Data were obtained independently by two authors who carried out a comprehensive and non-systematic search in the PubMed, Embase, LILACS, Cochrane, Scopus and SciELO databases. Search strategies included Medical Subject Heading terms for “urinary tract infection,” “CAKUT,” “renal scarring,” “vesicoureteral reflux,” “renal ultrasonography,” “renal scintigraphy,” “antibiotic prophylaxis,” and “chronic kidney disease.” No time or language restrictions were established. The search emphasized recent consensus statements, guidelines, meta-analyses, systematic reviews, randomized clinical trials, and prospective cohort studies. The publications were critically selected by the authors.

Host resistance to UTI depends for the most part on innate immune defenses, mainly during the acute phase of the disease. The response to uropathogenic E. coli is activated by P-fimbriae mediated adhesion to glycolipid receptors, leading to activation of TLRs, of which TLR4 has been considered the most important.45,46 Activation of TLR4 signaling results in the release of transcription factors such as IRF3, which trigger neutrophil recruitment and cytokine production in order to kill bacteria. These mechanisms determine the symptoms and signs of UTI. Urothelial cells produce interleukin-8 (IL-8), which attracts neutrophils to urinary tract leading to pyuria.24,25,47 Infection itself enhances the expression of IL-8 receptors, further stimulating neutrophil attraction and activation. Interleukin-6 (IL-6) is also secreted by urothelial cells. IL-6 activates C-reactive protein (CRP) production and stimulates the production of mucosal IgA.25

Another source of innate immune defense are the antimicrobial peptides (AMPs), which are natural antibiotics produced by nearly all organisms.48,49 AMPs are small cationic proteins expressed by phagocytic and epithelial cells, either constitutively or through induction by invading agents.48

Further supporting the role of innate immunity in UTI is the fact that genetic variation affecting innate immunity influences host susceptibility. For example, mutations in the TLR4 gene promoter lead to low expression of TLR4, which was detected in children with asymptomatic bacteriuria when compared to age-matched controls or children with acute pyelonephritis. In addition, single nucleotide polymorphisms (SNPs) in the gene promoter of the transcription factor IRF3 have been identified in about 80% of patients with recurrent episodes of acute pyelonephritis. Reduced expression of CXCR1, the IL-8 receptor, due to SNPs in the CXCR1 gene, was also found in children with frequent episodes of acute pyelonephritis.50–52 Individuals of blood group P lack functional receptors for P-fimbriae, while children with blood group P1 have an increased risk of acute pyelonephritis. Very few AMPs have been described in the human kidney and urinary tract, which include defensins, cathelicidin, hepcidin, and ribonuclease 7. Other proteins with antimicrobial activity present in the kidney and urinary tract are Tamm–Horsfall protein, lactoferrin, lipocalin, and secretory leukocyte proteinase inhibitor.48,49,53

It should also be mentioned that a specific immune response develops after three to seven days in patients with acute pyelonephritis. As an attempt to stimulate specific immune mechanisms, experimental vaccines against antigens of uropathogenic E. coli have been tested.54 Besides vaccines, other alternative methods and therapeutic strategies to prevent and/ or control UTIs include receptor analogues, pilicides and curlicides, bacterial interference, or phagotherapy.54

UTIs may be the sentinel event for underlying congenital anomalies of the kidney and urinary tract (CAKUT), although normal anatomy is more common.8 In 30% of children with CAKUT, UTI can be the first sign.9 If pediatricians fail to detect patients at risk of CAKUT, the upper urinary tract may be damaged.

Hypothetically, anatomical or functional alterations of normal urinary flux may certainly predispose to episodes of UTI, and these episodes probably occur in neonates or young infants. In this regard, the VUR has been associated with approximately 20% of neonatal cases of UTI, although the incidence of VUR is not significantly different between genders, birth weight, gestational age, or mode of delivery.55 In a study with infants less than 2 months of age from a neonatal intensive care unit, a rate of anatomic abnormalities in patients with UTI of less than 5% was detected. However, VUR was associated with a younger age at UTI presentation.56 In another study including 45 male infants with first UTI episode occurring early in life, renal ultrasound scan (RUS) and voiding cystourethrogram (VCUG) found CAKUT in half of the cases.57 The most common anomalies were VUR, duplicated collecting system, posterior urethral valves, ureteropelvic junction obstruction, and renal hypodysplasia.57 The DMSA scan revealed renal scars in those with VUR grade 3 or higher.22 Similarly, renal anomalies were found in 47% of febrile infants less than 30 days of age at the first UTI episode.56 However, even in the absence of any abnormalities detected on the RUS or VCUG, infants with UTI can have an abnormal DMSA scan, indicating renal cortical damage. The question is if the renal cortical damage would be an effect rather than a cause of a UTI.9

The main methods of urine collection include clean-catch, plastic bag, bladder catheterization, and suprapubic aspiration (SPA). These four methods have variable contamination rates and invasiveness.77

Most commonly urine is obtained from clean-catch urine samples, especially for toilet-trained children.69,78 In newborns, infants, and when voided specimens cannot be obtained, the best way to collect urine is still controversial. Clean-catch urine is also possible to obtain in non-toilet trained children. In these cases, the patient is placed in the lap of a parent or nurse holding a sterile foil bowl underneath the genitalia. A systematic review of five studies comparing clean voided urine specimens with bladder tap specimens reported a wide variation among studies, with sensitivity ranging between 75% and 100% and specificity varying between 57% and 100%.79 Conversely, Ramage et al.80 previously detected a good correlation between results of urine culture obtained by this method and by SPA. In regard to urine contamination, a study with 120 infants and children showed a 25% contamination rate with samples from clear-voided urine when compared to samples from SPA.81

Collection in a sterile plastic bag attached to the cleaned genitalia is a technique often used in several centers.82 Although a culture-negative urine bag sample is reliable, this technique has a high rate of false-positive cultures because of contamination by periurethral flora.82 In a cross-sectional study of 303 non toilet-trained children under age 3 years at risk for UTI, sensibility and specificity of the urinalysis collected by clean-voided bag were compared with catheter urine specimens using the catheter culture as the gold standard.83 The bag dipstick was more sensitive than the catheter dipstick for the entire study sample: 0.85 vs. 0.71, respectively. However, specificity was consistently lower for the bag specimens than for the catheter specimens: 0.62 vs. 0.97, respectively.83

International guidelines generally recommend that urine should be collected by bladder catheterization17,69,78 or SPA under ultrasound control.17,78 SPA is the most sensitive method for obtaining an uncontaminated urine sample. When urine is collected by SPA, any colony count is considered to represent significant bacteriuria. All other methods of urine collection (clean catch, bladder catheterization, and plastic bag collections) require passage of urine through the urethra. SPA has been considered the standard method for obtaining urine that is uncontaminated by perineal flora. Variable success rates for obtaining urine have been reported, ranging from 23% to 90%.69 When RUS guidance is used, success rates improve.84 Despite invasiveness, the technique has limited risks when employed by expert physicians. SPA is recommended for boys with severe phimosis, girls with tight labial adhesions, and in case of external genital infection or presence of complex genital abnormalities. Bladder catheterization is considered an alternative to SPA, although with higher rates of contamination. Urine obtained through catheterization for culture has a sensitivity of 95% and a specificity of 99% in comparison to that obtained via SPA.85

In conclusion, methods of urine collection in individual centers should be determined based on the accuracy of voided specimens.

Urine culture is still the gold standard for diagnosing UTI. In freshly voided urine, a growth of more than 108 colony-forming units (CFU) per liter (105 per mL) of a unique bacterium is regarded most frequently as the cutoff between contamination and UTI. However, what is not broadly understood is that CFU quantification is a semiquantitative test. The method is based on the microbiology technician unfailingly differentiating 10 and 100 separate CFUs on an agar plate, which has been streak plated with 1mL of urine. Considering the intrinsic imprecision of the method, physicians should take into account signs and symptoms of UTI to treat a child. It must be mentioned that some children with UTI do not reach the traditional diagnostic threshold of 108 CFU/L.

As an example, Upadhyay et al.86 found that 20% of children with UTI based on SPA had CFU below 108/L (105/mL) on voided specimens. The CFU of these children with UTI was 106/L (103/mL) to 107/L (104/mL). Indeed, different cutoffs for significant bacteriuria are adopted for SPA or catheter specimens based on the lower risk of contamination in such specimens. The cutoff used for bladder catheter specimens is > 107 CFU/L (> 104 CFU/mL), while any bacterial growth in urine obtained by SPA indicates a UTI.87

Most children undergo one or more imaging studies following their first UTI aiming to identify abnormalities, which increases the risk of recurrent UTI or kidney damage. In the last decade, however, newer guidelines assume that imaging is only of value if subsequent management reduces the risk of UTI, kidney damage, and its long-term sequelae. These guidelines were released by the National Institute of Health and Care Excellence (NICE) in the UK, from the AAP, and from the Italian Society of Pediatric Nephrology (ISPN).17,69,78 All of them suggest limited investigations for children with UTI. The NICE guidelines provide imaging recommendations for children of all ages, whereas the AAP guidelines apply to children aged 2–24 months, and the ISPN guidelines refer to children aged 2–36 months.17,69,78 The NICE guidelines recommend that children aged over 6 months with their first uncomplicated UTI require no investigations following the episode and that children under 6 months should have only RUS.17 The AAP and ISPN guidelines recommend that all infants aged 2–24 months with febrile UTIs should undergo RUS, although they recognize that prenatal US is likely to identify most serious urinary tract abnormalities.69,78 None of these recent guidelines recommend routine VCUG or DMSA scans, but they recommend further evaluation if the ultrasound is abnormal, if the child is critically ill and fails to respond promptly to antibiotics, and in case of recurrent infections. Some studies have evaluated the impact of fewer investigations and concluded that the recent guidelines are safe to follow.88–90 On the other hand, other authors consider that potentially important abnormalities will be missed if the newer guidelines are followed.91 It should also be mentioned that these guidelines assume that most serious urinary tract abnormalities would be identified in antenatal US and that high-quality RUSs interpreted by expert pediatric radiologists are always available. However, in many situations, those assumptions are not true.

In a spite of the imaging protocol adopted, RUS is generally considered the first-line investigation for urinary tract malformations, since the method is noninvasive and can identify structural anomalies including obstructive uropathies, kidney hypodysplasia, and urinary tract dilatations.17,69,78 However, the main limitations of RUS are the dependence on the equipment and the operator, and the impossibility to obtain data on renal function. Compared with VCUG and DMSA scans, RUSs are poor predictors of the presence of VUR or of kidney damage, respectively.17

The termed ‘bottom-up’ approach is traditionally adopted for imaging evaluation of UTI. RUS and VCUG are recommended after the first episode of UTI in all pediatric patients despite sex and age group. VCUG is regarded as the reference standard for identifying VUR and for providing information on the bladder and urethra. More recently, it has been debated whether the presence and severity of VUR on VCUG might influence decisions on the management of VUR. In this regard, subgroup analyses in randomized controlled trials have found no difference in the efficacy of antibiotics in preventing UTI between children with and without VUR92 or between mild (grades I or II) and severe (grades III or IV) VUR.93 Some authors consider that since the presence or severity of VUR does not influence the efficacy of treatment, routine VCUG following the first UTI is no longer justified. The remaining clear indication for a VCUG is to evaluate the bladder and urethra in children suspected of having obstructive uropathy, such as posterior urethral valves.

To avoid all children from having unnecessary VCUGs, some authors have suggested a “top-down” approach to imaging studies, with RUSs and DMSA scans performed first and VCUG only performed if the DMSA scan shows acute kidney parenchymal injury.94 The DMSA scan is a sensitive test for detecting acute parenchymal injury following UTI, with a sensitivity of 86% and specificity of 91%.95 However, DMSA scans cannot differentiate between damage due to UTI and congenital kidney damage. In addition, most acute changes resolve over time regardless of whether antibiotic prophylaxis is used.92,96 The present authors conducted a retrospective cohort study with the aim to evaluate the diagnostic accuracy of DMSA scan and RUS in identifying high-grade VUR in 533 children after a first episode of UTI.97 The findings showed that if a negative diagnosis was established only when both test results were normal, sensitivity was 97% and the diagnostic odds ratio was 25. Only nine children (6.3%) with severe reflux would be missed by an absence of alterations in both tests. Nevertheless, a systematic review of 13 studies evaluating DMSA scans for the identification of dilating VUR (grades III–V) concluded that DMSA scans are poor predictors of dilating VUR,98 with considerable heterogeneity between studies. It should be also taken into account that, in many countries, there is limited availability of DMSA scans and that these are expensive for families.

Both VCUG and DMSA scans are associated with significant radiation (both equivalent to 40–50 chest X-rays or four months of natural background radiation), and are unpleasant and time-consuming tests for the child and their families. In addition, a nationwide population-based retrospective cohort study in Taiwan found that the overall risk of cancer was 1.92-fold greater in children who had undergone VCUG compared with matched controls, with highest risk for genital and urinary system cancers.99

A recent line of investigation on the ideal imaging protocol is the use of machine learning algorithms to develop predictive models for the probability of recurrent UTI associated with VUR in children after first infection. In this regard, the Advanced Analytics Group of Pediatric Urology and the ORC Personalized Medicine Group evaluated 500 subjects, including 305 from the Randomized Intervention for Children with Vesico-Ureteral Reflux (RIVUR) and 195 from the Careful Urinary Tract Infection Evaluation (CUTIE) trials. Most subjects were females (90%) and they had a mean age of 21±19 months. Recurrence of UTI occurred in 72 subjects, of whom 53 also exhibited VUR. The final predictive model included age, sex, race, weight, systolic blood pressure percentile, dysuria, urine albumin-to-creatinine ratio, prior antibiotic exposure, and current medication. The model predicted recurrent UTI related to VUR, with an AUC of 0.761 (95% CI: 0.714–0.808).100

The debate on the ideal imaging protocol is still ongoing, but experts do agree that longitudinal prospective studies are still needed to establish tailored imaging protocols for the approach of UTI in childhood. An interesting approach was proposed by Marks et al.16 They suggested that targeting investigations for a selected group of children (as opposed to protocol-based investigations of all children with UTI) would be clinically safe and effective, and would avoid the distress and cost of unnecessary invasive investigations. Certain clinical risk factors have been defined in the literature and can help identify which infants and children with febrile UTI have a high risk of having an abnormal urinary tract, and consequently warrant investigation (Box 3).

The aims of the management of children with UTI are (1) resolution of the acute symptoms of the infection; (2) prompt recognition of concomitant bacteremia, particularly in infants less than 2 months of age and (3) prevention of renal damage by eradication of the bacterial pathogen, identification of abnormalities of the urinary tract, and avoidance of recurrent infections.101 Prompt treatment of UTI in preschool children might prevent renal scarring. For instance, Coulthard et al.102 reported that treating children’s UTI in less than three days after the onset of the symptoms more than halves the risk of them acquiring kidney scars. Accordingly, Shaikh et al.103 showed that there was a significant association between delay in treatment of febrile UTI and permanent renal scarring. The authors analyzed data of 482 children, 90% females and 78% with VUR, and found, after adjusting other covariates, that a delay of 48h or more would increase the odds of new renal scarring by about 47%.

The clinical management of UTIs in children should be tailored according to the age of the patient, severity of presentation, and infection location (cystitis vs. pyelonephritis). Antibiotic treatment is the cornerstone of treatment for acute UTI. The decision to initiate empiric treatment should be based on clinical suspicion of UTI that includes careful history and physical exam, and positive urinalysis in an appropriately collected urine specimen.73 The clinician should base the choice of agent on local antimicrobial sensitivity patterns (if available) and should adjust the choice according to sensitivity testing of the isolated uropathogen.69 Most patients can be treated in an outpatient basis with oral therapy, if the child has a nontoxic appearance, can tolerate oral medications, and the family complies with recommendations.73 On the other hand, inpatient parenteral therapy should be considered for acutely ill children, children who cannot tolerate oral therapy, or when adherence with the prescribed regimen is in question.6 The AAP currently recommends that parenteral antibiotic therapy and hospitalization be considered for children who appear to be severely ill or dehydrated and those who are unable to retain oral intake.69 Children with a renal or perinephric abscess should also be treated initially with parenteral therapy and surgical drainage should be considered. Parenteral therapy should also be considered in children who are immunocompromised and in those with indwelling devices.6

Infants aged 3 months or less with UTI should be treated initially with intravenous antibiotics due to the risk of urosepsis and the higher possibility of structural urinary tract anomaly, although data on prevalence of uropathies are imprecise.18,104–106 In addition, infants younger than 60–90 days are more likely to have their course of disease change abruptly because of their incompletely developed immune system.107,108 Broad coverage for group B streptococci and Enterobacteriaceae using the intravenous route is required during the first 12 weeks of life, pending results of blood and cerebrospinal fluid cultures. Once blood and cerebrospinal fluid cultures are confirmed as negative, the systemic signs have resolved, and the infant is afebrile, antimicrobial therapy may be completed using the oral route for a total duration of therapy of seven to 14 days.18,101,109 Antibiotic parenteral treatment regimens are detailed in Table 1.

Current treatment recommendations for children over the age of 3 months with clinical suspected pyelonephritis are based on eight randomized controlled trials and summarized in a Cochrane review.110 This review, based on three randomized trials (960 children), provides good evidence that oral antibiotics are an effective treatment for acute febrile pyelonephritis. For instance, Hoberman et al.111 compared three days of intravenous cefotaxime followed by 11 days of oral cefixime vs. 14 days of oral cefixime alone in 306 children 1–24 months of age; there was no difference in outcome. A more recent study involving 502 children (>1 month and <7 years of age) had similar results.96 Five trials (including 534 children) using intravenous antibiotics for 48–72h followed by oral antibiotics demonstrated no difference in DMSA abnormality or resolution of symptoms compared with seven to 14 days of intravenous antibiotics.110 Thus, it appears that oral antibiotics may be appropriate for the first febrile UTI in children older than 3 months of age. This review corroborates recent guidelines, which recommend that oral antibiotics should be given for seven to ten days unless the child is seriously unwell or unable to take oral antibiotics, in which case intravenous antibiotics are indicated.18

Empiric oral antibiotics usually recommended are detailed in Table 2. The initial choice of antibacterial therapy is preferably based on the knowledge of the predominant uropathogens in the patient’s age group, antibacterial sensitivity patterns in the practice area, the clinical status of the patient, and the opportunity for close follow-up.101

A common choice for treatment of UTI orally in the well-appearing child includes a sulfonamide-containing antimicrobial (trimethoprim-sulfamethoxazole [TMP-SMX]) or a cephalosporin. Antimicrobials that are excreted in the urine, but fail to achieve therapeutic concentrations in the bloodstream like nitrofurantoin, are not recommended for treatment of febrile infants or children in whom renal involvement is suspected.68 Of particular interest, Edlin et al.112 described resistance patterns in pediatric urinary isolates from 192 hospitals throughout the United States and found that up to 24% of E. coli cultured were resistant to TMP-SMX and 45% were resistant to ampicillin. On the other hand, resistance was found in less than 10% of E. coli for cephalosporins, amoxicillin-clavulanate, ciprofloxacin, and nitrofurantoin. Likewise, a surveillance study of E. coli isolates of 967 children with UTI in a tertiary hospital from 1992 to 1994 revealed that 30% of 1636 isolates were resistant to TMP-SMX.113 Risk factors associated with TMP-SMX resistance were young age, multiple inpatient hospital admissions, and previous antimicrobial therapy for greater than four weeks in the past six months. In Brazil, Reis et al.114 recently described a similar pattern. The authors conducted a retrospective study in 1641 patients with community-acquired UTI for five years (2010–2014). Resistance to ampicillin was observed in 55.9% of the isolated species, TMP-SMX showed 33.6% bacterial resistance, ciprofloxacin 18.4%, levofloxacin 18.0%, gentamicin 6.3%, cefepime 3.7%, and amikacin showed the lowest frequency, at 1.3%. Nevertheless, an important recent issue has emerged regarding the use of fluoroquinolones for the treatment of uncomplicated UTI in all age groups. Pharmacovigilance risk assessment committees from two leading international agencies, the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have released warnings that fluoroquinolones should not be prescribed for patients who have other treatment options for infectious diseases, including uncomplicated UTIs, because the risks outweigh the benefits in these patients and other antibiotics to treat these conditions are available.115,116

There is one systematic review with meta-analysis of six randomized controlled trials (RCTs) including 523 children (aged 2 weeks to 16 years) with microbiologically proven UTI and acute clinical pyelonephritis. These RCTs made comparisons of different classes of antibiotics. Reported outcomes were persistence of bacteriuria at 48–72h, resolution of clinical symptoms, symptomatic recurrence, and adverse effects. Three RCTs compared third generation cephalosporins with other antibiotics, including amoxicillin-clavulanate and TMP-SMX. There was no difference in the reduction of persistent bacteriuria at 48h (two RCTs, RR 5.5, 95% CI, 0.30–1.28), recurrent or persistent UTI five to ten days after the end of therapy (three RCTs, RR 0.42, 95% CI, 0.03–6.23), or the incidence of gastrointestinal adverse effects (three RCTs, n 5 108, RR 0.55, 95% CI, 0.10–3.16).110,117

Alternative options for outpatient management include outpatient parenteral therapy for patients with acute pyelonephritis. Several studies have reported that once-daily parenteral administration of gentamicin or ceftriaxone in a day treatment center is safe, functional, and cost effective in children with UTI.118,119

Treatment options for afebrile children and adolescents with cystitis symptoms are based on many well-conducted trials and systematic reviews.120–122 These studies have shown that short duration therapy (three to four days) is as effective as standard therapy (seven to 14 days) in eradicating urinary bacteria. The NICE guidelines recommend three days of treatment, with the choice of antibiotic directed by local guidelines.123

Prevention of recurrent UTI is a debatable issue in the pediatric setting. Patients with significant urinary tract abnormalities or frequent symptomatic UTIs may benefit from prophylactic antibiotics.101,124 The basis for this practice was established by Smellie et al.,125 who examined the effect of antibiotic prophylaxis in children with recurrent UTI and structurally normal urinary tracts. In this study, 45 children with radiologically normal urinary tracts were given prophylactic doses of cotrimoxazole or nitrofurantoin, or no prophylaxis, after treatment of a symptomatic UTI. During the initial 10 months of the study, the 25 children on prophylaxis had significantly fewer episodes of UTI. Further studies have confirmed that nitrofurantoin, sulfonamides, and cotrimoxazole are effective in reducing the recurrence rate of infection in patients with normal urinary tracts as long as the drug is given.126,127 More recently, in a multicenter clinical trial, Craig et al.92 demonstrated the efficacy of prophylaxis in predisposed children. The authors randomized 576 children to receive either daily TMP-SMX or placebo for 12 months. During the study, UTI developed in 36 of 288 patients (13%) in the group receiving TMP-SMX (antibiotic group) and in 55 of 288 patients (19%) in the placebo group (hazard ratio in the antibiotic group, 0.61; 95% CI, 0.40–0.93; p=0.02).

Nevertheless, the use of long-term antimicrobial prophylaxis to prevent UTI in children with and without VUR remains controversial.63 One meta-analysis investigated antibiotic prophylaxis in children and included six RCTs with a total of 388 participants, predominantly girls younger than 14 years of age, who were identified as being at risk of recurrent UTI, but without any predisposing anatomic or neurologic abnormalities.128 Compared with placebo, four studies reported that the incidence of recurrence was reduced in the antibiotic-treated group, although with a wide range (21%–69%) in the recurrence of repeat positive cultures (RR 0.44, 95% CI, 0.19–1.00). However, when analysis was limited to high-quality studies, the results were not statistically significant. The authors concluded that more evidence in the form of properly randomized double-blinded trials is needed to support the routine use of antibiotic prophylaxis in preventing recurrent UTI in children. Another issue is the effect of prophylaxis on developing a multidrug-resistant recurrent UTI. Selekman et al.129 recently demonstrated in a meta-analysis that children with VUR treated with prophylaxis were more likely to have a multidrug-resistant infection (33% vs. 6%, p<.001) and were more likely to receive broad-spectrum antibiotics (68% vs. 49%, p=.004). Those receiving prophylaxis had 6.4 times the odds (95% confidence interval: 2.7–15.6) of developing a multidrug-resistant infection. In 2007, NICE published its recommendations that healthcare professionals in the United Kingdom should not use antibiotic prophylaxis routinely in infants and children following first time UTI, and only selectively in recurrent UTI.130

Although the effectiveness of antimicrobial prophylaxis for the prevention of UTI has not been fully demonstrated, in the present authors’ experience, some selected patients with recurrent episodes may benefit from this approach by reducing the morbidity and possibly preventing kidney damage. First, following treatment of UTI, the present authors have used prophylactic antibiotic coverage for the young child until urinary tract abnormalities have been excluded by imaging studies. After, the decision regarding continuous antibiotic prophylaxis is based on the results of these imaging studies and/or clinical features, such as age and gender of the children. Concomitantly, it is important to establish fundamental interventions that might reduce recurrent UTI. In this regard, the prompt identification and adequate treatment of urinary tract abnormalities – such as vesicoureteral reflux, posterior urethral valves, or ureteropelvic obstruction – are relevant. It is beyond the scope of this review to explore the myriad facets of the treatment of specific uropathies. Additional interventions that have been associated with a decrease in symptomatic UTI in children with recurrent UTI include treatment of constipation and management of voiding dysfunction.101,131

Obstacles to the effectiveness of antimicrobial prophylaxis are adherence to a daily regimen, side effects associated with the various agents, and the potential for emergence of antimicrobial resistance. According to AAP, to overcome these issues, evidence of effectiveness with a well-tolerated, safe product would be required, and parents would need adequate education to understand the value and importance of adherence.69

Agents of choice for prophylaxis of recurrent UTI are nitrofurantoin and cotrimoxazole.101 In this regard, the earlier mentioned review also identified two RCTs that compared antibiotic classes in prophylaxis of UTI (nitrofurantoin versus trimethoprim, and nitrofurantoin versus cefixime).69 Nitrofurantoin was found to be superior to trimethoprim, but no different from cefixime in reducing the incidence of recurrent repeat-positive urine cultures. In turn, nitrofurantoin was three times more likely to be discontinued because of the adverse effects such as of nausea, vomiting, or stomachache.

In summary, there has been a tendency of less use of prophylaxis due to dispute about its efficacy, increasing bacterial resistance, and a propensity to low adherence. Alternative measures and management of risk factors for recurrent UTI should be emphasized. However, in selected patients carefully followed, prophylaxis can protect from recurrent UTI and long-term sequelae.132