Narrow Vs Broad-spectrum Antimicrobial Therapy forChildren Hospitalized With Pneumonia

WHATrsquoS KNOWN ON THIS SUBJECT Recent guidelines for themanagement of childhood pneumonia recommend narrow-spectrumantimicrobial agents (eg ampicillin) for most children however fewstudies have directly compared the effectiveness of narrow-spectrumagents to the broader spectrum third-generation cephalosporinscommonly used among children hospitalized with pneumonia

WHAT THIS STUDY ADDS By using data from 43 childrenrsquoshospitals in the United States we demonstrate equivalentoutcomes and costs for children hospitalized with pneumonia andtreated empirically with either narrow- (ampicillinpenicillin) orbroad-spectrum (ceftriaxonecefotaxime) antimicrobial therapy

abstractBACKGROUND The 2011 Pediatric Infectious Diseases SocietyInfectiousDiseases Society of America community-acquired pneumonia (CAP)guideline recommends narrow-spectrum antimicrobial therapy formost children hospitalized with CAP However few studies haveassessed the effectiveness of this strategy

METHODS Using data from 43 childrenrsquos hospitals we conducted a ret-rospective cohort study to compare outcomes and resource utilizationamong children hospitalized with CAP between 2005 and 2011 receivingeither parenteral ampicillinpenicillin (narrow spectrum) or ceftriaxonecefotaxime (broad spectrum) Children with complex chronic conditionsinterhospital transfers recent hospitalization or the occurrence of anyof the following during the first 2 calendar days of hospitalization wereexcluded pleural drainage procedure admission to intensive caremechanical ventilation death or hospital discharge

RESULTS Overall 13 954 children received broad-spectrum therapy (897)and 1610 received narrow-spectrum therapy (103) The median length ofstay was 3 days (interquartile range 3ndash4) in the broad- and narrow-spectrumtherapy groups (adjusted difference 012 days 95 confidence interval [CI]ndash002 to 026) One hundred fifty-six children (11) receiving broad-spectrumtherapy and 13 children (08) receiving narrow-spectrum therapy wereadmitted to intensive care (adjusted odds ratio 085 95 CI 027 to 273)Readmission occurred for 321 children (23) receiving broad-spectrum ther-apy and 39 children (24) receiving narrow-spectrum therapy (adjusted oddsratio 085 95 CI 045 to 163) Median costs for the hospitalization were$3992 and $4375 (adjusted difference ndash$144 95 CI ndash1771 to 1483)

CONCLUSIONS Clinical outcomes and costs for children hospitalizedwith CAP are not different when treatment is with narrow- compared withbroad-spectrum therapy Pediatrics 2013132e1141ndashe1148

AUTHORS Derek J Williams MD MPHa Matthew HallPhDb Samir S Shah MD MSCEc Kavita Parikh MDd AmyTyler MDe Mark I Neuman MD MPHf Adam L Hersh MDPhDg Thomas V Brogan MDh Anne J Blaschke MD PhDg

and Carlos G Grijalva MD MPHi

aDivision of Hospital Medicine Monroe Carell Jr ChildrenrsquosHospital at Vanderbilt and Department of Pediatrics VanderbiltUniversity School of Medicine Nashville Tennessee bTheChildrenrsquos Hospital Association Overland Park Kansas cDivisionsof Infectious Diseases and Hospital Medicine CincinnatiChildrenrsquos Hospital Medical Center and Department of PediatricsUniversity of Cincinnati College of Medicine Cincinnati OhiodDivision of Hospital Medicine Childrenrsquos National Medical Centerand Department of Pediatrics George Washington UniversitySchool of Medicine Washington District of Columbia eSection ofHospital Medicine Childrenrsquos Hospital Colorado and Departmentof Pediatrics University of Colorado School of Medicine AuroraColorado fDivision of Emergency Medicine Boston ChildrenrsquosHospital and Department of Pediatrics Harvard UniversitySchool of Medicine Boston Massachusetts gDivision of InfectiousDiseases Primary Childrenrsquos Medical Center and Department ofPediatrics University of Utah School of Medicine Salt Lake CityUtah hDivision of Critical Care Seattle Childrenrsquos Hospital andDepartment of Pediatrics University of Washington School ofMedicine Seattle Washington iDepartment of PreventiveMedicine Vanderbilt University School of Medicine NashvilleTennessee

KEY WORDSpneumonia antibiotic use effectiveness pediatrics

ABBREVIATIONSaDmdashadjusted differenceCAPmdashcommunity-acquired pneumoniaCImdashconfidence intervalIDSAmdashInfectious Diseases Society of AmericaIQRmdashinterquartile rangeLOSmdashlength of stayPHISmdashPediatric Health Information SystemPIDSmdashPediatric Infectious Diseases Society

Drs Williams and Grijalva participated in conceptualization andstudy design data analysis interpretation of results drafting ofinitial manuscript and critical review and manuscript revisionDr Hall participated in conceptualization and study design dataanalysis interpretation of results and critical review andmanuscript revision Drs Shah Parikh Tyler Neuman HershBrogan and Blaschke participated in conceptualization andstudy design interpretation of results and critical review andmanuscript revision all authors reviewed and approved thefinal manuscript as submitted

(Continued on last page)

PEDIATRICS Volume 132 Number 5 November 2013 e1141

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by guest on March 16 2016Downloaded from

The 2011 Pediatric Infectious DiseasesSocietyInfectious Diseases Society ofAmerica (PIDSIDSA) guideline for themanagementof childrenwithcommunity-acquired pneumonia (CAP) recommendsnarrow-spectrum antimicrobial ther-apy for most hospitalized children1

Reasons for this recommendation in-clude the recognition of Streptococcuspneumoniae as the leading bacterialpneumonia pathogen among children2ndash4

reductions in pneumococcal diseasecaused by penicillin-resistant strainsafter introduction of pneumococcalconjugate vaccines5ndash8 and demon-strated effectiveness of higher-dosedpenicillin-based therapies for relativelyresistant pneumococcal infections out-side of the central nervous system910

Implicit in these recommendations isalso the desire to increase awarenessabout the epidemic of antimicrobial re-sistance due in part to overprescribingof broad-spectrum antibiotics for upperand lower respiratory tract infections1112

Evidencenotwithstanding theguidelinerecommendation for parenteral peni-cillin or ampicillin as empirical therapyfor children hospitalized with CAP rep-resents a significant departure fromquotidian practice in the United StatesA retrospective study of children hos-pitalized with CAP at 29 US hospitalsbetween 2005 and 2010 demonstratedthat 10 received penicillin or am-picillin as empirical therapy13 Oneargument against the guideline rec-ommendation is that the increaseddosing frequency of the relatively in-expensive narrow-spectrum antibioticsmay increase hospitalization costsAnother is the perception that broad-spectrum therapy results in faster re-covery and better clinical outcomescompared with narrow-spectrum ther-apy14 Nevertheless few studies havedirectly compared the effectiveness ofnarrow-spectrum agents to the broaderspectrum third-generation cephalosporins

commonly used among hospitalizedchildren with CAP

We sought to compare clinical out-comes and resource utilization amongchildrenhospitalizedwithCAPreceivingempirical parenteral therapy with ei-ther narrow- (ampicillin or penicillin)or broad-spectrum (ceftriaxone orcefotaxime) antimicrobial agents

METHODS

Data Source and Patient Population

We used data from the Pediatric HealthInformation System (PHIS) database(Childrenrsquos Hospital Association OverlandPark KS) The PHIS administrativedatabase contains clinical and billingdata from 43 freestanding tertiarycare childrenrsquos hospitals and accountsfor sim20 of all US pediatric hospital-izations Data quality is ensured througha joint effort between the ChildrenrsquosHospital Association and participatinghospitals as described previously15 Inaccordance with the Common Rule (45CFR 46102(f)) and the policies of theCincinnati Childrenrsquos Hospital MedicalCenter Institutional Review Board thisresearch using a deidentified data setwas not considered human subjectsresearch

Children aged 6 months to 18 yearswere eligible for inclusion if they werehospitalized between July 1 2005 andJune 30 2011 with an InternationalClassification of Diseases Ninth Re-vision Clinical Modificationndashcoded di-agnosis of pneumonia (480ndash486 4871)16

The lower age limit sought to minimizethe inclusion of children with2 dosesof routine childhood immunizations(including Haemophilus influenzae andStreptococcus pneumoniae) Becausethere are no validated disease severitymeasures for childhood CAP severaldesign restrictions were created tominimize concerns regarding confound-ing by severity We excluded childrenwithpotentially severe pneumonia or those at

risk for health carendashassociated infec-tions including children with $1 com-plex chronic conditions17 interhospitaltransfers previous hospitalization at aPHIS hospital within 30 days of the ad-mission date and children with any ofthe following during the first 2 calendardays of hospitalization pleural drainageprocedure admission to intensive caremechanical ventilation or death In ad-dition to exclude children with mild dis-ease (ie brief hospitalization) and toensure a consistent ascertainment ofempirical antimicrobial exposures wealso required children to have $2 cal-endar days of hospitalization

Exposures

Antimicrobial therapy was classified asnarrow- or broad-spectrum based onantimicrobial agents received duringthe first 2 calendar days of hospitali-zation Narrow-spectrum therapy wasdefined by the exclusive use of paren-teral penicillin or ampicillin and broad-spectrum therapy was defined by theexclusive use of parenteral ceftriaxoneor cefotaxime With the exception ofmacrolides or oseltamivir childrenreceiving other antimicrobial agentsduring the first 2 calendar days ofhospitalization were excluded as werethose with antibiotic class switching(eg from ceftriaxone to ampicillin)because antimicrobial changes duringthe first 2 days of therapy are likely notrelated to treatment failure

Outcomes

The main outcome measure was totalhospital length of stay (LOS) for theindex hospitalization Additional out-comes included admission to intensivecare (after thefirst 2 calendardays) 14-day all-cause readmission and totalcosts for the admission and the entireepisode of illness (accounting for 14-dayreadmissions) Cost data were esti-mated using hospital-specific cost-to-charge ratios and adjusted for hospital

e1142 WILLIAMS et alby guest on March 16 2016Downloaded from

location using the Centers for Medicareand Medicaid pricewage index

Covariates

Model covariates included patient de-mographics (age gender raceethnicitypayer) calendar time (hospitalizationyearandmonth) hospitalizationat PHIShospital within the preceding 6monthsasthma comorbidity (asthma-relatedhospitalization within the preceding 6months or use of chronic asthma con-troller medications on the first day ofhospitalization)17 and resource utili-zation during the first 2 calendar daysof hospitalization including oxygentherapy advanced imaging (ultrasoundor computed tomography) blood gasanalysis receipt of blood products orreceipt of other selected medications(macrolides oseltamivir bronchodila-tors and corticosteroids)

Analysis

Characteristics of the exposure groupswere summarized using frequenciesand percentages for categorical vari-ables and median and interquartileranges (IQRs) for continuous variablesBivariate comparisons used x2 andrank-sum tests as appropriate Multi-variable linear and logistic regressionmodels evaluated the association be-tween narrow- versus broad-spectrumantimicrobial use and outcomes whileaccounting for study covariates Con-tinuous outcomes with nonnormal dis-tributions were log transformed andnormality was verified before modelfitting with appropriate back trans-formation for reporting

To further address the possibility ofresidual confounding by indication weapplied a propensity score matchingstrategy Study covariates were used inthe calculation of a propensity score byusing a multivariable logistic regres-sion model with antibiotic therapy(narrowversus broad spectrum)as thedependent variable (model c statistic

= 068) Observations from exposuregroups were matched 11 on propensityscore using nearest-neighbor matchingwith a caliper set at one-quarter of theSD of the logit of the propensity scores18

Visual inspection of the distribution ofpropensity scores between antibioticgroups revealed good overlap aftermatching

A planned subgroup analysis for chil-dren with and without acute wheezingwas also performed for LOS Childrenpresenting with acute wheezing andconcurrent evidence of pneumoniaimpose clinical uncertainty regardingthe diagnosis (eg pneumonia versusatelectasis in the setting of acuteasthma)andthepotential etiology (viralor atypical pathogens versus typicalbacterial pathogens) Children withwheezing are also often treated withbronchodilators and corticosteroidswhich may hasten recovery and in-fluence outcomes For this analysisbronchodilator therapy was consid-ered a proxy for acute wheezing Chil-dren receiving bronchodilator therapyon the first 2 calendar days of hospi-talization were categorized as havingacute wheezing

RESULTS

Study Population

There were 149 853 children hospital-ized with CAP during the study periodAfter exclusion criteria were applied(Fig 1) 15 564 children remained andconstituted the study population Broad-spectrum therapy was administeredto 13 954 (897) children and 1610(103) children received narrow-spectrum therapy Children receivingbroad-spectrum therapy were slightlyolder and more likely to be male ofnon-Hispanic white or Hispanic raceethnicity and to have private insur-ance compared with children receivingnarrow-spectrum therapy Those re-ceiving broad-spectrum therapy were

also more likely to receive advancedimaging blood gas analysis and mac-rolides but were less likely to have hada recent hospitalization a history ofasthma or to receive bronchodilatoror corticosteroid therapy (Table 1)Only 1 child died

LOS

ThemedianLOS for thestudypopulationwas 3 days (IQR 3ndash4) The median LOSwas shorter among those receivingnarrow-spectrum therapy comparedwith those receiving broad-spectrumtherapy in bivariate analysis howeverthese differences were not significantafter adjustment for potential con-founders (adjusted difference [aD] 012days P = 11 Table 2)

Intensive Care Admission and14-Day Readmission

One hundred and fifty six (11) childrenreceiving broad-spectrum therapy and13 (08) children receiving narrow-spectrum therapy were admitted to in-tensive care after the first 2 days ofhospitalization (P = 26) Readmissionswithin 14 days of discharge did not dif-fer between those receiving broad-spectrum therapy (n = 321 23) andnarrow-spectrum therapy (n = 39 24P = 76) In multivariable analyses theodds of admission to intensive care and14-day readmission did not significantlydiffer between children treated withbroad- versus narrow-spectrum antimi-crobial therapy (Table 2)

Costs

Unadjusted costs were higher amongthose receiving narrow-spectrum ther-apy for both the index hospitalization(median costs $4375 vs $3992 P 001)and the total episode of illness ($4407 ]vs $4036 P 001) However in adjustedanalyses differences in costs were notstatistically significant (aD ndash$144 P= 78for index hospitalization aD ndash$19 P = 71for episode of illness Table 2)

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Propensity Score-Matched Cohort

Propensity score matching retained1044 children in each exposure groupThere were no baseline differences incharacteristics of the study populationbetween the 2 groups (Table 1) Resultsof the matched analysis did not differfrom those of the primary analysesThere were no significant differencesbetween groups with respect to LOS(aD 001 days P = 71) admission tointensive care (adjusted odds ratio 10P = 43) 14-day readmission (adjustedodds ratio 10 P = 48) or costs (aD

2$109 P = 71 for index hospitaliza-tion aD ndash$47 P = 2 for episode of ill-ness Table 3)

Subgroup Analysis

There were 4876 children in the broad-spectrum therapy group (349) and476 in the narrow-spectrum therapygroup (296) with acute wheezingChildren in the acute wheezing sub-group had similar median LOS com-pared with the nonwheezing subgroup(3 days [IQR 3ndash4] vs 4 days [IQR 3ndash4]P = 71) We observed no significant

differences in LOS between antibioticexposure groups in both the acute wheez-ing (aD 01 days P = 5) and nonwheezing(aD 015 days P = 21) subgroups

DISCUSSION

Among 15 000 children hospitalizedwith CAP there were no differences inLOS costs need for intensive care orreadmissions between those treatedwith parenteral ampicillin or penicillinand those treated with broaderspectrum third-generation cephalo-sporin therapy Our findings suggestthat the effectiveness of narrow-spectrum therapy is similar to that ofbroad-spectrum therapy for childrenhospitalized with CAPand provides newevidence to support the 2011 PIDSIDSACAP management guideline The lowfrequency of narrow-spectrum therapyusage observed in our study highlightsa substantial opportunity to promotegreater use of narrow-spectrum anti-microbial agents for children hospi-talized with CAP

The effectiveness of narrow- versusbroad-spectrum antimicrobial therapyfor pediatric CAP that required hospi-talization has been compared in a fewsmall randomized trials but no large-scale randomized controlled trial hasconclusively addressed this questionA randomized trial that studied 154children 5 years of age hospitalizedwith severe CAP in Brazil found thatempirical therapy with parenteralamoxicillinclavulanic acid was as effi-cacious as combination therapy withoxacillin and ceftriaxone The studydemonstrated no differences in thetime to stability (duration of fever orsupplemental oxygen requirement) orthe need for expanded antimicrobialcoverage between the 2 treatmentgroups19 In fact children treatedwith amoxicillinclavulanic acid had ashorter duration of tachypnea andshorter hospital LOS In a similar study154 Finnish children with pneumonia

FIGURE 1Study population ICD-9-CM International Classification of Diseases Ninth Revision Clinical Mod-ificationa See reference Feudtner et al17 b Among these children 59 received broad-spectrumtherapy alone 13 narrow-spectrum therapy alone and 28 other antimicrobial agents

e1144 WILLIAMS et alby guest on March 16 2016Downloaded from

sepsis or other acute invasive bacte-rial infection requiring hospitalizationwere randomized to receive eitherparenteral penicillin or cefuroxime Ofthe included children 47 were di-agnosed with pneumonia and nearly40 had evidence of S pneumoniaeinfection There were no differences inoutcomes (time to recovery normali-zation of laboratory parameters or

treatment failure) between the 2 anti-biotic treatment groups20 These smalltrials were conducted in regions withrelatively low rates of pneumococcalresistance to penicillins comparedwith the United States or were notlimited to CAP Thus their findings maynot be directly applicable to childrenhospitalized with CAP in the UnitedStates

Observational studies have alsoassessed the effectiveness of narrow-spectrum antimicrobial therapy forthe treatment of CAP in children A studyamong 319 Israeli children2 years ofage hospitalized with CAP demon-strated no differences in duration ofoxygen requirement hospital LOS ortreatment failures between childrenreceiving parenteral aminopenicillins(n = 66) and those receiving paren-teral cefuroxime (n = 253)21 Afterthe implementation of an antibioticstewardship program and a localpractice guideline in a tertiary US child-renrsquos hospital Newman et al demon-strated a significant increase in use ofampicillin from 15 to 60 a corre-sponding decrease in ceftriaxone useand no significant difference in the rateof treatment failure among 1000 chil-dren hospitalized with uncomplicatedCAP22 That study was conducted in an

TABLE 1 Characteristics of the Study Population

Unmatched Cohort (n = 15 564) Propensity Score Matched Cohort (n = 2088)

CeftriaxoneCefotaxime(n = 13 954)

PenicillinAmpicillin(n = 1610)

P CeftriaxoneCefotaxime(n = 1044)

PenicillinAmpicillin(n = 1044)

P

DemographicsAge y 2 [1ndash5] 2 [1ndash4] 003 2 [1ndash4] 2 [1ndash4] 54Male gender 7216 (517) 785 (488) 025 497 (476) 494 (473) 90RaceethnicityNH white 5584 (427) 481 (335) 001 208 (199) 224 (215) 47NH African American 3619 (277) 574 (399) 479 (459) 491 (47)Hispanic 3199 (245) 286 (199) 264 (253) 256 (245)Asian 382 (29) 70 (49) 56 (54) 47 (45)Other 280 (21) 26 (18) 37 (35) 26 (25)

PayerGovernment 7075 (709) 1021 (873) 001 900 (862) 905 (867) 92Private 1586 (159) 92 (79) 89 (85) 88 (84)Other 1316 (132) 57 (49) 55 (53) 51 (49)

Asthma 5226 (375) 696 (432) 001 514 (492) 484 (464) 19Previous hospitalization 1049 (75) 162 (101) 001 101 (97) 120 (115) 18Resource utilizationa

Oxygen therapy 4880 (35) 532 (33) 124 396 (379) 403 (386) 75Blood products 17 (01) 2 (01) 979 0 (0) 1 (01) 32Chest CT 173 (12) 10 (06) 029 7 (07) 4 (04) 36Chest ultrasound 150 (11) 5 (03) 003 0 (0) 1 (01) 32Blood gas analysis 1577 (113) 77 (48) 001 63 (6) 59 (57) 71

Medicationsa

Macrolide 2607 (187) 216 (134) 001 149 (143) 147 (141) 90Bronchodilator 8296 (595) 1025 (637) 001 722 (692) 701 (671) 32Corticosteroid 4698 (337) 653 (406) 001 473 (453) 471 (451) 93Oseltamivir 520 (37) 73 (45) 109 41 (39) 42 (4) 91

Data presented as n () or median [IQR] CT computed tomography NH non-Hispanica Resource utilization and medication variables limited to first 2 calendar days of hospitalization

TABLE 2 Outcomes Among Children Hospitalized With CAP According to Empiric AntimicrobialTherapy (N = 15 564)

CeftriaxoneCefotaxime(n = 13 954)

PenicillinAmpicillin(n = 1610)

Adjusted MD orOR (95 CI)

LOS d 3 [3ndash4] 3 [3ndash4] MD 012 (ndash002 to 026)Cost ($) index

hospitalization3992 [2895ndash5713] 4375 [3390ndash5805] MD ndash144 (ndash1771 to 1483)

Cost ($) episodeof illness

4036 [2919ndash5857] 4407 [3405ndash5913] MD ndash186 (ndash194 to 1569)

ICU admission 156 (11) 13 (08) OR 085 (027 to 273)14-day readmission 321 (23) 39 (24) OR 085 (045 to 163)

Data presented as median [IQR] or n () Models adjusted for age gender raceethnicity payer asthma comorbidityprevious hospitalization month and year resource utilization (oxygen therapy blood products chest ultrasound andcomputed tomography blood gas analysis) and concomitant medication use (macrolides bronchodilators corticosteroidsoseltamivir) CI confidence interval MD mean difference OR odds ratio

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area with a relatively high rate ofpneumococcal resistance to penicillin(sim25 of isolates) Using PHIS datafrom 2006 to 2008 Ambroggio et alcompared the effectiveness of b-lactammonotherapy versus a b-lactam incombination with a macrolide anddemonstrated shorter LOS for thosereceiving macrolide combination ther-apy in children aged $6 years17 Asubgroup analysis comparing narrow-versus broad-spectrum b-lactammonotherapy showed no differences inLOS or readmissions However thatstudy included children with short LOS(eg admitted and discharged on thesame day) and those receiving oraltherapy only and did not exclude chil-dren with early antimicrobial classswitching (eg ceftriaxone for ampicil-lin) In contrast our study focused onthe direct comparison of specific par-enteral antibiotic regimens and ex-cluded children with mild disease

Antimicrobial selection for treatment ofpediatric CAP is nearly always madewithout direct knowledge of the caus-ativemicroorganism The findings fromour study suggest that narrower-spectrum therapies are not inferiorto broader-spectrum therapies Al-though the importance of virusesas causes of CAP among children isincreasingly recognized23ndash28 distin-guishing viral from bacterial etiologiesis difficult Without rapid and sensitive

bacterial diagnostics at the point ofcare or trials demonstrating the effi-cacy of no treatment our findings in-dicate therapy with narrow-spectrumantibiotics is effective for most chil-dren hospitalized with CAP as rec-ommended by the PIDSIDSA CAPmanagement guideline

Optimizing antimicrobial usage is im-portant for minimizing the spread ofantimicrobial resistance on a globalscaleMore than 150 000USchildrenarehospitalized with CAP annually makingit among the most common indicationsfor hospitalization in childhood29 Dis-couraging the use of unnecessarilybroad-spectrum antimicrobial agentsfor children hospitalized with CAPtherefore has the potential to markedlyreduce selective pressure for antimi-crobial resistance Our study notedthat only 10 of study childrenreceived empirical therapy with peni-cillin or ampicillin Wide variation inprescribing of antimicrobial agents forchildren hospitalized with CAP hasbeen observed across PHIS hospitalsalthough 5 of children with CAPreceive narrow-spectrum therapyat most hospitals13 Thus althoughsome institutions often used narrow-spectrum therapy for uncomplicatedCAP most did not highlighting an im-portant opportunity for improvementin antimicrobial selection Previousstudies have demonstrated the feasibility

and effectiveness of stewardship pro-grams and dissemination of localpractice guidelines on changing anti-microbial selection for CAP manage-ment2230ndash33 The publication of the firstconsensus guidelines for childhoodCAP management could serve as a cat-alyst for these initiatives

The overall cost of hospitalization didnotdifferbetweenchildren treatedwithnarrow- versus broad-spectrum anti-microbial therapy in our study Thisfinding suggests that routine use ofpenicillin or ampicillin does not con-tribute to substantial increases in hos-pitalization costs despite the increaseddosing frequency of these medicationscompared with some third-generationcephalosporins such as once-daily cef-triaxone Although pharmacy costs maydiffer in local environments differencesare likely small and not amajor driver ofhospital costs Thus other cost-savingmeasures such as promoting earlytransition to oral therapy improvingdiagnostics to facilitate reduced anti-microbialuseor interventions toreducehospital LOSmayprovemoreeffective inminimizing total hospital costs3435

Limitations of the study are largelyrelated to the observational study de-sign and include the potential for con-founding by indication absence ofetiologic and other clinical data anda relative lack of objective outcomemeasures In the absence of large ran-domized efficacy trials well-designedobservational studies provide valu-able data on the effectiveness of ther-apies and interventions on a largescale Several steps were taken to re-duce potential confounding due todifferential use of narrow- or broad-spectrum therapy based on illness se-verity First we excluded children withindicators of severe disease at or nearthe time of presentation (eg admissionto intensive care) We also excludedchildren with indicators of particularlymild disease (eg receipt of oral

TABLE 3 Outcomes Among Children Hospitalized With CAP According to Empiric AntimicrobialTherapy Propensity Score Matched Cohort (n = 2088)

CeftriaxoneCefotaxime(n = 1044)

PenicillinAmpicillin(n = 1044)

Adjusted MD orOR (95 CI)

LOS d 3 [3ndash5] 3 [3ndash4] MD 001 (ndash022 to 024)Cost ($) indexhospitalization

4017 [2872ndash5908] 4255 [3302ndash5651] MD ndash1088 (ndash3934 to 1759)

Cost ($) episodeof illness

4106 [2898ndash6057] 4274 [3305ndash5752] MD ndash469 (ndash3499 to 2651)

ICU admission 14 (13) 11 (11) OR 10 (0996 to 101)14-day readmission 28 (27) 25 (24) OR 10 (0994 to 101)

Data presented as median [IQR] or n () Variables used to estimate propensity score included age gender raceethnicitypayer asthma comorbidity previous hospitalization month and year resource utilization (oxygen therapy blood productschest ultrasound and computed tomography blood gas analysis) and concomitant medication use (macrolides broncho-dilators corticosteroids oseltamivir) Propensity score matching (11) retained 1044 children in the narrow-spectrumtherapy group (648) model c statistic 068 CI confidence interval MD mean difference OR odds ratio

e1146 WILLIAMS et alby guest on March 16 2016Downloaded from

antimicrobial agents on the first hos-pital day or hospital LOS 2 calendardays) Second a number of factors thatmay influence antimicrobial selectionincluding proxy measures of diseaseseverity were accounted for in ourmultivariable analyses Furthermoreour propensity score matched analy-sis which substantially minimized thedifferences between exposure groupsalso produced results similar to thosefrom the unmatched cohort lendingfurther support to our studyrsquos primaryresults Although we cannot eliminateresidual confounding due to un-measured covariates the careful se-lection of our study population as wellas the use of robust modeling techni-ques minimizes this concern The

distinction between bacterial and viralcauses of CAP in children is difficulteven in prospective studies Residualmisclassification after application ofselection criteria in this regard wouldbe expected to be nondifferentialbetween the 2 empirical treatmentgroups favoring the null hypothesisAlthough the PHIS database does notcontain results of microbiologic test-ing our study was restricted to chil-dren who received antimicrobialtherapy which suggests clinical sus-picion of and treatment of bacterialpneumonia Similarly hospital-specificdata such as the presence or absenceof local practice guidelines or stew-ardship programs was not availableFinally our assessment focused on the

evaluation of empirical antimicrobialtreatments but did not characterizeantimicrobial class switching after thefirst 2 days of hospitalization

CONCLUSIONS

Clinical outcomes and costs for chil-dren hospitalized with CAP are not dif-ferent when empirical treatment iswith narrow-spectrum compared withbroad-spectrum therapy Few institu-tions used narrow-spectrum therapyroutinely beforepublicationof thePIDSIDSA CAP management guidelinesPrograms promoting guideline imple-mentation and targeting judiciousantibiotic selection for CAP are neededto optimize management of childhoodCAP in the United States

REFERENCES

1 Bradley JS Byington CL Shah SS et alPediatric Infectious Diseases Society andthe Infectious Diseases Society of AmericaThe management of community-acquiredpneumonia in infants and children olderthan 3 months of age clinical practiceguidelines by the Pediatric Infectious Dis-eases Society and the Infectious DiseasesSociety of America Clin Infect Dis 201153(7)e25ndashe76

2 Michelow IC Olsen K Lozano J et al Epi-demiology and clinical characteristics ofcommunity-acquired pneumonia in hospi-talized children Pediatrics 2004113(4)701ndash707

3 Juveacuten T Mertsola J Waris M et al Etiologyof community-acquired pneumonia in 254hospitalized children Pediatr Infect Dis J200019(4)293ndash298

4 Heiskanen-Kosma T Korppi M Jokinen Cet al Etiology of childhood pneumonia se-rologic results of a prospective population-based study Pediatr Infect Dis J 199817(11)986ndash991

5 Pilishvili T Lexau C Farley MM et al Ac-tive Bacterial Core SurveillanceEmergingInfections Program Network Sustainedreductions in invasive pneumococcaldisease in the era of conjugate vaccine JInfect Dis 2010201(1)32ndash41

6 Kyaw MH Lynfield R Schaffner W et alActive Bacterial Core Surveillance of theEmerging Infections Program Network Ef-fect of introduction of the pneumococcalconjugate vaccine on drug-resistant Strep-tococcus pneumoniae N Engl J Med 2006354(14)1455ndash1463

7 Centers for Disease Control PreventionEffects of new penicillin susceptibilitybreakpoints for Streptococcus pneumo-niaemdashUnited States 2006ndash2007 MMWR200857(50)1353ndash1355

8 Hampton LM Farley MM Schaffner W et alPrevention of antibiotic-nonsusceptibleStreptococcus pneumoniae with conjugatevaccines J Infect Dis 2012205(3)401ndash411

9 Dagan R Hoberman A Johnson C et alBacteriologic and clinical efficacy of highdose amoxicillinclavulanate in childrenwith acute otitis media Pediatr Infect Dis J200120(9)829ndash837

10 Weinstein MP Klugman KP Jones RN Ra-tionale for revised penicillin susceptibilitybreakpoints versus Streptococcus pneu-moniae coping with antimicrobial suscep-tibility in an era of resistance Clin InfectDis 200948(11)1596ndash1600

11 Hersh AL Shapiro DJ Pavia AT Shah SSAntibiotic prescribing in ambulatory pedi-atrics in the United States Pediatrics 2011128(6)1053ndash1061

12 Kronman MP Hersh AL Feng R Huang YSLee GE Shah SS Ambulatory visit rates andantibiotic prescribing for children withpneumonia 1994ndash2007 Pediatrics 2011127(3)411ndash418

13 Brogan TV Hall M Williams DJ et al Vari-ability in processes of care and outcomesamong children hospitalized with community-acquired pneumonia Pediatr Infect Dis J201231(10)1036ndash1041

14 Schouten JA Hulscher ME Natsch SKullberg BJ van der Meer JW Grol RPBarriers to optimal antibiotic use forcommunity-acquired pneumonia at hospi-tals a qualitative study Qual Saf HealthCare 200716(2)143ndash149

15 Mongelluzzo J Mohamad Z Ten Have TRShah SS Corticosteroids and mortality inchildren with bacterial meningitis JAMA2008299(17)2048ndash2055

16 Williams DJ Shah SS Myers AM et alIdentifying pediatric community-acquiredpneumonia hospitalizations accuracy ofadministrative billing codes [publishedonline ahead of print July 29 2013] JAMAPediatr doi 101001jamapediatrics2013186

17 Feudtner C Christakis DA Connell FA Pe-diatric deaths attributable to complexchronic conditions a population-basedstudy of Washington State 1980ndash1997 Pe-diatrics 2000106(1 Pt 2)205ndash209

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PEDIATRICS Volume 132 Number 5 November 2013 e1147by guest on March 16 2016Downloaded from

18 Rosenbaum PR Rubin DB Constructinga control-group using multivariate matchedsampling methods that incorporate thepropensity score Am Stat 198539(1)33ndash38

19 Ribeiro CF Ferrari GF Fioretto JR Antibiotictreatment schemes for very severe com-munity-acquired pneumonia in childrena randomized clinical study Revista PanamSalud Publica 201129(6)444ndash450

20 Vuori-Holopainen E Peltola H Kallio MJSE-TU Study Group Narrow- versus broad-spectrum parenteral antimicrobials againstcommon infections of childhood a pro-spective and randomised comparisonbetween penicillin and cefuroxime EurJ Pediatr 2000159(12)878ndash884

21 Dinur-Schejter Y Cohen-Cymberknoh MTenenbaum A et al Antibiotic treatment ofchildren with community-acquired pneu-monia comparison of penicillin or ampi-cillin versus cefuroxime Pediatr Pulmonol201348(1)52ndash58

22 Newman RE Hedican EB Herigon JCWilliams DD Williams AR Newland JG Im-pact of a guideline on management ofchildren hospitalized with community-acquired pneumonia Pediatrics 2012129(3) Available at wwwpediatricsorgcgicontentfull1293e597

23 Garciacutea-Garciacutea ML Calvo C Pozo F VilladangosPA Peacuterez-Brentildea P Casas I Spectrum ofrespiratory viruses in children withcommunity-acquired pneumonia PediatrInfect Dis J 201231(8)808ndash813

24 Esposito S Daleno C Prunotto G et al Im-pact of viral infections in children withcommunity-acquired pneumonia results ofa study of 17 respiratory viruses InfluenzaOther Respi Viruses 20137(1)18ndash26

25 Wolf DG Greenberg D Shemer-Avni YGivon-Lavi N Bar-Ziv J Dagan R Associationof human metapneumovirus with radio-logically diagnosed community-acquiredalveolar pneumonia in young childrenJ Pediatr 2010156(1)115ndash120

26 Cilla G Ontildeate E Perez-Yarza EG Montes MVicente D Perez-Trallero E Viruses incommunity-acquired pneumonia in chil-dren aged less than 3 years old high rateof viral coinfection J Med Virol 200880(10)1843ndash1849

27 Hammitt LL Kazungu S Morpeth SC et al Apreliminary study of pneumonia etiologyamong hospitalized children in Kenya ClinInfect Dis 201254(suppl 2)S190ndashS199

28 Mermond S Zurawski V DrsquoOrtenzio E et alLower respiratory infections among hospi-talized children in New Caledonia a pilotstudy for the Pneumonia Etiology Researchfor Child Health project Clin Infect Dis201254(suppl 2)S180ndashS189

29 AHRQ National estimates on use of hospi-tals by children from the HCUP Kidsrsquo In-patient Database (KID) 2009 Available athttphcupnetahrqgovHCUPnetjspId=F3D2E7DF566C8BCCampForm=SelPATampJS=YampAction=3E3ENext3E3Eamp_InPatChar=Yesamp_InHospChar=Yesamp_PatChar= AccessedMarch 22 2012

30 Neuman MI Hall M Hersh AL et alInfluence of hospital guidelines on man-agement of children hospitalized withpneumonia Pediatrics 2012130(5) Avail-able at wwwpediatricsorgcgicontentfull1305e823

31 McIntosh KA Maxwell DJ Pulver LK et al Aquality improvement initiative to improveadherence to national guidelines for em-piric management of community-acquiredpneumonia in emergency departments IntJ Qual Health Care 201123(2)142ndash150

32 Smith MJ Kong M Cambon A Woods CREffectiveness of antimicrobial guidelinesfor community-acquired pneumonia inchildren Pediatrics 2012129(5) Availableat wwwpediatricsorgcgicontentfull1295e1326

33 Ambroggio L Thomson J Kurowski EMet al Quality improvement increases ap-propriate antibiotic prescribing for child-hood community acquired pneumoniaPediatrics 2013131(5) Available at wwwpediatricsorgcgicontentfull1315e1623

34 Carratalagrave J Garcia-Vidal C Ortega L et alEffect of a 3-step critical pathway to reduceduration of intravenous antibiotic therapyand length of stay in community-acquiredpneumonia a randomized controlled trialArch Intern Med 2012172(12)922ndash928

35 Lorgelly PK Atkinson M Lakhanpaul Met al Oral versus iv antibiotics forcommunity-acquired pneumonia in chil-dren a cost-minimisation analysis EurRespir J 201035(4)858ndash864

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1614

doi101542peds2013-1614

Accepted for publication Aug 27 2013

Address correspondence to Derek J Williams MD MPH 1161 21st Ave South CCC 5311 Medical Center North Nashville TN 37232 E-mail derekwilliamsvanderbiltedu

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2013 by the American Academy of Pediatrics

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

FUNDING No external funding

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

e1148 WILLIAMS et alby guest on March 16 2016Downloaded from

The 2011 Pediatric Infectious DiseasesSocietyInfectious Diseases Society ofAmerica (PIDSIDSA) guideline for themanagementof childrenwithcommunity-acquired pneumonia (CAP) recommendsnarrow-spectrum antimicrobial ther-apy for most hospitalized children1

Reasons for this recommendation in-clude the recognition of Streptococcuspneumoniae as the leading bacterialpneumonia pathogen among children2ndash4

reductions in pneumococcal diseasecaused by penicillin-resistant strainsafter introduction of pneumococcalconjugate vaccines5ndash8 and demon-strated effectiveness of higher-dosedpenicillin-based therapies for relativelyresistant pneumococcal infections out-side of the central nervous system910

Implicit in these recommendations isalso the desire to increase awarenessabout the epidemic of antimicrobial re-sistance due in part to overprescribingof broad-spectrum antibiotics for upperand lower respiratory tract infections1112

Evidencenotwithstanding theguidelinerecommendation for parenteral peni-cillin or ampicillin as empirical therapyfor children hospitalized with CAP rep-resents a significant departure fromquotidian practice in the United StatesA retrospective study of children hos-pitalized with CAP at 29 US hospitalsbetween 2005 and 2010 demonstratedthat 10 received penicillin or am-picillin as empirical therapy13 Oneargument against the guideline rec-ommendation is that the increaseddosing frequency of the relatively in-expensive narrow-spectrum antibioticsmay increase hospitalization costsAnother is the perception that broad-spectrum therapy results in faster re-covery and better clinical outcomescompared with narrow-spectrum ther-apy14 Nevertheless few studies havedirectly compared the effectiveness ofnarrow-spectrum agents to the broaderspectrum third-generation cephalosporins

commonly used among hospitalizedchildren with CAP

We sought to compare clinical out-comes and resource utilization amongchildrenhospitalizedwithCAPreceivingempirical parenteral therapy with ei-ther narrow- (ampicillin or penicillin)or broad-spectrum (ceftriaxone orcefotaxime) antimicrobial agents

METHODS

Data Source and Patient Population

We used data from the Pediatric HealthInformation System (PHIS) database(Childrenrsquos Hospital Association OverlandPark KS) The PHIS administrativedatabase contains clinical and billingdata from 43 freestanding tertiarycare childrenrsquos hospitals and accountsfor sim20 of all US pediatric hospital-izations Data quality is ensured througha joint effort between the ChildrenrsquosHospital Association and participatinghospitals as described previously15 Inaccordance with the Common Rule (45CFR 46102(f)) and the policies of theCincinnati Childrenrsquos Hospital MedicalCenter Institutional Review Board thisresearch using a deidentified data setwas not considered human subjectsresearch

Children aged 6 months to 18 yearswere eligible for inclusion if they werehospitalized between July 1 2005 andJune 30 2011 with an InternationalClassification of Diseases Ninth Re-vision Clinical Modificationndashcoded di-agnosis of pneumonia (480ndash486 4871)16

The lower age limit sought to minimizethe inclusion of children with2 dosesof routine childhood immunizations(including Haemophilus influenzae andStreptococcus pneumoniae) Becausethere are no validated disease severitymeasures for childhood CAP severaldesign restrictions were created tominimize concerns regarding confound-ing by severity We excluded childrenwithpotentially severe pneumonia or those at

risk for health carendashassociated infec-tions including children with $1 com-plex chronic conditions17 interhospitaltransfers previous hospitalization at aPHIS hospital within 30 days of the ad-mission date and children with any ofthe following during the first 2 calendardays of hospitalization pleural drainageprocedure admission to intensive caremechanical ventilation or death In ad-dition to exclude children with mild dis-ease (ie brief hospitalization) and toensure a consistent ascertainment ofempirical antimicrobial exposures wealso required children to have $2 cal-endar days of hospitalization

Exposures

Antimicrobial therapy was classified asnarrow- or broad-spectrum based onantimicrobial agents received duringthe first 2 calendar days of hospitali-zation Narrow-spectrum therapy wasdefined by the exclusive use of paren-teral penicillin or ampicillin and broad-spectrum therapy was defined by theexclusive use of parenteral ceftriaxoneor cefotaxime With the exception ofmacrolides or oseltamivir childrenreceiving other antimicrobial agentsduring the first 2 calendar days ofhospitalization were excluded as werethose with antibiotic class switching(eg from ceftriaxone to ampicillin)because antimicrobial changes duringthe first 2 days of therapy are likely notrelated to treatment failure

Outcomes

The main outcome measure was totalhospital length of stay (LOS) for theindex hospitalization Additional out-comes included admission to intensivecare (after thefirst 2 calendardays) 14-day all-cause readmission and totalcosts for the admission and the entireepisode of illness (accounting for 14-dayreadmissions) Cost data were esti-mated using hospital-specific cost-to-charge ratios and adjusted for hospital

e1142 WILLIAMS et alby guest on March 16 2016Downloaded from

location using the Centers for Medicareand Medicaid pricewage index

Covariates

Model covariates included patient de-mographics (age gender raceethnicitypayer) calendar time (hospitalizationyearandmonth) hospitalizationat PHIShospital within the preceding 6monthsasthma comorbidity (asthma-relatedhospitalization within the preceding 6months or use of chronic asthma con-troller medications on the first day ofhospitalization)17 and resource utili-zation during the first 2 calendar daysof hospitalization including oxygentherapy advanced imaging (ultrasoundor computed tomography) blood gasanalysis receipt of blood products orreceipt of other selected medications(macrolides oseltamivir bronchodila-tors and corticosteroids)

Analysis

Characteristics of the exposure groupswere summarized using frequenciesand percentages for categorical vari-ables and median and interquartileranges (IQRs) for continuous variablesBivariate comparisons used x2 andrank-sum tests as appropriate Multi-variable linear and logistic regressionmodels evaluated the association be-tween narrow- versus broad-spectrumantimicrobial use and outcomes whileaccounting for study covariates Con-tinuous outcomes with nonnormal dis-tributions were log transformed andnormality was verified before modelfitting with appropriate back trans-formation for reporting

To further address the possibility ofresidual confounding by indication weapplied a propensity score matchingstrategy Study covariates were used inthe calculation of a propensity score byusing a multivariable logistic regres-sion model with antibiotic therapy(narrowversus broad spectrum)as thedependent variable (model c statistic

= 068) Observations from exposuregroups were matched 11 on propensityscore using nearest-neighbor matchingwith a caliper set at one-quarter of theSD of the logit of the propensity scores18

Visual inspection of the distribution ofpropensity scores between antibioticgroups revealed good overlap aftermatching

A planned subgroup analysis for chil-dren with and without acute wheezingwas also performed for LOS Childrenpresenting with acute wheezing andconcurrent evidence of pneumoniaimpose clinical uncertainty regardingthe diagnosis (eg pneumonia versusatelectasis in the setting of acuteasthma)andthepotential etiology (viralor atypical pathogens versus typicalbacterial pathogens) Children withwheezing are also often treated withbronchodilators and corticosteroidswhich may hasten recovery and in-fluence outcomes For this analysisbronchodilator therapy was consid-ered a proxy for acute wheezing Chil-dren receiving bronchodilator therapyon the first 2 calendar days of hospi-talization were categorized as havingacute wheezing

RESULTS

Study Population

There were 149 853 children hospital-ized with CAP during the study periodAfter exclusion criteria were applied(Fig 1) 15 564 children remained andconstituted the study population Broad-spectrum therapy was administeredto 13 954 (897) children and 1610(103) children received narrow-spectrum therapy Children receivingbroad-spectrum therapy were slightlyolder and more likely to be male ofnon-Hispanic white or Hispanic raceethnicity and to have private insur-ance compared with children receivingnarrow-spectrum therapy Those re-ceiving broad-spectrum therapy were

also more likely to receive advancedimaging blood gas analysis and mac-rolides but were less likely to have hada recent hospitalization a history ofasthma or to receive bronchodilatoror corticosteroid therapy (Table 1)Only 1 child died

LOS

ThemedianLOS for thestudypopulationwas 3 days (IQR 3ndash4) The median LOSwas shorter among those receivingnarrow-spectrum therapy comparedwith those receiving broad-spectrumtherapy in bivariate analysis howeverthese differences were not significantafter adjustment for potential con-founders (adjusted difference [aD] 012days P = 11 Table 2)

Intensive Care Admission and14-Day Readmission

One hundred and fifty six (11) childrenreceiving broad-spectrum therapy and13 (08) children receiving narrow-spectrum therapy were admitted to in-tensive care after the first 2 days ofhospitalization (P = 26) Readmissionswithin 14 days of discharge did not dif-fer between those receiving broad-spectrum therapy (n = 321 23) andnarrow-spectrum therapy (n = 39 24P = 76) In multivariable analyses theodds of admission to intensive care and14-day readmission did not significantlydiffer between children treated withbroad- versus narrow-spectrum antimi-crobial therapy (Table 2)

Costs

Unadjusted costs were higher amongthose receiving narrow-spectrum ther-apy for both the index hospitalization(median costs $4375 vs $3992 P 001)and the total episode of illness ($4407 ]vs $4036 P 001) However in adjustedanalyses differences in costs were notstatistically significant (aD ndash$144 P= 78for index hospitalization aD ndash$19 P = 71for episode of illness Table 2)

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PEDIATRICS Volume 132 Number 5 November 2013 e1143by guest on March 16 2016Downloaded from

Propensity Score-Matched Cohort

Propensity score matching retained1044 children in each exposure groupThere were no baseline differences incharacteristics of the study populationbetween the 2 groups (Table 1) Resultsof the matched analysis did not differfrom those of the primary analysesThere were no significant differencesbetween groups with respect to LOS(aD 001 days P = 71) admission tointensive care (adjusted odds ratio 10P = 43) 14-day readmission (adjustedodds ratio 10 P = 48) or costs (aD

2$109 P = 71 for index hospitaliza-tion aD ndash$47 P = 2 for episode of ill-ness Table 3)

Subgroup Analysis

There were 4876 children in the broad-spectrum therapy group (349) and476 in the narrow-spectrum therapygroup (296) with acute wheezingChildren in the acute wheezing sub-group had similar median LOS com-pared with the nonwheezing subgroup(3 days [IQR 3ndash4] vs 4 days [IQR 3ndash4]P = 71) We observed no significant

differences in LOS between antibioticexposure groups in both the acute wheez-ing (aD 01 days P = 5) and nonwheezing(aD 015 days P = 21) subgroups

DISCUSSION

Among 15 000 children hospitalizedwith CAP there were no differences inLOS costs need for intensive care orreadmissions between those treatedwith parenteral ampicillin or penicillinand those treated with broaderspectrum third-generation cephalo-sporin therapy Our findings suggestthat the effectiveness of narrow-spectrum therapy is similar to that ofbroad-spectrum therapy for childrenhospitalized with CAPand provides newevidence to support the 2011 PIDSIDSACAP management guideline The lowfrequency of narrow-spectrum therapyusage observed in our study highlightsa substantial opportunity to promotegreater use of narrow-spectrum anti-microbial agents for children hospi-talized with CAP

The effectiveness of narrow- versusbroad-spectrum antimicrobial therapyfor pediatric CAP that required hospi-talization has been compared in a fewsmall randomized trials but no large-scale randomized controlled trial hasconclusively addressed this questionA randomized trial that studied 154children 5 years of age hospitalizedwith severe CAP in Brazil found thatempirical therapy with parenteralamoxicillinclavulanic acid was as effi-cacious as combination therapy withoxacillin and ceftriaxone The studydemonstrated no differences in thetime to stability (duration of fever orsupplemental oxygen requirement) orthe need for expanded antimicrobialcoverage between the 2 treatmentgroups19 In fact children treatedwith amoxicillinclavulanic acid had ashorter duration of tachypnea andshorter hospital LOS In a similar study154 Finnish children with pneumonia

FIGURE 1Study population ICD-9-CM International Classification of Diseases Ninth Revision Clinical Mod-ificationa See reference Feudtner et al17 b Among these children 59 received broad-spectrumtherapy alone 13 narrow-spectrum therapy alone and 28 other antimicrobial agents

e1144 WILLIAMS et alby guest on March 16 2016Downloaded from

sepsis or other acute invasive bacte-rial infection requiring hospitalizationwere randomized to receive eitherparenteral penicillin or cefuroxime Ofthe included children 47 were di-agnosed with pneumonia and nearly40 had evidence of S pneumoniaeinfection There were no differences inoutcomes (time to recovery normali-zation of laboratory parameters or

treatment failure) between the 2 anti-biotic treatment groups20 These smalltrials were conducted in regions withrelatively low rates of pneumococcalresistance to penicillins comparedwith the United States or were notlimited to CAP Thus their findings maynot be directly applicable to childrenhospitalized with CAP in the UnitedStates

Observational studies have alsoassessed the effectiveness of narrow-spectrum antimicrobial therapy forthe treatment of CAP in children A studyamong 319 Israeli children2 years ofage hospitalized with CAP demon-strated no differences in duration ofoxygen requirement hospital LOS ortreatment failures between childrenreceiving parenteral aminopenicillins(n = 66) and those receiving paren-teral cefuroxime (n = 253)21 Afterthe implementation of an antibioticstewardship program and a localpractice guideline in a tertiary US child-renrsquos hospital Newman et al demon-strated a significant increase in use ofampicillin from 15 to 60 a corre-sponding decrease in ceftriaxone useand no significant difference in the rateof treatment failure among 1000 chil-dren hospitalized with uncomplicatedCAP22 That study was conducted in an

TABLE 1 Characteristics of the Study Population

Unmatched Cohort (n = 15 564) Propensity Score Matched Cohort (n = 2088)

CeftriaxoneCefotaxime(n = 13 954)

PenicillinAmpicillin(n = 1610)

P CeftriaxoneCefotaxime(n = 1044)

PenicillinAmpicillin(n = 1044)

P

DemographicsAge y 2 [1ndash5] 2 [1ndash4] 003 2 [1ndash4] 2 [1ndash4] 54Male gender 7216 (517) 785 (488) 025 497 (476) 494 (473) 90RaceethnicityNH white 5584 (427) 481 (335) 001 208 (199) 224 (215) 47NH African American 3619 (277) 574 (399) 479 (459) 491 (47)Hispanic 3199 (245) 286 (199) 264 (253) 256 (245)Asian 382 (29) 70 (49) 56 (54) 47 (45)Other 280 (21) 26 (18) 37 (35) 26 (25)

PayerGovernment 7075 (709) 1021 (873) 001 900 (862) 905 (867) 92Private 1586 (159) 92 (79) 89 (85) 88 (84)Other 1316 (132) 57 (49) 55 (53) 51 (49)

Asthma 5226 (375) 696 (432) 001 514 (492) 484 (464) 19Previous hospitalization 1049 (75) 162 (101) 001 101 (97) 120 (115) 18Resource utilizationa

Oxygen therapy 4880 (35) 532 (33) 124 396 (379) 403 (386) 75Blood products 17 (01) 2 (01) 979 0 (0) 1 (01) 32Chest CT 173 (12) 10 (06) 029 7 (07) 4 (04) 36Chest ultrasound 150 (11) 5 (03) 003 0 (0) 1 (01) 32Blood gas analysis 1577 (113) 77 (48) 001 63 (6) 59 (57) 71

Medicationsa

Macrolide 2607 (187) 216 (134) 001 149 (143) 147 (141) 90Bronchodilator 8296 (595) 1025 (637) 001 722 (692) 701 (671) 32Corticosteroid 4698 (337) 653 (406) 001 473 (453) 471 (451) 93Oseltamivir 520 (37) 73 (45) 109 41 (39) 42 (4) 91

Data presented as n () or median [IQR] CT computed tomography NH non-Hispanica Resource utilization and medication variables limited to first 2 calendar days of hospitalization

TABLE 2 Outcomes Among Children Hospitalized With CAP According to Empiric AntimicrobialTherapy (N = 15 564)

CeftriaxoneCefotaxime(n = 13 954)

PenicillinAmpicillin(n = 1610)

Adjusted MD orOR (95 CI)

LOS d 3 [3ndash4] 3 [3ndash4] MD 012 (ndash002 to 026)Cost ($) index

hospitalization3992 [2895ndash5713] 4375 [3390ndash5805] MD ndash144 (ndash1771 to 1483)

Cost ($) episodeof illness

4036 [2919ndash5857] 4407 [3405ndash5913] MD ndash186 (ndash194 to 1569)

ICU admission 156 (11) 13 (08) OR 085 (027 to 273)14-day readmission 321 (23) 39 (24) OR 085 (045 to 163)

Data presented as median [IQR] or n () Models adjusted for age gender raceethnicity payer asthma comorbidityprevious hospitalization month and year resource utilization (oxygen therapy blood products chest ultrasound andcomputed tomography blood gas analysis) and concomitant medication use (macrolides bronchodilators corticosteroidsoseltamivir) CI confidence interval MD mean difference OR odds ratio

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PEDIATRICS Volume 132 Number 5 November 2013 e1145by guest on March 16 2016Downloaded from

area with a relatively high rate ofpneumococcal resistance to penicillin(sim25 of isolates) Using PHIS datafrom 2006 to 2008 Ambroggio et alcompared the effectiveness of b-lactammonotherapy versus a b-lactam incombination with a macrolide anddemonstrated shorter LOS for thosereceiving macrolide combination ther-apy in children aged $6 years17 Asubgroup analysis comparing narrow-versus broad-spectrum b-lactammonotherapy showed no differences inLOS or readmissions However thatstudy included children with short LOS(eg admitted and discharged on thesame day) and those receiving oraltherapy only and did not exclude chil-dren with early antimicrobial classswitching (eg ceftriaxone for ampicil-lin) In contrast our study focused onthe direct comparison of specific par-enteral antibiotic regimens and ex-cluded children with mild disease

Antimicrobial selection for treatment ofpediatric CAP is nearly always madewithout direct knowledge of the caus-ativemicroorganism The findings fromour study suggest that narrower-spectrum therapies are not inferiorto broader-spectrum therapies Al-though the importance of virusesas causes of CAP among children isincreasingly recognized23ndash28 distin-guishing viral from bacterial etiologiesis difficult Without rapid and sensitive

bacterial diagnostics at the point ofcare or trials demonstrating the effi-cacy of no treatment our findings in-dicate therapy with narrow-spectrumantibiotics is effective for most chil-dren hospitalized with CAP as rec-ommended by the PIDSIDSA CAPmanagement guideline

Optimizing antimicrobial usage is im-portant for minimizing the spread ofantimicrobial resistance on a globalscaleMore than 150 000USchildrenarehospitalized with CAP annually makingit among the most common indicationsfor hospitalization in childhood29 Dis-couraging the use of unnecessarilybroad-spectrum antimicrobial agentsfor children hospitalized with CAPtherefore has the potential to markedlyreduce selective pressure for antimi-crobial resistance Our study notedthat only 10 of study childrenreceived empirical therapy with peni-cillin or ampicillin Wide variation inprescribing of antimicrobial agents forchildren hospitalized with CAP hasbeen observed across PHIS hospitalsalthough 5 of children with CAPreceive narrow-spectrum therapyat most hospitals13 Thus althoughsome institutions often used narrow-spectrum therapy for uncomplicatedCAP most did not highlighting an im-portant opportunity for improvementin antimicrobial selection Previousstudies have demonstrated the feasibility

and effectiveness of stewardship pro-grams and dissemination of localpractice guidelines on changing anti-microbial selection for CAP manage-ment2230ndash33 The publication of the firstconsensus guidelines for childhoodCAP management could serve as a cat-alyst for these initiatives

The overall cost of hospitalization didnotdifferbetweenchildren treatedwithnarrow- versus broad-spectrum anti-microbial therapy in our study Thisfinding suggests that routine use ofpenicillin or ampicillin does not con-tribute to substantial increases in hos-pitalization costs despite the increaseddosing frequency of these medicationscompared with some third-generationcephalosporins such as once-daily cef-triaxone Although pharmacy costs maydiffer in local environments differencesare likely small and not amajor driver ofhospital costs Thus other cost-savingmeasures such as promoting earlytransition to oral therapy improvingdiagnostics to facilitate reduced anti-microbialuseor interventions toreducehospital LOSmayprovemoreeffective inminimizing total hospital costs3435

Limitations of the study are largelyrelated to the observational study de-sign and include the potential for con-founding by indication absence ofetiologic and other clinical data anda relative lack of objective outcomemeasures In the absence of large ran-domized efficacy trials well-designedobservational studies provide valu-able data on the effectiveness of ther-apies and interventions on a largescale Several steps were taken to re-duce potential confounding due todifferential use of narrow- or broad-spectrum therapy based on illness se-verity First we excluded children withindicators of severe disease at or nearthe time of presentation (eg admissionto intensive care) We also excludedchildren with indicators of particularlymild disease (eg receipt of oral

TABLE 3 Outcomes Among Children Hospitalized With CAP According to Empiric AntimicrobialTherapy Propensity Score Matched Cohort (n = 2088)

CeftriaxoneCefotaxime(n = 1044)

PenicillinAmpicillin(n = 1044)

Adjusted MD orOR (95 CI)

LOS d 3 [3ndash5] 3 [3ndash4] MD 001 (ndash022 to 024)Cost ($) indexhospitalization

4017 [2872ndash5908] 4255 [3302ndash5651] MD ndash1088 (ndash3934 to 1759)

Cost ($) episodeof illness

4106 [2898ndash6057] 4274 [3305ndash5752] MD ndash469 (ndash3499 to 2651)

ICU admission 14 (13) 11 (11) OR 10 (0996 to 101)14-day readmission 28 (27) 25 (24) OR 10 (0994 to 101)

Data presented as median [IQR] or n () Variables used to estimate propensity score included age gender raceethnicitypayer asthma comorbidity previous hospitalization month and year resource utilization (oxygen therapy blood productschest ultrasound and computed tomography blood gas analysis) and concomitant medication use (macrolides broncho-dilators corticosteroids oseltamivir) Propensity score matching (11) retained 1044 children in the narrow-spectrumtherapy group (648) model c statistic 068 CI confidence interval MD mean difference OR odds ratio

e1146 WILLIAMS et alby guest on March 16 2016Downloaded from

antimicrobial agents on the first hos-pital day or hospital LOS 2 calendardays) Second a number of factors thatmay influence antimicrobial selectionincluding proxy measures of diseaseseverity were accounted for in ourmultivariable analyses Furthermoreour propensity score matched analy-sis which substantially minimized thedifferences between exposure groupsalso produced results similar to thosefrom the unmatched cohort lendingfurther support to our studyrsquos primaryresults Although we cannot eliminateresidual confounding due to un-measured covariates the careful se-lection of our study population as wellas the use of robust modeling techni-ques minimizes this concern The

distinction between bacterial and viralcauses of CAP in children is difficulteven in prospective studies Residualmisclassification after application ofselection criteria in this regard wouldbe expected to be nondifferentialbetween the 2 empirical treatmentgroups favoring the null hypothesisAlthough the PHIS database does notcontain results of microbiologic test-ing our study was restricted to chil-dren who received antimicrobialtherapy which suggests clinical sus-picion of and treatment of bacterialpneumonia Similarly hospital-specificdata such as the presence or absenceof local practice guidelines or stew-ardship programs was not availableFinally our assessment focused on the

evaluation of empirical antimicrobialtreatments but did not characterizeantimicrobial class switching after thefirst 2 days of hospitalization

CONCLUSIONS

Clinical outcomes and costs for chil-dren hospitalized with CAP are not dif-ferent when empirical treatment iswith narrow-spectrum compared withbroad-spectrum therapy Few institu-tions used narrow-spectrum therapyroutinely beforepublicationof thePIDSIDSA CAP management guidelinesPrograms promoting guideline imple-mentation and targeting judiciousantibiotic selection for CAP are neededto optimize management of childhoodCAP in the United States

REFERENCES

1 Bradley JS Byington CL Shah SS et alPediatric Infectious Diseases Society andthe Infectious Diseases Society of AmericaThe management of community-acquiredpneumonia in infants and children olderthan 3 months of age clinical practiceguidelines by the Pediatric Infectious Dis-eases Society and the Infectious DiseasesSociety of America Clin Infect Dis 201153(7)e25ndashe76

2 Michelow IC Olsen K Lozano J et al Epi-demiology and clinical characteristics ofcommunity-acquired pneumonia in hospi-talized children Pediatrics 2004113(4)701ndash707

3 Juveacuten T Mertsola J Waris M et al Etiologyof community-acquired pneumonia in 254hospitalized children Pediatr Infect Dis J200019(4)293ndash298

4 Heiskanen-Kosma T Korppi M Jokinen Cet al Etiology of childhood pneumonia se-rologic results of a prospective population-based study Pediatr Infect Dis J 199817(11)986ndash991

5 Pilishvili T Lexau C Farley MM et al Ac-tive Bacterial Core SurveillanceEmergingInfections Program Network Sustainedreductions in invasive pneumococcaldisease in the era of conjugate vaccine JInfect Dis 2010201(1)32ndash41

6 Kyaw MH Lynfield R Schaffner W et alActive Bacterial Core Surveillance of theEmerging Infections Program Network Ef-fect of introduction of the pneumococcalconjugate vaccine on drug-resistant Strep-tococcus pneumoniae N Engl J Med 2006354(14)1455ndash1463

7 Centers for Disease Control PreventionEffects of new penicillin susceptibilitybreakpoints for Streptococcus pneumo-niaemdashUnited States 2006ndash2007 MMWR200857(50)1353ndash1355

8 Hampton LM Farley MM Schaffner W et alPrevention of antibiotic-nonsusceptibleStreptococcus pneumoniae with conjugatevaccines J Infect Dis 2012205(3)401ndash411

9 Dagan R Hoberman A Johnson C et alBacteriologic and clinical efficacy of highdose amoxicillinclavulanate in childrenwith acute otitis media Pediatr Infect Dis J200120(9)829ndash837

10 Weinstein MP Klugman KP Jones RN Ra-tionale for revised penicillin susceptibilitybreakpoints versus Streptococcus pneu-moniae coping with antimicrobial suscep-tibility in an era of resistance Clin InfectDis 200948(11)1596ndash1600

11 Hersh AL Shapiro DJ Pavia AT Shah SSAntibiotic prescribing in ambulatory pedi-atrics in the United States Pediatrics 2011128(6)1053ndash1061

12 Kronman MP Hersh AL Feng R Huang YSLee GE Shah SS Ambulatory visit rates andantibiotic prescribing for children withpneumonia 1994ndash2007 Pediatrics 2011127(3)411ndash418

13 Brogan TV Hall M Williams DJ et al Vari-ability in processes of care and outcomesamong children hospitalized with community-acquired pneumonia Pediatr Infect Dis J201231(10)1036ndash1041

14 Schouten JA Hulscher ME Natsch SKullberg BJ van der Meer JW Grol RPBarriers to optimal antibiotic use forcommunity-acquired pneumonia at hospi-tals a qualitative study Qual Saf HealthCare 200716(2)143ndash149

15 Mongelluzzo J Mohamad Z Ten Have TRShah SS Corticosteroids and mortality inchildren with bacterial meningitis JAMA2008299(17)2048ndash2055

16 Williams DJ Shah SS Myers AM et alIdentifying pediatric community-acquiredpneumonia hospitalizations accuracy ofadministrative billing codes [publishedonline ahead of print July 29 2013] JAMAPediatr doi 101001jamapediatrics2013186

17 Feudtner C Christakis DA Connell FA Pe-diatric deaths attributable to complexchronic conditions a population-basedstudy of Washington State 1980ndash1997 Pe-diatrics 2000106(1 Pt 2)205ndash209

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PEDIATRICS Volume 132 Number 5 November 2013 e1147by guest on March 16 2016Downloaded from

18 Rosenbaum PR Rubin DB Constructinga control-group using multivariate matchedsampling methods that incorporate thepropensity score Am Stat 198539(1)33ndash38

19 Ribeiro CF Ferrari GF Fioretto JR Antibiotictreatment schemes for very severe com-munity-acquired pneumonia in childrena randomized clinical study Revista PanamSalud Publica 201129(6)444ndash450

20 Vuori-Holopainen E Peltola H Kallio MJSE-TU Study Group Narrow- versus broad-spectrum parenteral antimicrobials againstcommon infections of childhood a pro-spective and randomised comparisonbetween penicillin and cefuroxime EurJ Pediatr 2000159(12)878ndash884

21 Dinur-Schejter Y Cohen-Cymberknoh MTenenbaum A et al Antibiotic treatment ofchildren with community-acquired pneu-monia comparison of penicillin or ampi-cillin versus cefuroxime Pediatr Pulmonol201348(1)52ndash58

22 Newman RE Hedican EB Herigon JCWilliams DD Williams AR Newland JG Im-pact of a guideline on management ofchildren hospitalized with community-acquired pneumonia Pediatrics 2012129(3) Available at wwwpediatricsorgcgicontentfull1293e597

23 Garciacutea-Garciacutea ML Calvo C Pozo F VilladangosPA Peacuterez-Brentildea P Casas I Spectrum ofrespiratory viruses in children withcommunity-acquired pneumonia PediatrInfect Dis J 201231(8)808ndash813

24 Esposito S Daleno C Prunotto G et al Im-pact of viral infections in children withcommunity-acquired pneumonia results ofa study of 17 respiratory viruses InfluenzaOther Respi Viruses 20137(1)18ndash26

25 Wolf DG Greenberg D Shemer-Avni YGivon-Lavi N Bar-Ziv J Dagan R Associationof human metapneumovirus with radio-logically diagnosed community-acquiredalveolar pneumonia in young childrenJ Pediatr 2010156(1)115ndash120

26 Cilla G Ontildeate E Perez-Yarza EG Montes MVicente D Perez-Trallero E Viruses incommunity-acquired pneumonia in chil-dren aged less than 3 years old high rateof viral coinfection J Med Virol 200880(10)1843ndash1849

27 Hammitt LL Kazungu S Morpeth SC et al Apreliminary study of pneumonia etiologyamong hospitalized children in Kenya ClinInfect Dis 201254(suppl 2)S190ndashS199

28 Mermond S Zurawski V DrsquoOrtenzio E et alLower respiratory infections among hospi-talized children in New Caledonia a pilotstudy for the Pneumonia Etiology Researchfor Child Health project Clin Infect Dis201254(suppl 2)S180ndashS189

29 AHRQ National estimates on use of hospi-tals by children from the HCUP Kidsrsquo In-patient Database (KID) 2009 Available athttphcupnetahrqgovHCUPnetjspId=F3D2E7DF566C8BCCampForm=SelPATampJS=YampAction=3E3ENext3E3Eamp_InPatChar=Yesamp_InHospChar=Yesamp_PatChar= AccessedMarch 22 2012

30 Neuman MI Hall M Hersh AL et alInfluence of hospital guidelines on man-agement of children hospitalized withpneumonia Pediatrics 2012130(5) Avail-able at wwwpediatricsorgcgicontentfull1305e823

31 McIntosh KA Maxwell DJ Pulver LK et al Aquality improvement initiative to improveadherence to national guidelines for em-piric management of community-acquiredpneumonia in emergency departments IntJ Qual Health Care 201123(2)142ndash150

32 Smith MJ Kong M Cambon A Woods CREffectiveness of antimicrobial guidelinesfor community-acquired pneumonia inchildren Pediatrics 2012129(5) Availableat wwwpediatricsorgcgicontentfull1295e1326

33 Ambroggio L Thomson J Kurowski EMet al Quality improvement increases ap-propriate antibiotic prescribing for child-hood community acquired pneumoniaPediatrics 2013131(5) Available at wwwpediatricsorgcgicontentfull1315e1623

34 Carratalagrave J Garcia-Vidal C Ortega L et alEffect of a 3-step critical pathway to reduceduration of intravenous antibiotic therapyand length of stay in community-acquiredpneumonia a randomized controlled trialArch Intern Med 2012172(12)922ndash928

35 Lorgelly PK Atkinson M Lakhanpaul Met al Oral versus iv antibiotics forcommunity-acquired pneumonia in chil-dren a cost-minimisation analysis EurRespir J 201035(4)858ndash864

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1614

doi101542peds2013-1614

Accepted for publication Aug 27 2013

Address correspondence to Derek J Williams MD MPH 1161 21st Ave South CCC 5311 Medical Center North Nashville TN 37232 E-mail derekwilliamsvanderbiltedu

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2013 by the American Academy of Pediatrics

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

FUNDING No external funding

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

e1148 WILLIAMS et alby guest on March 16 2016Downloaded from

location using the Centers for Medicareand Medicaid pricewage index

Covariates

Model covariates included patient de-mographics (age gender raceethnicitypayer) calendar time (hospitalizationyearandmonth) hospitalizationat PHIShospital within the preceding 6monthsasthma comorbidity (asthma-relatedhospitalization within the preceding 6months or use of chronic asthma con-troller medications on the first day ofhospitalization)17 and resource utili-zation during the first 2 calendar daysof hospitalization including oxygentherapy advanced imaging (ultrasoundor computed tomography) blood gasanalysis receipt of blood products orreceipt of other selected medications(macrolides oseltamivir bronchodila-tors and corticosteroids)

Analysis

Characteristics of the exposure groupswere summarized using frequenciesand percentages for categorical vari-ables and median and interquartileranges (IQRs) for continuous variablesBivariate comparisons used x2 andrank-sum tests as appropriate Multi-variable linear and logistic regressionmodels evaluated the association be-tween narrow- versus broad-spectrumantimicrobial use and outcomes whileaccounting for study covariates Con-tinuous outcomes with nonnormal dis-tributions were log transformed andnormality was verified before modelfitting with appropriate back trans-formation for reporting

To further address the possibility ofresidual confounding by indication weapplied a propensity score matchingstrategy Study covariates were used inthe calculation of a propensity score byusing a multivariable logistic regres-sion model with antibiotic therapy(narrowversus broad spectrum)as thedependent variable (model c statistic

= 068) Observations from exposuregroups were matched 11 on propensityscore using nearest-neighbor matchingwith a caliper set at one-quarter of theSD of the logit of the propensity scores18

Visual inspection of the distribution ofpropensity scores between antibioticgroups revealed good overlap aftermatching

A planned subgroup analysis for chil-dren with and without acute wheezingwas also performed for LOS Childrenpresenting with acute wheezing andconcurrent evidence of pneumoniaimpose clinical uncertainty regardingthe diagnosis (eg pneumonia versusatelectasis in the setting of acuteasthma)andthepotential etiology (viralor atypical pathogens versus typicalbacterial pathogens) Children withwheezing are also often treated withbronchodilators and corticosteroidswhich may hasten recovery and in-fluence outcomes For this analysisbronchodilator therapy was consid-ered a proxy for acute wheezing Chil-dren receiving bronchodilator therapyon the first 2 calendar days of hospi-talization were categorized as havingacute wheezing

RESULTS

Study Population

There were 149 853 children hospital-ized with CAP during the study periodAfter exclusion criteria were applied(Fig 1) 15 564 children remained andconstituted the study population Broad-spectrum therapy was administeredto 13 954 (897) children and 1610(103) children received narrow-spectrum therapy Children receivingbroad-spectrum therapy were slightlyolder and more likely to be male ofnon-Hispanic white or Hispanic raceethnicity and to have private insur-ance compared with children receivingnarrow-spectrum therapy Those re-ceiving broad-spectrum therapy were

also more likely to receive advancedimaging blood gas analysis and mac-rolides but were less likely to have hada recent hospitalization a history ofasthma or to receive bronchodilatoror corticosteroid therapy (Table 1)Only 1 child died

LOS

ThemedianLOS for thestudypopulationwas 3 days (IQR 3ndash4) The median LOSwas shorter among those receivingnarrow-spectrum therapy comparedwith those receiving broad-spectrumtherapy in bivariate analysis howeverthese differences were not significantafter adjustment for potential con-founders (adjusted difference [aD] 012days P = 11 Table 2)

Intensive Care Admission and14-Day Readmission

One hundred and fifty six (11) childrenreceiving broad-spectrum therapy and13 (08) children receiving narrow-spectrum therapy were admitted to in-tensive care after the first 2 days ofhospitalization (P = 26) Readmissionswithin 14 days of discharge did not dif-fer between those receiving broad-spectrum therapy (n = 321 23) andnarrow-spectrum therapy (n = 39 24P = 76) In multivariable analyses theodds of admission to intensive care and14-day readmission did not significantlydiffer between children treated withbroad- versus narrow-spectrum antimi-crobial therapy (Table 2)

Costs

Unadjusted costs were higher amongthose receiving narrow-spectrum ther-apy for both the index hospitalization(median costs $4375 vs $3992 P 001)and the total episode of illness ($4407 ]vs $4036 P 001) However in adjustedanalyses differences in costs were notstatistically significant (aD ndash$144 P= 78for index hospitalization aD ndash$19 P = 71for episode of illness Table 2)

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PEDIATRICS Volume 132 Number 5 November 2013 e1143by guest on March 16 2016Downloaded from

Propensity Score-Matched Cohort

Propensity score matching retained1044 children in each exposure groupThere were no baseline differences incharacteristics of the study populationbetween the 2 groups (Table 1) Resultsof the matched analysis did not differfrom those of the primary analysesThere were no significant differencesbetween groups with respect to LOS(aD 001 days P = 71) admission tointensive care (adjusted odds ratio 10P = 43) 14-day readmission (adjustedodds ratio 10 P = 48) or costs (aD

2$109 P = 71 for index hospitaliza-tion aD ndash$47 P = 2 for episode of ill-ness Table 3)

Subgroup Analysis

There were 4876 children in the broad-spectrum therapy group (349) and476 in the narrow-spectrum therapygroup (296) with acute wheezingChildren in the acute wheezing sub-group had similar median LOS com-pared with the nonwheezing subgroup(3 days [IQR 3ndash4] vs 4 days [IQR 3ndash4]P = 71) We observed no significant

differences in LOS between antibioticexposure groups in both the acute wheez-ing (aD 01 days P = 5) and nonwheezing(aD 015 days P = 21) subgroups

DISCUSSION

Among 15 000 children hospitalizedwith CAP there were no differences inLOS costs need for intensive care orreadmissions between those treatedwith parenteral ampicillin or penicillinand those treated with broaderspectrum third-generation cephalo-sporin therapy Our findings suggestthat the effectiveness of narrow-spectrum therapy is similar to that ofbroad-spectrum therapy for childrenhospitalized with CAPand provides newevidence to support the 2011 PIDSIDSACAP management guideline The lowfrequency of narrow-spectrum therapyusage observed in our study highlightsa substantial opportunity to promotegreater use of narrow-spectrum anti-microbial agents for children hospi-talized with CAP

The effectiveness of narrow- versusbroad-spectrum antimicrobial therapyfor pediatric CAP that required hospi-talization has been compared in a fewsmall randomized trials but no large-scale randomized controlled trial hasconclusively addressed this questionA randomized trial that studied 154children 5 years of age hospitalizedwith severe CAP in Brazil found thatempirical therapy with parenteralamoxicillinclavulanic acid was as effi-cacious as combination therapy withoxacillin and ceftriaxone The studydemonstrated no differences in thetime to stability (duration of fever orsupplemental oxygen requirement) orthe need for expanded antimicrobialcoverage between the 2 treatmentgroups19 In fact children treatedwith amoxicillinclavulanic acid had ashorter duration of tachypnea andshorter hospital LOS In a similar study154 Finnish children with pneumonia

FIGURE 1Study population ICD-9-CM International Classification of Diseases Ninth Revision Clinical Mod-ificationa See reference Feudtner et al17 b Among these children 59 received broad-spectrumtherapy alone 13 narrow-spectrum therapy alone and 28 other antimicrobial agents

e1144 WILLIAMS et alby guest on March 16 2016Downloaded from

sepsis or other acute invasive bacte-rial infection requiring hospitalizationwere randomized to receive eitherparenteral penicillin or cefuroxime Ofthe included children 47 were di-agnosed with pneumonia and nearly40 had evidence of S pneumoniaeinfection There were no differences inoutcomes (time to recovery normali-zation of laboratory parameters or

treatment failure) between the 2 anti-biotic treatment groups20 These smalltrials were conducted in regions withrelatively low rates of pneumococcalresistance to penicillins comparedwith the United States or were notlimited to CAP Thus their findings maynot be directly applicable to childrenhospitalized with CAP in the UnitedStates

Observational studies have alsoassessed the effectiveness of narrow-spectrum antimicrobial therapy forthe treatment of CAP in children A studyamong 319 Israeli children2 years ofage hospitalized with CAP demon-strated no differences in duration ofoxygen requirement hospital LOS ortreatment failures between childrenreceiving parenteral aminopenicillins(n = 66) and those receiving paren-teral cefuroxime (n = 253)21 Afterthe implementation of an antibioticstewardship program and a localpractice guideline in a tertiary US child-renrsquos hospital Newman et al demon-strated a significant increase in use ofampicillin from 15 to 60 a corre-sponding decrease in ceftriaxone useand no significant difference in the rateof treatment failure among 1000 chil-dren hospitalized with uncomplicatedCAP22 That study was conducted in an

TABLE 1 Characteristics of the Study Population

Unmatched Cohort (n = 15 564) Propensity Score Matched Cohort (n = 2088)

CeftriaxoneCefotaxime(n = 13 954)

PenicillinAmpicillin(n = 1610)

P CeftriaxoneCefotaxime(n = 1044)

PenicillinAmpicillin(n = 1044)

P

DemographicsAge y 2 [1ndash5] 2 [1ndash4] 003 2 [1ndash4] 2 [1ndash4] 54Male gender 7216 (517) 785 (488) 025 497 (476) 494 (473) 90RaceethnicityNH white 5584 (427) 481 (335) 001 208 (199) 224 (215) 47NH African American 3619 (277) 574 (399) 479 (459) 491 (47)Hispanic 3199 (245) 286 (199) 264 (253) 256 (245)Asian 382 (29) 70 (49) 56 (54) 47 (45)Other 280 (21) 26 (18) 37 (35) 26 (25)

PayerGovernment 7075 (709) 1021 (873) 001 900 (862) 905 (867) 92Private 1586 (159) 92 (79) 89 (85) 88 (84)Other 1316 (132) 57 (49) 55 (53) 51 (49)

Asthma 5226 (375) 696 (432) 001 514 (492) 484 (464) 19Previous hospitalization 1049 (75) 162 (101) 001 101 (97) 120 (115) 18Resource utilizationa

Oxygen therapy 4880 (35) 532 (33) 124 396 (379) 403 (386) 75Blood products 17 (01) 2 (01) 979 0 (0) 1 (01) 32Chest CT 173 (12) 10 (06) 029 7 (07) 4 (04) 36Chest ultrasound 150 (11) 5 (03) 003 0 (0) 1 (01) 32Blood gas analysis 1577 (113) 77 (48) 001 63 (6) 59 (57) 71

Medicationsa

Macrolide 2607 (187) 216 (134) 001 149 (143) 147 (141) 90Bronchodilator 8296 (595) 1025 (637) 001 722 (692) 701 (671) 32Corticosteroid 4698 (337) 653 (406) 001 473 (453) 471 (451) 93Oseltamivir 520 (37) 73 (45) 109 41 (39) 42 (4) 91

Data presented as n () or median [IQR] CT computed tomography NH non-Hispanica Resource utilization and medication variables limited to first 2 calendar days of hospitalization

TABLE 2 Outcomes Among Children Hospitalized With CAP According to Empiric AntimicrobialTherapy (N = 15 564)

CeftriaxoneCefotaxime(n = 13 954)

PenicillinAmpicillin(n = 1610)

Adjusted MD orOR (95 CI)

LOS d 3 [3ndash4] 3 [3ndash4] MD 012 (ndash002 to 026)Cost ($) index

hospitalization3992 [2895ndash5713] 4375 [3390ndash5805] MD ndash144 (ndash1771 to 1483)

Cost ($) episodeof illness

4036 [2919ndash5857] 4407 [3405ndash5913] MD ndash186 (ndash194 to 1569)

ICU admission 156 (11) 13 (08) OR 085 (027 to 273)14-day readmission 321 (23) 39 (24) OR 085 (045 to 163)

Data presented as median [IQR] or n () Models adjusted for age gender raceethnicity payer asthma comorbidityprevious hospitalization month and year resource utilization (oxygen therapy blood products chest ultrasound andcomputed tomography blood gas analysis) and concomitant medication use (macrolides bronchodilators corticosteroidsoseltamivir) CI confidence interval MD mean difference OR odds ratio

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PEDIATRICS Volume 132 Number 5 November 2013 e1145by guest on March 16 2016Downloaded from

area with a relatively high rate ofpneumococcal resistance to penicillin(sim25 of isolates) Using PHIS datafrom 2006 to 2008 Ambroggio et alcompared the effectiveness of b-lactammonotherapy versus a b-lactam incombination with a macrolide anddemonstrated shorter LOS for thosereceiving macrolide combination ther-apy in children aged $6 years17 Asubgroup analysis comparing narrow-versus broad-spectrum b-lactammonotherapy showed no differences inLOS or readmissions However thatstudy included children with short LOS(eg admitted and discharged on thesame day) and those receiving oraltherapy only and did not exclude chil-dren with early antimicrobial classswitching (eg ceftriaxone for ampicil-lin) In contrast our study focused onthe direct comparison of specific par-enteral antibiotic regimens and ex-cluded children with mild disease

Antimicrobial selection for treatment ofpediatric CAP is nearly always madewithout direct knowledge of the caus-ativemicroorganism The findings fromour study suggest that narrower-spectrum therapies are not inferiorto broader-spectrum therapies Al-though the importance of virusesas causes of CAP among children isincreasingly recognized23ndash28 distin-guishing viral from bacterial etiologiesis difficult Without rapid and sensitive

bacterial diagnostics at the point ofcare or trials demonstrating the effi-cacy of no treatment our findings in-dicate therapy with narrow-spectrumantibiotics is effective for most chil-dren hospitalized with CAP as rec-ommended by the PIDSIDSA CAPmanagement guideline

Optimizing antimicrobial usage is im-portant for minimizing the spread ofantimicrobial resistance on a globalscaleMore than 150 000USchildrenarehospitalized with CAP annually makingit among the most common indicationsfor hospitalization in childhood29 Dis-couraging the use of unnecessarilybroad-spectrum antimicrobial agentsfor children hospitalized with CAPtherefore has the potential to markedlyreduce selective pressure for antimi-crobial resistance Our study notedthat only 10 of study childrenreceived empirical therapy with peni-cillin or ampicillin Wide variation inprescribing of antimicrobial agents forchildren hospitalized with CAP hasbeen observed across PHIS hospitalsalthough 5 of children with CAPreceive narrow-spectrum therapyat most hospitals13 Thus althoughsome institutions often used narrow-spectrum therapy for uncomplicatedCAP most did not highlighting an im-portant opportunity for improvementin antimicrobial selection Previousstudies have demonstrated the feasibility

and effectiveness of stewardship pro-grams and dissemination of localpractice guidelines on changing anti-microbial selection for CAP manage-ment2230ndash33 The publication of the firstconsensus guidelines for childhoodCAP management could serve as a cat-alyst for these initiatives

The overall cost of hospitalization didnotdifferbetweenchildren treatedwithnarrow- versus broad-spectrum anti-microbial therapy in our study Thisfinding suggests that routine use ofpenicillin or ampicillin does not con-tribute to substantial increases in hos-pitalization costs despite the increaseddosing frequency of these medicationscompared with some third-generationcephalosporins such as once-daily cef-triaxone Although pharmacy costs maydiffer in local environments differencesare likely small and not amajor driver ofhospital costs Thus other cost-savingmeasures such as promoting earlytransition to oral therapy improvingdiagnostics to facilitate reduced anti-microbialuseor interventions toreducehospital LOSmayprovemoreeffective inminimizing total hospital costs3435

Limitations of the study are largelyrelated to the observational study de-sign and include the potential for con-founding by indication absence ofetiologic and other clinical data anda relative lack of objective outcomemeasures In the absence of large ran-domized efficacy trials well-designedobservational studies provide valu-able data on the effectiveness of ther-apies and interventions on a largescale Several steps were taken to re-duce potential confounding due todifferential use of narrow- or broad-spectrum therapy based on illness se-verity First we excluded children withindicators of severe disease at or nearthe time of presentation (eg admissionto intensive care) We also excludedchildren with indicators of particularlymild disease (eg receipt of oral

TABLE 3 Outcomes Among Children Hospitalized With CAP According to Empiric AntimicrobialTherapy Propensity Score Matched Cohort (n = 2088)

CeftriaxoneCefotaxime(n = 1044)

PenicillinAmpicillin(n = 1044)

Adjusted MD orOR (95 CI)

LOS d 3 [3ndash5] 3 [3ndash4] MD 001 (ndash022 to 024)Cost ($) indexhospitalization

4017 [2872ndash5908] 4255 [3302ndash5651] MD ndash1088 (ndash3934 to 1759)

Cost ($) episodeof illness

4106 [2898ndash6057] 4274 [3305ndash5752] MD ndash469 (ndash3499 to 2651)

ICU admission 14 (13) 11 (11) OR 10 (0996 to 101)14-day readmission 28 (27) 25 (24) OR 10 (0994 to 101)

Data presented as median [IQR] or n () Variables used to estimate propensity score included age gender raceethnicitypayer asthma comorbidity previous hospitalization month and year resource utilization (oxygen therapy blood productschest ultrasound and computed tomography blood gas analysis) and concomitant medication use (macrolides broncho-dilators corticosteroids oseltamivir) Propensity score matching (11) retained 1044 children in the narrow-spectrumtherapy group (648) model c statistic 068 CI confidence interval MD mean difference OR odds ratio

e1146 WILLIAMS et alby guest on March 16 2016Downloaded from

antimicrobial agents on the first hos-pital day or hospital LOS 2 calendardays) Second a number of factors thatmay influence antimicrobial selectionincluding proxy measures of diseaseseverity were accounted for in ourmultivariable analyses Furthermoreour propensity score matched analy-sis which substantially minimized thedifferences between exposure groupsalso produced results similar to thosefrom the unmatched cohort lendingfurther support to our studyrsquos primaryresults Although we cannot eliminateresidual confounding due to un-measured covariates the careful se-lection of our study population as wellas the use of robust modeling techni-ques minimizes this concern The

distinction between bacterial and viralcauses of CAP in children is difficulteven in prospective studies Residualmisclassification after application ofselection criteria in this regard wouldbe expected to be nondifferentialbetween the 2 empirical treatmentgroups favoring the null hypothesisAlthough the PHIS database does notcontain results of microbiologic test-ing our study was restricted to chil-dren who received antimicrobialtherapy which suggests clinical sus-picion of and treatment of bacterialpneumonia Similarly hospital-specificdata such as the presence or absenceof local practice guidelines or stew-ardship programs was not availableFinally our assessment focused on the

evaluation of empirical antimicrobialtreatments but did not characterizeantimicrobial class switching after thefirst 2 days of hospitalization

CONCLUSIONS

Clinical outcomes and costs for chil-dren hospitalized with CAP are not dif-ferent when empirical treatment iswith narrow-spectrum compared withbroad-spectrum therapy Few institu-tions used narrow-spectrum therapyroutinely beforepublicationof thePIDSIDSA CAP management guidelinesPrograms promoting guideline imple-mentation and targeting judiciousantibiotic selection for CAP are neededto optimize management of childhoodCAP in the United States

REFERENCES

1 Bradley JS Byington CL Shah SS et alPediatric Infectious Diseases Society andthe Infectious Diseases Society of AmericaThe management of community-acquiredpneumonia in infants and children olderthan 3 months of age clinical practiceguidelines by the Pediatric Infectious Dis-eases Society and the Infectious DiseasesSociety of America Clin Infect Dis 201153(7)e25ndashe76

2 Michelow IC Olsen K Lozano J et al Epi-demiology and clinical characteristics ofcommunity-acquired pneumonia in hospi-talized children Pediatrics 2004113(4)701ndash707

3 Juveacuten T Mertsola J Waris M et al Etiologyof community-acquired pneumonia in 254hospitalized children Pediatr Infect Dis J200019(4)293ndash298

4 Heiskanen-Kosma T Korppi M Jokinen Cet al Etiology of childhood pneumonia se-rologic results of a prospective population-based study Pediatr Infect Dis J 199817(11)986ndash991

5 Pilishvili T Lexau C Farley MM et al Ac-tive Bacterial Core SurveillanceEmergingInfections Program Network Sustainedreductions in invasive pneumococcaldisease in the era of conjugate vaccine JInfect Dis 2010201(1)32ndash41

6 Kyaw MH Lynfield R Schaffner W et alActive Bacterial Core Surveillance of theEmerging Infections Program Network Ef-fect of introduction of the pneumococcalconjugate vaccine on drug-resistant Strep-tococcus pneumoniae N Engl J Med 2006354(14)1455ndash1463

7 Centers for Disease Control PreventionEffects of new penicillin susceptibilitybreakpoints for Streptococcus pneumo-niaemdashUnited States 2006ndash2007 MMWR200857(50)1353ndash1355

8 Hampton LM Farley MM Schaffner W et alPrevention of antibiotic-nonsusceptibleStreptococcus pneumoniae with conjugatevaccines J Infect Dis 2012205(3)401ndash411

9 Dagan R Hoberman A Johnson C et alBacteriologic and clinical efficacy of highdose amoxicillinclavulanate in childrenwith acute otitis media Pediatr Infect Dis J200120(9)829ndash837

10 Weinstein MP Klugman KP Jones RN Ra-tionale for revised penicillin susceptibilitybreakpoints versus Streptococcus pneu-moniae coping with antimicrobial suscep-tibility in an era of resistance Clin InfectDis 200948(11)1596ndash1600

11 Hersh AL Shapiro DJ Pavia AT Shah SSAntibiotic prescribing in ambulatory pedi-atrics in the United States Pediatrics 2011128(6)1053ndash1061

12 Kronman MP Hersh AL Feng R Huang YSLee GE Shah SS Ambulatory visit rates andantibiotic prescribing for children withpneumonia 1994ndash2007 Pediatrics 2011127(3)411ndash418

13 Brogan TV Hall M Williams DJ et al Vari-ability in processes of care and outcomesamong children hospitalized with community-acquired pneumonia Pediatr Infect Dis J201231(10)1036ndash1041

14 Schouten JA Hulscher ME Natsch SKullberg BJ van der Meer JW Grol RPBarriers to optimal antibiotic use forcommunity-acquired pneumonia at hospi-tals a qualitative study Qual Saf HealthCare 200716(2)143ndash149

15 Mongelluzzo J Mohamad Z Ten Have TRShah SS Corticosteroids and mortality inchildren with bacterial meningitis JAMA2008299(17)2048ndash2055

16 Williams DJ Shah SS Myers AM et alIdentifying pediatric community-acquiredpneumonia hospitalizations accuracy ofadministrative billing codes [publishedonline ahead of print July 29 2013] JAMAPediatr doi 101001jamapediatrics2013186

17 Feudtner C Christakis DA Connell FA Pe-diatric deaths attributable to complexchronic conditions a population-basedstudy of Washington State 1980ndash1997 Pe-diatrics 2000106(1 Pt 2)205ndash209

ARTICLE

PEDIATRICS Volume 132 Number 5 November 2013 e1147by guest on March 16 2016Downloaded from

18 Rosenbaum PR Rubin DB Constructinga control-group using multivariate matchedsampling methods that incorporate thepropensity score Am Stat 198539(1)33ndash38

19 Ribeiro CF Ferrari GF Fioretto JR Antibiotictreatment schemes for very severe com-munity-acquired pneumonia in childrena randomized clinical study Revista PanamSalud Publica 201129(6)444ndash450

20 Vuori-Holopainen E Peltola H Kallio MJSE-TU Study Group Narrow- versus broad-spectrum parenteral antimicrobials againstcommon infections of childhood a pro-spective and randomised comparisonbetween penicillin and cefuroxime EurJ Pediatr 2000159(12)878ndash884

21 Dinur-Schejter Y Cohen-Cymberknoh MTenenbaum A et al Antibiotic treatment ofchildren with community-acquired pneu-monia comparison of penicillin or ampi-cillin versus cefuroxime Pediatr Pulmonol201348(1)52ndash58

22 Newman RE Hedican EB Herigon JCWilliams DD Williams AR Newland JG Im-pact of a guideline on management ofchildren hospitalized with community-acquired pneumonia Pediatrics 2012129(3) Available at wwwpediatricsorgcgicontentfull1293e597

23 Garciacutea-Garciacutea ML Calvo C Pozo F VilladangosPA Peacuterez-Brentildea P Casas I Spectrum ofrespiratory viruses in children withcommunity-acquired pneumonia PediatrInfect Dis J 201231(8)808ndash813

24 Esposito S Daleno C Prunotto G et al Im-pact of viral infections in children withcommunity-acquired pneumonia results ofa study of 17 respiratory viruses InfluenzaOther Respi Viruses 20137(1)18ndash26

25 Wolf DG Greenberg D Shemer-Avni YGivon-Lavi N Bar-Ziv J Dagan R Associationof human metapneumovirus with radio-logically diagnosed community-acquiredalveolar pneumonia in young childrenJ Pediatr 2010156(1)115ndash120

26 Cilla G Ontildeate E Perez-Yarza EG Montes MVicente D Perez-Trallero E Viruses incommunity-acquired pneumonia in chil-dren aged less than 3 years old high rateof viral coinfection J Med Virol 200880(10)1843ndash1849

27 Hammitt LL Kazungu S Morpeth SC et al Apreliminary study of pneumonia etiologyamong hospitalized children in Kenya ClinInfect Dis 201254(suppl 2)S190ndashS199

28 Mermond S Zurawski V DrsquoOrtenzio E et alLower respiratory infections among hospi-talized children in New Caledonia a pilotstudy for the Pneumonia Etiology Researchfor Child Health project Clin Infect Dis201254(suppl 2)S180ndashS189

29 AHRQ National estimates on use of hospi-tals by children from the HCUP Kidsrsquo In-patient Database (KID) 2009 Available athttphcupnetahrqgovHCUPnetjspId=F3D2E7DF566C8BCCampForm=SelPATampJS=YampAction=3E3ENext3E3Eamp_InPatChar=Yesamp_InHospChar=Yesamp_PatChar= AccessedMarch 22 2012

30 Neuman MI Hall M Hersh AL et alInfluence of hospital guidelines on man-agement of children hospitalized withpneumonia Pediatrics 2012130(5) Avail-able at wwwpediatricsorgcgicontentfull1305e823

31 McIntosh KA Maxwell DJ Pulver LK et al Aquality improvement initiative to improveadherence to national guidelines for em-piric management of community-acquiredpneumonia in emergency departments IntJ Qual Health Care 201123(2)142ndash150

32 Smith MJ Kong M Cambon A Woods CREffectiveness of antimicrobial guidelinesfor community-acquired pneumonia inchildren Pediatrics 2012129(5) Availableat wwwpediatricsorgcgicontentfull1295e1326

33 Ambroggio L Thomson J Kurowski EMet al Quality improvement increases ap-propriate antibiotic prescribing for child-hood community acquired pneumoniaPediatrics 2013131(5) Available at wwwpediatricsorgcgicontentfull1315e1623

34 Carratalagrave J Garcia-Vidal C Ortega L et alEffect of a 3-step critical pathway to reduceduration of intravenous antibiotic therapyand length of stay in community-acquiredpneumonia a randomized controlled trialArch Intern Med 2012172(12)922ndash928

35 Lorgelly PK Atkinson M Lakhanpaul Met al Oral versus iv antibiotics forcommunity-acquired pneumonia in chil-dren a cost-minimisation analysis EurRespir J 201035(4)858ndash864

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1614

doi101542peds2013-1614

Accepted for publication Aug 27 2013

Address correspondence to Derek J Williams MD MPH 1161 21st Ave South CCC 5311 Medical Center North Nashville TN 37232 E-mail derekwilliamsvanderbiltedu

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2013 by the American Academy of Pediatrics

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

FUNDING No external funding

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

e1148 WILLIAMS et alby guest on March 16 2016Downloaded from

Propensity Score-Matched Cohort

Propensity score matching retained1044 children in each exposure groupThere were no baseline differences incharacteristics of the study populationbetween the 2 groups (Table 1) Resultsof the matched analysis did not differfrom those of the primary analysesThere were no significant differencesbetween groups with respect to LOS(aD 001 days P = 71) admission tointensive care (adjusted odds ratio 10P = 43) 14-day readmission (adjustedodds ratio 10 P = 48) or costs (aD

2$109 P = 71 for index hospitaliza-tion aD ndash$47 P = 2 for episode of ill-ness Table 3)

Subgroup Analysis

There were 4876 children in the broad-spectrum therapy group (349) and476 in the narrow-spectrum therapygroup (296) with acute wheezingChildren in the acute wheezing sub-group had similar median LOS com-pared with the nonwheezing subgroup(3 days [IQR 3ndash4] vs 4 days [IQR 3ndash4]P = 71) We observed no significant

differences in LOS between antibioticexposure groups in both the acute wheez-ing (aD 01 days P = 5) and nonwheezing(aD 015 days P = 21) subgroups

DISCUSSION

Among 15 000 children hospitalizedwith CAP there were no differences inLOS costs need for intensive care orreadmissions between those treatedwith parenteral ampicillin or penicillinand those treated with broaderspectrum third-generation cephalo-sporin therapy Our findings suggestthat the effectiveness of narrow-spectrum therapy is similar to that ofbroad-spectrum therapy for childrenhospitalized with CAPand provides newevidence to support the 2011 PIDSIDSACAP management guideline The lowfrequency of narrow-spectrum therapyusage observed in our study highlightsa substantial opportunity to promotegreater use of narrow-spectrum anti-microbial agents for children hospi-talized with CAP

The effectiveness of narrow- versusbroad-spectrum antimicrobial therapyfor pediatric CAP that required hospi-talization has been compared in a fewsmall randomized trials but no large-scale randomized controlled trial hasconclusively addressed this questionA randomized trial that studied 154children 5 years of age hospitalizedwith severe CAP in Brazil found thatempirical therapy with parenteralamoxicillinclavulanic acid was as effi-cacious as combination therapy withoxacillin and ceftriaxone The studydemonstrated no differences in thetime to stability (duration of fever orsupplemental oxygen requirement) orthe need for expanded antimicrobialcoverage between the 2 treatmentgroups19 In fact children treatedwith amoxicillinclavulanic acid had ashorter duration of tachypnea andshorter hospital LOS In a similar study154 Finnish children with pneumonia

FIGURE 1Study population ICD-9-CM International Classification of Diseases Ninth Revision Clinical Mod-ificationa See reference Feudtner et al17 b Among these children 59 received broad-spectrumtherapy alone 13 narrow-spectrum therapy alone and 28 other antimicrobial agents

e1144 WILLIAMS et alby guest on March 16 2016Downloaded from

sepsis or other acute invasive bacte-rial infection requiring hospitalizationwere randomized to receive eitherparenteral penicillin or cefuroxime Ofthe included children 47 were di-agnosed with pneumonia and nearly40 had evidence of S pneumoniaeinfection There were no differences inoutcomes (time to recovery normali-zation of laboratory parameters or

treatment failure) between the 2 anti-biotic treatment groups20 These smalltrials were conducted in regions withrelatively low rates of pneumococcalresistance to penicillins comparedwith the United States or were notlimited to CAP Thus their findings maynot be directly applicable to childrenhospitalized with CAP in the UnitedStates

Observational studies have alsoassessed the effectiveness of narrow-spectrum antimicrobial therapy forthe treatment of CAP in children A studyamong 319 Israeli children2 years ofage hospitalized with CAP demon-strated no differences in duration ofoxygen requirement hospital LOS ortreatment failures between childrenreceiving parenteral aminopenicillins(n = 66) and those receiving paren-teral cefuroxime (n = 253)21 Afterthe implementation of an antibioticstewardship program and a localpractice guideline in a tertiary US child-renrsquos hospital Newman et al demon-strated a significant increase in use ofampicillin from 15 to 60 a corre-sponding decrease in ceftriaxone useand no significant difference in the rateof treatment failure among 1000 chil-dren hospitalized with uncomplicatedCAP22 That study was conducted in an

TABLE 1 Characteristics of the Study Population

Unmatched Cohort (n = 15 564) Propensity Score Matched Cohort (n = 2088)

CeftriaxoneCefotaxime(n = 13 954)

PenicillinAmpicillin(n = 1610)

P CeftriaxoneCefotaxime(n = 1044)

PenicillinAmpicillin(n = 1044)

P

DemographicsAge y 2 [1ndash5] 2 [1ndash4] 003 2 [1ndash4] 2 [1ndash4] 54Male gender 7216 (517) 785 (488) 025 497 (476) 494 (473) 90RaceethnicityNH white 5584 (427) 481 (335) 001 208 (199) 224 (215) 47NH African American 3619 (277) 574 (399) 479 (459) 491 (47)Hispanic 3199 (245) 286 (199) 264 (253) 256 (245)Asian 382 (29) 70 (49) 56 (54) 47 (45)Other 280 (21) 26 (18) 37 (35) 26 (25)

PayerGovernment 7075 (709) 1021 (873) 001 900 (862) 905 (867) 92Private 1586 (159) 92 (79) 89 (85) 88 (84)Other 1316 (132) 57 (49) 55 (53) 51 (49)

Asthma 5226 (375) 696 (432) 001 514 (492) 484 (464) 19Previous hospitalization 1049 (75) 162 (101) 001 101 (97) 120 (115) 18Resource utilizationa

Oxygen therapy 4880 (35) 532 (33) 124 396 (379) 403 (386) 75Blood products 17 (01) 2 (01) 979 0 (0) 1 (01) 32Chest CT 173 (12) 10 (06) 029 7 (07) 4 (04) 36Chest ultrasound 150 (11) 5 (03) 003 0 (0) 1 (01) 32Blood gas analysis 1577 (113) 77 (48) 001 63 (6) 59 (57) 71

Medicationsa

Macrolide 2607 (187) 216 (134) 001 149 (143) 147 (141) 90Bronchodilator 8296 (595) 1025 (637) 001 722 (692) 701 (671) 32Corticosteroid 4698 (337) 653 (406) 001 473 (453) 471 (451) 93Oseltamivir 520 (37) 73 (45) 109 41 (39) 42 (4) 91

Data presented as n () or median [IQR] CT computed tomography NH non-Hispanica Resource utilization and medication variables limited to first 2 calendar days of hospitalization

TABLE 2 Outcomes Among Children Hospitalized With CAP According to Empiric AntimicrobialTherapy (N = 15 564)

CeftriaxoneCefotaxime(n = 13 954)

PenicillinAmpicillin(n = 1610)

Adjusted MD orOR (95 CI)

LOS d 3 [3ndash4] 3 [3ndash4] MD 012 (ndash002 to 026)Cost ($) index

hospitalization3992 [2895ndash5713] 4375 [3390ndash5805] MD ndash144 (ndash1771 to 1483)

Cost ($) episodeof illness

4036 [2919ndash5857] 4407 [3405ndash5913] MD ndash186 (ndash194 to 1569)

ICU admission 156 (11) 13 (08) OR 085 (027 to 273)14-day readmission 321 (23) 39 (24) OR 085 (045 to 163)

Data presented as median [IQR] or n () Models adjusted for age gender raceethnicity payer asthma comorbidityprevious hospitalization month and year resource utilization (oxygen therapy blood products chest ultrasound andcomputed tomography blood gas analysis) and concomitant medication use (macrolides bronchodilators corticosteroidsoseltamivir) CI confidence interval MD mean difference OR odds ratio

ARTICLE

PEDIATRICS Volume 132 Number 5 November 2013 e1145by guest on March 16 2016Downloaded from

area with a relatively high rate ofpneumococcal resistance to penicillin(sim25 of isolates) Using PHIS datafrom 2006 to 2008 Ambroggio et alcompared the effectiveness of b-lactammonotherapy versus a b-lactam incombination with a macrolide anddemonstrated shorter LOS for thosereceiving macrolide combination ther-apy in children aged $6 years17 Asubgroup analysis comparing narrow-versus broad-spectrum b-lactammonotherapy showed no differences inLOS or readmissions However thatstudy included children with short LOS(eg admitted and discharged on thesame day) and those receiving oraltherapy only and did not exclude chil-dren with early antimicrobial classswitching (eg ceftriaxone for ampicil-lin) In contrast our study focused onthe direct comparison of specific par-enteral antibiotic regimens and ex-cluded children with mild disease

Antimicrobial selection for treatment ofpediatric CAP is nearly always madewithout direct knowledge of the caus-ativemicroorganism The findings fromour study suggest that narrower-spectrum therapies are not inferiorto broader-spectrum therapies Al-though the importance of virusesas causes of CAP among children isincreasingly recognized23ndash28 distin-guishing viral from bacterial etiologiesis difficult Without rapid and sensitive

bacterial diagnostics at the point ofcare or trials demonstrating the effi-cacy of no treatment our findings in-dicate therapy with narrow-spectrumantibiotics is effective for most chil-dren hospitalized with CAP as rec-ommended by the PIDSIDSA CAPmanagement guideline

Optimizing antimicrobial usage is im-portant for minimizing the spread ofantimicrobial resistance on a globalscaleMore than 150 000USchildrenarehospitalized with CAP annually makingit among the most common indicationsfor hospitalization in childhood29 Dis-couraging the use of unnecessarilybroad-spectrum antimicrobial agentsfor children hospitalized with CAPtherefore has the potential to markedlyreduce selective pressure for antimi-crobial resistance Our study notedthat only 10 of study childrenreceived empirical therapy with peni-cillin or ampicillin Wide variation inprescribing of antimicrobial agents forchildren hospitalized with CAP hasbeen observed across PHIS hospitalsalthough 5 of children with CAPreceive narrow-spectrum therapyat most hospitals13 Thus althoughsome institutions often used narrow-spectrum therapy for uncomplicatedCAP most did not highlighting an im-portant opportunity for improvementin antimicrobial selection Previousstudies have demonstrated the feasibility

and effectiveness of stewardship pro-grams and dissemination of localpractice guidelines on changing anti-microbial selection for CAP manage-ment2230ndash33 The publication of the firstconsensus guidelines for childhoodCAP management could serve as a cat-alyst for these initiatives

The overall cost of hospitalization didnotdifferbetweenchildren treatedwithnarrow- versus broad-spectrum anti-microbial therapy in our study Thisfinding suggests that routine use ofpenicillin or ampicillin does not con-tribute to substantial increases in hos-pitalization costs despite the increaseddosing frequency of these medicationscompared with some third-generationcephalosporins such as once-daily cef-triaxone Although pharmacy costs maydiffer in local environments differencesare likely small and not amajor driver ofhospital costs Thus other cost-savingmeasures such as promoting earlytransition to oral therapy improvingdiagnostics to facilitate reduced anti-microbialuseor interventions toreducehospital LOSmayprovemoreeffective inminimizing total hospital costs3435

Limitations of the study are largelyrelated to the observational study de-sign and include the potential for con-founding by indication absence ofetiologic and other clinical data anda relative lack of objective outcomemeasures In the absence of large ran-domized efficacy trials well-designedobservational studies provide valu-able data on the effectiveness of ther-apies and interventions on a largescale Several steps were taken to re-duce potential confounding due todifferential use of narrow- or broad-spectrum therapy based on illness se-verity First we excluded children withindicators of severe disease at or nearthe time of presentation (eg admissionto intensive care) We also excludedchildren with indicators of particularlymild disease (eg receipt of oral

TABLE 3 Outcomes Among Children Hospitalized With CAP According to Empiric AntimicrobialTherapy Propensity Score Matched Cohort (n = 2088)

CeftriaxoneCefotaxime(n = 1044)

PenicillinAmpicillin(n = 1044)

Adjusted MD orOR (95 CI)

LOS d 3 [3ndash5] 3 [3ndash4] MD 001 (ndash022 to 024)Cost ($) indexhospitalization

4017 [2872ndash5908] 4255 [3302ndash5651] MD ndash1088 (ndash3934 to 1759)

Cost ($) episodeof illness

4106 [2898ndash6057] 4274 [3305ndash5752] MD ndash469 (ndash3499 to 2651)

ICU admission 14 (13) 11 (11) OR 10 (0996 to 101)14-day readmission 28 (27) 25 (24) OR 10 (0994 to 101)

Data presented as median [IQR] or n () Variables used to estimate propensity score included age gender raceethnicitypayer asthma comorbidity previous hospitalization month and year resource utilization (oxygen therapy blood productschest ultrasound and computed tomography blood gas analysis) and concomitant medication use (macrolides broncho-dilators corticosteroids oseltamivir) Propensity score matching (11) retained 1044 children in the narrow-spectrumtherapy group (648) model c statistic 068 CI confidence interval MD mean difference OR odds ratio

e1146 WILLIAMS et alby guest on March 16 2016Downloaded from

antimicrobial agents on the first hos-pital day or hospital LOS 2 calendardays) Second a number of factors thatmay influence antimicrobial selectionincluding proxy measures of diseaseseverity were accounted for in ourmultivariable analyses Furthermoreour propensity score matched analy-sis which substantially minimized thedifferences between exposure groupsalso produced results similar to thosefrom the unmatched cohort lendingfurther support to our studyrsquos primaryresults Although we cannot eliminateresidual confounding due to un-measured covariates the careful se-lection of our study population as wellas the use of robust modeling techni-ques minimizes this concern The

distinction between bacterial and viralcauses of CAP in children is difficulteven in prospective studies Residualmisclassification after application ofselection criteria in this regard wouldbe expected to be nondifferentialbetween the 2 empirical treatmentgroups favoring the null hypothesisAlthough the PHIS database does notcontain results of microbiologic test-ing our study was restricted to chil-dren who received antimicrobialtherapy which suggests clinical sus-picion of and treatment of bacterialpneumonia Similarly hospital-specificdata such as the presence or absenceof local practice guidelines or stew-ardship programs was not availableFinally our assessment focused on the

evaluation of empirical antimicrobialtreatments but did not characterizeantimicrobial class switching after thefirst 2 days of hospitalization

CONCLUSIONS

Clinical outcomes and costs for chil-dren hospitalized with CAP are not dif-ferent when empirical treatment iswith narrow-spectrum compared withbroad-spectrum therapy Few institu-tions used narrow-spectrum therapyroutinely beforepublicationof thePIDSIDSA CAP management guidelinesPrograms promoting guideline imple-mentation and targeting judiciousantibiotic selection for CAP are neededto optimize management of childhoodCAP in the United States

REFERENCES

1 Bradley JS Byington CL Shah SS et alPediatric Infectious Diseases Society andthe Infectious Diseases Society of AmericaThe management of community-acquiredpneumonia in infants and children olderthan 3 months of age clinical practiceguidelines by the Pediatric Infectious Dis-eases Society and the Infectious DiseasesSociety of America Clin Infect Dis 201153(7)e25ndashe76

2 Michelow IC Olsen K Lozano J et al Epi-demiology and clinical characteristics ofcommunity-acquired pneumonia in hospi-talized children Pediatrics 2004113(4)701ndash707

3 Juveacuten T Mertsola J Waris M et al Etiologyof community-acquired pneumonia in 254hospitalized children Pediatr Infect Dis J200019(4)293ndash298

4 Heiskanen-Kosma T Korppi M Jokinen Cet al Etiology of childhood pneumonia se-rologic results of a prospective population-based study Pediatr Infect Dis J 199817(11)986ndash991

5 Pilishvili T Lexau C Farley MM et al Ac-tive Bacterial Core SurveillanceEmergingInfections Program Network Sustainedreductions in invasive pneumococcaldisease in the era of conjugate vaccine JInfect Dis 2010201(1)32ndash41

6 Kyaw MH Lynfield R Schaffner W et alActive Bacterial Core Surveillance of theEmerging Infections Program Network Ef-fect of introduction of the pneumococcalconjugate vaccine on drug-resistant Strep-tococcus pneumoniae N Engl J Med 2006354(14)1455ndash1463

7 Centers for Disease Control PreventionEffects of new penicillin susceptibilitybreakpoints for Streptococcus pneumo-niaemdashUnited States 2006ndash2007 MMWR200857(50)1353ndash1355

8 Hampton LM Farley MM Schaffner W et alPrevention of antibiotic-nonsusceptibleStreptococcus pneumoniae with conjugatevaccines J Infect Dis 2012205(3)401ndash411

9 Dagan R Hoberman A Johnson C et alBacteriologic and clinical efficacy of highdose amoxicillinclavulanate in childrenwith acute otitis media Pediatr Infect Dis J200120(9)829ndash837

10 Weinstein MP Klugman KP Jones RN Ra-tionale for revised penicillin susceptibilitybreakpoints versus Streptococcus pneu-moniae coping with antimicrobial suscep-tibility in an era of resistance Clin InfectDis 200948(11)1596ndash1600

11 Hersh AL Shapiro DJ Pavia AT Shah SSAntibiotic prescribing in ambulatory pedi-atrics in the United States Pediatrics 2011128(6)1053ndash1061

12 Kronman MP Hersh AL Feng R Huang YSLee GE Shah SS Ambulatory visit rates andantibiotic prescribing for children withpneumonia 1994ndash2007 Pediatrics 2011127(3)411ndash418

13 Brogan TV Hall M Williams DJ et al Vari-ability in processes of care and outcomesamong children hospitalized with community-acquired pneumonia Pediatr Infect Dis J201231(10)1036ndash1041

14 Schouten JA Hulscher ME Natsch SKullberg BJ van der Meer JW Grol RPBarriers to optimal antibiotic use forcommunity-acquired pneumonia at hospi-tals a qualitative study Qual Saf HealthCare 200716(2)143ndash149

15 Mongelluzzo J Mohamad Z Ten Have TRShah SS Corticosteroids and mortality inchildren with bacterial meningitis JAMA2008299(17)2048ndash2055

16 Williams DJ Shah SS Myers AM et alIdentifying pediatric community-acquiredpneumonia hospitalizations accuracy ofadministrative billing codes [publishedonline ahead of print July 29 2013] JAMAPediatr doi 101001jamapediatrics2013186

17 Feudtner C Christakis DA Connell FA Pe-diatric deaths attributable to complexchronic conditions a population-basedstudy of Washington State 1980ndash1997 Pe-diatrics 2000106(1 Pt 2)205ndash209

ARTICLE

PEDIATRICS Volume 132 Number 5 November 2013 e1147by guest on March 16 2016Downloaded from

18 Rosenbaum PR Rubin DB Constructinga control-group using multivariate matchedsampling methods that incorporate thepropensity score Am Stat 198539(1)33ndash38

19 Ribeiro CF Ferrari GF Fioretto JR Antibiotictreatment schemes for very severe com-munity-acquired pneumonia in childrena randomized clinical study Revista PanamSalud Publica 201129(6)444ndash450

20 Vuori-Holopainen E Peltola H Kallio MJSE-TU Study Group Narrow- versus broad-spectrum parenteral antimicrobials againstcommon infections of childhood a pro-spective and randomised comparisonbetween penicillin and cefuroxime EurJ Pediatr 2000159(12)878ndash884

21 Dinur-Schejter Y Cohen-Cymberknoh MTenenbaum A et al Antibiotic treatment ofchildren with community-acquired pneu-monia comparison of penicillin or ampi-cillin versus cefuroxime Pediatr Pulmonol201348(1)52ndash58

22 Newman RE Hedican EB Herigon JCWilliams DD Williams AR Newland JG Im-pact of a guideline on management ofchildren hospitalized with community-acquired pneumonia Pediatrics 2012129(3) Available at wwwpediatricsorgcgicontentfull1293e597

23 Garciacutea-Garciacutea ML Calvo C Pozo F VilladangosPA Peacuterez-Brentildea P Casas I Spectrum ofrespiratory viruses in children withcommunity-acquired pneumonia PediatrInfect Dis J 201231(8)808ndash813

24 Esposito S Daleno C Prunotto G et al Im-pact of viral infections in children withcommunity-acquired pneumonia results ofa study of 17 respiratory viruses InfluenzaOther Respi Viruses 20137(1)18ndash26

25 Wolf DG Greenberg D Shemer-Avni YGivon-Lavi N Bar-Ziv J Dagan R Associationof human metapneumovirus with radio-logically diagnosed community-acquiredalveolar pneumonia in young childrenJ Pediatr 2010156(1)115ndash120

26 Cilla G Ontildeate E Perez-Yarza EG Montes MVicente D Perez-Trallero E Viruses incommunity-acquired pneumonia in chil-dren aged less than 3 years old high rateof viral coinfection J Med Virol 200880(10)1843ndash1849

27 Hammitt LL Kazungu S Morpeth SC et al Apreliminary study of pneumonia etiologyamong hospitalized children in Kenya ClinInfect Dis 201254(suppl 2)S190ndashS199

28 Mermond S Zurawski V DrsquoOrtenzio E et alLower respiratory infections among hospi-talized children in New Caledonia a pilotstudy for the Pneumonia Etiology Researchfor Child Health project Clin Infect Dis201254(suppl 2)S180ndashS189

29 AHRQ National estimates on use of hospi-tals by children from the HCUP Kidsrsquo In-patient Database (KID) 2009 Available athttphcupnetahrqgovHCUPnetjspId=F3D2E7DF566C8BCCampForm=SelPATampJS=YampAction=3E3ENext3E3Eamp_InPatChar=Yesamp_InHospChar=Yesamp_PatChar= AccessedMarch 22 2012

30 Neuman MI Hall M Hersh AL et alInfluence of hospital guidelines on man-agement of children hospitalized withpneumonia Pediatrics 2012130(5) Avail-able at wwwpediatricsorgcgicontentfull1305e823

31 McIntosh KA Maxwell DJ Pulver LK et al Aquality improvement initiative to improveadherence to national guidelines for em-piric management of community-acquiredpneumonia in emergency departments IntJ Qual Health Care 201123(2)142ndash150

32 Smith MJ Kong M Cambon A Woods CREffectiveness of antimicrobial guidelinesfor community-acquired pneumonia inchildren Pediatrics 2012129(5) Availableat wwwpediatricsorgcgicontentfull1295e1326

33 Ambroggio L Thomson J Kurowski EMet al Quality improvement increases ap-propriate antibiotic prescribing for child-hood community acquired pneumoniaPediatrics 2013131(5) Available at wwwpediatricsorgcgicontentfull1315e1623

34 Carratalagrave J Garcia-Vidal C Ortega L et alEffect of a 3-step critical pathway to reduceduration of intravenous antibiotic therapyand length of stay in community-acquiredpneumonia a randomized controlled trialArch Intern Med 2012172(12)922ndash928

35 Lorgelly PK Atkinson M Lakhanpaul Met al Oral versus iv antibiotics forcommunity-acquired pneumonia in chil-dren a cost-minimisation analysis EurRespir J 201035(4)858ndash864

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1614

doi101542peds2013-1614

Accepted for publication Aug 27 2013

Address correspondence to Derek J Williams MD MPH 1161 21st Ave South CCC 5311 Medical Center North Nashville TN 37232 E-mail derekwilliamsvanderbiltedu

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2013 by the American Academy of Pediatrics

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

FUNDING No external funding

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

e1148 WILLIAMS et alby guest on March 16 2016Downloaded from

sepsis or other acute invasive bacte-rial infection requiring hospitalizationwere randomized to receive eitherparenteral penicillin or cefuroxime Ofthe included children 47 were di-agnosed with pneumonia and nearly40 had evidence of S pneumoniaeinfection There were no differences inoutcomes (time to recovery normali-zation of laboratory parameters or

treatment failure) between the 2 anti-biotic treatment groups20 These smalltrials were conducted in regions withrelatively low rates of pneumococcalresistance to penicillins comparedwith the United States or were notlimited to CAP Thus their findings maynot be directly applicable to childrenhospitalized with CAP in the UnitedStates

Observational studies have alsoassessed the effectiveness of narrow-spectrum antimicrobial therapy forthe treatment of CAP in children A studyamong 319 Israeli children2 years ofage hospitalized with CAP demon-strated no differences in duration ofoxygen requirement hospital LOS ortreatment failures between childrenreceiving parenteral aminopenicillins(n = 66) and those receiving paren-teral cefuroxime (n = 253)21 Afterthe implementation of an antibioticstewardship program and a localpractice guideline in a tertiary US child-renrsquos hospital Newman et al demon-strated a significant increase in use ofampicillin from 15 to 60 a corre-sponding decrease in ceftriaxone useand no significant difference in the rateof treatment failure among 1000 chil-dren hospitalized with uncomplicatedCAP22 That study was conducted in an

TABLE 1 Characteristics of the Study Population

Unmatched Cohort (n = 15 564) Propensity Score Matched Cohort (n = 2088)

CeftriaxoneCefotaxime(n = 13 954)

PenicillinAmpicillin(n = 1610)

P CeftriaxoneCefotaxime(n = 1044)

PenicillinAmpicillin(n = 1044)

P

DemographicsAge y 2 [1ndash5] 2 [1ndash4] 003 2 [1ndash4] 2 [1ndash4] 54Male gender 7216 (517) 785 (488) 025 497 (476) 494 (473) 90RaceethnicityNH white 5584 (427) 481 (335) 001 208 (199) 224 (215) 47NH African American 3619 (277) 574 (399) 479 (459) 491 (47)Hispanic 3199 (245) 286 (199) 264 (253) 256 (245)Asian 382 (29) 70 (49) 56 (54) 47 (45)Other 280 (21) 26 (18) 37 (35) 26 (25)

PayerGovernment 7075 (709) 1021 (873) 001 900 (862) 905 (867) 92Private 1586 (159) 92 (79) 89 (85) 88 (84)Other 1316 (132) 57 (49) 55 (53) 51 (49)

Asthma 5226 (375) 696 (432) 001 514 (492) 484 (464) 19Previous hospitalization 1049 (75) 162 (101) 001 101 (97) 120 (115) 18Resource utilizationa

Oxygen therapy 4880 (35) 532 (33) 124 396 (379) 403 (386) 75Blood products 17 (01) 2 (01) 979 0 (0) 1 (01) 32Chest CT 173 (12) 10 (06) 029 7 (07) 4 (04) 36Chest ultrasound 150 (11) 5 (03) 003 0 (0) 1 (01) 32Blood gas analysis 1577 (113) 77 (48) 001 63 (6) 59 (57) 71

Medicationsa

Macrolide 2607 (187) 216 (134) 001 149 (143) 147 (141) 90Bronchodilator 8296 (595) 1025 (637) 001 722 (692) 701 (671) 32Corticosteroid 4698 (337) 653 (406) 001 473 (453) 471 (451) 93Oseltamivir 520 (37) 73 (45) 109 41 (39) 42 (4) 91

Data presented as n () or median [IQR] CT computed tomography NH non-Hispanica Resource utilization and medication variables limited to first 2 calendar days of hospitalization

TABLE 2 Outcomes Among Children Hospitalized With CAP According to Empiric AntimicrobialTherapy (N = 15 564)

CeftriaxoneCefotaxime(n = 13 954)

PenicillinAmpicillin(n = 1610)

Adjusted MD orOR (95 CI)

LOS d 3 [3ndash4] 3 [3ndash4] MD 012 (ndash002 to 026)Cost ($) index

hospitalization3992 [2895ndash5713] 4375 [3390ndash5805] MD ndash144 (ndash1771 to 1483)

Cost ($) episodeof illness

4036 [2919ndash5857] 4407 [3405ndash5913] MD ndash186 (ndash194 to 1569)

ICU admission 156 (11) 13 (08) OR 085 (027 to 273)14-day readmission 321 (23) 39 (24) OR 085 (045 to 163)

Data presented as median [IQR] or n () Models adjusted for age gender raceethnicity payer asthma comorbidityprevious hospitalization month and year resource utilization (oxygen therapy blood products chest ultrasound andcomputed tomography blood gas analysis) and concomitant medication use (macrolides bronchodilators corticosteroidsoseltamivir) CI confidence interval MD mean difference OR odds ratio

ARTICLE

PEDIATRICS Volume 132 Number 5 November 2013 e1145by guest on March 16 2016Downloaded from

area with a relatively high rate ofpneumococcal resistance to penicillin(sim25 of isolates) Using PHIS datafrom 2006 to 2008 Ambroggio et alcompared the effectiveness of b-lactammonotherapy versus a b-lactam incombination with a macrolide anddemonstrated shorter LOS for thosereceiving macrolide combination ther-apy in children aged $6 years17 Asubgroup analysis comparing narrow-versus broad-spectrum b-lactammonotherapy showed no differences inLOS or readmissions However thatstudy included children with short LOS(eg admitted and discharged on thesame day) and those receiving oraltherapy only and did not exclude chil-dren with early antimicrobial classswitching (eg ceftriaxone for ampicil-lin) In contrast our study focused onthe direct comparison of specific par-enteral antibiotic regimens and ex-cluded children with mild disease

Antimicrobial selection for treatment ofpediatric CAP is nearly always madewithout direct knowledge of the caus-ativemicroorganism The findings fromour study suggest that narrower-spectrum therapies are not inferiorto broader-spectrum therapies Al-though the importance of virusesas causes of CAP among children isincreasingly recognized23ndash28 distin-guishing viral from bacterial etiologiesis difficult Without rapid and sensitive

bacterial diagnostics at the point ofcare or trials demonstrating the effi-cacy of no treatment our findings in-dicate therapy with narrow-spectrumantibiotics is effective for most chil-dren hospitalized with CAP as rec-ommended by the PIDSIDSA CAPmanagement guideline

Optimizing antimicrobial usage is im-portant for minimizing the spread ofantimicrobial resistance on a globalscaleMore than 150 000USchildrenarehospitalized with CAP annually makingit among the most common indicationsfor hospitalization in childhood29 Dis-couraging the use of unnecessarilybroad-spectrum antimicrobial agentsfor children hospitalized with CAPtherefore has the potential to markedlyreduce selective pressure for antimi-crobial resistance Our study notedthat only 10 of study childrenreceived empirical therapy with peni-cillin or ampicillin Wide variation inprescribing of antimicrobial agents forchildren hospitalized with CAP hasbeen observed across PHIS hospitalsalthough 5 of children with CAPreceive narrow-spectrum therapyat most hospitals13 Thus althoughsome institutions often used narrow-spectrum therapy for uncomplicatedCAP most did not highlighting an im-portant opportunity for improvementin antimicrobial selection Previousstudies have demonstrated the feasibility

and effectiveness of stewardship pro-grams and dissemination of localpractice guidelines on changing anti-microbial selection for CAP manage-ment2230ndash33 The publication of the firstconsensus guidelines for childhoodCAP management could serve as a cat-alyst for these initiatives

The overall cost of hospitalization didnotdifferbetweenchildren treatedwithnarrow- versus broad-spectrum anti-microbial therapy in our study Thisfinding suggests that routine use ofpenicillin or ampicillin does not con-tribute to substantial increases in hos-pitalization costs despite the increaseddosing frequency of these medicationscompared with some third-generationcephalosporins such as once-daily cef-triaxone Although pharmacy costs maydiffer in local environments differencesare likely small and not amajor driver ofhospital costs Thus other cost-savingmeasures such as promoting earlytransition to oral therapy improvingdiagnostics to facilitate reduced anti-microbialuseor interventions toreducehospital LOSmayprovemoreeffective inminimizing total hospital costs3435

Limitations of the study are largelyrelated to the observational study de-sign and include the potential for con-founding by indication absence ofetiologic and other clinical data anda relative lack of objective outcomemeasures In the absence of large ran-domized efficacy trials well-designedobservational studies provide valu-able data on the effectiveness of ther-apies and interventions on a largescale Several steps were taken to re-duce potential confounding due todifferential use of narrow- or broad-spectrum therapy based on illness se-verity First we excluded children withindicators of severe disease at or nearthe time of presentation (eg admissionto intensive care) We also excludedchildren with indicators of particularlymild disease (eg receipt of oral

TABLE 3 Outcomes Among Children Hospitalized With CAP According to Empiric AntimicrobialTherapy Propensity Score Matched Cohort (n = 2088)

CeftriaxoneCefotaxime(n = 1044)

PenicillinAmpicillin(n = 1044)

Adjusted MD orOR (95 CI)

LOS d 3 [3ndash5] 3 [3ndash4] MD 001 (ndash022 to 024)Cost ($) indexhospitalization

4017 [2872ndash5908] 4255 [3302ndash5651] MD ndash1088 (ndash3934 to 1759)

Cost ($) episodeof illness

4106 [2898ndash6057] 4274 [3305ndash5752] MD ndash469 (ndash3499 to 2651)

ICU admission 14 (13) 11 (11) OR 10 (0996 to 101)14-day readmission 28 (27) 25 (24) OR 10 (0994 to 101)

Data presented as median [IQR] or n () Variables used to estimate propensity score included age gender raceethnicitypayer asthma comorbidity previous hospitalization month and year resource utilization (oxygen therapy blood productschest ultrasound and computed tomography blood gas analysis) and concomitant medication use (macrolides broncho-dilators corticosteroids oseltamivir) Propensity score matching (11) retained 1044 children in the narrow-spectrumtherapy group (648) model c statistic 068 CI confidence interval MD mean difference OR odds ratio

e1146 WILLIAMS et alby guest on March 16 2016Downloaded from

antimicrobial agents on the first hos-pital day or hospital LOS 2 calendardays) Second a number of factors thatmay influence antimicrobial selectionincluding proxy measures of diseaseseverity were accounted for in ourmultivariable analyses Furthermoreour propensity score matched analy-sis which substantially minimized thedifferences between exposure groupsalso produced results similar to thosefrom the unmatched cohort lendingfurther support to our studyrsquos primaryresults Although we cannot eliminateresidual confounding due to un-measured covariates the careful se-lection of our study population as wellas the use of robust modeling techni-ques minimizes this concern The

distinction between bacterial and viralcauses of CAP in children is difficulteven in prospective studies Residualmisclassification after application ofselection criteria in this regard wouldbe expected to be nondifferentialbetween the 2 empirical treatmentgroups favoring the null hypothesisAlthough the PHIS database does notcontain results of microbiologic test-ing our study was restricted to chil-dren who received antimicrobialtherapy which suggests clinical sus-picion of and treatment of bacterialpneumonia Similarly hospital-specificdata such as the presence or absenceof local practice guidelines or stew-ardship programs was not availableFinally our assessment focused on the

evaluation of empirical antimicrobialtreatments but did not characterizeantimicrobial class switching after thefirst 2 days of hospitalization

CONCLUSIONS

Clinical outcomes and costs for chil-dren hospitalized with CAP are not dif-ferent when empirical treatment iswith narrow-spectrum compared withbroad-spectrum therapy Few institu-tions used narrow-spectrum therapyroutinely beforepublicationof thePIDSIDSA CAP management guidelinesPrograms promoting guideline imple-mentation and targeting judiciousantibiotic selection for CAP are neededto optimize management of childhoodCAP in the United States

REFERENCES

1 Bradley JS Byington CL Shah SS et alPediatric Infectious Diseases Society andthe Infectious Diseases Society of AmericaThe management of community-acquiredpneumonia in infants and children olderthan 3 months of age clinical practiceguidelines by the Pediatric Infectious Dis-eases Society and the Infectious DiseasesSociety of America Clin Infect Dis 201153(7)e25ndashe76

2 Michelow IC Olsen K Lozano J et al Epi-demiology and clinical characteristics ofcommunity-acquired pneumonia in hospi-talized children Pediatrics 2004113(4)701ndash707

3 Juveacuten T Mertsola J Waris M et al Etiologyof community-acquired pneumonia in 254hospitalized children Pediatr Infect Dis J200019(4)293ndash298

4 Heiskanen-Kosma T Korppi M Jokinen Cet al Etiology of childhood pneumonia se-rologic results of a prospective population-based study Pediatr Infect Dis J 199817(11)986ndash991

5 Pilishvili T Lexau C Farley MM et al Ac-tive Bacterial Core SurveillanceEmergingInfections Program Network Sustainedreductions in invasive pneumococcaldisease in the era of conjugate vaccine JInfect Dis 2010201(1)32ndash41

6 Kyaw MH Lynfield R Schaffner W et alActive Bacterial Core Surveillance of theEmerging Infections Program Network Ef-fect of introduction of the pneumococcalconjugate vaccine on drug-resistant Strep-tococcus pneumoniae N Engl J Med 2006354(14)1455ndash1463

7 Centers for Disease Control PreventionEffects of new penicillin susceptibilitybreakpoints for Streptococcus pneumo-niaemdashUnited States 2006ndash2007 MMWR200857(50)1353ndash1355

8 Hampton LM Farley MM Schaffner W et alPrevention of antibiotic-nonsusceptibleStreptococcus pneumoniae with conjugatevaccines J Infect Dis 2012205(3)401ndash411

9 Dagan R Hoberman A Johnson C et alBacteriologic and clinical efficacy of highdose amoxicillinclavulanate in childrenwith acute otitis media Pediatr Infect Dis J200120(9)829ndash837

10 Weinstein MP Klugman KP Jones RN Ra-tionale for revised penicillin susceptibilitybreakpoints versus Streptococcus pneu-moniae coping with antimicrobial suscep-tibility in an era of resistance Clin InfectDis 200948(11)1596ndash1600

11 Hersh AL Shapiro DJ Pavia AT Shah SSAntibiotic prescribing in ambulatory pedi-atrics in the United States Pediatrics 2011128(6)1053ndash1061

12 Kronman MP Hersh AL Feng R Huang YSLee GE Shah SS Ambulatory visit rates andantibiotic prescribing for children withpneumonia 1994ndash2007 Pediatrics 2011127(3)411ndash418

13 Brogan TV Hall M Williams DJ et al Vari-ability in processes of care and outcomesamong children hospitalized with community-acquired pneumonia Pediatr Infect Dis J201231(10)1036ndash1041

14 Schouten JA Hulscher ME Natsch SKullberg BJ van der Meer JW Grol RPBarriers to optimal antibiotic use forcommunity-acquired pneumonia at hospi-tals a qualitative study Qual Saf HealthCare 200716(2)143ndash149

15 Mongelluzzo J Mohamad Z Ten Have TRShah SS Corticosteroids and mortality inchildren with bacterial meningitis JAMA2008299(17)2048ndash2055

16 Williams DJ Shah SS Myers AM et alIdentifying pediatric community-acquiredpneumonia hospitalizations accuracy ofadministrative billing codes [publishedonline ahead of print July 29 2013] JAMAPediatr doi 101001jamapediatrics2013186

17 Feudtner C Christakis DA Connell FA Pe-diatric deaths attributable to complexchronic conditions a population-basedstudy of Washington State 1980ndash1997 Pe-diatrics 2000106(1 Pt 2)205ndash209

ARTICLE

PEDIATRICS Volume 132 Number 5 November 2013 e1147by guest on March 16 2016Downloaded from

18 Rosenbaum PR Rubin DB Constructinga control-group using multivariate matchedsampling methods that incorporate thepropensity score Am Stat 198539(1)33ndash38

19 Ribeiro CF Ferrari GF Fioretto JR Antibiotictreatment schemes for very severe com-munity-acquired pneumonia in childrena randomized clinical study Revista PanamSalud Publica 201129(6)444ndash450

20 Vuori-Holopainen E Peltola H Kallio MJSE-TU Study Group Narrow- versus broad-spectrum parenteral antimicrobials againstcommon infections of childhood a pro-spective and randomised comparisonbetween penicillin and cefuroxime EurJ Pediatr 2000159(12)878ndash884

21 Dinur-Schejter Y Cohen-Cymberknoh MTenenbaum A et al Antibiotic treatment ofchildren with community-acquired pneu-monia comparison of penicillin or ampi-cillin versus cefuroxime Pediatr Pulmonol201348(1)52ndash58

22 Newman RE Hedican EB Herigon JCWilliams DD Williams AR Newland JG Im-pact of a guideline on management ofchildren hospitalized with community-acquired pneumonia Pediatrics 2012129(3) Available at wwwpediatricsorgcgicontentfull1293e597

23 Garciacutea-Garciacutea ML Calvo C Pozo F VilladangosPA Peacuterez-Brentildea P Casas I Spectrum ofrespiratory viruses in children withcommunity-acquired pneumonia PediatrInfect Dis J 201231(8)808ndash813

24 Esposito S Daleno C Prunotto G et al Im-pact of viral infections in children withcommunity-acquired pneumonia results ofa study of 17 respiratory viruses InfluenzaOther Respi Viruses 20137(1)18ndash26

25 Wolf DG Greenberg D Shemer-Avni YGivon-Lavi N Bar-Ziv J Dagan R Associationof human metapneumovirus with radio-logically diagnosed community-acquiredalveolar pneumonia in young childrenJ Pediatr 2010156(1)115ndash120

26 Cilla G Ontildeate E Perez-Yarza EG Montes MVicente D Perez-Trallero E Viruses incommunity-acquired pneumonia in chil-dren aged less than 3 years old high rateof viral coinfection J Med Virol 200880(10)1843ndash1849

27 Hammitt LL Kazungu S Morpeth SC et al Apreliminary study of pneumonia etiologyamong hospitalized children in Kenya ClinInfect Dis 201254(suppl 2)S190ndashS199

28 Mermond S Zurawski V DrsquoOrtenzio E et alLower respiratory infections among hospi-talized children in New Caledonia a pilotstudy for the Pneumonia Etiology Researchfor Child Health project Clin Infect Dis201254(suppl 2)S180ndashS189

29 AHRQ National estimates on use of hospi-tals by children from the HCUP Kidsrsquo In-patient Database (KID) 2009 Available athttphcupnetahrqgovHCUPnetjspId=F3D2E7DF566C8BCCampForm=SelPATampJS=YampAction=3E3ENext3E3Eamp_InPatChar=Yesamp_InHospChar=Yesamp_PatChar= AccessedMarch 22 2012

30 Neuman MI Hall M Hersh AL et alInfluence of hospital guidelines on man-agement of children hospitalized withpneumonia Pediatrics 2012130(5) Avail-able at wwwpediatricsorgcgicontentfull1305e823

31 McIntosh KA Maxwell DJ Pulver LK et al Aquality improvement initiative to improveadherence to national guidelines for em-piric management of community-acquiredpneumonia in emergency departments IntJ Qual Health Care 201123(2)142ndash150

32 Smith MJ Kong M Cambon A Woods CREffectiveness of antimicrobial guidelinesfor community-acquired pneumonia inchildren Pediatrics 2012129(5) Availableat wwwpediatricsorgcgicontentfull1295e1326

33 Ambroggio L Thomson J Kurowski EMet al Quality improvement increases ap-propriate antibiotic prescribing for child-hood community acquired pneumoniaPediatrics 2013131(5) Available at wwwpediatricsorgcgicontentfull1315e1623

34 Carratalagrave J Garcia-Vidal C Ortega L et alEffect of a 3-step critical pathway to reduceduration of intravenous antibiotic therapyand length of stay in community-acquiredpneumonia a randomized controlled trialArch Intern Med 2012172(12)922ndash928

35 Lorgelly PK Atkinson M Lakhanpaul Met al Oral versus iv antibiotics forcommunity-acquired pneumonia in chil-dren a cost-minimisation analysis EurRespir J 201035(4)858ndash864

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1614

doi101542peds2013-1614

Accepted for publication Aug 27 2013

Address correspondence to Derek J Williams MD MPH 1161 21st Ave South CCC 5311 Medical Center North Nashville TN 37232 E-mail derekwilliamsvanderbiltedu

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2013 by the American Academy of Pediatrics

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

FUNDING No external funding

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

e1148 WILLIAMS et alby guest on March 16 2016Downloaded from

area with a relatively high rate ofpneumococcal resistance to penicillin(sim25 of isolates) Using PHIS datafrom 2006 to 2008 Ambroggio et alcompared the effectiveness of b-lactammonotherapy versus a b-lactam incombination with a macrolide anddemonstrated shorter LOS for thosereceiving macrolide combination ther-apy in children aged $6 years17 Asubgroup analysis comparing narrow-versus broad-spectrum b-lactammonotherapy showed no differences inLOS or readmissions However thatstudy included children with short LOS(eg admitted and discharged on thesame day) and those receiving oraltherapy only and did not exclude chil-dren with early antimicrobial classswitching (eg ceftriaxone for ampicil-lin) In contrast our study focused onthe direct comparison of specific par-enteral antibiotic regimens and ex-cluded children with mild disease

Antimicrobial selection for treatment ofpediatric CAP is nearly always madewithout direct knowledge of the caus-ativemicroorganism The findings fromour study suggest that narrower-spectrum therapies are not inferiorto broader-spectrum therapies Al-though the importance of virusesas causes of CAP among children isincreasingly recognized23ndash28 distin-guishing viral from bacterial etiologiesis difficult Without rapid and sensitive

bacterial diagnostics at the point ofcare or trials demonstrating the effi-cacy of no treatment our findings in-dicate therapy with narrow-spectrumantibiotics is effective for most chil-dren hospitalized with CAP as rec-ommended by the PIDSIDSA CAPmanagement guideline

Optimizing antimicrobial usage is im-portant for minimizing the spread ofantimicrobial resistance on a globalscaleMore than 150 000USchildrenarehospitalized with CAP annually makingit among the most common indicationsfor hospitalization in childhood29 Dis-couraging the use of unnecessarilybroad-spectrum antimicrobial agentsfor children hospitalized with CAPtherefore has the potential to markedlyreduce selective pressure for antimi-crobial resistance Our study notedthat only 10 of study childrenreceived empirical therapy with peni-cillin or ampicillin Wide variation inprescribing of antimicrobial agents forchildren hospitalized with CAP hasbeen observed across PHIS hospitalsalthough 5 of children with CAPreceive narrow-spectrum therapyat most hospitals13 Thus althoughsome institutions often used narrow-spectrum therapy for uncomplicatedCAP most did not highlighting an im-portant opportunity for improvementin antimicrobial selection Previousstudies have demonstrated the feasibility

and effectiveness of stewardship pro-grams and dissemination of localpractice guidelines on changing anti-microbial selection for CAP manage-ment2230ndash33 The publication of the firstconsensus guidelines for childhoodCAP management could serve as a cat-alyst for these initiatives

The overall cost of hospitalization didnotdifferbetweenchildren treatedwithnarrow- versus broad-spectrum anti-microbial therapy in our study Thisfinding suggests that routine use ofpenicillin or ampicillin does not con-tribute to substantial increases in hos-pitalization costs despite the increaseddosing frequency of these medicationscompared with some third-generationcephalosporins such as once-daily cef-triaxone Although pharmacy costs maydiffer in local environments differencesare likely small and not amajor driver ofhospital costs Thus other cost-savingmeasures such as promoting earlytransition to oral therapy improvingdiagnostics to facilitate reduced anti-microbialuseor interventions toreducehospital LOSmayprovemoreeffective inminimizing total hospital costs3435

Limitations of the study are largelyrelated to the observational study de-sign and include the potential for con-founding by indication absence ofetiologic and other clinical data anda relative lack of objective outcomemeasures In the absence of large ran-domized efficacy trials well-designedobservational studies provide valu-able data on the effectiveness of ther-apies and interventions on a largescale Several steps were taken to re-duce potential confounding due todifferential use of narrow- or broad-spectrum therapy based on illness se-verity First we excluded children withindicators of severe disease at or nearthe time of presentation (eg admissionto intensive care) We also excludedchildren with indicators of particularlymild disease (eg receipt of oral

TABLE 3 Outcomes Among Children Hospitalized With CAP According to Empiric AntimicrobialTherapy Propensity Score Matched Cohort (n = 2088)

CeftriaxoneCefotaxime(n = 1044)

PenicillinAmpicillin(n = 1044)

Adjusted MD orOR (95 CI)

LOS d 3 [3ndash5] 3 [3ndash4] MD 001 (ndash022 to 024)Cost ($) indexhospitalization

4017 [2872ndash5908] 4255 [3302ndash5651] MD ndash1088 (ndash3934 to 1759)

Cost ($) episodeof illness

4106 [2898ndash6057] 4274 [3305ndash5752] MD ndash469 (ndash3499 to 2651)

ICU admission 14 (13) 11 (11) OR 10 (0996 to 101)14-day readmission 28 (27) 25 (24) OR 10 (0994 to 101)

Data presented as median [IQR] or n () Variables used to estimate propensity score included age gender raceethnicitypayer asthma comorbidity previous hospitalization month and year resource utilization (oxygen therapy blood productschest ultrasound and computed tomography blood gas analysis) and concomitant medication use (macrolides broncho-dilators corticosteroids oseltamivir) Propensity score matching (11) retained 1044 children in the narrow-spectrumtherapy group (648) model c statistic 068 CI confidence interval MD mean difference OR odds ratio

e1146 WILLIAMS et alby guest on March 16 2016Downloaded from

antimicrobial agents on the first hos-pital day or hospital LOS 2 calendardays) Second a number of factors thatmay influence antimicrobial selectionincluding proxy measures of diseaseseverity were accounted for in ourmultivariable analyses Furthermoreour propensity score matched analy-sis which substantially minimized thedifferences between exposure groupsalso produced results similar to thosefrom the unmatched cohort lendingfurther support to our studyrsquos primaryresults Although we cannot eliminateresidual confounding due to un-measured covariates the careful se-lection of our study population as wellas the use of robust modeling techni-ques minimizes this concern The

distinction between bacterial and viralcauses of CAP in children is difficulteven in prospective studies Residualmisclassification after application ofselection criteria in this regard wouldbe expected to be nondifferentialbetween the 2 empirical treatmentgroups favoring the null hypothesisAlthough the PHIS database does notcontain results of microbiologic test-ing our study was restricted to chil-dren who received antimicrobialtherapy which suggests clinical sus-picion of and treatment of bacterialpneumonia Similarly hospital-specificdata such as the presence or absenceof local practice guidelines or stew-ardship programs was not availableFinally our assessment focused on the

evaluation of empirical antimicrobialtreatments but did not characterizeantimicrobial class switching after thefirst 2 days of hospitalization

CONCLUSIONS

Clinical outcomes and costs for chil-dren hospitalized with CAP are not dif-ferent when empirical treatment iswith narrow-spectrum compared withbroad-spectrum therapy Few institu-tions used narrow-spectrum therapyroutinely beforepublicationof thePIDSIDSA CAP management guidelinesPrograms promoting guideline imple-mentation and targeting judiciousantibiotic selection for CAP are neededto optimize management of childhoodCAP in the United States

REFERENCES

1 Bradley JS Byington CL Shah SS et alPediatric Infectious Diseases Society andthe Infectious Diseases Society of AmericaThe management of community-acquiredpneumonia in infants and children olderthan 3 months of age clinical practiceguidelines by the Pediatric Infectious Dis-eases Society and the Infectious DiseasesSociety of America Clin Infect Dis 201153(7)e25ndashe76

2 Michelow IC Olsen K Lozano J et al Epi-demiology and clinical characteristics ofcommunity-acquired pneumonia in hospi-talized children Pediatrics 2004113(4)701ndash707

3 Juveacuten T Mertsola J Waris M et al Etiologyof community-acquired pneumonia in 254hospitalized children Pediatr Infect Dis J200019(4)293ndash298

4 Heiskanen-Kosma T Korppi M Jokinen Cet al Etiology of childhood pneumonia se-rologic results of a prospective population-based study Pediatr Infect Dis J 199817(11)986ndash991

5 Pilishvili T Lexau C Farley MM et al Ac-tive Bacterial Core SurveillanceEmergingInfections Program Network Sustainedreductions in invasive pneumococcaldisease in the era of conjugate vaccine JInfect Dis 2010201(1)32ndash41

6 Kyaw MH Lynfield R Schaffner W et alActive Bacterial Core Surveillance of theEmerging Infections Program Network Ef-fect of introduction of the pneumococcalconjugate vaccine on drug-resistant Strep-tococcus pneumoniae N Engl J Med 2006354(14)1455ndash1463

7 Centers for Disease Control PreventionEffects of new penicillin susceptibilitybreakpoints for Streptococcus pneumo-niaemdashUnited States 2006ndash2007 MMWR200857(50)1353ndash1355

8 Hampton LM Farley MM Schaffner W et alPrevention of antibiotic-nonsusceptibleStreptococcus pneumoniae with conjugatevaccines J Infect Dis 2012205(3)401ndash411

9 Dagan R Hoberman A Johnson C et alBacteriologic and clinical efficacy of highdose amoxicillinclavulanate in childrenwith acute otitis media Pediatr Infect Dis J200120(9)829ndash837

10 Weinstein MP Klugman KP Jones RN Ra-tionale for revised penicillin susceptibilitybreakpoints versus Streptococcus pneu-moniae coping with antimicrobial suscep-tibility in an era of resistance Clin InfectDis 200948(11)1596ndash1600

11 Hersh AL Shapiro DJ Pavia AT Shah SSAntibiotic prescribing in ambulatory pedi-atrics in the United States Pediatrics 2011128(6)1053ndash1061

12 Kronman MP Hersh AL Feng R Huang YSLee GE Shah SS Ambulatory visit rates andantibiotic prescribing for children withpneumonia 1994ndash2007 Pediatrics 2011127(3)411ndash418

13 Brogan TV Hall M Williams DJ et al Vari-ability in processes of care and outcomesamong children hospitalized with community-acquired pneumonia Pediatr Infect Dis J201231(10)1036ndash1041

14 Schouten JA Hulscher ME Natsch SKullberg BJ van der Meer JW Grol RPBarriers to optimal antibiotic use forcommunity-acquired pneumonia at hospi-tals a qualitative study Qual Saf HealthCare 200716(2)143ndash149

15 Mongelluzzo J Mohamad Z Ten Have TRShah SS Corticosteroids and mortality inchildren with bacterial meningitis JAMA2008299(17)2048ndash2055

16 Williams DJ Shah SS Myers AM et alIdentifying pediatric community-acquiredpneumonia hospitalizations accuracy ofadministrative billing codes [publishedonline ahead of print July 29 2013] JAMAPediatr doi 101001jamapediatrics2013186

17 Feudtner C Christakis DA Connell FA Pe-diatric deaths attributable to complexchronic conditions a population-basedstudy of Washington State 1980ndash1997 Pe-diatrics 2000106(1 Pt 2)205ndash209

ARTICLE

PEDIATRICS Volume 132 Number 5 November 2013 e1147by guest on March 16 2016Downloaded from

18 Rosenbaum PR Rubin DB Constructinga control-group using multivariate matchedsampling methods that incorporate thepropensity score Am Stat 198539(1)33ndash38

19 Ribeiro CF Ferrari GF Fioretto JR Antibiotictreatment schemes for very severe com-munity-acquired pneumonia in childrena randomized clinical study Revista PanamSalud Publica 201129(6)444ndash450

20 Vuori-Holopainen E Peltola H Kallio MJSE-TU Study Group Narrow- versus broad-spectrum parenteral antimicrobials againstcommon infections of childhood a pro-spective and randomised comparisonbetween penicillin and cefuroxime EurJ Pediatr 2000159(12)878ndash884

21 Dinur-Schejter Y Cohen-Cymberknoh MTenenbaum A et al Antibiotic treatment ofchildren with community-acquired pneu-monia comparison of penicillin or ampi-cillin versus cefuroxime Pediatr Pulmonol201348(1)52ndash58

22 Newman RE Hedican EB Herigon JCWilliams DD Williams AR Newland JG Im-pact of a guideline on management ofchildren hospitalized with community-acquired pneumonia Pediatrics 2012129(3) Available at wwwpediatricsorgcgicontentfull1293e597

23 Garciacutea-Garciacutea ML Calvo C Pozo F VilladangosPA Peacuterez-Brentildea P Casas I Spectrum ofrespiratory viruses in children withcommunity-acquired pneumonia PediatrInfect Dis J 201231(8)808ndash813

24 Esposito S Daleno C Prunotto G et al Im-pact of viral infections in children withcommunity-acquired pneumonia results ofa study of 17 respiratory viruses InfluenzaOther Respi Viruses 20137(1)18ndash26

25 Wolf DG Greenberg D Shemer-Avni YGivon-Lavi N Bar-Ziv J Dagan R Associationof human metapneumovirus with radio-logically diagnosed community-acquiredalveolar pneumonia in young childrenJ Pediatr 2010156(1)115ndash120

26 Cilla G Ontildeate E Perez-Yarza EG Montes MVicente D Perez-Trallero E Viruses incommunity-acquired pneumonia in chil-dren aged less than 3 years old high rateof viral coinfection J Med Virol 200880(10)1843ndash1849

27 Hammitt LL Kazungu S Morpeth SC et al Apreliminary study of pneumonia etiologyamong hospitalized children in Kenya ClinInfect Dis 201254(suppl 2)S190ndashS199

28 Mermond S Zurawski V DrsquoOrtenzio E et alLower respiratory infections among hospi-talized children in New Caledonia a pilotstudy for the Pneumonia Etiology Researchfor Child Health project Clin Infect Dis201254(suppl 2)S180ndashS189

29 AHRQ National estimates on use of hospi-tals by children from the HCUP Kidsrsquo In-patient Database (KID) 2009 Available athttphcupnetahrqgovHCUPnetjspId=F3D2E7DF566C8BCCampForm=SelPATampJS=YampAction=3E3ENext3E3Eamp_InPatChar=Yesamp_InHospChar=Yesamp_PatChar= AccessedMarch 22 2012

30 Neuman MI Hall M Hersh AL et alInfluence of hospital guidelines on man-agement of children hospitalized withpneumonia Pediatrics 2012130(5) Avail-able at wwwpediatricsorgcgicontentfull1305e823

31 McIntosh KA Maxwell DJ Pulver LK et al Aquality improvement initiative to improveadherence to national guidelines for em-piric management of community-acquiredpneumonia in emergency departments IntJ Qual Health Care 201123(2)142ndash150

32 Smith MJ Kong M Cambon A Woods CREffectiveness of antimicrobial guidelinesfor community-acquired pneumonia inchildren Pediatrics 2012129(5) Availableat wwwpediatricsorgcgicontentfull1295e1326

33 Ambroggio L Thomson J Kurowski EMet al Quality improvement increases ap-propriate antibiotic prescribing for child-hood community acquired pneumoniaPediatrics 2013131(5) Available at wwwpediatricsorgcgicontentfull1315e1623

34 Carratalagrave J Garcia-Vidal C Ortega L et alEffect of a 3-step critical pathway to reduceduration of intravenous antibiotic therapyand length of stay in community-acquiredpneumonia a randomized controlled trialArch Intern Med 2012172(12)922ndash928

35 Lorgelly PK Atkinson M Lakhanpaul Met al Oral versus iv antibiotics forcommunity-acquired pneumonia in chil-dren a cost-minimisation analysis EurRespir J 201035(4)858ndash864

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1614

doi101542peds2013-1614

Accepted for publication Aug 27 2013

Address correspondence to Derek J Williams MD MPH 1161 21st Ave South CCC 5311 Medical Center North Nashville TN 37232 E-mail derekwilliamsvanderbiltedu

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2013 by the American Academy of Pediatrics

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

FUNDING No external funding

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

e1148 WILLIAMS et alby guest on March 16 2016Downloaded from

antimicrobial agents on the first hos-pital day or hospital LOS 2 calendardays) Second a number of factors thatmay influence antimicrobial selectionincluding proxy measures of diseaseseverity were accounted for in ourmultivariable analyses Furthermoreour propensity score matched analy-sis which substantially minimized thedifferences between exposure groupsalso produced results similar to thosefrom the unmatched cohort lendingfurther support to our studyrsquos primaryresults Although we cannot eliminateresidual confounding due to un-measured covariates the careful se-lection of our study population as wellas the use of robust modeling techni-ques minimizes this concern The

distinction between bacterial and viralcauses of CAP in children is difficulteven in prospective studies Residualmisclassification after application ofselection criteria in this regard wouldbe expected to be nondifferentialbetween the 2 empirical treatmentgroups favoring the null hypothesisAlthough the PHIS database does notcontain results of microbiologic test-ing our study was restricted to chil-dren who received antimicrobialtherapy which suggests clinical sus-picion of and treatment of bacterialpneumonia Similarly hospital-specificdata such as the presence or absenceof local practice guidelines or stew-ardship programs was not availableFinally our assessment focused on the

evaluation of empirical antimicrobialtreatments but did not characterizeantimicrobial class switching after thefirst 2 days of hospitalization

CONCLUSIONS

Clinical outcomes and costs for chil-dren hospitalized with CAP are not dif-ferent when empirical treatment iswith narrow-spectrum compared withbroad-spectrum therapy Few institu-tions used narrow-spectrum therapyroutinely beforepublicationof thePIDSIDSA CAP management guidelinesPrograms promoting guideline imple-mentation and targeting judiciousantibiotic selection for CAP are neededto optimize management of childhoodCAP in the United States

REFERENCES

1 Bradley JS Byington CL Shah SS et alPediatric Infectious Diseases Society andthe Infectious Diseases Society of AmericaThe management of community-acquiredpneumonia in infants and children olderthan 3 months of age clinical practiceguidelines by the Pediatric Infectious Dis-eases Society and the Infectious DiseasesSociety of America Clin Infect Dis 201153(7)e25ndashe76

2 Michelow IC Olsen K Lozano J et al Epi-demiology and clinical characteristics ofcommunity-acquired pneumonia in hospi-talized children Pediatrics 2004113(4)701ndash707

3 Juveacuten T Mertsola J Waris M et al Etiologyof community-acquired pneumonia in 254hospitalized children Pediatr Infect Dis J200019(4)293ndash298

4 Heiskanen-Kosma T Korppi M Jokinen Cet al Etiology of childhood pneumonia se-rologic results of a prospective population-based study Pediatr Infect Dis J 199817(11)986ndash991

5 Pilishvili T Lexau C Farley MM et al Ac-tive Bacterial Core SurveillanceEmergingInfections Program Network Sustainedreductions in invasive pneumococcaldisease in the era of conjugate vaccine JInfect Dis 2010201(1)32ndash41

6 Kyaw MH Lynfield R Schaffner W et alActive Bacterial Core Surveillance of theEmerging Infections Program Network Ef-fect of introduction of the pneumococcalconjugate vaccine on drug-resistant Strep-tococcus pneumoniae N Engl J Med 2006354(14)1455ndash1463

7 Centers for Disease Control PreventionEffects of new penicillin susceptibilitybreakpoints for Streptococcus pneumo-niaemdashUnited States 2006ndash2007 MMWR200857(50)1353ndash1355

8 Hampton LM Farley MM Schaffner W et alPrevention of antibiotic-nonsusceptibleStreptococcus pneumoniae with conjugatevaccines J Infect Dis 2012205(3)401ndash411

9 Dagan R Hoberman A Johnson C et alBacteriologic and clinical efficacy of highdose amoxicillinclavulanate in childrenwith acute otitis media Pediatr Infect Dis J200120(9)829ndash837

10 Weinstein MP Klugman KP Jones RN Ra-tionale for revised penicillin susceptibilitybreakpoints versus Streptococcus pneu-moniae coping with antimicrobial suscep-tibility in an era of resistance Clin InfectDis 200948(11)1596ndash1600

11 Hersh AL Shapiro DJ Pavia AT Shah SSAntibiotic prescribing in ambulatory pedi-atrics in the United States Pediatrics 2011128(6)1053ndash1061

12 Kronman MP Hersh AL Feng R Huang YSLee GE Shah SS Ambulatory visit rates andantibiotic prescribing for children withpneumonia 1994ndash2007 Pediatrics 2011127(3)411ndash418

13 Brogan TV Hall M Williams DJ et al Vari-ability in processes of care and outcomesamong children hospitalized with community-acquired pneumonia Pediatr Infect Dis J201231(10)1036ndash1041

14 Schouten JA Hulscher ME Natsch SKullberg BJ van der Meer JW Grol RPBarriers to optimal antibiotic use forcommunity-acquired pneumonia at hospi-tals a qualitative study Qual Saf HealthCare 200716(2)143ndash149

15 Mongelluzzo J Mohamad Z Ten Have TRShah SS Corticosteroids and mortality inchildren with bacterial meningitis JAMA2008299(17)2048ndash2055

16 Williams DJ Shah SS Myers AM et alIdentifying pediatric community-acquiredpneumonia hospitalizations accuracy ofadministrative billing codes [publishedonline ahead of print July 29 2013] JAMAPediatr doi 101001jamapediatrics2013186

17 Feudtner C Christakis DA Connell FA Pe-diatric deaths attributable to complexchronic conditions a population-basedstudy of Washington State 1980ndash1997 Pe-diatrics 2000106(1 Pt 2)205ndash209

ARTICLE

PEDIATRICS Volume 132 Number 5 November 2013 e1147by guest on March 16 2016Downloaded from

18 Rosenbaum PR Rubin DB Constructinga control-group using multivariate matchedsampling methods that incorporate thepropensity score Am Stat 198539(1)33ndash38

19 Ribeiro CF Ferrari GF Fioretto JR Antibiotictreatment schemes for very severe com-munity-acquired pneumonia in childrena randomized clinical study Revista PanamSalud Publica 201129(6)444ndash450

20 Vuori-Holopainen E Peltola H Kallio MJSE-TU Study Group Narrow- versus broad-spectrum parenteral antimicrobials againstcommon infections of childhood a pro-spective and randomised comparisonbetween penicillin and cefuroxime EurJ Pediatr 2000159(12)878ndash884

21 Dinur-Schejter Y Cohen-Cymberknoh MTenenbaum A et al Antibiotic treatment ofchildren with community-acquired pneu-monia comparison of penicillin or ampi-cillin versus cefuroxime Pediatr Pulmonol201348(1)52ndash58

22 Newman RE Hedican EB Herigon JCWilliams DD Williams AR Newland JG Im-pact of a guideline on management ofchildren hospitalized with community-acquired pneumonia Pediatrics 2012129(3) Available at wwwpediatricsorgcgicontentfull1293e597

23 Garciacutea-Garciacutea ML Calvo C Pozo F VilladangosPA Peacuterez-Brentildea P Casas I Spectrum ofrespiratory viruses in children withcommunity-acquired pneumonia PediatrInfect Dis J 201231(8)808ndash813

24 Esposito S Daleno C Prunotto G et al Im-pact of viral infections in children withcommunity-acquired pneumonia results ofa study of 17 respiratory viruses InfluenzaOther Respi Viruses 20137(1)18ndash26

25 Wolf DG Greenberg D Shemer-Avni YGivon-Lavi N Bar-Ziv J Dagan R Associationof human metapneumovirus with radio-logically diagnosed community-acquiredalveolar pneumonia in young childrenJ Pediatr 2010156(1)115ndash120

26 Cilla G Ontildeate E Perez-Yarza EG Montes MVicente D Perez-Trallero E Viruses incommunity-acquired pneumonia in chil-dren aged less than 3 years old high rateof viral coinfection J Med Virol 200880(10)1843ndash1849

27 Hammitt LL Kazungu S Morpeth SC et al Apreliminary study of pneumonia etiologyamong hospitalized children in Kenya ClinInfect Dis 201254(suppl 2)S190ndashS199

28 Mermond S Zurawski V DrsquoOrtenzio E et alLower respiratory infections among hospi-talized children in New Caledonia a pilotstudy for the Pneumonia Etiology Researchfor Child Health project Clin Infect Dis201254(suppl 2)S180ndashS189

29 AHRQ National estimates on use of hospi-tals by children from the HCUP Kidsrsquo In-patient Database (KID) 2009 Available athttphcupnetahrqgovHCUPnetjspId=F3D2E7DF566C8BCCampForm=SelPATampJS=YampAction=3E3ENext3E3Eamp_InPatChar=Yesamp_InHospChar=Yesamp_PatChar= AccessedMarch 22 2012

30 Neuman MI Hall M Hersh AL et alInfluence of hospital guidelines on man-agement of children hospitalized withpneumonia Pediatrics 2012130(5) Avail-able at wwwpediatricsorgcgicontentfull1305e823

31 McIntosh KA Maxwell DJ Pulver LK et al Aquality improvement initiative to improveadherence to national guidelines for em-piric management of community-acquiredpneumonia in emergency departments IntJ Qual Health Care 201123(2)142ndash150

32 Smith MJ Kong M Cambon A Woods CREffectiveness of antimicrobial guidelinesfor community-acquired pneumonia inchildren Pediatrics 2012129(5) Availableat wwwpediatricsorgcgicontentfull1295e1326

33 Ambroggio L Thomson J Kurowski EMet al Quality improvement increases ap-propriate antibiotic prescribing for child-hood community acquired pneumoniaPediatrics 2013131(5) Available at wwwpediatricsorgcgicontentfull1315e1623

34 Carratalagrave J Garcia-Vidal C Ortega L et alEffect of a 3-step critical pathway to reduceduration of intravenous antibiotic therapyand length of stay in community-acquiredpneumonia a randomized controlled trialArch Intern Med 2012172(12)922ndash928

35 Lorgelly PK Atkinson M Lakhanpaul Met al Oral versus iv antibiotics forcommunity-acquired pneumonia in chil-dren a cost-minimisation analysis EurRespir J 201035(4)858ndash864

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1614

doi101542peds2013-1614

Accepted for publication Aug 27 2013

Address correspondence to Derek J Williams MD MPH 1161 21st Ave South CCC 5311 Medical Center North Nashville TN 37232 E-mail derekwilliamsvanderbiltedu

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2013 by the American Academy of Pediatrics

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

FUNDING No external funding

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

e1148 WILLIAMS et alby guest on March 16 2016Downloaded from

18 Rosenbaum PR Rubin DB Constructinga control-group using multivariate matchedsampling methods that incorporate thepropensity score Am Stat 198539(1)33ndash38

19 Ribeiro CF Ferrari GF Fioretto JR Antibiotictreatment schemes for very severe com-munity-acquired pneumonia in childrena randomized clinical study Revista PanamSalud Publica 201129(6)444ndash450

20 Vuori-Holopainen E Peltola H Kallio MJSE-TU Study Group Narrow- versus broad-spectrum parenteral antimicrobials againstcommon infections of childhood a pro-spective and randomised comparisonbetween penicillin and cefuroxime EurJ Pediatr 2000159(12)878ndash884

21 Dinur-Schejter Y Cohen-Cymberknoh MTenenbaum A et al Antibiotic treatment ofchildren with community-acquired pneu-monia comparison of penicillin or ampi-cillin versus cefuroxime Pediatr Pulmonol201348(1)52ndash58

22 Newman RE Hedican EB Herigon JCWilliams DD Williams AR Newland JG Im-pact of a guideline on management ofchildren hospitalized with community-acquired pneumonia Pediatrics 2012129(3) Available at wwwpediatricsorgcgicontentfull1293e597

23 Garciacutea-Garciacutea ML Calvo C Pozo F VilladangosPA Peacuterez-Brentildea P Casas I Spectrum ofrespiratory viruses in children withcommunity-acquired pneumonia PediatrInfect Dis J 201231(8)808ndash813

24 Esposito S Daleno C Prunotto G et al Im-pact of viral infections in children withcommunity-acquired pneumonia results ofa study of 17 respiratory viruses InfluenzaOther Respi Viruses 20137(1)18ndash26

25 Wolf DG Greenberg D Shemer-Avni YGivon-Lavi N Bar-Ziv J Dagan R Associationof human metapneumovirus with radio-logically diagnosed community-acquiredalveolar pneumonia in young childrenJ Pediatr 2010156(1)115ndash120

26 Cilla G Ontildeate E Perez-Yarza EG Montes MVicente D Perez-Trallero E Viruses incommunity-acquired pneumonia in chil-dren aged less than 3 years old high rateof viral coinfection J Med Virol 200880(10)1843ndash1849

27 Hammitt LL Kazungu S Morpeth SC et al Apreliminary study of pneumonia etiologyamong hospitalized children in Kenya ClinInfect Dis 201254(suppl 2)S190ndashS199

28 Mermond S Zurawski V DrsquoOrtenzio E et alLower respiratory infections among hospi-talized children in New Caledonia a pilotstudy for the Pneumonia Etiology Researchfor Child Health project Clin Infect Dis201254(suppl 2)S180ndashS189

29 AHRQ National estimates on use of hospi-tals by children from the HCUP Kidsrsquo In-patient Database (KID) 2009 Available athttphcupnetahrqgovHCUPnetjspId=F3D2E7DF566C8BCCampForm=SelPATampJS=YampAction=3E3ENext3E3Eamp_InPatChar=Yesamp_InHospChar=Yesamp_PatChar= AccessedMarch 22 2012

30 Neuman MI Hall M Hersh AL et alInfluence of hospital guidelines on man-agement of children hospitalized withpneumonia Pediatrics 2012130(5) Avail-able at wwwpediatricsorgcgicontentfull1305e823

31 McIntosh KA Maxwell DJ Pulver LK et al Aquality improvement initiative to improveadherence to national guidelines for em-piric management of community-acquiredpneumonia in emergency departments IntJ Qual Health Care 201123(2)142ndash150

32 Smith MJ Kong M Cambon A Woods CREffectiveness of antimicrobial guidelinesfor community-acquired pneumonia inchildren Pediatrics 2012129(5) Availableat wwwpediatricsorgcgicontentfull1295e1326

33 Ambroggio L Thomson J Kurowski EMet al Quality improvement increases ap-propriate antibiotic prescribing for child-hood community acquired pneumoniaPediatrics 2013131(5) Available at wwwpediatricsorgcgicontentfull1315e1623

34 Carratalagrave J Garcia-Vidal C Ortega L et alEffect of a 3-step critical pathway to reduceduration of intravenous antibiotic therapyand length of stay in community-acquiredpneumonia a randomized controlled trialArch Intern Med 2012172(12)922ndash928

35 Lorgelly PK Atkinson M Lakhanpaul Met al Oral versus iv antibiotics forcommunity-acquired pneumonia in chil-dren a cost-minimisation analysis EurRespir J 201035(4)858ndash864

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1614

doi101542peds2013-1614

Accepted for publication Aug 27 2013

Address correspondence to Derek J Williams MD MPH 1161 21st Ave South CCC 5311 Medical Center North Nashville TN 37232 E-mail derekwilliamsvanderbiltedu

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2013 by the American Academy of Pediatrics

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

FUNDING No external funding

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

e1148 WILLIAMS et alby guest on March 16 2016Downloaded from

DOI 101542peds2013-1614 originally published online October 28 2013 2013132e1141Pediatrics

GrijalvaNeuman Adam L Hersh Thomas V Brogan Anne J Blaschke and Carlos G

Derek J Williams Matthew Hall Samir S Shah Kavita Parikh Amy Tyler Mark IWith Pneumonia

Narrow Vs Broad-spectrum Antimicrobial Therapy for Children Hospitalized

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rights reserved Print ISSN 0031-4005 Online ISSN 1098-4275Grove Village Illinois 60007 Copyright copy 2013 by the American Academy of Pediatrics All and trademarked by the American Academy of Pediatrics 141 Northwest Point Boulevard Elkpublication it has been published continuously since 1948 PEDIATRICS is owned published PEDIATRICS is the official journal of the American Academy of Pediatrics A monthly

by guest on March 16 2016Downloaded from

DOI 101542peds2013-1614 originally published online October 28 2013 2013132e1141Pediatrics

GrijalvaNeuman Adam L Hersh Thomas V Brogan Anne J Blaschke and Carlos G

Derek J Williams Matthew Hall Samir S Shah Kavita Parikh Amy Tyler Mark IWith Pneumonia

Narrow Vs Broad-spectrum Antimicrobial Therapy for Children Hospitalized

content1325e1141fullhtml

located on the World Wide Web at The online version of this article along with updated information and services is

of Pediatrics All rights reserved Print ISSN 0031-4005 Online ISSN 1098-4275Boulevard Elk Grove Village Illinois 60007 Copyright copy 2013 by the American Academy published and trademarked by the American Academy of Pediatrics 141 Northwest Pointpublication it has been published continuously since 1948 PEDIATRICS is owned PEDIATRICS is the official journal of the American Academy of Pediatrics A monthly

by guest on March 16 2016Downloaded from

DOI 101542peds2013-1614 originally published online October 28 2013 2013132e1141Pediatrics

GrijalvaNeuman Adam L Hersh Thomas V Brogan Anne J Blaschke and Carlos G

Derek J Williams Matthew Hall Samir S Shah Kavita Parikh Amy Tyler Mark IWith Pneumonia

Narrow Vs Broad-spectrum Antimicrobial Therapy for Children Hospitalized

content1325e1141fullhtml

located on the World Wide Web at The online version of this article along with updated information and services is

of Pediatrics All rights reserved Print ISSN 0031-4005 Online ISSN 1098-4275Boulevard Elk Grove Village Illinois 60007 Copyright copy 2013 by the American Academy published and trademarked by the American Academy of Pediatrics 141 Northwest Pointpublication it has been published continuously since 1948 PEDIATRICS is owned PEDIATRICS is the official journal of the American Academy of Pediatrics A monthly

by guest on March 16 2016Downloaded from