Follow-up after infants younger than 2 months of age with urinary tract infection in Southern Israel: epidemiologic, microbiologic and disease recurrence characteristics

ww w . e l s e v i e r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

Article

Follow-up

after

infants

younger

than

2

months

of

age

with

urinary

tract

infection

in

Southern

Israel:

epidemiologic,

microbiologic

and

disease

recurrence

characteristics

Evgenia

Gurevich

,

Dov

Tchernin

,

Ruth

Schreyber

,

Robert

Muller

,

Eugene

Leibovitz

a_{PediatricDepartment“A”,SorokaUniversityMedicalCenter,FacultyofHealthSciences,Ben-GurionUniversity,Beer-Sheva,Israel} b_{PediatricNephrologyClinics,SorokaUniversityMedicalCenter,FacultyofHealthSciences,Ben-GurionUniversity,Beer-Sheva,Israel} c_{PediatricEmergencyMedicineDepartment,SorokaUniversityMedicalCenter,FacultyofHealthSciences,Ben-GurionUniversity,}

Beer-Sheva,Israel

d_{PediatricNephrologyDepartment,IVthPediatricClinic,UniversityChildrenHospital“St.Mary”,G.T.PopaUniversityofMedicineand}

Pharmacy,Iasi,Romania

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received27June2015 Accepted11September2015 Availableonline19November2015

Keywords:

Antibiotics

E.coli

Urinarytractinfection Recurrence

a

b

s

t

r

a

c

t

Background:Thetimingofmostrecurrencesafterneonatalurinarytractinfectionisduring thefirstyearoflife,withpeakincidence2–6monthsaftertheinitialinfection.Information onthemicrobiologiccharacteristicsofrecurrenturinarytractinfectionepisodesinrelation tothemicrobiologyoftheinitialepisodesislimited.

Objectives: Toanalyzetheepidemiologic/microbiologicalcharacteristicsof1standrecurrent urinarytractinfectionininfants<2monthsofage.

Methods:Aretrospectivestudyincludingallinfants<2monthsofagewithurinarytract infectionadmittedduring2005–2009andfollowedtilltheageof1year.

Results:151 neonates were enrolled (2.7% of all 5617 febrileinfants <2 monthsof age admitted). The overall incidenceof urinarytractinfection occurring during the first 2 months of life was 151/73,480 (0.2%) live births during 2005–2009 in southern Israel (2.1 cases/1000 live births). One pathogen was isolated in 133 (88.1%); Escherichia coli,

Klebsiella spp., Enterococcus spp., Morganella morganii, Proteus spp., and Enterobacter spp. representedthemostcommonpathogens(57.9%,12.2%,7.9%,6.7%,6.1%,and5%, respec-tively).Trimethoprim/sulfamethoxazole,ampicillin,andcefuroxime-axetilwerethemost commonly recommended prophylactic antibiotics (45%, 13.2%, and 8%, respectively). Twenty-threerecurrenturinarytractinfectionepisodeswererecordedin20(13.2%)patients; 6/23(26%)werediagnosedwithinonemonthfollowing1stepisode.E.coliwasthemost fre-quentrecurrenturinarytractinfectionpathogen(12/23,52.2%).Nodifferenceswererecorded

∗ _{Correspondingauthorat:PediatricEmergencyMedicineDepartment,SorokaUniversityMedicalCenter,P.O.Box151,Beer-Sheva84101,}

Israel.

E-mailaddress:[email protected](E.Leibovitz).

http://dx.doi.org/10.1016/j.bjid.2015.09.003

20

inE.colidistributionbetweenfirsturinarytractinfectionvs.recurrenturinarytract infec-tion.Seventeen(74%)recurrenturinarytractinfectionepisodeswerecausedbypathogens different(phenotypically)fromthoseisolatedin1stepisode.Recurrenturinarytract infec-tionoccurredin25.0%,8.3%,and0patientsrecommendedtrimethoprim/sulfamethoxazole, cefuroxime-axetil,oramoxicillinprophylaxis,respectively.

Conclusions: (1)Thestudy determinedthe incidenceofurinarytractinfection infebrile infants<2monthsofageinSouthernIsrael;(2) E.coliwasresponsibleforthemajority offirstandrecurrenturinarytractinfection;(3)recurrenturinarytractinfectionwascaused mostlybypathogensdifferentthanthepathogensisolatedatinitialepisode.

©2015ElsevierEditoraLtda.Allrightsreserved.

Introduction

Theincidenceofurinary tract infections (UTI)is3–4.6% in neonates,0.7–5.9%ininfantsupto1yearofage,1–3%atthe ageof1–5yearsand0.71–2.3%atschoolage.1,2_{Approximately}

7–8%ofgirlsand2%ofboyswilldevelopanUTIduringthefirst 8yearsoflife.3_{ThemostcommonpathogenisEscherichiacoli,}

causingupto70–90%ofallUTIs.4,5

DiagnosisofUTI isofmajor importance,particularly in youngages,becausetheinfectionmayrepresent,potentially, thefirstsignofacongenitaldefectoftheurinarytract.Early diagnosis andtreatment areconsidered toprevent compli-cationssuchasrenalscarring,deterioratingrenalfunction, andhypertension,especiallyinyounginfantsandchildren<5 yearsofage.6_{Themostcommonabnormalitydiagnosedby}

imaginginvestigationisvesico-uretheralreflux(VUR).6–9_The

rateofVURinchildren<1yearofageisbetween18–35%.6,8,9

Itisknowntodaythat severeVUR may beassociatedwith developmentofrenalscarsbyupto4–6timesmorethan a lowgradeVURand 8–10timesmorelikelythan inpatients withoutVUR.6,8,9

ThetimingofmostUTIrecurrencesafterneonatalUTIis duringthefirstyearoflife,withpeakincidence2–6months postinfection.10_{Ingeneral,UTIrecurrenceoccursin30–40%}

ofthechildrenwithUTIandaround60%ofthemwillhavethe recurrenceduringthefirsttwoyearsoflife.Inaretrospective studycompleted between1978and 1984andincluding 262 children<1yearofagefollowedforthreeyearsafterthefirst episode,35%boysand32%girlsdevelopedrecurrentUTIand therecurrentUTIincidencewashigherinchildrenwithhigher (III–V)degreesofreflux.11

Information on the microbiologic characteristics of the recurrentUTIepisodesinrelationtothemicrobiologyofthe initialepisodesislimited.Theobjectivesofourstudyareto describeandcharacterizethe 1stUTIepisodeininfants<2 monthsofageadmittedatourcenterduring2005–2009, to determinetheincidenceofUTIinthispopulationin South-ernIsrael, toestablish the ratesof recurrent UTIepisodes untiltheageof1yearandthemicrobiologiccharacteristics oftheseepisodes, andtodiscusstheappropriateantibiotic treatmentpoliciesforthetreatmentandprophylaxisofUTIin infants.

Patients

and

methods

Thiswasaretrospectivestudyperformedduring2005–2009 andincludingalltheinfants<2monthsofageadmittedtothe pediatricdepartmentsoftheSorokaUniversityMedicalCenter withthediagnosisofUTIprovenbyurineculture(obtainedby supra-pubicaspirationorbladdercatheterization).Our hospi-talistheonlyprimaryandtertiarymedicalcenterinSouthern Israelandtakescareofapopulationofapproximately1million patients,outofthemaround250,000children.3

Infants <2 months of age, following the hospitaliza-tion with UTI, were discharged with the recommendation for antibiotic prophylaxis and for imaging investigations of the urinary tract during the period of two months fol-lowing the original UTI episode, according tothe available recommendations.6,8 _{The medical records of the admitted}

infants, laboratoryfindings fromthe bacteriological labora-tory and imagingdatafrom theradiology department and thenuclearmedicineinstitute,weresearched.Age,sexand ethnicityoftheinfantswithUTIweredocumented.Allurine cultures were obtained (at the initial and also the recur-rentUTIepisode)bycatheterizationorsuprapubicaspiration. Therecoveredurineculturespathogenswereconsideredtrue uropathogens according to treatmentphysiciansand addi-tional recommendationsbythepediatricinfectious disease unit of the hospital. Pseudomonas aeruginosa, Staphylococ-cus aureus, and Candida albicans were not considered true uropathogens in single pathogen or mixed pathogens-UTI caseswithoutanadditionalrenalanatomicabnormality.

A comparative analysis of the microbiological factors responsibleforthefirstandfortherecurrentUTIepisodeswas performed.Theantibioticcoverageanddurationoftreatment ofUTIweredocumented.ThetimingoftheUTIrecurrence wasanalyzedinrelationtotheinitialUTIepisode.Anatomical abnormalitiesdiagnosedduringthefirstepisodeofUTIwere documentedaswellasallimagingfindingcompletedduring the follow-upperiod.When VURdiagnosis waspresent,its severitydegreewasreported.

Theantibioticprophylaxispolicywasnotwelldefinedat thepediatricdepartmentduringthestudyperiod,leavingat thephysicians’decisionthespecificantibiotictobe adminis-tered.However,thelocalguidelinesrecommendedantibiotic

prophylaxisforall infants<2 monthsofagewith firstUTI episodesuntilthecompletionofimagingstudies.

Therecommendedimagingstudiesduringthestudyperiod includedthecompletionofanultrasound(US)examination duringhospitalizationorafterhospitalizationinallcasesof infants <2 monthsof age with UTI and performance of a voidingcystourethrogram(VCUG)after6–8weeksfollowing the discharge from the hospital. Additional investigations, likeTechnetium-Dimercaptosuccinic(DMSA)scan,inspecific cases,wereperformedaccordingtonephrologist’s recommen-dations.

Thestudy wasapprovedbythe ethicscommitteeofthe hospital.

Statisticalanalysis

DatawererecordedusingtheAccessMicrosoftOfficesoftware. StatisticalanalysiswasperformedusingtheSPSS16.0 soft-ware.Contingencytableanalysisforcomparingratesbetween unmatched samples was performed using the Chi-square orFisher’sexacttest,asappropriate.Student’sindependent samplest-testorANOVAwereusedtocomparecontinuous variables.

Results

Overall,151infants<2monthofagediagnosedwiththe1stUTI episodeinlife,wereenrolled.Theseinfantsrepresented2.7% ofall5617infants<2monthsofageadmittedatthepediatric departmentsduringthestudyyears(22/1129[1.9%],34/1205 [2.8%],45/1302[3.4%],24/1217[2.0%],and26/1029[2.5%]during 2005,2006,2007,2008,and2009,respectively).

The overall incidence of UTI occurring during the first twomonthsoflifewas 151/73,480(0.2%)live birthsduring 2005–2009intheNegevareaofSouthernIsrael,representing anincidenceof2.1cases/1000livebirths.Therespective num-bersforeach year ofthe study were: 1.5,2.4, 3.1,1.6, and 1.7/1000livebirthsduring2005,2006,2007, 2008,and 2009 respectively.

Themean±standarddeviationage(indays)atUTI diag-nosiswas42.26±31.25daysforthewholestudypopulation; no differences were recorded in the mean age atfirst UTI diagnosisbetweenmaleandfemaleneonates(38.24±15.8vs. 42.26±31.25,p=0.06).Therewere85(56.3%)malepatients(all circumcised)and102(67.5%)patientsofMoslemBedouin eth-nicity.

Onehundredandtwenty(79.5%)younginfantswithUTI didnotsufferfromanypreviouspathologicconditions.The remaining31(21.5%)werediagnosedwithvariousanomalies, ofthem9(5.9%)withrenalanomalies(6withhydronephrosis). Concomitant pathologieswere diagnosed atthetime of UTIdiagnosisin25(16.6%)patientswithUTI;pneumoniaand bronchiolitiswerediagnosedconcomitantlyin8(5.3%)cases eachandbacterialmeningitisin5(3.3%).

Microbiology

One pathogen was isolated in 133 (88.1%) UTI episodes.

Escherichia coli, Klebsiella spp., Enterococcus spp., Morganella

Table1–Pathogendistribution:151episodesoffirstUTI occurringin151neonates<2monthsofage.

Pathogens n(%) (1)Pathogen 133(88.1) Escherichiacoli 85(56.3) Klebsiellaspp. 16(10.6) Enterococcusspp. 8(5.2) Morganellamorganii 8(5.2) Proteusspp. 7(4.5) Enterobacterspp. 6(3.9) Citrobacterspp. 2(1.3) Serratiamarcescens 1(0.6)

(2)Pathogens(mixedinfection) 18(11.9)

Escherichiacoli+Enterococcusspp. 3(1.9) Escherichiacoli+Klebsiellaspp. 2(1.3) Escherichiacoli+Proteusspp. 2(1.3) Escherichiacoli+typebHaemophilusinfluenzae 1(0.6) Escherichiacoli+Morganellamorganii 1(0.6) Escherichiacoli+Acinetobacterspp. 1(0.6) Klebsiellaspp.+Enterococcusspp. 1(0.6) Klebsiellaspp.+Pseudomonasspp. 1(0.6) Morganellamorganii+Enterococcusspp. 1(0.6) Morganellamorganii+Klebsiellaspp. 1(0.6) Enterobacterspp.+Enterococcusspp. 1(0.6) Enterobacterspp.+Proteusspp. 1(0.6) Proteusspp.+Enterococcusspp. 1(0.6) Enterococcusspp.+Staphylococcusaureus 1(0.6)

morganii,Proteusspp.,andEnterobacterspp.werethemost fre-quentlyisolatedpathogens(53.3%,10.6%,5.2%,5.2%,4.5%,and 3.9%ofallepisodes,respectively)–Table1.Mixedinfection causedbytwoorganismsconsideredastrueUTIpathogens was recordedin18(11.9%)episodes, withE.coliisolatedin 6/18 (33.3%)episodes. In the twopatients with mixed UTI withrecoveryofP.aeruginosaandS.aureus(togetherwith Kleb-siella spp. and Enterococcus spp., respectively), bothisolates were consideredastrueuropathogensduetothe concomi-tant presenceofrenal tractanatomic anomalies(moderate hydronephrosisandVURdegreeIV,respectively).

Overall,therewere169uropathogens,ofthem95(57.9%)E. coliisolates.Klebsiellaspp.,Enterococcusspp.,M.morganii, Pro-teusspp.,andEnterobacterspp.representedthemostcommon UTI pathogens isolated (in decreasing frequency) following

E.coli(12.2%,7.9%,6.7%,6.1%,and5%ofallpathogens, respec-tively).

NostatisticaldifferenceswererecordedbetweenE.coli-UTI cases recorded inmale vs.female patients (68.2% vs.56%,

p=0.5).SignificantlymoreE.coli-UTIcaseswererecordedin Bedouin patientscomparedwith Jewishpatients(70.6% vs. 46.9%,p=0.005).

AntibioticprophylaxisfollowingthefirstUTIepisodes

Trimethoprim/sulfamethoxazole (TMP/SMX) was the most common prophylactic antibiotic recommended (68, 45% of allenrolledpatients)inthestudypatientsfollowingthefirst UTI episodes. Amoxicillin and cefuroxime-axetil were the next most common prophylactic antibiotic recommended (20 [13.2%]and 12 [8%] of all enrolled patients). Forty-five (29.8%)ofthepatientsenrolledinthestudy didnotreceive

22

Table2–Epidemiologic,microbiologic,andtherapeuticcharacteristics:20patients(23episodes)withUTIrecurrence.

No. M/F Ageat

recurrence (months)

Renalbackground

pathology

Pathogenin1stepisode Pathogenin2nd

episode Antimicrobial prophylaxisafter firstUTI 1 F 12 E.coli E.coli TMP/SMX 2 M 1 Proteusspp. C.albicans TMP/SMX 3 F 2 Proteusspp. P.aeruginosa TMP/SMX 4 F 3 E.coli Citrobacterspp. TMP/SMX

5 M 2 Enterobacterspp.+Enterococcusspp. E.coli TMP/SMX

6 F 2 E.coli Enterobacterspp. NA

7 M 2 E.coli Klebsiellaspp. NA

8 M 3 E.coli E.coli TMP/SMX

9 F 3 E.coli E.coli Cefuroxime-axetil

10 M 6 E.coli E.coli TMP/SMX

11 F 4 M.morganii E.coli TMP/SMX

12 M 7 E.coli E.coli TMP/SMX

13 M 6 E.coli E.coli TMP/SMX

14 F 11 Proteusspp. E.coli NA

15 M 11 Hydronephrosis Enterobacterspp. Enterococcusspp. TMP/SMX

16 M 10 Hydronephrosis Enterobacterspp. Enterobacterspp. TMP/SMX

17 M 4 E.coli E.coli NA 18.1 M 7 Klebsiellaspp. Proteusspp. TMP/SMX 18.2 9 Klebsiellaspp. E.coli TMP/SMX 19.1 M 3 Congenital megaurether,UVJ obstruction, hydronephrosis Klebsiellaspp. S.aureus TMP/SMX 19.2 7 Klebsiellaspp. C.albicans TMP/SMX 19.3 10 Klebsiellaspp. E.coli TMP/SMX 20 M 12 Klebsiellaspp. Klebsiellaspp. NA

TMP/SMX,trimethoprim/sulfamethoxazole;NA,notadministered;UVJ,urethero-vesicularjunction.

anyrecommendationforantibioticprophylaxisfollowingthe initialUTIepisode.

Imagingstudies

USwasperformedin83(54.9%)patients;68(81.9%)ofthese examinationswerereportedasnormal.Theabnormal find-ingsdiagnosedin15(18.1%)patientsincluded:mildtosevere hydronephrosisinallcases,onemegaureterandonecase sus-pectedofnephrolithiasis.VCUGwasperformedin66(43.7%) andwasdiagnosedasnormalin52(78.8%);VURofdegrees IV–Vwasfoundinthreepatients.

RecurrentUTI(Table2)

Recurrent UTI episodes were recorded in 20/151 (13.2%) patients.OnepatientdevelopedtwoUTIrecurrencesduring thefirstyearoflifeandonepatientdevelopedthreeUTI recur-renceswithinthefirstyearoflife.RecurrentUTIwasrecorded in13malesandsevenfemalepatients;6/23(26%)recurrent UTIepisodewerediagnosedwithinonemonthfollowingthe dischargeafterthefirstUTIepisode.Threeofthepatientswith recurrentUTIhadapreviouslydiagnosedrenalabnormality (allthreewithhydronephrosis,oneofthemwith urethero-vesicularobstruction)

Five of the patients with recurrent UTI did not receive any antibiotic prophylaxis following the first UTI episode. Therewere23uropathogens;nomixedpathogensrecurrent UTI episodes were recorded. E. coliwas the most frequent UTIpathogenrecoveredinrecurrentUTI(12/23,52.2%ofall recurrentUTIepisodes).Nodifferenceswererecordedinthe representationofE.coliamongallthepathogensisolatedinthe

firstUTIepisodescomparedwiththerecurrentUTIepisodes (95/151,62.9%vs.12/23,52.2%,p=0.30).

Seventeen(74%)ofthe23episodesofrecurrentUTIwere caused by pathogens different (phenotypically) from the pathogen isolated at thefirst UTI episode. Intwo ofthese episodes, theinitialandrecurrentUTIpathogen wasE.coli

withadifferentantibioticsusceptibilityprofile.Six(26%)ofthe 23episodesofrecurrentUTIwerecausedbythesame (phe-notypically)pathogensasthosecausingthefirstUTIepisode: fourE.coli,oneKlebsiellaspp.andoneEnterobacterspp.

Recurrent UTI episodes occurred in 17/68 (25.0%), 1/12 (8.3%),and0/20ofpatientsreceivinginitialprophylaxiswith TMP/SMX,cefuroxime-axetil,oramoxicillin,respectively.

Antibioticsusceptibilitiesofuropathogensisolatedatthe initialandrecurrentUTIepisode(Table3)

AttheinitialUTIepisode,theantibioticresistanceofE.coli iso-latestothemostcommonlyusedoralantibioticswas57.9%, 13.5%, 9.9%,and 5.4%for ampicillin,amoxicillin/clavulanic acid,TMP/SMX,andcefuroxime-axetil.Therespective num-bersforthetwomostcommonlyusedIM/IVantibioticdrugs were 3.9% and 2.1% for ceftriaxone and gentamicin. The antibioticresistanceofKlebsiellaspp.isolatestothemost com-monlyusedoralantibioticswas90.0%,21.4%,14.3%,and6.3% forampicillin,amoxicillin/clavulanicacid,cefuroxime-axetil, andTMP/SMX.Therespectivenumbersforthetwomost com-monly usedIM/IV antibiotic drugswere 6.3%and 4.8%for ceftriaxoneandgentamicin.All11M.morganiiisolateswere resistant toampicillin.All 13Enterococcusspp.isolateswere susceptibletoampicillin.

b r a z j i n f e c t d i s . 2 0 1 6; 2 0(1) :19–25

23

UTIepisodetiming

I** n=95 II** n=12 I n=21 II n=2 I n=11 II n=0 I n=11 II n=1 I n=8 II n=2 I n=14 II n=1 Ampicillin 55/95(57.9) 7/12(58.3) 18/20(90) 2/2(100) 11/11(100) 7/11(63.6) 2/2(100) 7/8(87.5) 2/2(100) 0/13 1/1(100) TMP/SMX 7/71(9.9) 0/10 1/16(6.3) 0/2 2/8(25) 0/5 1/1(100) 0/6 – 2/10(20) – Cefuroxime 5/92(5.4) 0/10 3/21(14.3) 1/2(50) 1/10(10) 0/11 0/1 1/7(14.3) 2/2(100) 3/10(30) – Ceftriaxone 3/77(3.9) 2/12(100) 1/16(6.3) 0/1 2/9(22.2) 1/11(9.1) – 0/7 2/2(100) 3/8(37.5) – Gentamicin 2/94(2.1) 0/12 1/21(4.8) – 3/11(27.3) 0/11 0/1 0/8 0/2 2/13(15.4) 0/1 Amoxicillin/clavulanicacid 5/37(13.5) 4/5(80) 3/14(21.4) – 1/4(25) 4/9(44.4) – 1/1(100) 1/1(100) 3/7(42.9) – Ciprofloxacin 3/29(10.3) 0/1 2/5(40) – 1/3(33.3) 2/5(40) – 0/1 – 6/7(85.7) –

∗ _{Antibioticsusceptibilitiesforsomeantibioticdrugsnotdeterminedforallpathogens.}

∗∗ _{I,initialUTIepisode;II,recurrentUTIepisode.}

24

Theantibioticresistanceofthe 12 E. coliisolates recov-eredinR-UTIpatientswas58.3%,0%,and0%forampicillin, TMP/SMX, and cefuroxime-axetil, respectively. Four of the five E. coli isolates examined showed resistance to amoxi-cillin/clavulanic acid. The respective numbers for the two mostcommonlyusedIM/IVantibioticdrugswere16.6%and0 forceftriaxoneandgentamicin.

Discussion

Themost recentlypublished informationon the diagnosis andmanagementofaninitialUTIepisodeinfebrileinfants andyoungchildrenareincludedinthelast(2011)technical reportofthesubcommitteeofUTIoftheAmericanAcademyof Pediatrics.7_{Ameta-analysiswasperformedonafinalamount}

of159 relevant publications and revealed a consistentUTI prevalence of 5% among infants and young children 2–24 monthsofagewithfeverwithoutobvioussource.Evidence wasfoundthatdelayintheinstitutionofappropriate treat-mentofpyelonephritisincreasestheriskofrenaldamage.A prevalenceofVURof18–35%amonginfants/youngchildren withUTIwasreported.Thereportemphasizedthatnormal prenatal US findings may not be sufficient to obviate the needfor additional studies if a UTI occurs ininfancy and thatthe accumulatedevidencewasnotsupporting antimi-crobialprophylaxistopreventUTIwhenVURisfoundthrough VCUG.Finally,performanceofVCUGafterthefirstUTIfor chil-drenbetween2and24monthsofagewasnotrecommended anymore.7 _{Thefollowing(2011) guidelinesofthe American}

AcademyofPediatricsdidnotsupporttheuseof antimicro-bial prophylaxis topreventfebrile recurrent UTIin infants withoutgradeI–IVVUR.9_{VCUGwasnotrecommended}

any-moreroutinelyafterthefirstUTI,butisstillindicatedifrenal and bladder ultrasonography reveals hydronephrosis, scar-ing,orotherfinding suggestiveofeitherhighgradeVURor obstructiveuropathyandinotheratypicalorcomplexclinical circumstances.TheperformanceofVCUG,however,is recom-mendedinthepresenceofarecurrenceoffebrileUTI.9

FewdataexistintheliteratureregardingUTIsoccurringin infants<2monthsofage.Themajorpurposeofour retrospec-tivestudywastoanalyzetheepidemiological,microbiological, imaging,andtherapeuticalaspectsofthefirstepisodesofUTI ininfants<2monthsofageandtofollowtheseinfantsuntil theageofoneyear,inordertotracktheoccurrenceof recur-rentUTIepisodesandtostudytheappropriatenessofcurrent imagingandantibiotictherapeuticguidelines.Themajor find-ingsofthisstudywere:(1)theUTIincidencewas2.1cases/1000 livebirthsamonginfants<2monthsofageinSouthernIsrael; (2)E. coliwas responsibleforthe majorityoffirst and also recurrentUTIepisodes;(3)nodifferenceswererecordedinthe percentagesofE.coliamongthepathogensisolatedatthefirst andtherecurrentUTIepisodes;(4)theadherencetodiagnostic imagingguidelinesforinfants<2monthsofagewithfirstUTI episodeswaspartial;(5)recurrentUTIepisodeswererecorded inrelativelyfew(13.2%)patientsandwerecausedmostlyby pathogens phenotypically different than the pathogen iso-latedattheinitialepisode;(6)whilehighratesofresistance toampicillinwere recorded amongthe E.coliand Klebsiella

spp.isolatesinthefirstUTIepisodeandamongE.coliisolates

atUTIrecurrence,theresistancerateofthesepathogensto TMP/SMXandcefuroxime-axetilwerelow.

Wecalculatedinourstudy anUTIincidenceof2.1/1000 livebirthsamonginfantsaged0–2monthslivingintheNegev areaofSouthernIsraelandaprevalenceof2.7%casesoffirst UTIepisodeinlifeamongfebrileinfants<2months admit-tedatthepediatricdepartmentsofourhospitalduringthe studyyears.Theprevalenceratesarelowerthanthefigures publishedinthemedicalliterature(reportingarateofaround 5%).1,4,5,8_{Theincidenceratereportedinourstudyshouldbe}

considered reliable,becauseallourfindingsarereportedin thisstudyaspopulation-based,takingintoconsiderationthat theSorokaUniversityMedicalCenteristheonlymedical cen-tertreatinginfantsandchildrenintheNegevareaofsouthern Israel.

E.coliwasresponsibleforthemajorityofcasesoffirstUTI. Ourdataaresimilartodatapreviouslypublishedinthe lit-erature showinga representationofE. coliamongfirst UTI episodesof60–89%.8,12,13_{Thecurrentguidelinesforthe}

treat-ment ofneonatalUTItake intoconsideration thesefinding butmayoftenbeinappropriateforhospitalizedinfantswith non-E.coliUTI,causedingeneralbypathogensresistantto antibioticsandthereforemoredifficulttotreat.13 _TheE.coli

isolatesrecoveredfromourpatientsatthefirstUTIepisode, althoughresistant,inmostpatients,toampicillin andalso inaconsiderablenumberofcasestoamoxicillin/clavulanic acid,showed afavorableantibioticsusceptibility profilevs. TMP/SMX,cefuroxime,ceftriaxone,andgentamicin. Further-more,theresistanceratesofKlebsiellaspp.toTMP/SMXwere alsoverylow.Therefore,andnotinaccordancewiththe pub-lishedliterature,TMP/SMX mayrepresent, atleastinolder children,anacceptablefirstlineempiricantibioticinthe treat-mentofUTIinyounginfants.

TheR-UTIratesrecordedinourstudyreached13.2% fol-lowing aninitialUTIepisodeoccurringduringthefirsttwo monthsoflife.Mostpriorstudieshaveshownmuchhigher recurrencerate(20–48%)ofUTI6–12monthsafteraninitialUTI episode.7,9,14_{Interestingly,onlyafewofthepatients}

develop-ingR-UTIepisodesinourstudyhadapreviouslydiagnosed renal pathology. Theinfluence ofthe antibiotic prophylac-tictreatmentadministeredafterthefirstUTIepisodecould notbeclearlydeterminedinourstudy.However,25%ofthe patients receivingprophylaxis withTMP/SMXdeveloped R-UTIepisodes(despitelowresistancetothis antibioticdrug) whilenocasesofrecurrentUTIwere diagnosedinpatients receivingamoxicillinprophylaxis(despiteanunfavorable sus-ceptibilityprofileofthemostfrequentlyisolatespathogens recoveredinthisstudy).Theeffectivenessoflong-term pro-phylactic antibiotictreatment is yet unclear.6,7,8,9 _Williams

etal.15_{showedthatlong-termantibioticprophylaxisis}

effec-tive inpreventing UTI recurrences, but this effect wasnot sustainedaftertheinterruptionoftheantibiotictreatment. Shahetal.determinedthatprophylacticantibioticis recom-mendedforchildren<8yearsofagewithVURandfrequent symptomaticrecurrencesofUTI(≥2 UTIepisodesover a 6-month period) and in young children <18 months of age withacutepyelonephritiswithoutanydiagnosedrefluxusing

99m_{Tc-DMSA scan.}16 _{On theother hand,Garin et al.}

deter-minedthatthepresenceofVURofmildormoderatedegree doesnotincreasetheriskforR-UTI,pyelonephritis,orkidney

scarringandthereisnoreasonforprophylacticantibiotic.17

Conwayetal.10_{reportedratesof0.007episodesper}

person-yearofprimaryUTIuptotheageofoneyearand0.12episodes perperson-yearofrecurrentUTI.Theauthorsfoundthatthe riskfactorsforrecurrenceofUTIincludedwhiterace,ageof 4–5years,andaVURofdegrees4–5.Prophylactic antibiotic treatmentwasnotassociatedwithadecreaseintheriskofUTI recurrence,butwasariskfactorfordevelopmentof antimicro-bialresistanceamongchildrenwithrecurrentUTI.10_In2014,

inatwo-year,multisite,randomized,placebo-controlledtrial involving607childrenwithVUR(80.4%withgradeIIorIIIVUR) diagnosedafterafirstorsecondfebrileorsymptomatic uri-narytractinfection,antimicrobialprophylaxiswithTMP/SMX wasassociatedwithasubstantiallyreducedriskofrecurrence (50%)butnotofrenalscarring.18

Wecouldestablishinthisstudythattheoveralletiology oftherecurrentUTIepisodeswassimilartothatofthe ini-tialUTIepisodeintermsofE.coliandnon-E.coliorganisms representationandalso,importantly,thatthemajority(64%) oftherecurrentUTIepisodeswerecausedbypathogens dif-ferentthan thoseisolatedatthefirst UTIepisode.Ourlast findings,basedonsimilaritybetweentheantimicrobial pro-filesoftheisolates,werenotdefinitivelyconfirmedbygenetic testsdemonstratingunequivocallythissimilarity,andthisis oneofthelimitationsofourstudy.

Theimagingguidelinesinuseatthepediatricdivisionof ourhospitalduringthestudyperiodrecommendedthe per-formanceofUSexaminationduringhospitalizationorshortly afterhospitalizationinall casesofUTIinyounginfants, a VCUGexaminationafter6–8weeksfollowingthedischarge fromthehospital.Theseguidelineswereimplementedonly partiallyintheenrolledpatients.

Inconclusion,ourstudy showedthatE.coliwas respon-sible for the majority offirst UTI in neonatesand also in therecurrentUTI episodesofthesepatients.Wecould not find any differences inthe percentages ofE. coliand

non-E. coli organisms between the first and the recurrent UTI episodes.RecurrentUTIepisodeswererecordedinrelatively fewpatientsandwere causedmostlybypathogens pheno-typicallydifferent than thepathogen isolated atthe initial episode.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

r

e

f

e

r

e

n

c

e

s

1. HobermanA,ChaoHP,KellerDM,HickeyR,DavisHW,EllisD. Prevalenceofurinarytractinfectioninfebrileinfants.J Pediatr.1993;123:17–23.

2.MironD,ShatzbergG,LandauD,HalevyR.Treatmentof community-acquiredurinarytractinfections.IsraelJPediatr. 2001;38:7–15.

3.IsraeliCentralBureauofStatistics,StatisticalAbstractsof Israel,2005-2009,DataonBeer-Shevasub-districtpopulation. 4.IsmailiK,LolinK,DamryN,AlexanderM,LepageP,HallM.

Febrileurinarytractinfectionsin0-to3-month-oldinfants:a prospectivefollow-upstudy.JPediatr.2011;158:91–4.

5.RobertsKB,CharneyE,SwerenRJ,AhonkhaiVI,BergmanDA, CoulterMP,etal.Urinarytractinfectionininfantswith unexplainedfever:acollaborativestudy.JPediatr. 1983;103:864–7.

6.AmericanAcademyofPediatrics.CommitteeonQuality Improvement.SubcommitteeonUrinaryTractInfection. Practiceparameter:thediagnosis,treatment,andevaluation oftheinitialurinarytractinfectioninfebrileinfantsand youngchildren.Pediatrics.1999;103:843–52.

7.FinnellSME,CarrollAE,Downs.SMandtheSubcommitteeon UrinaryTractInfection.Technicalreport-diagnosisand managementofaninitialUTIinfebrileinfantsandyoung children.AmericanAcademyofPediatrics.Pediatrics. 2011;128:e749–70.

8.RobertsKB.Urinarytractinfectiontreatmentandevaluation. Update.PediatrInfectDisJ.2004;23:1163–4.

9.SubcommitteeonUrinaryTractInfection.Steeringcommittee onQualityImprovementandManagement:ClinicalPractice GuidelinefortheDiagnosisandManagementoftheInitial UTIinFebrileInfantsandChildren2to24months.American AcademyofPediatrics.Pediatrics.2011;128:595–610.

10.ConwayPH,CnaanA,ZaoutisT,HenryBV,GrundmeierRW, Keren.Recurrenturinarytractinfectionsinchildren.Risk factorsandassociationwithprophylacticantimicrobials. JAMA.2007;298:179–87.

11.NuutinenM,UhariM.Recurrenceandfollow-upafterurinary tractinfectionundertheageof1year.PediatrNephrol. 2001;16:69–72.

12.IsmailiK,WissingKM,LolinK,LePQ,ChristopheC,LepageP, etal.Characteristicsoffirsturinarytractinfectionwithfever inchildren–aprospectiveclinicalandimagingstudy.Pediatr InfectDisJ.2011;30:371–4.

13.MarcusN,AshkenaziS,YaariA,SamraZ,LivniG.

Non-EscherichiacoliversusEscherichiacolicommunity-acquired urinarytractinfectioninchildrenhospitalizedinatertiary center-relativefrequency,riskfactors,antimicrobial resistanceandoutcome.PediatrInfectDisJ.2005;24:581–5.

14.WaldER.Vesicoureteralreflux:theroleofantibiotic prophylaxis.Pediatrics.2006;117:919–22.

15.WilliamsG,LeeA,CraigJ.Antibioticsforthepreventionof urinarytractinfectioninchildren:asystematicreviewof randomizedcontrolledtrials.JPediatrics.2001;138:868–74.

16.ShahG,UpadhyayJ.Controversiesinthediagnosisand managementorurinarytractinfectionsinchildren.Pediatr Drugs.2005;7:339–46.

17.GarinE,OlavarriaF,NietoVG,ValencianoB,CamposA,Young L.Clinicalsignificanceofprimaryvesicoureteralrefluxand urinaryantibioticprophylaxisafteracutepyelonephritis:a multicenter,randomized,controlledstudy.Pediatrics. 2006;117:626–32.

18.TheRIVURTrialInvestigators.Antimicrobialprophylaxisfor childrenwithvesicoureteralreflux.NEnglJMed.2014,