6weeks of life (95% CI; 3-25 infants).Will this intervention work in otherpopulations in other settings? In theone other randomized controlled trialof fluconazole for the prophylaxis ofcolonization with Candida in very lowbirth weight infants, Kicklighter et al1

studied the effect of fluconazole dur-

Abstracts from the literatureEDITORS NOTE: Journals reviewed for this issue: Archives of Disease in Childhood, BMJ, Clinical Pedi-atrics, JAMA, Lancet, New England Journal of Medicine, and Pediatric Infectious Disease Journal.

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VOLUME 141, NUMBER 1

ing the first 28 days of life on rectalcolonization with Candida in 103 lowbirth weight (<1500 g) infants. Rectalcolonization with Candida species wasdetected in 15.1% of the fluconazole-treated patients and in 46% of theplacebo-treated infants. Invasive Can-dida infection developed in 2 infants ineach group. In this study, which in-cluded infants with a higher birthweight, fluconazole did not prevent in-vasive fungal infection. Fluconazoleprophylaxis reduces fungal coloniza-tion and possibly invasive fungal in-fections in low birth weight infants.Further multicenter randomized con-trolled trials of adequate sample size,and with follow-up beyond 6 weeks oflife and into early childhood, are need-ed before this promising interventionbecomes part of routine care.

Arne Ohlsson, MD, MScMount Sinai Hospital and

University of TorontoToronto, Ontario M5G 1X5, Canada

REFERENCE1. Kicklighter SD, Springer SC, Cox T,

Hulsey TC, Turner RB. Fluconazole forprophylaxis against Candidal rectal col-onization in the very low birth weightinfant. Pediatrics 2001;107:293-8.

Sensitivity of a clinicalexamination to predict need forradiography in children with ankleinjuries:A prospective study

Boutis K, Komar L, Jaramillo D,Babyn P, Alman B, Snyder B, et al.Lancet 2001;358:2118-21

Context: Radiographs are ordered rou-tinely for children with ankle trauma.

Objectives: To assess the predictivevalue of a clinical examination to iden-tify a predefined group of low-risk in-juries, management of which wouldnot be affected by the absence of a ra-diograph, and to compare the potentialreduction in radiography in children

with low-risk examinations with thatobtained by application of the Ottawaankle rules (OAR).

Design: Prospective, independentcomparison of standard clinical ex-amination, the OAR, and subsequentradiographs.

Setting: Two tertiary-care pediatricemergency departments in NorthAmerica.

Patients: Healthy children (n = 607,aged 3-16 years) with acute ankle in-juries.

Description of prediction rule: A low-riskexamination of an ankle consisted ofisolated pain, tenderness, or both, withor without edema or ecchymosis of thedistal fibula and/or over the adjacentlateral ligaments. All other findingswere classified as high risk.

Main outcome measure: Number of high-risk fractures (all fractures except avul-sion, buckle, and nondisplacedSalter-Harris I and II fractures of thedistal fibula) in children with low riskcompared with children without low-risk examination.

Results: Five hundred eighty-one chil-dren ( 95.7%) received follow-up. Noneof the 381 children with low-risk exam-inations had a high-risk fracture (sensi-tivity 100% [95% CI = 93.3-100],negative predictive value 100% [99.2-100]). Radiographs could be omitted in62.8% of children with low-risk exami-nations, compared with only 12.0% re-duction obtained by application of theOAR (P < .0001).

Conclusion: A low-risk clinical examina-tion in children with ankle injuries iden-tifies 100% of high-risk diagnoses andmay result in greater reduction of radi-ographic referrals than the OAR.

Comment: The goal of this study, to re-duce unnecessary ankle radiographs, is

laudable. The authors’ description of alow-risk examination is clear, but ahigh-risk exam is simply described as“any other finding” and no formal inter-observer reliability is reported. It is un-clear if inability to bear weight wouldindicate a high-risk examination. It isalso important to note that lateral talaravulsion fractures, and fractures of thedistal fibula including nondisplacedSalter-Harris I and II, metaphysealbuckle, and epiphyseal avulsion frac-tures, are considered low-risk injuriesnot requiring radiographic studies. Theauthors classified these injuries as low-risk because of their stable nature andgood prognosis but comment that theoptimal management of these injuries iscontroversial. All previous studies ofthe OAR in children have defined a sig-nificant fracture as any fracture or afracture fragment ≥3 mm. Although theuse of the authors’ low-risk and high-risk examination would result in a dra-matically greater reduction in rate ofradiographs taken than the use of theOAR, the value of this comparison isdebatable given the different outcomemeasures that the 2 guidelines aremeant to detect. It is this difference thatraises perhaps the most important is-sues: (1) Which fractures need to bedocumented by x-ray? (2) What is alow-risk injury? and (3) What is the op-timal management of these injuries? Aclinician comfortable with the definitionby Boutis et al of low-risk injury mayfeel comfortable using their clinical ex-amination guideline, whereas clinicianswho wish to detect any fracture maywish to use the OAR.

Amy Plint, MDChildren’s Hospital of Eastern Ontario

University of OttawaOttawa, Ontario, K1S 2P4 Canada

Outcomes in young adulthood forvery-low-birth-weight infants

Hack M, Flannery DJ, Schluchter M,Cartar L, Borawski E, Klein N. NEngl J Med 2002;346:149-57

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Context: Very-low-birth-weight (VLBW)infants (those weighing <1500 g) bornduring the initial years of neonatal inten-sive care have now reached young adult-hood.

Design: Cohort study with comparisongroup.

Patients: A cohort of 242 survivorsamong VLBW infants born between1977 and 1979 (mean birth weight,1179 g; mean gestational age at birth,29.7 weeks) with 233 controls from thesame population who had normal birthweights.

Setting: Cleveland, Ohio.

Main outcome measures: Level of educa-tion, cognitive and academic achieve-ment, and rates of chronic illness andrisk-taking behavior at 20 years of age.Outcomes were adjusted for sex and so-ciodemographic status.

Results: Fewer VLBW young adultsthan normal-birth-weight youngadults had graduated from highschool (74% vs 83%, P = .04). VLBWmen, but not women, were signifi-cantly less likely than normal-birth-weight controls to be enrolled inpostsecondary study (30% vs 53%, P= .002). VLBW participants had alower mean intelligence quotient (87vs 92) and lower academic achieve-ment scores (P < .001 for both com-parisons). They had higher rates ofneurosensory impairments (10% vs

<1%, P < .001) and subnormal height(10% vs 5%, P = .04). The VLBWgroup reported less alcohol and druguse and had lower rates of pregnancythan normal-birth-weight controls;these differences persisted whencomparisons were restricted to theparticipants without neurosensoryimpairment.

Conclusion: Educational disadvantageassociated with VLBW persists intoearly adulthood.

Comment: This report describing the 20-year outcomes of a cohort of VLBW birth weight infants pro-vides important insights into long-term consequences of preterm birth,unique features of prolonged cohortstudies, and influences on long-termdevelopment. When these cohortswere assembled, the outcomes of in-fants weighing ≤1500 g were viewedwith skepticism. Critical questions inthe current era relate to even smallerinfants at the edge of viability or in-fants receiving invasive interventions.This brings out the dilemma infollow-up studies: short-term out-comes of concurrent care give incom-plete pictures, whereas long-termoutcomes of remote care may reflectoutdated management. Regardless,findings over prolonged times are im-portant to families and persons bornat very low birth weights. Cohortsfollowed longitudinally may haveunique features. An example is thecohort effect whereby an age restrict-

ed cohort has specific, unique expo-sures that make their later outcomesnongeneralizable. Any group studiedfor a prolonged period may changesimply because of repeated observa-tions or membership in a cohort.Long-term development is affected ina complex way by influences duringthe perinatal and postneonatal peri-ods, nurturance, education, changinggender roles and opportunities, andpeer group interactions. Hack et alprovided interesting food for thoughtregarding ongoing studies of VLBWinfant outcome.

Reg Sauve, MDThe University of Calgary

Calgary, Alberta, T2N 4N1, Canada

ALSO NOTED

Fusidic acid cream in thetreatment of impetigo in generalpractice: Double-blind random-ized placebo-controlled trial

Koning S, van Suijlekom-Smit LWA,Nouwen JL, Verduin CM, BernsenRMD, Oranje AP, et al. BMJ2002;324:1-5

This placebo-controlled trial demon-strated a substantial benefit for the useof topical antisepsis and treatment withfusidic acid cream (which has similar ef-ficacy to mupirocin) compared withtopical antisepsis alone.