Introduction

Urinary tract infection (UTI) affects approximately 7% to 8% of girls and 2% of boys during the first 8 years of life. Febrile UTI (fUTI) is most common in infants and children less than 1 year old, whereas nonfebrile UTI predominates in girls more than 3 years old. It is now the most common serious bacterial infection of childhood. Vesicoureteral reflux (VUR), the abnormal retrograde flow of urine from the bladder to the upper urinary tract, is present in 30% to 40% of symptomatic documented UTIs. This association of VUR with fUTI diminishes with increasing age, because lower grades of VUR, in particular, are most likely to resolve spontaneously over time.

The most important clinical sequelae of VUR include fUTI/acute pyelonephritis (APN) and, potentially, renal scarring. The severity (higher grades) of VUR and increased frequency of fUTI are directly related to the risk of scarring. APN, defined as inflammation or infection of the kidneys, affects an estimated 60% of children with fUTI. High fever with temperature of 39.5°C or more is the single best predictive parameter. The risk of APN increases when bladder infection occurs in patients with VUR, because colonized lower tract urine then has direct retrograde access to the upper tracts. Furthermore, results of the International Reflux Study Committee (IRSC) have shown that successful antireflux surgery reduces the risk of fUTI by a factor of 3. Additional risk factors for APN include other anatomic urologic and neurologic disorders, bowel-bladder dysfunction (BBD), recurrent UTIs, female gender for children more than 1 year old, and certain social situations, especially those that lead to delayed treatment. It is estimated that 15% of all children develop renal scarring after a first UTI, with VUR itself a risk factor for renal scarring.

However, patients with fUTI may also develop scarring in the absence of VUR. Moreover, most children with VUR and fUTI do not develop acquired (secondary) scars. Despite the finding of chronic photopenic areas on dimercaptosuccinic acid (DMSA) scans that are thought to represent scars, there is controversy as to their ultimate physiologic and clinical significance. A better understanding of which patients are most likely to develop renal scarring, and, of paramount importance, identifying the significance of such scarring in a given individual patient, is essential to enable better management selection.

Issues in pediatric UTI: development of guidelines

Clinical practice guidelines are developed to help physicians, patients, and their families make sound decisions about specific clinical situations. However, guidelines reflect interpretations of available data, and are thus subjective and tend to differ between different groups of experts. Furthermore, guidelines are most applicable to a large group of patients who fulfill specific clinical criteria rather than to the individual patient; this is particularly problematic in pediatric medicine, in which parents may be more prone to make treatment decisions for their children based on present symptoms and family history rather than what is published in academic journals. It is even more difficult in a tertiary referral practice to follow algorithmic protocols, rather than to individualize care to a patient who is being evaluated for expert care.

The management landscape of fUTI is constantly evolving as past tradition and dogma are questioned, and more is learnt about the pathophysiology and treatment outcomes. As a result, pediatric UTI guidelines are appropriately updated with expanding data and knowledge. In recent years, the UK National Institute for Health and Clinical Excellence (NICE), the American Urological Association (AUA), and the American Academy of Pediatrics (AAP) have updated their pediatric UTI and VUR guidelines. The NICE guidelines, which were published in 2007, were developed to achieve more consistent clinical practice based on accurate diagnosis and effective management. With respect to diagnosis, the NICE guidelines underscore the importance of urine culture in patients with fever without a source (FWS), and they distinguish between upper and lower UTI. The AUA guidelines published in 2010 are specific to VUR, and reflect the limited amount of evidence-based knowledge about this condition. However, these guidelines contribute to the understanding of several issues specifically in patients with UTI and VUR, including the relevance of renal scarring, usefulness of continuous antibiotic prophylaxis (CAP), appropriate use of imaging, and consideration of BBD. The AAP guidelines, which were published in August 2011, have been long awaited and have led to confusion among practitioners because of major investigational protocol changes that have been made compared with the 1999 guidelines. In particular, the AAP guidelines have been cited for stating that CAP is not useful in preventing recurrent fUTI and that routine voiding cystourethrogram (VCUG) is not indicated after first fUTI if ultrasonography results are normal. However, these guidelines were developed for a specific age group (pre–potty-trained infants and children age 2 to 24 months) and they should not be extrapolated to older or younger patients, or to those with complex situations. Key issues in pediatric UTI management are discussed later; where pertinent, a discussion of the guidelines regarding these issues is also presented.

Issues in pediatric UTI: development of guidelines

Clinical practice guidelines are developed to help physicians, patients, and their families make sound decisions about specific clinical situations. However, guidelines reflect interpretations of available data, and are thus subjective and tend to differ between different groups of experts. Furthermore, guidelines are most applicable to a large group of patients who fulfill specific clinical criteria rather than to the individual patient; this is particularly problematic in pediatric medicine, in which parents may be more prone to make treatment decisions for their children based on present symptoms and family history rather than what is published in academic journals. It is even more difficult in a tertiary referral practice to follow algorithmic protocols, rather than to individualize care to a patient who is being evaluated for expert care.

The management landscape of fUTI is constantly evolving as past tradition and dogma are questioned, and more is learnt about the pathophysiology and treatment outcomes. As a result, pediatric UTI guidelines are appropriately updated with expanding data and knowledge. In recent years, the UK National Institute for Health and Clinical Excellence (NICE), the American Urological Association (AUA), and the American Academy of Pediatrics (AAP) have updated their pediatric UTI and VUR guidelines. The NICE guidelines, which were published in 2007, were developed to achieve more consistent clinical practice based on accurate diagnosis and effective management. With respect to diagnosis, the NICE guidelines underscore the importance of urine culture in patients with fever without a source (FWS), and they distinguish between upper and lower UTI. The AUA guidelines published in 2010 are specific to VUR, and reflect the limited amount of evidence-based knowledge about this condition. However, these guidelines contribute to the understanding of several issues specifically in patients with UTI and VUR, including the relevance of renal scarring, usefulness of continuous antibiotic prophylaxis (CAP), appropriate use of imaging, and consideration of BBD. The AAP guidelines, which were published in August 2011, have been long awaited and have led to confusion among practitioners because of major investigational protocol changes that have been made compared with the 1999 guidelines. In particular, the AAP guidelines have been cited for stating that CAP is not useful in preventing recurrent fUTI and that routine voiding cystourethrogram (VCUG) is not indicated after first fUTI if ultrasonography results are normal. However, these guidelines were developed for a specific age group (pre–potty-trained infants and children age 2 to 24 months) and they should not be extrapolated to older or younger patients, or to those with complex situations. Key issues in pediatric UTI management are discussed later; where pertinent, a discussion of the guidelines regarding these issues is also presented.

Issues in pediatric UTI: diagnosis

Fever in children, especially in young children, is a cause of concern for parents and caregivers and is the most common reason for children to be taken to the doctor or hospital. Of 5.4 million emergency department (ED) visits per year with fever, an estimated 6% to 14% have an FWS; UTIs occur in approximately 7% of boys 6 months old or younger and 8% of girls 1 year old or younger with an FWS. Thus, testing for the presence of UTI seems to be warranted in this patient population, in particular if certain risk criteria are met. The AAP guideline analyzes risk factors that can be addressed to define the at-risk populations: sex, age, fever greater than 39°C, sustained fever of more than 2 days, white more than black race, and uncircumcised status. This analysis is reflected in recent guidelines from major organizations, as summarized in Box 1 . An important component of diagnosis is proper collection of urine. A clean-catch urine specimen is preferred, when possible, in older, potty-trained patients, although catheterization or suprapubic aspiration (SPA) must be performed in younger patients, especially if a urine sample collected by other means (such as bag collection) is suspicious for the diagnosis of UTI. If the treating physician decides that a febrile infant requires antimicrobial therapy, and the urinary tract is considered a most likely source, then collection bag specimens, by themselves, are not generally considered to be acceptable to support the diagnosis. The 2011 AAP guidelines recommend that in patients 2 to 24 months old, both a urinalysis with pyuria and/or bacteriuria and a culture with at least 50,000 colony-forming units of a uropathogen per milliliter, are essential to establish a diagnosis of UTI.

Issues in pediatric UTI: treatment

Once the diagnosis and decision to treat have been made, oral antimicrobial or parenteral treatment may be administered, because they are equally effective. The 2011 AAP guideline states that the route of administration should be based on practical considerations, such as whether the child can retain orally administered fluids and medications. Choice of agent should be based on antimicrobial susceptibility of the isolated uropathogen and may include ceftriaxone, cefotaxime, ceftazidime, gentamicin, tobramycin, or piperacillin for parenteral treatment and amoxicillin plus clavulanic acid, trimethoprim-sulfamethoxazole, sulfisoxazole, or a cephalosporin for oral treatment. The duration of antimicrobial therapy should be 7 to 14 days. The AAP guideline recommends against agents such as nitrofurantoin and others that predominantly are excreted in urine to treat fUTI in infants, because the serum antimicrobial concentration attained is not sufficient to treat pyelonephritis or urosepsis.

Issues in pediatric UTI follow-up: CAP

The goals of follow-up after initial treatment of fUTI are to reduce the risk of developing another fUTI, to prevent renal injury, and to minimize the morbidity of being recurrently ill. The use of CAP to prevent recurrent UTI has been a contentious issue, although it has been a gold standard for 5 decades. The benefit of CAP must be weighed against the risks (eg, development of antibiotic resistance), cost, and inconvenience of therapy.

Several risk factors for recurrent UTI have been proposed in the literature. The risk of experiencing a UTI recurrence seems to depend on general patient characteristics, such as age and gender, as well as certain patient-specific characteristics. One proposed risk factor is high-grade VUR. VUR is commonly classified into 5 grades according to the International Classification of Vesicouretal Reflux, with grade V being the most severe ( Table 1 ). Although higher grade VUR is associated with an increased risk of UTI recurrence, no clear cutoff VUR grade for which CAP is or is not indicated has been established.

BBD can influence VUR outcomes; the AUA guidelines recommend that the presence of BBD should be determined in patients with VUR. Furthermore, these guidelines state that in children older than 1 year with grades I to IV VUR and BBD, and/or in patients with renal cortical abnormalities, CAP is recommended. Even the NICE guidelines suggest that CAP might be appropriate in those with recurrent fUTI rather than after a first episode. In contrast, although the AAP guidelines define some similar risk criteria for determining whether or not to use CAP, they, like the NICE guidelines, do not comment on the importance of BBD. In addition to a lack of anatomic abnormalities such as BBD, factors associated with a low risk of recurrent UTI are listed in Box 2 . Children possessing these characteristics may be considered to be low-risk patients who are not expected to have another UTI that could lead to scarring ; such patients would accordingly derive less benefit from CAP compared with high-risk patients.

Six important clinical studies have addressed the usefulness of CAP in preventing fUTI recurrence. The results of 4 of these studies indicated no benefit of CAP versus observation ; however, few of the patients in these studies had grade IV or V VUR. Thus, because high-grade VUR has been shown to be associated with an increased risk of UTI recurrence, the results of these studies are not considered to be definitive. Moreover, and given that these studies were not North American, circumcision status in boys was not reported. The Australian Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric Reflux and Normal Renal Tracts (PRIVENT) study was designed to test the efficacy of CAP in preventing recurrence in children who had had 1 or more fUTIs. A total of 576 children were randomly assigned to receive CAP versus placebo for 12 months. Although the results of this study suggested a benefit of CAP in reducing the incidence of UTI recurrence, this benefit was not convincing: 15 children had to be treated for 12 months to prevent a single UTI. This study also did not have sufficient statistical power to assess risk according to VUR grade. Renal scarring was not studied and it is likely that many more children would have required treatment to prevent a single significant renal scar.

The Swedish Reflux Trial is the only clinical trial to specifically evaluate children with higher grade (grade III–V) VUR. This study enrolled 203 children (128 girls, 75 boys) aged 1 to 2 years with VUR. The results indicated that CAP and endoscopic injection (EI) were comparable in reducing fUTI recurrences compared with cohorts who were only observed. Although they were unable to recruit their desired number of patients into the study, they showed, that girls were at risk of developing new scars, with boys seemingly having resilient kidneys to new scars. Thus, the body of literature regarding the usefulness of CAP in preventing UTI recurrence remains unsatisfactory.

The practitioner is placed in the position of determining whether to administer CAP to a given patient, or to consider the benefits versus risks of surveillance; that is, of not using CAP. The potential benefits of not using CAP include cost, bacterial resistance, side effects, and the parental inconvenience of administering it on a daily basis (ie, compliance). In a surveillance protocol, each child (and family) becomes his or her own stress test and pits the risk aversion of VUR against treatment-associated morbidity. The AAP reviewed raw data from the 6 randomized clinical trials mentioned earlier and compiled a data set of 1091 infants aged 2 to 24 months. They performed a meta-analysis and found no statistically significant benefit of prophylaxis in preventing recurrent fUTI/pyelonephritis in infants without reflux or in those with grades I to IV VUR.

Especially in the presence of documented VUR, if the child does clinically well and renal units remain stable, further invasive imaging (eg, VCUG) becomes superfluous. Regardless, it is imperative to address other overt and covert factors, in particular BBD. The team from pediatric urologist to primary provider to patient and family must completely accept the concept that surveillance does not mean nontreatment. Its success depends on the patient’s family being educated about vigilantly watching for signs and symptoms of UTI recurrence and the importance of prompt evaluation and treatment.

The ongoing RIVUR (Randomized Intervention for Children with Vesicoureteral Reflux) study may help identify acquired renal changes in patients receiving CAP versus observation. This multicenter trial sponsored by the US National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases was initiated in 2005 and will close in 2013. The intended enrollment is 600 children aged 2 to 72 months (ie, 6 years) with grade I to IV VUR identified after fUTI or symptomatic UTI, who will be randomized to CAP versus placebo. The primary outcome measure is UTI recurrence; secondary end points include time to UTI recurrence, renal scarring, treatment failure, renal function, resource utilization, and development of antimicrobial resistance in stool flora. The results of this trial are expected to further contribute to the body of data regarding the use of CAP in children with fUTI.