anaerobic antimicrobial therapy after necrotizing enterocolitis in vlbw infants

Anaerobic Antimicrobial TherapyAfter Necrotizing Enterocolitis inVLBW InfantsJulie Autmizguine, MD, MHSa, Christoph P. Hornik, MD, MPHa,b, Daniel K. Benjamin Jr, MD, PhD, MPHa,b,Matthew M. Laughon, MD, MPHc, Reese H. Clark, MDd, C. Michael Cotten, MD, MHSb, Michael Cohen-Wolkowiez, MD, PhDa,b,Daniel K. Benjamin, PhDe, P. Brian Smith, MD, MPH, MHSa,b, on behalf of the Best Pharmaceuticals for Children Act—PediatricTrials Network Administrative Core Committee

abstractOBJECTIVE: To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) onclinical outcomes in very low birth weight (#1500 g) infants.

METHODS:We identified very low birth weight infants with NEC from 348 US NICUs from 1997 to 2012. Anaerobicantimicrobial therapy was defined by antibiotic exposure on the first day of NEC. We matched (1:1) infantsexposed to anaerobic antimicrobial therapy with infants who were not exposed by using a propensity scorestratified by NEC severity (medical and surgical). The primary composite outcome was in-hospital death orintestinal stricture. We assessed the relationship between anaerobic antimicrobial therapy and outcome by usinga conditional logistic regression on the matched cohort.

RESULTS: A total of 1390 infants exposed to anaerobic antimicrobial therapy were matched with 1390 infantsnot exposed. Mean gestational age and birth weight were 27 weeks and 946 g, respectively, and weresimilar in both groups. We found no significant difference in the combined outcome of death or strictures,but strictures as a single outcome were more common in the anaerobic antimicrobial therapy group (oddsratio 1.73; 95% confidence interval, 1.11–2.72). Among infants with surgical NEC, mortality was lesscommon with anaerobic antimicrobial therapy (odds ratio 0.71; 95% confidence interval, 0.52–0.95).

CONCLUSIONS: Anaerobic antimicrobial therapy was not associated with the composite outcome of death orstrictures but was associated with an increase in intestinal strictures. This higher incidence of intestinalstrictures may be explained by the fact that death is a competing outcome for intestinal strictures,and mortality was slightly lower in the anaerobic cohort. Infants with surgical NEC who receivedanaerobic antimicrobial therapy had lower mortality.

WHAT’S KNOWN ON THIS SUBJECT: Necrotizingenterocolitis is associated with high mortalityand morbidity in premature infants. Anaerobicantimicrobial therapy has been associated withincreased risk of intestinal strictures in a smallrandomized trial. Optimal antimicrobial therapyfor necrotizing enterocolitis is unknown.

WHAT THIS STUDY ADDS: Anaerobic antimicrobialtherapy was associated with increased risk ofstricture formation. Infants with surgical necrotizingenterocolitis treated with anaerobic antimicrobialtherapy had lower mortality. For infants withmedical necrotizing enterocolitis, there was noadded benefit associated with anaerobicantimicrobial therapy.

aDuke Clinical Research Institute, and bDepartment of Pediatrics, Duke University Medical Center, Durham, NorthCarolina; cDivision of Neonatal–Perinatal Medicine, School of Medicine, The University of North Carolina at ChapelHill, Chapel Hill, North Carolina; dPediatrix-Obstetrix Center for Research and Education, Sunrise, Florida; andeJohn E. Walker Department of Economics, Clemson University, Clemson, South Carolina

Dr Autmizguine conceptualized and designed the study, carried out the analyses, and drafted the initialmanuscript; Drs Hornik, Cohen-Wolkowiez, and Benjamin supervised the analyses and revised the articlecritically for important intellectual content; Drs Benjamin, Laughon, Clark, and Cotten conceptualized anddesigned the study and revised the article critically for important intellectual content; Dr Smithconceptualized and designed the study, drafted the initial manuscript, and revised the article critically forimportant intellectual content; and all authors approved the final manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-2141

DOI: 10.1542/peds.2014-2141

Accepted for publication Oct 22, 2014

PEDIATRICS Volume 135, number 1, January 2015 ARTICLEby guest on June 16, 2016Downloaded from

Necrotizing enterocolitis (NEC)is a common and devastatingintestinal complication ofprematurity. Incidence of NEC rangesfrom 3% in infants with birth weight(BW) of 1251 to 1500 g to 11% forinfants born weighing ,750 g.1

Despite treatment, 15% of infantswho develop NEC die, and mortalityapproaches 50% in infants withsurgical NEC.2,3 Survivors oftensuffer from complications includingintestinal stricture, shortbowel syndrome, and poorneurodevelopmental outcomes.4–6

The pathogenesis of NEC involvesa combination of factors, includinggenetic predisposition, immaturityof the intestinal tract, imbalancein microvascular tone, abnormalmicrobial intestinal colonization, andinfectious agents.7–10 Although nosingle microorganism has beenidentified, infection probably playsa key role in the disease process,as demonstrated by bacterialovergrowth in the intestinalmucosa and the occurrence of NECoutbreaks.8,11,12 A wide range ofpathogens are associated with NEC,including aerobic and anaerobicbacteria.10,13–19 Therapy for NECincludes broad-spectrum antibioticswith coverage of bacteria from theintestinal tract. In a small cohortof infants with NEC, a randomizedcontrolled trial with 42 infantsobserved no difference in mortalityor intestinal perforation in thosewho received an antibiotic regimenof ampicillin, gentamicin, andclindamycin compared with thosewho received only ampicillin andgentamicin.20 However, there wasa higher rate of intestinal stricturesin the clindamycin group. Despitethis finding, clindamycin is oftenused for NEC in the nursery, and thesafety and efficacy of other antibioticregimens for NEC have not beenestablished.20–22 The objective of thecurrent study was to assess theassociation of anaerobic antimicrobialtherapy and subsequent clinical

outcomes in very low birth weight(VLBW, #1500 g BW) infants.

METHODS

Study Design and Setting

We identified all VLBW infants withmedical or surgical NEC dischargedfrom 348 NICUs managed by thePediatrix Medical Group from 1997 to2012. The Pediatrix Medical Groupmaintains a data warehouse that ispopulated from an electronic medicalrecord that prospectively capturesinformation from notes generated byclinicians. Data on multiple aspects ofcare are entered into the system togenerate admission notes, dailyprogress notes, procedure notes, anddischarge summaries. Information iscollected on maternal history anddemographics, medications,respiratory support, laboratoryresults, culture results, procedures,and diagnoses. The study wasapproved by the Duke UniversityInstitutional Review Board withoutthe need for written informedconsent because the data werecollected without identifiers.

Definitions

Antimicrobials were considered toprovide anaerobic coverage if theywere previously reported as havingin vitro activity against the majorobligate anaerobic bacilli from theintestinal flora. These antimicrobialagents included metronidazole,clindamycin, cefoxitin, any carbapenem,moxifloxacin, piperacillin–tazobactam,ticarcillin–clavulanate,ampicillin–sulbactam, andamoxicillin–sulbactam. An infantwas defined as receiving anaerobicantimicrobial therapy based onantibiotics received on the first dayof NEC. The diagnosis and severityof NEC were assigned at each site bythe attending neonatologist andincluded either medical NEC orsurgical NEC. Surgical indicationincluded the need for a peritonealdrain. The assessment of NEC severitywas not based on standardized

criteria and was assigned daily by thetreating physician. NEC severitywas defined on the first day of thecourse of NEC regardless of changein severity thereafter. Infantswere excluded if they receivedantimicrobial agents for ,5consecutive days from the start ofNEC, unless they died during this5-day period. Mortality was definedas in-hospital death from anycause. Mortality status was definedas missing for infants withnonconvalescent transfers of care.Presence of intestinal stricture wasdefined as any diagnosis ofnoncongenital intestinal obstructionafter the start of the NEC episode.The diagnosis of intestinalobstruction was assigned by thetreating physician in the electronicmedical record, and methods used toassign this diagnosis were notavailable. If an infant had .1 episodeof NEC, only the first episode wasconsidered in the analysis.

Demographic data included gender,race, BW, gestational age (GA),postnatal age, and Apgar score at 5minutes. Surrogates for severity ofillness on the first day of NEC werecollected and included ventilatorsupport (yes or no), highest level offraction of inspired oxygen (FIO2), andinotropic support (yes or no).

Statistical Methods

The primary outcome was in-hospitaldeath or development of an intestinalstricture. Secondary outcomesconsisted of death or stricturesanalyzed individually. An additionalsecondary outcome was assessedamong the subgroup of infants withmedical NEC: the composite ofprogression from medical to surgicalNEC or death within the first 7 daysof the NEC episode. Outcomes werecompared between infants exposedand not exposed to anaerobicantimicrobial therapy. Becauseinfants with more severe illness aremore likely to receive anaerobicantimicrobial therapy, propensityscore (PS) 1:1 matching was used to

e118 AUTMIZGUINE et alby guest on June 16, 2016Downloaded from

ensure comparison of similarinfants.23 We used baselinedemographics and surrogates forseverity of illness that might predictboth anaerobic antimicrobial therapyand primary outcome to build thePS model by using a multivariablelogistic regression.24 The PS modelwas stratified by NEC severity andderived from the following covariates:postnatal age, ventilator support, FIO2requirement, inotropic support onday 1 of NEC, GA, small-for-GAstatus, gender, race, Apgar score at5 minutes, discharge year, and site.Because site was analyzed as a fixedeffect in the PS model, no PS couldbe estimated for infants belongingto a site with an insufficient numberof observations or a site where everyinfant had the same anaerobiccoverage status. We included thedischarge year as a categoricalvariable in the PS model to adjust forchanges in care over the study period.We assessed covariate balance acrosstreatment groups by comparingcovariate means. Histograms andkernel density plots of PS acrossgroups were also examined. Weperformed 1:1 matching by using thenearest neighbor withoutreplacement, and it was allowed onlyif the difference in PS between caseand control was ,0.01. On thePS-matched cohort, we assessed theeffect of anaerobic antimicrobialtherapy on clinical outcomes by usinga logistic regression conditioned onthe matched pair.23

Because of previous literature linkingclindamycin with intestinal strictures,we investigated the effects ofclindamycin specifically, as a secondaryanalysis. We built a separate PS modelestimating the conditional probabilityof receiving clindamycin among infantswho were exposed to clindamycin andthose who were not exposed toanaerobic antimicrobial therapy, byusing the same covariates as in theprimary analysis. We then comparedoutcomes by using a conditionallogistic regression after 1:1 matchingbased on PS.

Finally, we performed a multivariablelogistic regression without matchingto compare outcomes between infantsexposed and not exposed to anyanaerobic antimicrobial therapy,adjusting for the same covariatesused in the PS of the primary analysis.

Demographic and baselinecharacteristics were summarized andcompared between 2 groups: infantsexposed and not exposed toanaerobic antimicrobial therapy onthe first day of NEC. A x2 test forcategorical variables and a Wilcoxonrank-sum test or a t test forcontinuous variables were used toassess differences between groups.We performed statistical analyses byusing Stata 12 (Stata Corp, CollegeStation, TX). All statistical tests were2-sided, with significance defined asP , .05.

RESULTS

We identified 6737 infants meetingthe inclusion criteria, of whom 3358(50%) were exposed to anaerobicantimicrobial therapy and 3379(50%) were not. Overall, 4958 (74%)had medical NEC, and 1779 (26%)had surgical NEC. The mean GA was27 weeks (5th, 95th percentile:23, 31) and 27 weeks (5th, 95th

percentile: 24, 31) in the anaerobicantimicrobial therapy and controlgroups, respectively. The mean BWwas 936 g (5th, 95th percentile: 530,1417) and 952 g (5th, 95thpercentile: 540, 1420) in infantsexposed to anaerobic antimicrobialtherapy and those who were not,respectively. Infants who wereexposed to anaerobic antimicrobialtherapy were more likely to be onventilation (2152 [64%] vs 1467[45%], P , .001) and vasopressortherapy (839 [25%] vs 283 [8%],P , .001) and had a higher medianFIO2 (30% vs 25%, P , .001)compared with infants not exposed toanaerobic antimicrobial therapy.

After nearest-neighbor PS matching,1390 infants exposed to anaerobicantimicrobial therapy were matchedto infants who were not exposed toanaerobic antimicrobial therapy toyield a final cohort of 2780 infants(41% of the initial cohort) (Fig 1).PS matching provided a well-balancedcohort based on baselinecharacteristics (Table 1), and PS wasequally distributed in both treatmentgroups (Supplemental Fig 3). Themean GA and BW of the cohort were27 weeks (23, 32) and 946 g (540,1421), respectively. In the matchedcohort, 75% (n = 2074) of infants had

FIGURE 1Study population flowchart.

PEDIATRICS Volume 135, number 1, January 2015 e119by guest on June 16, 2016Downloaded from

http://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2014-2141/-/DCSupplemental

medical NEC, and 706 (25%) hadsurgical NEC. Among infants withanaerobic antimicrobial therapy,clindamycin was the most frequentlyused anaerobic antibiotic (56%),followed by metronidazole (29%)and piperacillin–tazobactam (9%).However, clindamycin use decreasedand metronidazole use increasedduring the study period (Fig 2).

Overall, 26% (n = 725) of matchedcohort infants died before dischargeor developed intestinal strictures;23% of infants (n = 645) died, and3% (n = 84) developed strictures(4 infants had strictures beforedeath). Fewer infants experiencedthe composite outcome of deathor strictures in the anaerobicantimicrobial therapy group, but therisk was not significantly different

(odds ratio [OR] 0.96; 95%confidence interval [CI], 0.80–1.14;Table 2). We observed similar resultsfor the individual outcome of death(OR 0.87; 95% CI, 0.72–1.05).Conversely, more infants developedstrictures in the anaerobicantimicrobial therapy groupcompared with the control group (OR1.73; 95% CI, 1.11–2.72).

Among infants with medical NEC(n = 2074), all covariates used in thePS model were well balanced aftermatching (Supplemental Table 4).In this subgroup, we observeda nonsignificant increase in death orstrictures in infants treated withanaerobic antimicrobial therapy (OR1.09; 95% CI, 0.87–1.37; Table 2).Death rates were similar in bothtreatment groups (OR 0.99; 95% CI,

0.78–1.26). Strictures were morecommon in infants exposed toanaerobic antimicrobial therapy(OR 1.60; 95% CI, 0.97–2.64),although this result was notstatistically significant. The numberof infants with medical NEC whoprogressed to surgical NEC or diedwithin the first 7 days of the episodewas similar in both treatment groups,with 121 (12%) and 126 (12%)infants in the nonanaerobic andanaerobic antimicrobial treatmentgroups, respectively (OR 1.05; 95%CI, 0.80–1.37).

Among infants with surgical NEC(n = 706), baseline clinicalcharacteristics were well balancedacross treatment groups after PSmatching (Supplemental Table 4).In this subgroup, fewer infants eitherdied or developed strictures in theanaerobic antimicrobial therapygroup, although this result was notstatistically significant (OR 0.77; 95%CI, 0.57–1.03; Table 2). Death wassignificantly less common in infantsexposed to anaerobic antimicrobialtherapy (OR 0.70; 95% CI,0.52–0.95), whereas we observeda nonsignificant increase in stricturesin exposed infants (OR 2.40; 95% CI,0.85–6.81).

When we restrict the anaerobiccohort to the infants who receivedonly clindamycin, the matched cohortincluded 1922 infants, of whom 961(50%) were exposed to clindamycinand 961 (50%) were not exposed toany anaerobic antimicrobial therapy.Baseline characteristics used in thePS were well balanced in bothtreatment groups (SupplementalTable 5). The composite outcome ofdeath or stricture was similar in theclindamycin and control groups, aswere the outcomes of death alone andstricture alone (Table 3).

In addition to our primary analysis,the multivariable logistic regressionmodel developed in the full,prematched cohort (N = 6737)yielded similar results to thoseobtained under matching but with

TABLE 1 Demographics and Clinical Characteristics of the Matched Cohort

Anaerobic AntimicrobialTherapy

P

No, n = 1390 Yes, n = 1390

GA, wk .96,25 228 (16) 233 (17)25–28 737 (53) 736 (53).28 425 (31) 421 (30)

BW, g .39,750 428 (31) 406 (29)751–1000 414 (30) 391 (28)1001–1250 302 (22) 330 (24)1251–1500 246 (18) 263 (19)

Small for GA 275 (20) 270 (19) .81Male 736 (53) 742 (53) .82Day of lifea .49#7 124 (9) 107 (8)8–30 832 (60) 849 (61)$31 434 (31) 434 (31)

Race or ethnicity .91White 574 (41) 569 (41)African American 425 (31) 415 (30)Hispanic 329 (24) 345 (25)Other 62 (5) 61 (4)

5-min Apgar score .83,3 70 (5) 68 (5)4–6 293 (21) 306 (22)7–10 1027 (74) 1016 (73)

NEC stagea ..99Medical 1037 (75) 1037 (75)Surgical 353 (25) 353 (25)

Mechanical ventilationa 747 (54) 743 (53) .88Inotropic supporta 185 (13) 193 (14) .66Highest fraction of supplemental oxygen,a

median (5th, 95th percentile)27 (21, 100) 26 (21, 100) .81

Data presented as frequency (%) unless specified otherwise.a On the first day of the NEC episode.






a statistically significant differencein death and strictures betweentreatment groups (OR of death orstrictures 0.90; 95% CI, 0.76–1.07;OR of death 0.80; 95% CI, 0.67–0.97;OR of strictures 1.67; 95% CI,1.16–2.39).

DISCUSSION

We found no significant difference inthe risk of the composite outcome ofdeath or strictures in all infants withNEC exposed or not exposed toanaerobic antimicrobial therapy. Wedid observe lower mortality in infantswith surgical NEC treated withanaerobic antimicrobial therapy and

higher risk of strictures amongall infants with NEC who receivedanaerobic antimicrobial therapy.

The overall mortality we observed(26%) is consistent with previousdata from cohorts combining infantswith medical and surgical NEC(15%–25%),20,21,25 but the incidenceof intestinal strictures is in the lowerrange reported in the literature(3% vs 4%–30%).4,20,21,26–30 Thewide range of stricture incidencereported is probably a result ofinconsistent definitions leading toascertainment bias; some studies mightreport all strictures as diagnosedwith radiologic tests, whereas others

might report only symptomaticstrictures. The diagnosis of stricturein our data is limited to thosereported by the treating physician inthe electronic medical record. Themethods used to assign the stricturediagnosis were not standardized andmay have varied between infants.

For adults and older children,evidence strongly supports therecommendation of anaerobicantimicrobial therapy as part of theempirical regimen for complicatedintra-abdominal infections.31 On theother hand, optimal antimicrobialtherapy for NEC is unknown,including whether to use empiricalanaerobic antimicrobial therapy. Onetrial randomly assigned 42 infantswith NEC receiving ampicillin andgentamicin to clindamycin or noadditional therapy.20 Clindamycindid not affect mortality, intestinalperforation, or gangrene but wasassociated with significantly moreintestinal strictures (6/15 survivors[40%] vs 1/18 [5%] in the controlgroup; P = .02). Of note, infants in thisprevious trial were excluded ifintestinal perforation occurred,12 hours after randomization andtherefore are most comparable toour subgroup of infants with medicalNEC. For infants with medical NEC,our findings are consistent withprevious results demonstratingno added benefit of anaerobicantimicrobial therapy on mortality,but we observed only a slightnonsignificant increased risk ofstricture.20 In addition, anaerobicantimicrobial therapy did not preventprogression to surgical NEC ormortality within 7 days of the NECepisode. In contrast, anaerobicantimicrobial therapy was associatedwith lower mortality in infants withsurgical NEC.

Post-NEC stricture is an intestinalobstruction resulting from woundhealing, most prominently in theintestinal submucosa.26 Stricture isprobably a marker of severity of NEC,and it is possible that the lower rate

FIGURE 2Distribution of therapy among infants receiving anaerobic antimicrobial therapy on the first dayof NEC. Cohort after PS matching. Others = moxifloxacin, ticarcillin–clavulanate, cefoxitin, andampicillin–sulbactam.

TABLE 2 Anaerobic Antimicrobial Therapy and Clinical Outcomes

Outcomes Anaerobic AntimicrobialTherapy

OR (95% CI) P

No, n (%) Yes, n (%)

Overall, N = 2780a

Death or strictures 368 (26) 357 (26) 0.96 (0.80–1.14) .62Death 338 (24) 307 (22) 0.87 (0.72–1.05) .14Strictures 31 (2) 53 (4) 1.73 (1.11–2.72) .02

Medical NEC, N = 2074Death or strictures 186 (18) 199 (19) 1.09 (0.87–1.37) .45Death 162 (16) 161 (16) 0.99 (0.78–1.26) .95Strictures 25 (2) 40 (4) 1.60 (0.97–2.64) .07

Surgical NEC, N = 706Death or strictures 182 (52) 158 (45) 0.77 (0.57–1.03) .08Death 176 (50) 146 (41) 0.71 (0.52–0.95) .02Strictures 6 (2) 13 (4) 2.40 (0.85–6.81) .10

a Four infants were diagnosed with strictures before death.


of strictures in the nonanaerobictreatment group was a function of thedeath of infants with the most severecases of NEC, which precluded theoccurrence of strictures. Stricturesmay also be directly related toa specific drug such as clindamycin,although the biological mechanism isunknown. Moreover, other than thestudy from Faix et al,20 we found noreport in the literature linkingclindamycin (or any antibiotics) tointestinal strictures. The fact that weobserved similar results when welimited our analysis to infants treatedwith clindamycin compared withinfants with no anaerobic treatmentsuggests that clindamycin may drivethis effect, but the number of infantsreceiving each anaerobicantimicrobial therapy was insufficientto compare outcomes for eachindividual therapy.

The differential effect of anaerobicantimicrobial therapy on mortality inmedical and surgical NEC that weobserved suggests that anaerobicbacteria play a more prominent rolein the disease process of infants withsurgical NEC. A wide range ofpathogens are associated with NEC.15

Several case series of infants withNEC have reported the presence ofanaerobic bacteria, includingClostridium perfringens andBacteroides fragilis, in the blood orperitoneal fluid.17,19,32–36 A studyincluding 25 infants with NECshowed that infants who hadClostridium spp. recovered fromperitoneal fluid had more severedisease with more extensivepneumatosis intestinalis, higherincidence of portal venous gas, andmore extensive gangrene.33 Although

the exact relationship betweenanaerobic bacteria and thepathophysiology of NEC has not beenestablished, our findings suggest theyare contributing to the diseaseprocess, especially in infantspresenting with surgical NEC.

Anaerobic antimicrobial usechanged dramatically over the studyperiod (Fig 2); clindamycin usedecreased, whereas metronidazoleand piperacillin–tazobactam useincreased. Factors that led to thesefindings might include safetyconcerns linking clindamycin tointestinal stricture in theliterature,20 increasing clindamycinresistance in anaerobic bacteria suchas B fragilis,37 and growing clinicalexperience with other therapeuticoptions. Our data do not providesufficient information on specificagents for us to conclude whichanaerobic antimicrobial should bepreferred for empirical therapy. Thisquestion may be answered by anongoing phase II/III clinical trial ininfants with complicated intra-abdominal infection(NCT01994993).

This study is the largest evaluation ofantibiotic treatment in VLBW infantswith NEC. Strengths of this reportinclude its large sample size,representing a large number ofNICUs. However, despite our largecohort, matching resulted in theexclusion of nearly 60% of the samplepopulation, which might haveresulted in loss of power to detectdifferences between the 2 treatmentgroups. As a secondary analysis,a multivariable logistic regressionwithout matching yielded similarresults, but differences between

groups (lower mortality and morestrictures in the anaerobicantimicrobial therapy group) werestatistically significant. Nevertheless,we believe matching based on PSprovides more robust results bylimiting the analysis to a cohort ofinfants who had similar conditionalprobabilities of receiving anaerobicantimicrobial therapy, given theirclinical characteristics.38 Our studyis limited by its cohort design andlack of randomization; therefore,we could not completely avoid therisk of unobserved confounders. Forexample, documentation of clinicalsigns is lacking. There are alsolimitations surrounding diagnosisdefinitions. The diagnosis was notbased on standardized criteria butwas assigned by the treatingphysician. Another limitation is thepotential overlap of spontaneousintestinal perforation and NECdiagnosis in the data set. Althoughthese 2 conditions representseparate diagnoses in the dataset, differentiating spontaneousintestinal perforation from NECis difficult clinically, and thediagnosis is often not confirmeduntil laparotomy. Despite theselimitations, this large observationalstudy based on electronic medicalrecords is an efficient way tocompare treatment strategies ininfants with NEC. A randomizedcontrolled trial is unlikely becausea sample size of .7000 VLBWinfants would be necessary to detecta difference of 3% in outcomes ifthe incidence of such outcomes was30% in the susceptible population(power of 80%; .05 2-sidedsignificance level).

Our study demonstrates differentialeffects of empirical anaerobicantimicrobial therapy in infants withmedical compared with surgical NEC.Infants with surgical NEC treatedwith anaerobic antimicrobial therapyhad lower mortality. For infants withmedical NEC, there was no survivalbenefit associated with anaerobicantimicrobial therapy.

TABLE 3 Outcomes and Clindamycin Therapy

Outcomes No Anaerobic AntimicrobialTherapy, n (%)

Clindamycin, n (%) OR (95% CI) P

Overall, N = 1922a

Death or strictures 291 (30) 279 (29) 0.94 (0.76–1.15) .53Death 267 (28) 242 (25) 0.87 (0.70–1.07) .18Strictures 27 (3) 42 (4) 1.56 (0.96–2.52) .07

a Eight infants were diagnosed with strictures before death.


ACKNOWLEDGMENTS

The Pediatric Trials NetworkAdministrative Core Committee:

Jeffrey Barrett, Children’s Hospital ofPhiladelphia, Philadelphia, PA;Katherine Y. Berezny, Duke ClinicalResearch Institute, Durham, NC;Edmund Capparelli, University ofCalifornia–San Diego, San Diego, CA;Gregory L. Kearns, Children’s MercyHospital, Kansas City, MO; AndreMuelenaer, Virginia Tech CarilionSchool of Medicine, Roanoke, VA;T. Michael O’Shea, Wake ForestBaptist Medical Center, WinstonSalem, NC; Ian M. Paul, Penn StateCollege of Medicine, Hershey, PA; Johnvan den Anker, George WashingtonUniversity School of Medicine andHealth, Washington, DC; Kelly Wade,Children’s Hospital of Philadelphia,Philadelphia, PA; and Thomas J.Walsh, Weill Cornell Medical Collegeof Cornell University, New York, NY.

The Eunice Kennedy Shriver NationalInstitute of Child Health and HumanDevelopment: Alice Pagan, DavidSiegel, Perdita Taylor-Zapata, andAnne Zajicek.

The EMMES Corporation (DataCoordinating Center): Ravinder Anand,Traci Clemons, and Gina Simone.

Dr Hornik receives salary support forresearch from the National Center forAdvancing Translational Sciences ofthe National Institutes of Health(NIH) (UL1TR001117). Dr Benjaminreceives support from the USgovernment for his work in pediatricand neonatal clinical pharmacology(1R01HD057956-05,1K24HD058735-05, UL1TR001117,and National Institute of Child Healthand Human Development [NICHD]contract HHSN275201000003I).Dr Laughon receives support from theUS government for his work inpediatric and neonatal clinical

pharmacology (government contractHHSN267200700051C, PI: Benjaminunder the Best Pharmaceuticals forChildren Act) and from the NICHD(K23HD068497). Dr Cotten receivessalary support for research onneonatal health and outcomes fromthe NICHD (5U10 HD040492-10) andthe National Heart, Lung, and BloodInstitute (1R01 HL105702 01A1).Dr Cohen-Wolkowiez receivessupport for research from theNational Center for AdvancingTranslational Sciences(UL1TR001117), the Food and DrugAdministration (1U01FD004858-01),and the Biomedical AdvancedResearch and Development Authority(HHSO100201300009C). Dr Smithreceives salary support for researchfrom the NIH and the National Centerfor Advancing Translational Sciences(HHSN267200700051C,HHSN275201000003I, andUL1TR001117).

Address correspondence to P. Brian Smith, MD, MPH, MHS, Department of Pediatrics, Duke University, Duke Clinical Research Institute, PO Box 17969, Durham, NC

27715. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2015 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: Dr Benjamin receives support from the nonprofit organization Thrasher Research Fund for his work in neonatal candidiasis (www.

thrasherresearch.org); he also has consulted for Astellas, Cubist, Johnson & Johnson, Merck, and Pfizer. Dr Laughon has consulted and served on the Data Safety

Monitoring Board for Pfizer. Dr Cohen-Wolkowiez receives support for research from the nonprofit organization Thrasher Research Fund (www.thrasherresearch.

org); he has also consulted for GlaxoSmithKline. Dr Smith has consulted for GlaxoSmithKline, Astellas, and Pfizer. The other authors have indicated they have no

financial relationships relevant to this article to disclose.

FUNDING: Funded under National Institute of Child Health and Human Development contract HHSN275201000003I for the Pediatric Trials Network. Research reported

in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award UL1TR001117.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funded by the

National Institutes of Health (NIH).

POTENTIAL CONFLICT OF INTEREST: Dr Benjamin receives support from the nonprofit organization Thrasher Research Fund for his work in neonatal candidiasis

(www.thrasherresearch.org); he also has consulted for Astellas, Cubist, Johnson & Johnson, Merck, and Pfizer. Dr Laughon has consulted and served on the Data

Safety Monitoring Board for Pfizer. Dr Cohen-Wolkowiez receives support for research from the nonprofit organization Thrasher Research Fund (www.

thrasherresearch.org); he has also consulted for GlaxoSmithKline. Dr Smith has consulted for GlaxoSmithKline, Astellas, and Pfizer. The other authors have indicated

they have no potential conflicts of interest to disclose.

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DOI: 10.1542/peds.2014-2141; originally published online December 15, 2014;Pediatrics

Pediatric Trials Network Administrative Core Committee−−Benjamin, P. Brian Smith and on behalf of the Best Pharmaceuticals for Children Act

Laughon, Reese H. Clark, C. Michael Cotten, Michael Cohen-Wolkowiez, Daniel K. Julie Autmizguine, Christoph P. Hornik, Daniel K. Benjamin Jr, Matthew M.

InfantsAnaerobic Antimicrobial Therapy After Necrotizing Enterocolitis in VLBW

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Pediatric Trials Network Administrative Core Committee−−Benjamin, P. Brian Smith and on behalf of the Best Pharmaceuticals for Children Act

Laughon, Reese H. Clark, C. Michael Cotten, Michael Cohen-Wolkowiez, Daniel K. Julie Autmizguine, Christoph P. Hornik, Daniel K. Benjamin Jr, Matthew M.

InfantsAnaerobic Antimicrobial Therapy After Necrotizing Enterocolitis in VLBW

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