Update on Recent Guidelines for the Management of.14

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REVIEW

CURRENTOPINION Update on recent guidelines for the management

of urinary tract infections in children: theshifting paradigm

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www.co-pediatrics.com

Elijah Paintsil

Purpose of review

Recent guidelines on the management of urinary tract infections (UTIs) in children have seen a shift fromaggressive imaging studies and the use of prophylactic antibiotics to a more restrictive and targetedapproach. This review focuses on new additions to the literature on management of UTI from January 2011to September 2012.

Recent findings

The causal relationship between UTI–vesicoureteral reflux (VUR) and renal scarring has been challenged byseveral studies. Concerns about unnecessary exposure to ionizing radiation, invasiveness of some of theprocedures, and risk of infection have also been raised. With improved prenatal ultrasound, a ‘top-down’approach to investigating febrile UTI in children using renal bladder ultrasound alone as an initial studyhas become popular. Several studies have reported that prophylactic antibiotics and imaging studies afterfirst UTI can be reduced substantially without affecting the risk of recurrent UTI or renal scarring.

Summary

The use of targeted imaging approach in evaluating febrile UTI in children may lead to improved resourceuse and reduction of potential harmful procedures and interventions, without affecting outcomes of UTI inchildren. Providers using current guidelines should endeavor to collect practice-based evidence to validateand inform future guidelines.

Keywords

antibiotic prophylaxis, renal scars, renal ultrasound, urinary tract infection, vesicoureteral reflux

Departments of Pediatrics and Pharmacology, Yale School of Medicine,New Haven, Connecticut, USA

Correspondence to Elijah Paintsil, Departments of Pediatrics andPharmacology, Yale School of Medicine, 333 Cedar Street, New Haven,CT 06520-8064, USA. Tel: +1 203 785 6101; fax: +1 203 785 6961;e-mail: [email protected]

Curr Opin Pediatr 2013, 25:88–94

DOI:10.1097/MOP.0b013e32835c14cc

INTRODUCTION

Approximately 1% of boys and 3–5% of girls have atleast one episode of urinary tract infection (UTI)during childhood and 30–50% of these childrenwill have at least one recurrence. There are about1.5 million ambulatory visits for UTIs in children inthe United States annually [1

&

]. Since the 1950s, themanagement of UTI in children has been predicatedon the conception that recurrent UTIs, particularlywith vesicoureteral reflux (VUR), increase the risk ofchronic kidney disease (CKD), hypertension, andultimately end-stage renal disease. Renal scarringafter UTI is implicated in these long-term sequelae[2]. Therefore, guidelines for the management ofUTI have advocated aggressive treatment and exten-sive imaging studies to detect VUR and renal scar-ring [3,4]. Concerns about unnecessary exposure toionizing radiation, invasiveness of some of the pro-cedures, and risk of infection have been raised [5].Furthermore, recent studies have questioned the

iams & Wilkins. Unautho

causal relationship between UTI–VUR and renalscarring and the value of the historic approach tomanaging UTI.

In this review, the management of UTI follow-ing the UTI clinical practice guidelines of theNational Institute for Health and Clinical Excellence(NICE–2007, United Kingdom) [6] and the Ameri-can Academy of Pediatrics (AAP–2011, USA) [7

&&

] isdiscussed. The review excludes management of UTIin neonates, which was recently featured in thisjournal [8

&

].

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Volume 25 � Number 1 � February 2013

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KEY POINTS

� The key to the prevention of UTI complications inchildren is early diagnosis and initiation of appropriateantibiotic treatment.

� There is a paradigm shift in the understanding of thecausal association between recurrent UTI and renalscarring.

� Ongoing research and practices support restrictive andtargeted imaging studies as recommended by recentguidelines.

� There is a need for further research in host risk factorsand genetic susceptibility to renal scarring after UTI.

Management of urinary tract infections in children Paintsil

PATHOGENESIS OF URINARY TRACTINFECTION

Escherichia coli is the prototypic and most predom-inant uropathogen. Pathogenesis of UTI is mainlybased on E. coli models. UTI results from bacterialcolonization of the urinary tract mucosa, evasion ofhost defenses, bacterial multiplication, and damageto host cells [9,10

&&

]. The perturbation of host cellreceptors by pathogens activates different signalpathways leading to a cascade of innate immuneresponse effectors such as defensins, cytokines,inflammatory cells, and specific immunity [10

&&

].The localization and severity of UTIs depend on themagnitude of the immune response resulting frombacteria–host interaction [11]. Using an in-vitrocytokine [interleukin (IL)-6] assay, Storm et al.[12

&

] demonstrated that E. coli producing high levelsof cytokine were more likely to cause cystitis com-pared with pyelonephritis. Infection with bacteriathat elicit high cytokine levels results in high blad-der inflammation, which sequesters the bacteriawithin the bladder and reduces ascent to the kidneys(upper tract) [13]. Uropathogens causing upper tractinfections produced more virulence genotypes (e.g.,adhesion, toxin production, siderophores, capsulesynthesis, and invasion) compared with those caus-ing lower tract infections [14].

Individual differences in clinical presentationand severity of UTI underscore the importance ofhost factors and genetic variation in susceptibility tobacterial invasion and infection. Several studieshave linked individual susceptibility to uropatho-gens to defects in the genes that modulate innateimmune responses to bacterial clearance and elim-ination. Genotyping of the promoter regions andgenes encoding Toll-like receptor-4 (TLR-4), IL-8,and IL-8 receptors CXCR1 and CXCR2 in childrenwith UTI found that the AA genotype and A allele ofthe IL-8 single-nucleotide polymorphism (SNP) was

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related to susceptibility to and severity of upper UTI[15

&

].

LONG-TERM SEQUELAE OF URINARYTRACT INFECTION

Renal scarring is the main culprit for the long-termclinical sequelae of UTI such as hypertension,preeclampsia during pregnancy, proteinuria, andchronic renal insufficiency [10

&&

]. The prevalenceof permanent scarring after UTI ranges from 15 to60% of affected children. This wide range has beenattributed to heterogeneity of studies. Recent stud-ies have reported prevalence rates less than orclose to the lower limit of the range. It is becomingevident that UTI has been overcredited for renalscarring, thus underestimating the contribution ofcongenital renal and urinary tract abnormalities.

Salo et al. [16&&

] assessed the causal relation-ship between childhood UTIs and chronic kidneydisease by reviewing literature and medical recordsof patients with chronic kidney diseases at OuluUniversity Hospital, Oulu, Finland. Of 366 livingpatients with CKD who were monitored at OuluUniversity Hospital, only three had recurrent UTIsin childhood. The authors concluded that theetiologic fraction of recurrent childhood UTIs asa main cause of CKD was less than 1%, and that achild with normal kidneys is not at significant riskof developing CKD with recurrent UTIs [16

&&

].Clearly, the management of UTI has focused onthe care of individual children in preventingCKD without considering the fact that hundredsof children who had UTI have not developedCKD [17].

Reported risk factors for renal scarring in chil-dren with UTI include age at diagnosis, sex, race/ethnicity, delayed treatment, recurrent infections,peak of fever, laboratory indices of inflammationsuch as total white blood cell count and C-reactiveprotein (CRP) concentration, presence of VUR, andextent of renal parenchymal lesions. In a retrospec-tive study of 545 children with first episode of UTI,Cheng et al. [18

&

] found that the incidence of renalscarring was significantly higher in patients withnephromegaly than in those without (90 vs. 32%,P<0.001). In a prospective study, Lee et al. [19

&

]found that 6 months after therapy 17.4% (37 of 213)of children had renal scars. The presence of VUR wasthe only independent risk factor for renal scaringafter acute UTI in this study. A meta-analysis ofrecent studies on genetic susceptibility to renal scarformation after UTI showed a moderate associationbetween scarring and inflammation and vasomotorgenes [20

&

]. In a study by Akil et al. [21], the fre-quency of polymorphism of TLR-4 gene in the

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Infectious diseases and immunization

patients with scar was two times higher than inthose without scars.

DIAGNOSIS OF URINARY TRACTINFECTION

The diagnosis of UTI may be suggested by certainsigns and symptoms depending on the age of thechild. However, a definitive diagnosis is made on thebasis of positive urinalysis and quantitative urineculture results from samples obtained appropriatelyaccording to age [7

&&

]. The results of urinalysis can beinfluenced by the transit time of urine in the bladderand how long it takes to process the sample aftercollection (ideally within 1 h of collection) [22]. Inthe new AAP guidelines, physicians are encouragedto evaluate the likelihood of a child having UTIbefore proceeding to the work up. This approachis based on the fact that certain host risk factorsincrease the likelihood of UTI [7

&&

].

ANTIBIOTIC THERAPY OF ACUTEURINARY TRACT INFECTION

The key to management of UTI is early diagnosis andtimely initiation of appropriate antibiotics (Fig. 1).For presumed UTI, the following factors should beconsidered in the choice and route of adminis-tration of empiric antibiotics: age of patient, severityof clinical presentation, location of infection, pres-ence of complications, and local antibiotic resist-ance prevalence and pattern [23

&

]. Table 1 listsantibiotics commonly used for febrile UTIs. Recentguidelines have weighed favorably toward oraltherapy for UTI [7

&&

]. In a multicenter randomizedtrial comparing a 10-day course of oral cefixime witha 4-day course of intravenous ceftriaxone followedby a 6-day course of oral cefixime for the treatmentof acute pyelonephritis in children aged 1–36months, there was no difference between the twogroups in the prevalence of renal scarring 6–8months after UTI [24

&&

]. The total course of anti-biotic therapy should be 7–14 days.

A study of antibiotic susceptibility pattern ofuropathogens in a tertiary care hospital in Greeceshowed that E. coli was responsible for about 70% ofUTI [25]. The prevalence of E. coli isolates resistant toampicillin was 50%. Marcus et al. [26] reviewed theUTI pathogens and their antibiotic susceptibility inSchneider Children’s Medical Center of Israel from2001 to 2005. Of the 355 culture-proven UTI epi-sodes, 26 (6.2%)were due toEnterococcus spp., and theremaining 333 (93.8%) to Gram-negative bacteria,mainly E. coli, Klebsiella spp., and Pseudomonas aeru-ginosa. The Gram-negative isolates showed 24, 7, and5% resistance to first-generation, second-generation,

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and third-generation cephalosporins, respectively.There has been no significant difference in theoutcome of children with UTI due to extended spec-trum b-lactamases (ESBL)-producing uropathogenscompared with those with non-ESBL-producing uro-pathogens [27

&

].

POST-URINARY TRACT INFECTIONIMAGING

When and which imaging studies to obtain forevaluation of a child with UTI still remain contro-versial. The main question fueling the debate is therelevance of VUR in the causal pathway between UTIand renal scarring. Based on the answer to thisquestion, two approaches have evolved: ‘top-down’and ‘bottom-up’ [5]. The ‘top-down’ approachfocuses on kidney involvement during UTI with agoal of ruling in or out acute pyelonephritis, renaldysplasia, or acquired renal scarring. Proponents of‘top-down’ approach recommend the use of renalbladder ultrasonography (RBUS) and dimercapto-succinic acid (DMSA) renal scan first. Vesicouretero-gram (VCUG) is performed only if renalinvolvement is observed. The ‘bottom-up’ approachfocuses on bladder involvement during UTI with agoal of diagnosing VUR; therefore, VCUG isobtained first. The NICE guidelines discourage rou-tine imaging of all children after a first UTI [6]. RBUSis reserved for only atypical or recurrent UTI or forchildren less than 6 months of age. DMSA is recom-mended only in children less than 3 years of agewith atypical or recurrent UTI and it is performed 4–6 months after UTI. The new AAP guidelines also donot recommend routine imaging studies for first UTIin children aged between 2 and 24 months. How-ever, it is recommended that febrile infants with firstUTI should have RBUS to detect anatomic abnor-malities that may require further evaluation [7

&&

].Thus, VCUG and DMSA are no longer routine inves-tigations after first febrile UTI, as evidence supportsthat the yield of actionable findings from imaging isrelatively low [7

&&

].Pennesi et al. [28] reported on 11 years of experi-

ence in management of children with UTI using aprotocol with reduced numbers of invasive studies;consistent with current guidelines. Children withtheir first UTI between the ages of 1 and 36 monthsunderwent RBUS examination and only childrenwith abnormal RBUS or recurrence were subjectedto VCUG and DMSA renal scans. Of the 406 chil-dren, only 7.4 and 4.4% had abnormal RBUS withtheir first UTI and recurrence of UTI, respectively.The authors concluded that the application of selec-tive imaging approach did not result in missing anyuseful diagnoses or compromising the child’s health



Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

aDoes the child haveage appropriate

symptoms/risk forUTI?

Consider alternatediagnosis

bObtain urine for urinalysisand culture via ageappropriate sample

Treat with empiric antibioticsaccording to local sensitivitypatterns: Oral or Parenteral

Discontinue antibiotics andconsider alternate diagnosis

Obtain RBUS any time after UTIis confirmed

Instruct parents to seekprompt medical attention ifsymptoms recur

Obtain VCUG and seek urologicmanagement as indicated by imaging

Yes

No

No

Yes

No

Yes

Are both urinalysisand culturepositive?

Is this a recurrentUTI or RBUS isabnormal?

FIGURE 1. Management of urinary tract infection in children at a glance. Data from the AAP Clinical Practice GuidelineAlgorithm [7&&]. This is a simplified overview of the management of UTI in children of all ages. aThe evaluation of UTI depends onthe age of the child. The clinical presentations generally shift from nonspecific to more specific complaints with age. The providershould use clinical judgment. bThe source of urine for urinalysis and particularly for culture depends on age. For children up to24 months of age, bladder catheterization or suprapubic aspiration is required. For children who are toilet trained or older,midstream clean catch may suffice. All samples should be processed within 1 h of collection. If for any reason this is not possible,samples should be refrigerated at 4–88C pending processing. AAP, American Academy of Pediatrics; UTI, urinary tract infection.


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Table 1. Antimicrobial agents for treatment of urinary tract infections

Antimicrobial agent Dosage

Parenteral

Ceftriaxone 75 mg/kg, every 24 h

Cefotaxime 150 mg/kg per day, divided every 6–8 h

Ceftazidime 100–150 mg/kg per day, divided every 8 h

Gentamicin 7.5mg/kg per day, divided every 8 h

Tobramycin 5mg/kg per day, divided every 8 h

Piperacillin 300 mg/kg per day, divided every 6–8 h

Oral

Amoxicillin clavulanate 20–40 mg/kg per day in three doses

Trimethoprim sulfamethoxazole 6–12 mg/kg trimethoprim and 30–60mg/kgsulfamethoxazole per day in two doses

Sulfisoxazole 120–150 mg/kg per day in four doses

Cefixime 8mg/kg per day in one dose

Cefpodoxime 10 mg/kg per day in two doses

Cefprozil 30 mg/kg per day in two doses

Cefuroxime axetil 20–30 mg/kg per day in two doses

Cephalexin 50–100 mg/kg per day in four doses

Adapted with permission from the AAP Clinical Practice Guidelines [7&&

].


[28]. Schroeder et al. [29&&

] retrospectively comparedthe outcomes of UTI in children under 2 years of agebefore and after adopting the NICE restrictive imag-ing guidelines in their hospital. They found thatprophylactic antibiotics and VCUG use werereduced substantially without affecting the risk ofUTI recurrence within 6 months.

Tsai et al. [30&

] recently assessed four imagingapproaches: RBUS alone, DMSA scan alone, RBUSor DMSA scan (abnormality on either study or onboth was an indication for VCUG), and RBUS andDMSA (abnormality on both studies was requiredfor performance of VCUG). They found that 136 of220 (61.8%) and 111 of 220 (50.5%) had abnormalRBUS and DMSA scans, respectively. The sensi-tivities for high-grade VUR on RBUS alone andDMSA alone were 76.9 and 82.1%, respectively.With RBUS or DMSA strategy, the sensitivityincreased to 92.3% with negative predictive valueof 94.3%. Their study validated the current recom-mendation of ‘top-down’ approach to imaging.Other studies have concluded that RBUS couldbe used alone in the initial evaluation of childrenwith UTI [31,32].

PREVENTION OF URINARY TRACTINFECTION

Ultimately, ‘an ounce of prevention is better than apound of cure.’ The role of prophylactic antibiotics,cranberry juice, management of dysfunctional



elimination syndrome, probiotics, and circumcisionin preventing UTI is discussed below.

Prophylactic antibiotics have been used on theassumption that they prevent recurrent UTI, renaldamage, or both in young children with UTI with orwithout VUR. Several studies have discredited thisassumption. Moreover, chronic antibiotic use has anumber of disadvantages for the individual as wellas the population as a whole. The NICE guidelinesdo not recommend routine antibiotic prophylaxisin infants and children after first UTI. The recentAAP guidelines also do not recommend prophylac-tic antibiotics after first UTI in children aged 2–24months [7

&&

]. Islek et al. [33] followed infants(n¼84) with prenatal ureteropelvic junctionobstruction without antibiotic prophylaxis for 12–24 months and none of the patients had UTI or renalscar during the follow-up period.

There is resurgence in the use of cranberry prod-ucts to prevent recurrence of UTI. The proposedmechanism of action is inhibition of uropathogenicE. coli at the uroepithelium. In a recent systematicreview of published randomized clinical trials, Wa-ng et al. [34] found that consumption of cranberryproducts may protect against UTIs in certain popu-lations. However, they concluded on a cautiousnote, based on the substantial heterogeneity acrosstrials. Stapleton et al. [35] randomized 176 women totwo arms (120 to cranberry juice and 56 to placebo)and followed them for a median of 168 days. Thecumulative rate of UTI was 0.29 in the cranberry




juice group and 0.37 in the placebo group (P¼0.82).The adjusted hazard ratio for UTI in the cranberryjuice group vs. the placebo group was 0.68 (95%confidence interval 0.33–1.39; P¼0.29). They con-cluded that, though cranberry juice did not signifi-cantly reduce UTI risk compared with placebo, thepotential protective effect observed warrants confir-mation in larger, well-powered studies. Salo et al.[36

&

] randomized 263 children with UTI to receiveeither cranberry juice (n¼129) or placebo (n¼134)for 6 months and followed them for a year in sevenFinnish hospitals. The intervention did not signifi-cantly reduce the number of children who experi-enced a recurrence of UTI.

Dysfunctional elimination syndrome is a knowncause of UTI. The syndrome comprises of inability toeffectively empty the bladder, incontinence, consti-pation, and other voiding symptoms. Biofeedbacktherapy has been helpful in improving voiding symp-toms in children with dysfunctional voiding. Thepooled estimate from 27 studies reviewed by Desantiset al. [37] showed 83% (95% confidence interval76–86%) improvement in UTI with biofeedbacktherapy in children less than 18 years of age. Theauthors concluded that well-designed trials areneeded to evaluate the effectiveness of biofeedbackin prevention of UTI in children.

The use of probiotics to prevent UTI is beingexplored. Probiotics contain a live microorganismgiven to confer health benefit to the host withoutcausing infection or untoward effects. The use ofprobiotics in prevention of bacterial infections hasreceived mixed reviews. Probiotics work by displac-ing pathogenic bacteria from the gut as well asboosting the innate immunity of the gut. In a pro-spective randomized study comparing conventionalantibiotics and probiotics in treating children withprimary VUR, the incidence of recurrent UTI wascomparable in both groups of children [38,39]. In anin-vitro study, Storm et al. [40

&

] found that ‘Muta-flor’ (a probiotic containing E. coli Nissle 1917) hadbactericidal effect against a wide range of uropath-ogens. They concluded that probiotics may be effec-tive in preventing and eliminating the colonizationof pathogenic bacteria in the gut and that such areduction in the fecal load of uropathogens willtranslate to a reduction in the incidence of recur-rence of UTI.

Will the cutting of the foreskin become thecutting-edge of prevention of UTI in boys? Previousstudies have established an association betweencircumcision and reduced risk of UTI in boys. How-ever, the number of circumcisions needed to pre-vent one UTI is reported to be about 111 in thegeneral population [10

&&

]. Is this a cost-effectivestrategy for the general population or should it be

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reserved for boys at high risk of UTI? The AAPrecently highlighted the benefits of male circum-cision and concluded that the health benefits ofnewborn male circumcision outweigh the risks[41]. They encouraged providers to explain thebenefits and risks of circumcision to parents andto leave the final decision for or against circum-cision to the parents.

CONCLUSION

With high suspicion for UTI and early treatment, UTIcomplications including renal scarring could beavoided. Patients and their families should be giventhe message that UTI is an acute infection and, withappropriate and timely treatment, UTI usuallyresolves with no untoward consequences. However,certain individuals may have a predilection for recur-rences and occasionally this is a marker of congenitalrenal abnormalities or urinary tract obstruction.These conditions may be screened for with RBUS[17]. Further research is needed to elucidate andvalidate host factors and genetic variations predis-posing to renal scarring. These factors should beconsidered in future clinical practice guidelines forUTI in order to further avoid unnecessary invasiveprocedures. Providers using current guidelinesshould endeavor to collect practice-based evidenceto validate and inform future guidelines.

Acknowledgements

Thanks to Dr Allison Langs-Barlow for her critical read-ing of the manuscript.E.P. is supported by a grant from the National Institute ofHealth (K08AI074404).

Conflicts of interest

There are no conflicts of interest.

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