Pediatrics 2011 Finnell Peds.2011 1332

Technical ReportDiagnosis and Management of anInitial UTI in Febrile Infants and Young Children

abstractOBJECTIVES: The diagnosis and management of urinary tract infec-tions (UTIs) in young children are clinically challenging. This report wasdeveloped to inform the revised, evidence-based, clinical guideline re-garding the diagnosis and management of initial UTIs in febrile infantsand young children, 2 to 24 months of age, from the American Academyof Pediatrics Subcommittee on Urinary Tract Infection.

METHODS: The conceptual model presented in the 1999 technical re-port was updated after a comprehensive review of published litera-ture. Studies with potentially new information or with evidence thatreinforced the 1999 technical report were retained. Meta-analyses onthe effectiveness of antimicrobial prophylaxis to prevent recurrent UTIwere performed.

RESULTS: Review of recent literature revealed new evidence in thefollowing areas. Certain clinical ndings and new urinalysis methodscan help clinicians identify febrile children at very low risk of UTI. Oralantimicrobial therapy is as effective as parenteral therapy in treatingUTI. Data from published, randomized controlled trials do not supportantimicrobial prophylaxis to prevent febrile UTI when vesicoureteralreux is found through voiding cystourethrography. Ultrasonographyof the urinary tract after the rst UTI has poor sensitivity. Early antimi-crobial treatment may decrease the risk of renal damage from UTI.

CONCLUSIONS: Recent literature agrees with most of the evidencepresented in the 1999 technical report, but meta-analyses of data fromrecent, randomized controlled trials do not support antimicrobial pro-phylaxis to prevent febrile UTI. This nding argues against voiding cys-tourethrography after the rst UTI. Pediatrics 2011;128:e749e770

S. Maria E. Finnell, MD, MS, Aaron E. Carroll, MD, MS,Stephen M. Downs, MD, MS, and the Subcommittee onUrinary Tract Infection

KEY WORDSurinary tract infection, infants, children, vesicoureteral reux,voiding cystourethrography, antimicrobial, prophylaxis,antibiotic prophylaxis, pyelonephritis

ABBREVIATIONSUTIurinary tract infectionVURvesicoureteral reuxVCUGvoiding cystourethrographyCIcondence intervalRRrisk ratioRCTrandomized controlled trialLRlikelihood ratioSPAsuprapubic aspiration

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave led conict of interest statements with the AmericanAcademy of Pediatrics. Any conicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.

The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.

www.pediatrics.org/cgi/doi/10.1542/peds.2011-1332

doi:10.1542/peds.2011-1332

All technical reports from the American Academy of Pediatricsautomatically expire 5 years after publication unless reafrmed,revised, or retired at or before that time.

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

Copyright 2011 by the American Academy of Pediatrics

COMPANION PAPERS: Companions to this article can be foundon pages 572 and 595, and online at www.pediatrics.org/cgi/doi/10.1542/peds.2011-1818 and www.pediatrics.org/cgi/doi/10.1542/peds.2011-1330.

FROM THE AMERICAN ACADEMY OF PEDIATRICS

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In 1999, the Subcommittee on UrinaryTract Infection of the American Acad-emy of Pediatrics released its guide-line on detection, diagnosis, and man-agement for children between 2 and 24months of age with febrile urinarytract infections (UTIs).1 The guidelinewas supported by a technical report2

that included a critical review of therelevant literature and a cost-effectiveness analysis. Consistent withthe policies of the American Academyof Pediatrics, the subcommittee hasundertaken a revision of the guideline.This technical report was developed tosupport the guideline.3

The revised technical report was to bebased on a selective review of the liter-ature, focusing on changes in the evi-dence regarding detection, diagnosis,and management of UTIs in these chil-dren. The original technical report wasdesigned around an evidence model(Fig 1). Each cell (numbered 14) cor-responded to a stage in the recogni-tion, diagnosis, or management of UTI.The boxes represented steps the clini-cian must follow, and the arrows rep-resented the process of moving fromone step to the next. Downward arrowsrepresented undesirable consequencesin management.4

In cell 1, the clinician must combinepatient demographic data and otherpresenting clinical data to arrive at anassessment of the risk of UTI. Failure todo so results in a missed opportunityto make the diagnosis. In cell 2, the cli-

nician must undertake a diagnosticstrategy, primarily involving labora-tory testing, to arrive at a posterior(posttest) probability of UTI, ruling thediagnosis in or out. Poor test choicesor interpretation of results can lead tomisdiagnosis. In cell 3, the clinicianmust choose a treatment for acute UTI;in cell 4, the clinician must considerthe possibility of structural or func-tional anomalies of the urinary tractand diagnose them appropriately toavoid ongoing renal damage.

Implicit in cell 4 is the idea that anom-alies of the urinary tract, such as vesi-coureteral reux (VUR) and obstruc-tions, may, if left untreated, lead tosignicant renal damage, resulting inhypertension or end-stage renal dis-ease. Furthermore, it is assumed thattreatment with medical or surgicaltherapies can prevent these conse-quences successfully.

The conclusions of the 1999 technicalreport were that there were high-quality data regarding the prevalenceof UTI among febrile infants, the per-formance of standard diagnostic testsfor UTI, and the prevalence of urinarytract abnormalities among childrenwith UTI. The evidence indicating thatcertain patient characteristics (age,gender, and circumcision status) af-fected the probability of UTI wasweaker. The evidence supporting therelationship between urinary tract ab-normalities and future complications,such as hypertension or renal failure,

was considered very poor, and the ef-fectiveness of treatments to preventthese complications was not ad-dressed directly but was assumed.

The cost-effectiveness analysis usingthese data led to the conclusion thatdiagnosis and treatment of UTI andevaluation for urinary tract anomalieshad borderline cost-effectiveness,costing approximately $700 000 percase of hypertension or end-stage re-nal disease prevented. On the basis ofthese results, the subcommittee rec-ommended testing all children be-tween 2 and 24 months of age with fe-ver with no obvious source for UTI, byculturing urine obtained through blad-der tap or catheterization. As an optionfor children who were not going to re-ceive immediate antimicrobial treat-ment, the committee recommendedruling out UTI through urinalysis ofurine obtained with any convenientmethod. The committee concluded thatchildren found to have a UTI should un-dergo renal ultrasonography and void-ing cystourethrography (VCUG) forevaluation for urinary tract abnormal-ities, most frequently VUR.

Ten years later, the subcommittee hasundertaken a review of the technicalanalysis for a revised guideline. Thestrategy for this technical report wasto survey the medical literature pub-lished in the past 10 years for studiesof UTIs in young children. The literaturewas examined for any data that variedsignicantly from those analyzed in the

FIGURE 1Evidence model from the 1999 technical report on the diagnosis and treatment of infants and children with UTIs.

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rst technical report. This surveyfound an emerging body of literatureaddressing the effectiveness of antimi-crobial agents to prevent recurrentUTI. Therefore, the authors conducteda critical literature review and meta-analysis focused on that specic issue.

METHODS

Surveillance of Recent Literature

The authors searched Medline for arti-cles published in the past 10 yearswith the medical subject headingsurinary tract infection and child(all). The original search was con-ducted in 2007, but searches were re-peated at intervals (approximately ev-ery 3 months) to identify new reportsas the guideline was being developed.Titles were reviewed by 2 authors (DrsDowns and Carroll) to identify all arti-cles that were potentially relevant andseemed to contain original data. All ti-tles that were considered potentiallyrelevant by either reviewer were re-tained. Abstracts of selected articleswere reviewed, again to identify arti-cles that were relevant to the guidelineand that seemed to contain originaldata. Review articles that were rele-vant also were retained for review.Again, all abstracts that were consid-ered potentially relevant by either re-viewer were retained. In addition,members of the subcommittee submit-ted articles that they thought were rel-evant to be included in the review.

Selected articles were reviewed andsummarized by 2 reviewers (DrsFinnell and Downs). The summarieswere reviewed, and articles present-ing potentially new information wereretained. In addition, representativearticles reinforcing evidence in the1999 technical report were retained.

The most signicant area of change inthe UTI landscapewas a new and grow-ing body of evidence regarding the ef-fectiveness of antimicrobial prophy-laxis to prevent recurrent infections in

children with VUR. To explore this par-ticular issue, a second, systematic, tar-geted literature search and formalmeta-analysis were conducted to esti-mate the effectiveness of antimicro-bial prophylaxis to prevent renal dam-age in children with VUR. In addition, 1author (Dr Finnell) and the chairper-son of the guideline committee (DrRoberts) contacted the authors ofthose studies to obtain original datapermitting subgroup analyses.

Targeted Literature Search andMeta-analysis

To examine specically the effective-ness of antimicrobial prophylaxis toprevent recurrent UTI and pyelone-phritis in children with VUR, a formalmeta-analysis of randomized con-trolled trials (RCTs) was conducted.First, a systematic literature review fo-cused on RCTs, including studies inpress, was performed.

Inclusion Criteria

RCTs published in the past 15 years(19932009) that compared antimicro-bial treatment versus no treatment orplacebo treatment for the preventionof recurrent UTI and included a mini-mum of 6months of follow-upmonitor-ing were included. Published articles,articles in press, and published ab-stracts were included. There were nolanguage restrictions. To be included,studies needed to enroll children whohad undergone VCUG for determina-tion of the presence and grade of VUR.Studies that examined antibiotic pro-phylaxis versus no treatment or pla-cebo treatment were included.

Outcome Measures

The primary outcome was the numberof episodes of pyelonephritis or febrileUTI diagnosed on the basis of the pres-ence of fever and bacterial growth inurine cultures. A secondary outcomewas an episode of any type of UTI, in-cluding cystitis, nonfebrile UTI, and

asymptomatic bacteriuria in additionto the cases of pyelonephritis or fe-brile UTI.

Search Methods

The initial literature search was con-ducted on June 24, 2008, and thesearch was repeated on April 14, 2009.Studies were obtained from the follow-ing databases: Medline (1993 to June2008), Embase (1993 to June 2008), Co-chrane Central Register for ControlledTrials, bibliographies of identied rel-evant articles and reviews, and theWeb site www.ClinicalTrials.gov.

The search terms vesico-ureteral re-ux, VUR, vesicoureter*, vesicoureter*, vesicourethral, or vesicourethral and antibiotic, anti biotic,antibacterial, anti bacterial, anti-microbial, anti microbial, antiinfec-tive, or anti infective were used. Theasterisk represents the truncation orwild card symbol, which indicates thatall sufxes and variants were included.The search was limited to the publica-tion types and subject headings for allclinical trials and included all key-word variants for random in Medlineand Embase.5 In addition, the Web sitewww.ClinicalTrials.gov was searchedon May 20, 2010.

The search strategy and the screeningof the titles for selection of potentiallyrelevant abstracts were completed by1 reviewer (Dr Finnell). Two reviewers(Drs Finnell and Downs) screened se-lected abstracts to identify appropri-ate articles. Published articles and ab-stracts that met the inclusion criteriawere included in themeta-analysis. Addi-tional information was sought from au-thorswhosearticles orabstractsdidnotcontain the information needed for a de-cision regarding inclusion. The selectionprocess is summarized in Fig 2.

Assessment of Studies

The quality of selected articles and ab-stracts was assessed with the scoring



system described by Downs and Blackin 1998.6 Each study received scores(from 2 assessors) on a scale from 0 to32. Six of the articles and abstractswere included in a rst meta-analysis,

which evaluated febrile UTI or pyelone-phritis as the outcome. A secondmeta-analysis, which included all studieswith the outcome all UTI, also wasconducted.

Meta-analyses

All statistical tests were performed byusing Review Manager 5.1 (Nordic Co-chrane Centre, Copenhagen, Den-mark). The following settings wereused for the analyses: dichotomousoutcome and Mantel-Haenzel statisti-cal method. Data were analyzed with arandom-effects model. When no statis-tically signicant effect and no statisti-cal heterogeneity were detected, dataalso were analyzed with a xed-effectsmodel, because that type of analysis ismore likely to detect a difference. Theeffect measure was presented as arisk ratio (RR). The results for the pri-mary outcome (pyelonephritis or fe-brile UTI) and the secondary outcome(any type of UTI, including cystitis, non-febrile UTI, and asymptomatic bacteri-uria) were calculated as point esti-mates with corresponding 95%condence intervals (CIs). Heterogene-ity was analyzed by using the Q statisticwith a threshold of P .05. The num-ber of studies was insufcient for as-sessment of publication bias with afunnel plot.

Meta-analyses of Data According toVUR Grade and for Children 2 to 24Months of Age

The published data on which the meta-analyses were based did not containsubgroup data relevant to the practiceguideline. Specically, some studiesdid not report outcomes according tothe severity of VUR, and some did notreport outcomes specic to the agerange of interest (224 months).Therefore, the committee chairpersoncontacted the authors of the reportsincluded in the meta-analysis, to ob-tain original data. Data on recurrenceaccording to VUR grade and for thesubgroup of children 2 to 24 months ofage were received from the authors,and these data were analyzed in sepa-rate meta-analyses.

FIGURE 2Study selection for meta-analyses.


RESULTS

Surveillance of Recent Literature

The surveillance of recent literatureyielded 1308 titles. Of those, 297 ab-stracts were selected for review. Fromamong the abstracts, 159 articleswere selected for full review. The re-sults of this surveillance, as well as thefull review and meta-analyses, are or-ganized according to the evidence dia-gram in Fig 1.

Box 1: Prevalence and Risk Factorsfor UTI

The Presence of UTI Should BeConsidered for Any Child 2 Monthsto 2 Years of Age With UnexplainedFever

The previous technical report de-scribed a very consistent UTI preva-lence of 5% among children 2 to 24months of age with a fever without ob-vious source. In 1996, Hoberman et al7

conducted a study of urine diagnostictests with a cohort of 4253 infants withfever and found a prevalence of 5%.Similarly, in a 1999 cohort study of 534children 3 to 36 months of age with atemperature of more than 39C and noapparent source of fever, UTI preva-lence was determined to be 5%.8 In a1998 cohort study of 2411 children(boys and girls12months of age andgirls 1224 months of age) seen in theemergency department with a temper-ature of more than 38.5C, Shaw et al9

determined the prevalence of UTI to be3.3%. Because 84% of those childrenwere black, this estimate may be lowfor the general population (see below).In a meta-analysis of 14 studies, thepooled prevalence of UTI was 7% (95%CI: 5.5%8.4%) among febrile children0 to 24 months of age, of both genders,with or without additional symptomsof UTI.10 In the 6- to 12-month agegroup, however, the prevalence was5.4%; in the 12- to 24-month age group,the prevalence was 4.5%. Taken to-

gether, these estimates are consistentwith a pooled prevalence of 5% deter-mined in earlier studies.

The previous technical report exam-ined the effects of age, gender, and cir-cumcision status on the prevalence ofUTI. The conclusionwas that boysmorethan 1 year of age who had been cir-cumcised were at sufciently low riskof UTI (1%) that evaluation of thissubpopulation would not be cost-effective. New work conrms an ap-proximately threefold to fourfold de-creased risk of UTI among circumcisedboys.10 The difference seems to begreater for younger children.11 Addi-tional clinical characteristics wereshown more recently to affect the riskof UTI among febrile infants and chil-dren. From a study by Shaikh et al,12 aset of likelihood ratios (LRs) for vari-ous risk factors for UTI was derived(Table 1).

A simpliedway to examine the data onboys from Shaikh et al12 is rst to ex-

clude boys with a history of UTI, be-cause the guideline addresses onlyrst-time UTIs, and to exclude thosewith ill appearance, because they arelikely to require antimicrobial agents,in which case a urine specimen wouldbe required. Finally, boys with andwithout circumcision should be con-sidered separately. This leaves 4 riskfactors for boys who present with fe-ver, namely, temperature above 39C,fever for more than 24 hours, no ap-parent fever source, and nonblackrace. All 4 have similar LRs. If 2 as-sumptions aremade, then the decisionrule can be simplied. The rst as-sumption is that, as a rst approxima-tion, each risk factor has a positive LRof 1.4 and a negative LR of 0.7. The sec-ond assumption is that the presence ofeach risk factor is conditionally inde-pendent of the others, given the pres-ence or absence of UTI. With these rea-sonable assumptions, Table 2 appliesto boys with no previous history of UTI

TABLE 1 LRs and Posttest Probabilities of UTI for Infant Boys According to Number of FindingsPresent

Finding LR Posttest Probability, %

All Boys Circumcised Boys UncircumcisedBoys

Positive Negative AfterPositiveResults

AfterNegativeResults

AfterPositiveResults


AfterPositiveResults


Uncircumcised 2.8 0.33 5.9 0.7 History of UTI 2.6 0.96 5.5 2.1 1.8 0.7 14.0 5.7Temperature of39C 1.4 0.76 3.1 1.7 1.0 0.5 8.1 4.5Fever without apparentsource

1.4 0.69 3.1 1.5 1.0 0.5 8.1 4.1

Ill appearance 1.9 0.68 4.1 1.5 1.3 0.5 10.6 4.1Fever for24 h 2.0 0.9 4.3 2.0 1.4 0.6 11.1 5.3Nonblack race 1.4 0.52 3.1 1.2 1.0 0.4 8.1 3.2

TABLE 2 LRs and Posttest Probabilities of UTI for Febrile Infant Boys According to Number ofFindings Present

No. of Risk Factors LR Posttest Probability, %

All Boys Uncircumcised Circumcised

0 0.34 0.8 2.1 0.21 0.69 1.5 4.1 0.52 1.37 3.0 7.9 1.03 2.74 5.8 14.7 1.94 5.49 11.0 25.6 3.7

Risk factors: temperature above 39C, fever for more than 24 hours, no apparent fever source, and nonblack race.



and do not appear ill. The LR is calcu-lated as LR (1.4)p (0.7)n, where pis the number of positive ndings andn is the number of negative ndings.This assumes that the clinician has as-sessed all 4 risk factors. It should benoted that, for uncircumcised boys,the risk of UTI never decreases below2%. For circumcised boys, the proba-bility exceeds 1% if there are 2 ormorerisk factors.

Other studies have shown that thepresence of another, clinically obvioussource of infection,13 particularly doc-umented viral infections,14 such as re-spiratory syncytial virus infections,15

reduces the risk of UTI by one-half. In aseries of studies conducted by Gore-lick, Shaw, and others,9,16,17 male gen-der, black race, and no history of UTIwere all found to reduce the risk. Theauthors derived a prediction rule spe-cically for girls, with 95% sensitivityand 31% specicity. In a subsequentvalidation study, they conrmed thatthese ndings had predictive power,but the validation study used aweaker,retrospective, case-control design,compared with the more-robust, pro-spective, cohort design of the originalderivation study. On the basis of theearlier cohort study and starting witha baseline risk of 5%, a child scoringlow on the prediction rule wouldhave a slightly less than 1% risk ofUTI. To score this low on the predic-tion rule, a young girl would have toexhibit no more than 1 of the follow-ing features: less than 12 months of

age, white race, temperature ofmore than 39C, fever for at least 2days, or absence of another sourceof infection.

However, those authors evaluatedtheir decision rule with several differ-ent cutoff points, to determine thescore below which the risk of UTI de-creased below a test threshold of 1%.Unfortunately, the published articledid not include the set of negative LRsneeded to reproduce the posteriorprobabilities.17 However, it was possi-ble to approximate them through ex-trapolation from the receiver operat-ing characteristic curve presented. Onthe basis of these estimated negativeLRs and the positive LRs provided inthe article,17 Table 3 was derived. Foreach cutoff value in the number of riskfactors, Table 3 shows the posteriorprobability for children with fewer thanthat number of risk factors (below thecutoff value) and for those with thatnumber of risk factors or more. There-fore, the posttest probability is not therisk of UTI for children with exactly that

number of risk factors. Similar resultscould be derived from the validationstudy and are shown in Table 4. How-ever, because the second study had aweaker design, the values in Table 3are more reliable.

These studies provide criteria forpractical decision rules that clini-cians can use to select patients whoneed urine samples for analysisand/or culture. They do not establisha threshold or maximal risk of UTIabove which a urine sample isneeded. However, in surveys of pedi-atricians, Roberts et al18 found thatonly 10% of clinicians thought that aurine culture is indicated if the prob-ability of UTI is less than 1%. In addi-tion, the cost-effectiveness analysispublished in the 1999 technical re-port set a threshold of 1%. However,circumstances such as risk of loss tofollow-up monitoring or other clini-cian concerns may shift this thresh-old up or down.

TABLE 3 LRs and Posttest Probabilities of UTI for Febrile Infant Girls According to Number ofFindings Present (Prospective Original Study)

Cutoff Value, No.of Factors

LR Posttest Probability, %

Positive Negative(Approximate)

BelowCutoff Value

At or AboveCutoff Value

1 1.04 0.20 0.8 5.12 1.35 0.17 0.8 6.53 2.5 0.42 2.1 11.44 9.4 0.79 3.9 33.05 15.8 0.95 4.7 45.0

Risk factors: less than 12 months of age, white race, temperature 39C, fever for at least 2 days, and absence of anothersource of infection.

TABLE 4 LRs and Posttest Probabilities of UTIfor Febrile Infant Girls According toNumber of Findings Present(Retrospective Validation Study)

No. ofFindings

LR PosttestProbability, %

0 or 1 1.02 0.82 1.10 0.93 1.26 1.04 3.04 2.45 2.13 1.7

Risk factors: less than 12 months of age, white race, tem-perature 39C, fever for at least 2 days, and absence ofanother source of infection.

TABLE 5 List of Test Characteristics of Diagnostic Tests for UTI Reported in 1999 Technical Report2

Test Sensitivity, % Specicity, %

Range Median Mean Range Median Mean

Leukocyte esterase test 6794 84 83 6492 77 78Nitrite test 1582 58 53 90100 99 98Blood assessment 2564 53 47 6089 85 78Protein assessment 4055 53 50 6784 77 76Microscopy, leukocytes 32100 78 73 4598 87 81Microscopy, bacteria 1699 88 81 11100 93 83Leukocyte esterase or nitrite test 90100 92 93 5891 70 72Any positive test results in urinalysis 99100 100 99.8 6092 63 70


Box 2: Diagnostic Tests for UTI

The 1999 technical report reviewed alarge number of studies that de-scribed diagnostic tests for UTI. The re-sults are summarized in Table 5. Thisupdated review of the literaturelargely reinforced the ndings of theoriginal technical report.

More-recent work compared micros-copy, including the use of hemocytom-eters and counting chambers (en-hanced urinalysis), with routineurinalysis or dipslide reagents (Table6). Lockhart et al19 found that the ob-servation of any visible bacteria in anuncentrifuged, Gram-stained, urinesample had better sensitivity andspecicity than did combined dipslideleukocyte esterase and nitrite test re-sults. Hoberman et al7 in 1996 andShaw et al20 in 1998 both evaluated en-hanced urinalysis, consisting of morethan 10 white blood cells in a countingchamber or any bacteria seen in 10 oilemersion elds; they found sensitivityof 94% to 96% and specicity of 84%to 93%. In 2000, Lin et al21 found thata count of at least 10 white bloodcells per L in a hemocytometer wasless sensitive (83%) but quite spe-cic (89%). Given the sensitivity ofenhanced urinalysis, the probabilityof UTI for a typical febrile infant witha previous likelihood of UTI of 5%would be reduced to 0.2% to 0.4%with negative enhanced urinalysisresults.

Obtaining a Urine Sample

In the UTI practice parameters from1999, the subcommittee dened thegold standard of a UTI to be growth ofbacteria on a culture of urine obtainedthrough suprapubic aspiration (SPA).In the previous technical report, SPAwas reported to have success ratesranging from 23% to 90%,2224 althoughhigher success rates have beenachievedwhen SPA is conducted underultrasonographic guidance.25,26 SPA isconsidered more invasive than cathe-terization and, in RCTs from 200627 and2010,28 pain scores associated withSPA were signicantly higher thanthose associated with catheterization.This result was found for both boysand girls. Similar to previous studies,these RCTs also revealed lower suc-cess rates for SPA (66% and 60%),compared with catheterization (83%and 78%).27,28 In comparison with SPAresults, cultures of urine specimensobtained through catheterization are95% sensitive and 99% specic.7,11,12

Cultures of bag specimens are difcultto interpret. In the original technicalreport, sensitivity was assumed to be100%but the specicity of bag cultureswas shown to range between 14% and84%.2 Our updated surveillance of theliterature did not show that these num-bers have improved.2933 One articlesuggested that a new type of collectionbag may result in improved specicity,34

but that study was not controlled. With aprevalence of 5% and specicity of 70%,

the positive predictive value of a positiveculture result for urine obtained in a bagwouldbe15%. Thismeans that, of all pos-itive culture results for urine obtained ina bag, 85% would be false-positiveresults.

Box 3: Short-term Treatment of UTIs

General Principles of Treatment

Published evidence regarding the short-term treatment of UTIs supports 4 mainpoints. First, complications, such as bac-teremia or renal scarring, are suf-ciently common to necessitate early,thorough treatment of febrile UTIs in in-fants.35 Second, treatmentwith orally ad-ministered antimicrobial agents is as ef-fective as parenteral therapy.36,37 Third,bacterial sensitivity to antimicrobialagents is highly variable across timeandgeographic areas, which suggests thattherapy should be guided initially by lo-cal sensitivity patterns and should be ad-justed on the basis of sensitivities ofisolated pathogens.38,39 Fourth, meta-analyses have suggested that shorterdurations of oral therapymay not have adisadvantage over longer courses forUTIs. However, those studies largely ex-cluded febrile UTI and pyelonephritis.40

Experimental and Clinical DataSupport the Concept That Delays inthe Institution of AppropriateTreatment for Pyelonephritis Increasethe Risk of Renal Damage

The 1999 technical report cited evi-dence that febrile UTIs in children less

TABLE 6 Test Characteristics of Laboratory Tests for UTI in Children

Study Test Population n Sensitivity, % Specicity, %

Lockhart et al19 (1995) Leukocyte esterase or nitrite test resultspositive

Prospective sample,6 mo ofage, ED

207 67 79

Any bacteria with Gram-stainingHoberman et al7 (1996) 10 white blood cells per counting chamber

or any bacteria per 10 oil emersion elds2 y of age, 95% febrile, ED 4253 96 93

Shaw et al9 (1998) Enhanced urinalysis Infants12 mo of age and girls2 y of age,38.5C, ED

3873 94 84Dipslide or standard urinalysis 83 87

Lin et al20 (2000) Hemocytometer,10 cells per L Systematic review, febrile infantshospitalized, febrile UTI

NA 83 89

ED indicates emergency department; NA, not applicable.



than 2 years of age are associated withbacterial sepsis in 10% of cases.35 Fur-thermore, renal scarring is commonamong children who have febrile UTIs.The risk is higher among those withhigher grades of VUR41 but occurs withall grades, even when there is no VUR.Although it was not conrmed in allstudies,42,43 older work2 and newerstudies44 demonstrated an increasedrisk of scarring with delayed treat-ment. Children whose treatment is de-layed more than 48 hours after onsetof fever may have a more than 50%higher risk of acquiring a renal scar.

Oral Versus Intravenous Therapy

In a RCT from 1999, Hoberman et al36

studied children 1 to 24 months of agewith febrile UTIs. They compared 14days of oral cexime treatment with 3days of intravenous cefotaxime treat-ment followed by oral cexime treat-ment to complete a 14-day course. Theinvestigators found no difference inoutcomes between children who weretreated with an orally administered,third-generation cephalosporin aloneand those who received intravenoustreatment.

In a Cochrane review, Hodson et al37

evaluated studies with children 0 to 18years of age, examining oral versus in-travenous therapy. No signicant dif-ferences were found in duration of fe-ver (2 studies; mean difference: 2.05hours [95% CI:0.84 to 4.94 hours]) or

renal parenchymal damage at 6 to 12months (3 studies; RR: 0.80 [95% CI:0.501.26]) between oral antimicro-bial therapy (1014 days) and intrave-nous antimicrobial treatment (3 days)followed by oral antimicrobial treat-ment (11 days).

Duration of Therapy

In the 1999 technical report, dataslightly favoring longer-duration (710days) over shorter-duration (1 dose to3 days) antimicrobial therapy for pedi-atric patients with UTIs were pre-sented.2 Since then, several meta-analyses with different conclusionshave been published on this topic.40,45,46

A 2003 Cochrane review addressingthe question analyzed studies that ex-amined the difference in rates of re-currence for positive urine cultures af-ter treatment.40 It compared short(24 days) and standard (714 days)duration of treatment for UTIs andfound no signicant difference in thefrequency of bacteriuria after comple-tion of treatment (8 studies; RR: 1.06[95% CI: 0.641.76]). Although the au-thors of the review did not excludestudies of children with febrile UTIs orpyelonephritis, each individual studyincluded in the meta-analysis had al-ready excluded such children. To date,there are no conclusive data on the du-ration of therapy for children with fe-brile UTIs or pyelonephritis.

Proof of Cure

Data supporting routine repeat culturesof urineduringor after completionof an-timicrobial therapy were not availablefor the 1999 technical report. Retrospec-tive studies did not show proof of bacte-riologic cure cultures to be bene-cial.47,48 Studies demonstrating thatclinical response alone ensures bacteri-ologic cure are not available.

Box 4: Evaluation and Managementof Urinary Tract Abnormalities

Prevalence of VUR

Several cohort studies published sincethe 1999 technical report provide esti-mates of the prevalence of VUR of var-ious grades among infants and chil-dren with UTIs (Table 7). Overall, theseestimates are reasonably consistentwith those reported in earlier studies,although the grades of reux are nowreported more consistently, by usingthe international system of radio-graphic grading of VUR.49

The prevalence of VUR among childrenin these studies varies between 18%and 35%. The weighted average preva-lence is 34%, but this is largely drivenby the enormous retrospective studyby Chand et al.56 Most studies report arate of 24% or less, which is less thanthe estimate of VUR prevalence in the1999 technical report.

Data on the prevalence of VUR amongchildrenwithout a history of UTI do not

TABLE 7 Recent Studies Documenting the Prevalence of VUR Among Children With UTI

Study Description n Prevalence, %

Sargent and Stringer50 (1995) Retrospective study of rst VCUG for UTI in children 1 wk to 15 y of age 309 30Craig et al51 (1997) Cross-sectional study of children5 y of age with rst UTI 272 28McDonald et al52 (2000) Retrospective chart review of children with VCUG after UTI 176 19Oostenbrink et al53 (2000) Cross-sectional study of children5 y of age with rst UTI 140 26Mahant et al54 (2001) Retrospective chart review of children with VCUG after UTI 162 22Mahant et al55 (2002) Retrospective review of VCUG in children5 y of age admitted with rst UTI 162 22Chand et al56 (2003) Retrospective review of VCUG or radionuclide cystogram in children7 y of age 15 504 35Fernandez-Menendez et al44 (2003) Prospective cohort study of 158 children5 y of age (85% 2 y) with rst UTI 158 22Camacho et al41 (2004) Prospective cohort study of children 1 mo to 12 y of age (mean age: 20 mo) with

rst febrile UTI152 21

Hansson et al57 (2004) Retrospective cross-sectional study of children2 y of age with rst UTI 303 26Pinto58 (2004) Retrospective chart review of rst VCUG for UTI in children 1 mo to 14 y of age 341 30Zamir et al59 (2004) Cohort study of children 05 y of age hospitalized with rst UTI 255 18


exist. Using a retrospective approachand existing urine culture data, Han-nula and Ventola and colleagues,60,61 in2 separate publications, found similarrates of prevalence of any grade of VURamong children with proven (37.4%) orcertain (36%) UTI versus false (34.8%) orimprobable (36%)UTI. These results sug-gest that VUR is prevalent even amongchildren without a history of UTI.

The prevalence of VUR decreases withage. This was approximated by analy-sis across studies in the 1999 technicalreport. Since then, Chand et al56 re-ported the prevalence VUR within agesubstrata of their cohort. Figure 3shows the prevalence of VUR plotted asa function of the midpoint of each agestratum.

Seven studies reported the preva-lence of different grades of reux, byusing the international grading sys-tem.41,44,51,56,57,62,63 The distributions ofdifferent reux grades among childrenwho had VUR are shown in Fig 4. Thereis signicant variability in the relative

predominance of each reux grade,but grades II and III consistently arethe most common. With the exceptionof the study by Camacho et al,41 allstudies showed grades IV and V to bethe least frequent, and grade V ac-counted for 0% to 5% (weighted aver-age: 3%) of reux. With that value mul-tiplied by the prevalence of VUR amongyoung children with a rst UTI, we

would expect grade V reux to be pres-ent in1% of children with a rst UTI.

It has been suggested that the risk ofVUR and, more specically, high-grade VUR may be higher for chil-dren with recurrent UTI than for chil-dren with a rst UTI. Although it wasnot tested directly in the studies re-viewed, this idea can be tested andthe magnitude of the effect can beestimated from the data found in theliterature search for this meta-anal-ysis.6470 These data clearly demon-strate that the risk of UTI recurrence isassociated with VUR (Fig 5). Further-more, this relationship allows the like-lihood of each grade of reux (giventhat a UTI recurrence has occurred) tobe estimated by using Bayes theorem,as follows:

p(VURi|UTI)

p(UTI|VURi) p(VURi)

i0

V p(UTI|VURi) p(VURi),

where p(UTI|VURi) refers to the proba-bility of VUR of grade i given the recur-rence of UTI. If it is assumed that theconditional probabilities remain thesame with second or third UTIs, thenBayes theorem can be reapplied for athird UTI as well.

By using estimates of p(UTI VUR) (Fig 5)and the previously determined distri-

FIGURE 3Prevalence of VUR as a function of the midpoint of each age stratum, as reported by Chand et al.56

FIGURE 4Distribution of reux grades among children with VUR.41,44,51,56,57,62,63

FIGURE 5Probability of a recurrent febrile UTI as a function of VUR grade among infants 2 to 24 months of agein the control groups of the studies included in meta-analyses.64,6670



butions of VUR grades (Fig 4), a veryapproximate estimate of the distribu-tion of VUR grades after the rst, sec-ond, and third UTI can be made (Fig 6).The likelihood that there is no VUR de-creases rapidly. Conversely, the likeli-hood of VUR grades III to V increasesrapidly. The risk of grades I and IIchanges little.

Ultrasonography

Ultrasonography is used as a noninva-sive technique to identify renal abnor-malities in children after UTI. The sensi-tivity of the test varies greatly and hasbeen reported to be as low as 5% fordetection of renal scarring7173 and 10%for detection of VUR.74 However, moststudies report moderate specicity.

One possible reason for a decrease inspecicity is that, in animal models,Escherichia coli endotoxin has beenshown to produce temporary dilationof the urinary tract during acute infec-tion.75 Therefore, use of routine ultra-sonography for children with UTIs dur-ing acute infection may increase thefalse-positive rate. However, no humandata are available to conrm thishypothesis.

Ultrasonography is used during acuteinfection to identify renal or perirenalabscesses or pyonephrosis in childrenwho fail to experience clinical improve-ment despite antimicrobial therapy.The sensitivity of ultrasonography forsuch complications is thought to be

very high, approaching 100%.76 There-fore, ultrasonography in the case of achild with a UTI who is not respondingto therapy as expected can be veryhelpful in ruling out these infectiouscomplications.

Ultrasonography also is advocated forscreening for renal abnormalitiessuch as hydronephrosis, suggestingposterior urethral valves, ureteropel-vic junction obstruction, or ureteroce-les. The evidence model illustrates theexpected outcomes from routine ultra-sonography of the kidneys, ureters,and bladder after the rst febrile UTI ininfants and young children (Fig 7). Themodel is based on the study resultsdocumented in Tables 8 and 9 and astrategy of performing kidney andbladder ultrasonography for all in-fants with UTIs. The numbers are notexact for 2 reasons, namely, (1) studypopulations vary and do not alwayspreciselymeet the denitions of 2 to 24months of age and febrile without an-

other fever source and, (2) even withinsimilar populations, reported ratesvary widely.

Ultrasonography yields15% positiveresults. However, it has a70% false-negative rate for reux, scarring, andother abnormalities. Limited data existregarding the false-negative rate forhigh-grade VUR (grade IV and V), butthe studies reviewed presented 0% to40% false-negative rates for detectionof grade IV reux through ultrasonog-raphy.59,74 Among the 15% of resultsthat are positive, between 1% and 24%are false-positive results. Of the true-positive results, 40% representsome dilation of the collecting system,such aswould be found on a VCUG; 10%represent abnormalities that are po-tentially surgically correctable (eg,ureteroceles or ureteropelvic junctionobstruction). Approximately one-halfrepresent ndings such as horseshoekidneys or renal scarring, for whichthere is no intervention but whichmight lead to further evaluations, suchas technetium-99mlabeled dimercap-tosuccinic acid renal scintigraphy. The40% with dilation of the collectingsystem are problematic. This repre-sents only a small fraction of children(15% 88% 40% 5%) with rstUTIs who would be expected to haveVUR before ultrasonography. Ultra-sonography does not seem to be en-riching for this population (althoughultrasonography might identify a pop-ulation with higher-grade VUR).

FIGURE 6Distribution of VUR grades after different numbers of UTIs.

FIGURE 7Evidence model for ultrasonography after a rst UTI.


Prenatal Ultrasonography

Urinary tract abnormalities also maybe identied during prenatal ultra-sonography,8587 which theoreticallywould decrease the number of new ab-normalities found through later ultra-sonography.81 However, the extent towhich normal prenatal ultrasono-graphic ndings decrease the need forlater studies remains in doubt.

Miron et al88 studied 209 children whounderwent ultrasonography prena-tally and again after a UTI. They foundthat, among 9 children with abnormalultrasonographic results after UTI, 7 hadnormal prenatal ultrasonographic re-sults. These cases included 3 cases ofhydronephrosis, 3 cases of moderate di-lation, and 1 case of double collectingsystem. Similarly, in a study by Lakhoo etal89 in 1996, 22 of 39 children with UTIshad normal prenatal ultrasonographicresults but abnormal post-UTI ultra-sonographic results; the abnormalities

were not described. These studies sug-gest that normal prenatal ultrasono-graphic ndingsmay not be sufcient toobviate the need for additional studies ifa UTI occurs in infancy.

Results of Targeted LiteratureReview and Meta-analysis onProphylaxis to Prevent RecurrentUTI

Study Identication

For the meta-analysis of studies on theeffectiveness of antimicrobial agents toprevent recurrent UTI in children withVUR, we reviewed a total of 213 titlesfrom our primary literature search. Ofthose, 45 were retained for abstract re-view on the basis of the title, of which 7were selected for full review. Six of thestudiesmet the inclusion criteria. Figure2 summarizes the selection process.

Thirty-eight abstracts were excludedbefore full review (Fig 2). Eight of those

studies were RCTs comparing prophy-lactic antimicrobial agent use withsome type of surgical intervention.None of those studies included a pla-cebo arm.9097 One study compared dif-ferent lengths of antimicrobial prophy-laxis.98 Another study compareddifferent antimicrobial regimens butdid not include a placebo arm.99 Six-teen studies were determined, oncloser inspection, to be not clinicaltrials but prospective cohort studies,reviews, systematic reviews, ormeta-analyses. Twelve studies werefound twice, either in Medline or Em-base and the Cochrane Clinical TrialsRegistry.

One article was excluded after full re-view (Fig 2). That study compared pro-phylactic antimicrobial agent use withprobiotic use.65 The study was not in-cluded in the meta-analysis, but the re-sults are described separately.

There are RCTs of antimicrobial pro-phylaxis that are older than 15 years.In 4 studies from the 1970s, a total of179 children were enrolled.100103

Less than 20% of those children hadVUR. Because of limited reporting ofresults in that subgroup, those olderstudies were not included in theanalyses.

Two additional RCTs comparing antimi-crobial prophylaxis and placebo treat-ment for children were published inOctober 2009.69,70 The rst trial en-rolled children 0 to 18 years of age af-ter a rst UTI, with 2% of enrolled chil-dren (12 of 576 children) being morethan 10 years of age. The second trialenrolled children diagnosed as havingVUR after a rst UTI (194 [96%] of 203children) or after prenatal ultrasonog-raphy (9 [4%] of 203 children), whowere then assigned randomly to re-ceive antimicrobial prophylaxis, sur-veillance, or endoscopic therapy, at 1to 2 years of age. The majority of thesechildren (132 children [65%]) hadbeen diagnosed as having VUR before 1

TABLE 8 Summary of Ultrasonography Literature

Study n/N (%) Comments

False-negative rateScarringSmellie et al73 (1995) 7/20 (35)Barry et al77 (1998) 23/170 (14)Moorthy et al71 (2004) 219/231 (95)Sinha et al78 (2007) 61/79 (77) Reported as renal unitsMontini et al79 (2009) 33/45 (73)

VURSmellie et al73 (1995) 21/36 (58)Mahant et al55 (2002) 14/35 (40)Hoberman et al74 (2003) 104/117 (90)Zamir et al59 (2004) 38/47 (81)Montini et al79 (2009) 48/66 (73)

OtherSmellie et al74 (1995) 5/5 (100) Duplex kidney

False-positive rateScarringBarry et al77 (1998) 11/478 (2)Moorthy et al71 (2004) 12/699 (1.7)Sinha et al78 (2007) 9/870 (1)Monitini et al79 (2009) 26/255 (10)

VURSmellie et al73 (1995) 2/12 (17) Normal VCUG, DMSA, and IVU resultsMahant et al55 (2002) 30/127 (24)Hoberman et al74 (2003) 17/185 (10)Zamir et al59 (2004) 27/208 (13)

OtherGiorgi et al80 (2005) 21/203 (10)

IVU indicates intravenous urography; DMSA, dimercaptosuccinic acid.



year of age and thus had been receiv-ing prophylaxis before random assign-ment. These studies were included inthe meta-analysis.

Description of Included Studies

Table 10 presents characteristics ofthe 8 included studies.64,6670,104,105 Fourstudies enrolled children after diagno-sis of a rst episode of pyelonephri-tis.64,6668 In those 4 studies, pyelone-phritis was described as fever of morethan 38C or 38.5C and positive urineculture results. In 1 of those studies,67

dimercaptosuccinic acid scanning re-sults consistent with acute pyelone-phritis represented an additionalrequirement for inclusion. The remain-ing studies had slightly different inclu-sion criteria. In the study by Craig etal71 from 2009, symptoms consistentwith UTI and positive urine culture re-sults were required for inclusion. Fe-ver was documented for 79% of en-rolled children (454 of 576 children). Inthe study by Brandstrm et al,70 96% ofenrolled children (194 of 203 children)had pyelonephritis, dened in a similarmanner as in the 6 initial studies. Theremaining patients were enrolled af-ter prenatal diagnosis of VUR. The 2included abstracts described studiesthat enrolled any child with VUR andnot only children who had had pyelone-phritis.104,105 Seven of the 8 studies (allexcept the study by Reddy et al108) re-ported a gender ratio. Among thosestudies, there were 67% girls and 33%boys. Six studies compared antimicro-bial treatment with no treatment. Only2 studies were placebo controlled, andthose 2 were the only blinded stud-ies.69,105 The grade of VUR among theenrolled children varied from 0 to V,but few of the children had grade VVUR.

The ages of children included in theinitial meta-analyses were 0 to 18years; therefore, some children wereincluded who were outside the target

TABLE 9 Distribution of Positive Ultrasonographic Findings

Study n/N (%)

Alon and Ganapathy62 (1999) 19/124 (15)Minimal unilateral changesVUR 2 (1.6)Normal VCUG ndings 2 (1.6)Resolved on repeat study 2 (1.6)Not monitored further 3 (2.4)

Major changes 8 (6.5)VUR 1 (1.6)Normal ndings 1 (1.6)Posterior urethral valve 1 (1.6)Hydroureternephrosis 1 (1.6)

Gelfand et al81 (2000) 141/844 (16.7)Bladder wall thickening 31 (3.7)Hydroureter 6 (0.7)Parenchymal abnormalities 42 (5.0)Pelvocalyceal dilation 27 (3.2)Renal calculus 1 (0.1)Simple renal cyst 1 (0.1)Urethelial thickening 31 (3.7)

Jothilakshmi et al82 (2001) 42/262 (16)Duplex kidney 3 (1)Crossed renal ectopia 1 (0.38)Horseshoe kidney 1 (0.38)Hydronephrosis 5 (1.9)Megaureter 6 (2.3)Polycystic kidney 1 (0.38)Pelviureteric junction obstruction 1 (0.38)Posterior urethral valve 2 (0.76)Renal calculus 3 (0.01)Rotated kidney 2 (0.76)Ureterocele 2 (0.76)VUR 7 (2.7)

Hoberman et al74 (2003) 37/309 (12)Dilated pelvis 13 (4.2)Pelvocaliectasis 12 (3.9)Hydronephrosis 2 (0.6)Dilated ureter 9 (2.9)Double collecting system 3 (1.0)Extrarenal pelvis 1 (0.3)Calculus 1 (0.3)

Zamir et al59 (2004) 36/255 (14.1)Mild unilateral pelvis dilation 32 (12.5)Moderate unilateral pelvis dilation 1 (0.04)Enlargement kidney 1 (0.04)Small renal cyst 1 (0.04)Double collecting system and severe hydronephrosis 1 (0.04)

Jahnukainen et al83 (2006)a 23/155 (14.8)Hydronephrosis 8 (5)Double collecting system 11 (7)Multicystic dysplasia 1 (0.6)Renal hypoplasia 1 (0.6)Solitary kidney 1 (0.6)Horseshoe kidney 1 (0.6)

Huang et al84 (2008) 112/390 (28.7)Nephromegaly 46 (11.8)Isolated hydronephrosis 20 (5.1)Intermittent hydronephrosis 3 (0.8)Hydroureter 8 (2.1)Hydroureter and hydronephrosis 3 (0.8)Thickened bladder wall 11 (2.8)Small kidneys 8 (2.1)Simple ureterocele 5 (1.3)Double collecting systems 4 (1.0)Increased echogenicity 3 (0.8)Horseshoe kidney 1 (0.3)

Montini et al79 (2009) 38/300 (13)Dilated pelvis, ureter, or pelvis and calyces 12 (4)Renal swelling or local parenchymal changes 10 (3.3)Increased bladder wall or pelvic mucosa, thickness 6 (2)Other 10 (3.3)

a Hospitalized children with UTI.


age range for this report and forwhomother factors (eg, voiding and bowelhabits) might have played a role. Themedian age of the included children,however, was not above 3 years in anyof the included studies in which it wasreported. Separate meta-analyseswere subsequently performed for thesubgroup of children who were 2 to 24months of age. The duration of antimi-crobial treatment and follow-up moni-toring ranged from 12 to 48 months.The antimicrobial agents used weretrimethoprim-sulfamethoxazole (12or 510 mg/kg),64,68,69,105 trimethoprim-sulfamethoxazole or amoxicillin-clavulanicacid (15 mg/kg),66 trimethoprim-sulfamethoxazole or nitrofurantoin,67,104 ortrimethoprim-sulfamethoxazole, ce-fadroxil, or nitrofurantoin.70 Urine col-lection methods differed among stud-ies. Bag specimens were reported for3 studies.64,66,70 In an additional 4 stud-ies, the description of the urine collec-tionmethods did not exclude the use ofbag specimens.67,68,104,105 Recurrent UTIwas described as (1) asymptomatic bac-teriuria (diagnosed through screeningcultures), (2) cystitis, (3) febrile UTI, and(4) pyelonephritis (diagnosed on the ba-sis of focal or diffuse uptake on di-

mercaptosuccinic acid scans) in the dif-ferent articles.

Quality Assessment

The included studies received scores(from 2 assessors) from 7 to 26 (scalerange: 032)with the scoring systemde-scribed by Downs and Black,6 with a me-dian score of 16. Score deductions re-sulted from lack of blinding of patients(all except 2 studies69,105), lack of blindingof assessors (all except 2 studies69,105),limited or no information about patientslost to follow-up monitoring (3 stud-ies64,67,104), lack of reporting of adverseeffects (all except 2 studies66,69), andsmall sample sizes. The lowest scores, 7and 12, were received by the 2 abstractsbecause of lack of details in the descrip-tions of the methods.104,105

Antimicrobial Therapy Versus NoTreatment

Overview of FindingsDescribed here are the results of

several meta-analyses, subdivided ac-cording to type of recurrence (pyelo-nephritis versus UTI), degree of VUR(none to grade V), and patient age. Insummary, antimicrobial prophylaxisdoesnot seemto reducesignicantly the

rates of recurrenceof pyelonephritis, re-gardless of age or degree of reux. Al-though prophylaxis seems to reduce sig-nicantly but only slightly the risk of UTIwhen all formsare included,most of thiseffect is attributable to reductions inrates of cystitis or asymptomatic bacte-riuria, which would not be expected tolead to ongoing renal damage.

Recurrence of Pyelonephritis/FebrileUTI Among All Studied Children WithVUR of Any GradeRecurrence of pyelonephritis was

reported in 6 of the 8 studies. The studyby Pennesi et al68 presented the resultsas recurrence of pyelonephritis, butrecurrence was dened as episodes offever or symptoms of UTI. When con-tacted, this author conrmed that allreported recurrences were charac-terized by fever above 38.5C. There-fore, the article was included in themeta-analysis. With a random-effectsmodel, there was no signicant dif-ference in rates of recurrence of py-elonephritis for children who re-ceived antimicrobial therapy andthose who did not. This meta-analysis yielded a RR of 0.77 (95% CI:0.471.24) (Fig 8). Heterogeneity test-

TABLE 10 Studies Included in Meta-analysis

Study Study Sites n Age VUR Grade Antimicrobial Agents Control Follow-upPeriod,mo

Outcome

VUR NoVUR

Craig et al105 (2002) Australia 46 0 03 mo IV TMP-SMX Placebo 36 UTI and renal damageCraig et al69 (2009) Australia 243 234 018 y IV TMP-SMX Placebo 12 Symptomatic UTI, febrile UTI,

hospitalization, and renalscarring

Garin et al67 (2006) Chile, Spain,United States

113 105 3 mo to 18 y 0III TMP-SMX/nitrofurantoin

No treatment 12 Asymptomatic UTI, cystitis,pyelonephritis, and renalscarring

Brandstrm et al70

(2010)Sweden 203 0 12 y IIIIV TMP-SMX/cefadroxil,

nitrofurantoinNo treatment 48 Febrile UTI, reux status,

and renal scarringMontini et al66 (2008) Italy 128 210 2 mo to 7 y 0III TMP-SMX/amoxicillin-

clavulanateNo treatment 12 Febrile UTI and renal

scarringPennesi et al68 (2008) Italy 100 0 030 mo IIIV TMP-SMX No treatment 48 UTI and renal scarringReddy et al104 (1997) United States 29 0 110 y IV TMP-SMX/

nitrofurantoinNo treatment 24 UTI, progression of disease,

need for surgery,parental compliance

Roussey-Kesler et al64

(2008)France 225 0 136 m IIII TMP-SMX No treatment 18 Febrile and afebrile UTI

TMP-SMX indicates trimethoprim-sulfamethoxazole.



ing results were signicant (P .04),which indicated statistical heteroge-neity between studies.

Recurrence of Pyelonephritis/Febrile UTI Among Children of AllAges Without VURThere was no signicant difference

in rates of recurrence of pyelonephri-tis for children without VUR who re-ceived antimicrobial therapy andthosewho did not. With random-effectsmodeling, the meta-analysis yielded aRR of 0.62 (95% CI: 0.301.27) (Fig 9).Heterogeneity testing results were notsignicant (P .39). Because no dif-ference was detected with a random-effects model and there was no statis-tical heterogeneity in this analysis,analysis also was conducted with axed-effects model. With xed-effectsmodeling, the meta-analysis yielded aRR of 0.61 (95% CI: 0.311.23).

Recurrence of Pyelonephritis/FebrileUTI Among Children of All Ages WithVUR, According to GradeTable 11 summarizes the results of

separate meta-analyses of subpopula-

tions from each study with differentgrades of VUR. None of those analysesshowed a statistically signicant dif-ference in rates of recurrence withrandom- or xed-effects modeling.Random-effects modeling results arepresented.

Recurrence of Pyelonephritis/FebrileUTI Among Children 2 to 24 Months ofAge With VUR of Any Grade

There was no signicant differ-ence in rates of recurrence of pyelo-nephritis for children 2 to 24 monthsof age with VUR who received antimi-crobial agents and those who didnot. With random-effects modeling,the meta-analysis yielded a RR of 0.78

(95% CI: 0.48 1.26) (Fig 10). Hetero-geneity testing results were not signif-icant (P .07). With xed-effects mod-eling, the meta-analysis yielded a RR of0.79 (95% CI: 0.581.07). Heterogeneitytesting results were not signicant(P .07).

Recurrence of Pyelonephritis/FebrileUTI Among Children 2 to 24 Months ofAge With No VURThere was no signicant difference

in rates of recurrence of pyelonephri-tis for children 2 to 24 months of agewithout VUR who received antimicro-bial agents and those who did not. Withrandom-effects modeling, the meta-analysis yielded a RR of 0.55 (95% CI:

FIGURE 8Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children with VUR, from random-effects modeling. RRs and95% CIs are shown. M-H indicates Mantel-Haenszel.

FIGURE 9Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children without VUR, from random-effects modeling. RRsand 95% CIs are shown. M-H indicates Mantel-Haenszel.

TABLE 11 Combined Estimates of Effect of Antimicrobial Prophylaxis on Prevention ofPyelonephritis for All Children According to Grade of VUR

VUR Grade No. of Children No. of Studies RR (95% CI)a

0 549 3 0.62 (0.301.27)III 455 5 0.94 (0.491.80)III 347 6 0.74 (0.421.29)IV 122 3 0.69 (0.391.20)V 5 1 0.40 (0.081.90)

a From random-effects model.


0.152.08) (Fig 11). Heterogeneity test-ing results were not signicant (P .25). With xed-effects modeling, themeta-analysis yielded a RR of 0.48 (95%CI: 0.181.27). Heterogeneity testingresults were not signicant (P .25).

Recurrence of Pyelonephritis/FebrileUTI Among Children 2 to 24 Months ofAge According to Grade of VURWhen results were analyzed ac-

cording to VUR grade, therewas no sig-nicant difference in rates of recur-rence of pyelonephritis for children 2to 24 months of age who received anti-microbial agents and those who didnot in any of the analyses, with

random- or xed-effects modeling. Re-sults of random-effects modeling arepresented in Figs 12 through 16. Heter-ogeneity testing results were not sig-nicant in any of the analyses.

Recurrence of Any Type of UTI AmongChildren of All AgesWith VUR of Any GradeIn this meta-analysis, in which the 2

published abstracts that never re-sulted in published articles were in-cluded, there was a statistically signif-icant difference in rates of recurrenceof any type of UTI for children with VURwho received antimicrobial agents andthosewho did not. With random-effectsmodeling, the meta-analysis yielded a

RR of 0.70 (95% CI: 0.510.96) (Fig 17).Heterogeneity testing results were notsignicant (P .20).The inclusion of the published ab-

stracts104,105 in these meta-analysescan be criticized, because the investi-gators in those studies enrolled allchildren with VUR and not just thosewho had been diagnosed as having UTI;therefore, recurrent UTIs were not mea-sured. With exclusion of the 2 abstractsfromthemeta-analyses forpreventionofanyUTI, the RRwith random-effectsmod-eling would be 0.73 (95% CI: 0.531.01).Heterogeneity testing results were notsignicant (P .16).

FIGURE 10Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age with any grade of VUR, fromrandom-effects modeling. RRs and 95% CIs are shown. M-H indicates Mantel-Haenszel.

FIGURE 11Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age without VUR, fromrandom-effects modeling. RRs and 95% CIs are shown. M-H indicates Mantel-Haenszel.

FIGURE 12Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age with grade I VUR, fromrandom-effects modeling. RRs and 95% CIs are shown. M-H indicates Mantel-Haenszel.



Recurrence of Any Type of UTIAmong Children of All Ages WithoutVURThere was no signicant difference

in rates of recurrence of any type of UTIfor children without VUR who received

antimicrobial agents and those whodid not. With random-effects modeling,the meta-analysis yielded a RR of 0.72(95% CI: 0.431.20) (Fig 18). Heteroge-neity testing results were not signi-cant (P .37).

Effect on Studies of Inclusion of BagSpecimensWith the exception of the study by

Craig et al,69 no studies reported thatbag urine specimens were excluded.The inclusion of such specimens might

FIGURE 13Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age with grade II VUR, fromrandom-effects modeling. RRs and 95% CIs are shown. M-H indicates Mantel-Haenszel.

FIGURE 14Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age with grade III VUR, fromrandom-effects modeling. RRs and 95% CIs are shown. M-H indicates Mantel-Haenszel.

FIGURE 15Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age with grade IV VUR, fromrandom-effects modeling. RRs and 95% CIs are shown. M-H indicates Mantel-Haenszel.

FIGURE 16Estimate of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age with grade V VUR, from random-effectsmodeling. RRs and 95% CIs are shown. M-H indicates Mantel-Haenszel.


have resulted in increased numbers offalse-positive urine culture results inboth the antimicrobial prophylaxis andcontrol groups, yielding a bias towardthe null hypothesis in those studies.

Results of Excluded Study

The study by Lee et al65 was excludedfrom the meta-analysis because itcompared antimicrobial prophylaxiswith probiotic treatment. A total of 120children 13 to 36 months of age with ahistory of UTI and VUR of grade I to Vwho had been receiving trimethoprim-sulfamethoxazole once daily for 1 yearwere again assessed for VUR; if VURpersisted, then children were as-signed randomly either to continue toreceive trimethoprim-sulfamethoxazole orto receive Lactobacillus acidophilustwice daily for 1 additional year. Thestudy showed no statistical differencein recurrent UTI rates between the 2groups during the second year offollow-up monitoring.

Antimicrobial Prophylaxis andAntimicrobial Resistance

The antimicrobial resistance patterns ofthe pathogens isolated during UTI recur-rences were assessed in 5 of the RCTsincluded in themeta-analyses.64,66,6870 Allauthors concluded that UTI recur-rences with antimicrobial-resistantbacteria were more common in thegroups of children assigned randomlyto receive antimicrobial prophylaxis. Inthe placebo/surveillance groups, theproportions of resistant bacteria rangedfrom 0% to 39%; in the antimicrobial pro-phylaxis groups, the proportions of resis-tant bacteria ranged from 53% to 100%.Theseresultsaresupportedbyotherstud-ies in which antimicrobial prophylaxis hasbeen shown to promote resistantorganisms.106,107

Surgical Intervention VersusAntimicrobial Prophylaxis

Data on the effectiveness of surgicalinterventions for VUR are quite limited.

To date, only 1 RCT has compared sur-gical intervention (only endoscopictherapy) for VUR with placebo treat-ment.70 In that study, there was a sta-tistically signicant difference in therates of recurrence of febrile UTI forgirls treated with endoscopic therapyand those under surveillance (10 of 43vs 24 of 42 girls; P .0014). No suchdifference was noted among boys, forwhom the results trended in the oppo-site direction (4 of 23 vs 1 of 26 boys). Ameta-analysis examined the outcomesof UTIs and febrile UTIs in children as-signed randomly to either reux cor-rection plus antimicrobial therapy orantimicrobial therapy alone.108 By 2years, the authors found no signicantreduction in the risk of UTI in the sur-gery plus antimicrobial therapy group,compared with the antimicrobialtherapy-only group (4 studies; RR: 1.07[95% CI: 0.552.09]). The frequency offebrile UTIs was reported in only 2studies. Children in the surgery plus

FIGURE 17Combined estimates of the effect of antimicrobial prophylaxis on prevention of any UTI in childrenwith any grade of VUR, from random-effectsmodeling. RRsand 95% CIs are shown. M-H indicates Mantel-Haenszel.

FIGURE 18Combined estimates of the effect of antimicrobial prophylaxis on prevention of any UTI in children without VUR, from random-effects modeling. RRs and 95%CIs are shown. M-H indicates Mantel-Haenszel.



antimicrobial therapy group had sig-nicantly fewer febrileUTIs thandidchil-dren in the antimicrobial therapy-onlygroup between 0 and 5 years after inter-vention (RR: 0.43 [95% CI: 0.270.70]). Al-though there may be some promise inendoscopic interventions for childrenwith VUR, to date there are insufcientdata to show whether and for whomsuch interventions may be helpful.

Long-term Consequences of VUR

The link between VUR discovered afterthe rst UTI and subsequent hyperten-sion and end-stage renal disease re-mains tenuous at best. There have beenno longitudinal studies monitoring chil-dren long enough to quantify these out-comes. Retrospective studies evaluatedhighly selected populations, and theirndings might not apply to otherwisehealthy children with a rst UTI.109112

Ecologic data from Australia demon-strated no changes in the rates of hy-pertension and renal failure since thewidespread introduction of antimicrobialprophylaxis and ureteric reimplantationsurgery for VUR in the 1960s.113

DISCUSSION

Review of the evidence regarding diag-nosis and management of UTIs in 2- to24-month-old children yields the fol-lowing. First, the prevalence of UTI infebrile infants remains about thesame, at 5%. Studies have provideddemographic features (age, race, andgender) and clinical characteristics(height and duration of fever, othercauses of fever, and circumcision) thatcan help clinicians identify febrile in-fantswhose low risk of UTI obviates theneed for further evaluation.

Among children who do not receive im-mediate antimicrobial therapy, UTI canbe ruled out on the basis of completelynegative urinalysis results. For thispurpose, enhanced urinalysis is pref-erable. However, facilities for urinemi-croscopy with counting chambers andGram staining may not be available in

all settings. A urine reagent strip withnegative nitrite and leukocyte esterasereaction results is sufcient to rule outUTI if the pretest risk is moderate(5%). Diagnosis of UTI is bestachieved with a combination of cultureand urinalysis. Cultures of urine col-lected through catheterization, com-pared with SPA, are nearly as sensitiveand specic but have higher successrates and theprocess is less painful. Cul-tures of urine collected in bags have un-acceptably high false-positive rates.

The previous guideline recommendedVCUG after the rst UTI for children be-tween 2 and 24months of age. The ratio-nale for this recommendation was thatantimicrobial prophylaxis among chil-dren with VUR could reduce subsequentepisodes of pyelonephritis and addi-tional renal scarring. However, evidencedoes not support antimicrobial prophy-laxis to prevent UTI when VUR is foundthrough VCUG. The only statistically sig-nicant effect of antimicrobial prophy-laxis was in preventing UTI that includedcystitis and asymptomatic bacteriuria.Statistically signicant differences in therates of febrile UTI or pyelonephritiswere not seen. Moreover, VCUG is one ofthe most uncomfortable radiologic pro-cedures performed with children.114116

Even if additional studieswere to show astatistically signicant effect of prophy-laxis in preventing pyelonephritis, ourpoint estimates suggest that the RRwould be0.80, corresponding to a re-duction in RR of 20%. If we take into ac-count the prevalence of VUR, the risk ofrecurrent UTI in those children, and thismodest potential effect, we can deter-mine that100 children would need toundergo VCUG for prevention of 1 UTI inthe rst year. Even more striking is thefact that the evidence of benet is thesame (or better) for children with noVUR, which makes the benet of VCUGmore dubious. Taken in light of the mar-ginal cost-effectiveness of the procedurefound under the more-optimistic as-

sumptions in the 1999 technical report,these data argue against VCUG after therst UTI. VCUG after a second or third UTIwould have a higher yield of highergrades of reux, but the optimal care forinfants with higher-grade reux is stillnot clear. Ultrasonography of the kid-neys, ureters, and bladder after a rstUTI has poor sensitivity and only a mod-est yield of actionable ndings. How-ever, the procedure is less invasive, lessuncomfortable, and less risky (in termsof radiation) than is VCUG.

There is a signicant risk of renal scar-ring among children with febrile UTI,and some evidence suggests that earlyantimicrobial treatment mitigates thatrisk. It seems prudent to recommendearly evaluation (in the 24- to 48-hourtime frame) of subsequent fevers andprompt treatment of UTI to minimizesubsequent renal scarring.

LEAD AUTHORSS. Maria E. Finnell, MD, MSAaron E. Carroll, MD, MSStephen M. Downs, MD, MS

SUBCOMMITTEE ON URINARY TRACTINFECTION, 20092011Kenneth B. Roberts, MD, ChairStephen M. Downs, MD, MSS. Maria E. Finnell, MD, MSStanley Hellerstein, MDLinda D. Shortliffe, MDEllen R. Wald, MDJ. Michael Zerin, MD

OVERSIGHT BY THE STEERINGCOMMITTEE ON QUALITYIMPROVEMENT AND MANAGEMENT,20092011

STAFFCaryn Davidson, MA

ACKNOWLEDGMENTSThe committee gratefully acknowledgesthe generosity of the researchers whograciously shared their data to permitthe data set with data for 1096 infants 2to 24 months of age according to gradeof VUR to be compiled, that is, Drs PerBrandstrm, Jonathan Craig, EduardoGarin, Giovanni Montini, Marco Pennesi,and Gwenaelle Roussey-Kesler.


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