The Role of the Urinary Microbiome in the Prevention of Pediatric Urinary Tract Infections: A Narrative Review

Article information

Urogenit Tract Infect. 2025;20(2):82-95

Publication date (electronic) : 2025 August 31

doi : https://doi.org/10.14777/uti.2550016008

Department of Urology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea

Corresponding author: Byeongdo Song Department of Urology, Hanyang University Guri Hospital, 153, Gyeongchun-ro, Guri 11923, Korea Email: dreamofkgr@naver.com

Received 2025 February 27; Revised 2025 March 22; Accepted 2025 April 28.

Abstract

Urinary tract infections (UTIs) are a common condition in children and often lead to hospitalization. A considerable proportion of children with UTIs (up to 30%) experience at least one recurrence, placing them at risk for long-term complications such as renal scarring. Since the concept of the microbiome was first introduced in 2001, increasing attention has been given to the role of the urinary tract microbiome in maintaining urinary tract homeostasis. Dysbiosis of the urinary microbiome has been recognized as a factor associated with an increased risk of various urinary tract diseases, including UTIs. However, the specific role of the urinary microbiome in the pathophysiology of pediatric UTIs remains incompletely understood. The present review examines recent studies on the urinary microbiome in children and summarizes current strategies for modulating the urinary microbiome to prevent UTI recurrence in the pediatric population.

Keywords: Urinary microbiome; Urobiome; Urinary tract infection; Pediatric urobiome

HIGHLIGHTS

This study explores the vital roles of the urinary microbiome in pediatric urinary tract infection. It highlights the concurrent nonantibiotics prophylaxis strategies which modulating urinary microbiomes in children.

INTRODUCTION

Urinary tract infection (UTI) is common in the general population. Approximately 50%–80% of women experience acute uncomplicated cystitis at least once in the lifetime, and the recurrence rate ranges from 30% to 44%, often within 3 months [1].

For children, UTI is also one of the most frequent infections [2], resulting in frequent hospitalization and a high economic burden [3]. The prevalence of UTI is approximately 7.0% in febrile infants aged <24 months and 7.8% in older children, accounting for 5%–14 % of pediatric emergency room visit [4]. Among the pediatric patients with prior UTI, the rate of UTI recurrence within the first 6 to 12 months ranges from 12% to 30%, with risk of long-term morbidity [5-7]. Moreover, recurrent UTI could induce renal scaring, resulting in chronic renal insufficiency [8]. Therefore, it is necessary for clinicians to understand the pathophysiology of UTI recurrence and proper strategies to prevent recurrence of UTI in children.

Since the concept of microbiome was first suggested by Lederberg and McCray [9], multiple studies have demonstrated that gastrointestinal, vaginal and urinary microbiome are associated with homeostasis of urinary tract [10], and the imbalance of microbiome could result in urinary disease, including UTI. However, there are only a few studies on the role of microbiome in pathophysiology and prevention of pediatric UTI. Therefore, the current review aimed to characterize the role of urinary microbiome in pediatric UTI based on the recent literature, and to summarize contemporary strategies modulating microbiome to prevent UTI recurrence in children.

DIAGNOSTIC TECHNIQUES FOR URINARY MICROBIOME IN CHILDREN

From the 1950s, standard urine culture supported the paradigm that urine is sterile except in the case of infection [11]. Conventional urine culture has been the gold standard diagnostic test for UTI since the 1950s, which utilizes 5% sheep blood agar and MacConkey agar, aerobically incubated at 35℃ for 24 hours [12]. The cutoff value of ≥105 CFU (colony-forming unit)/mL has been universally suggested across all bacterial species to define UTI, but with the issue of oversimplification [13]. Indeed, the validity of the standard urine culture is questionable with approximately 90% of false-negative rate [12]. Moreover, the detection ability of urine culture is rather limited, favoring aerobic and fast-growing Gram-negative uropathogens [14,15]

However, with novel techniques to diagnose UTI in a culture-independent manner, such as whole-genome sequencing, and next-generation sequencing including 16S ribosomal RNA sequencing, the notion that normal urine is sterile has become obsolete [15,16]. Indeed, the Human Microbiome Project, the first large-scale mapping of the human microbiome, clearly showed that microbiome of various anatomical sites contribute to multiple and diverse human health and disease states [17]. With high concordance with urine culture in children, 16S ribosomal RNA analysis provides an additional detective value in children with equivocal culture analysis [18].

Furthermore, to overcome a methodological challenge which is the inability of the culture-independent genomic sequencing technique to differentiate DNA from live versus dead bacteria [16,19], an enhanced quantitative urine culture (EQUC) protocol, using multiple culture media and incubation conditions to cultivate bacteria which do not grow under standard conditions, was developed [14,20]. The EQUC protocol provides the 84% detection of uropathogens compared to 33% by the conventional standard urine culture [20].

URINE SAMPLING IN CHILDREN

To assess urinary microbiome, proper urine sampling should be performed. As the bladder capacity of children is smaller than that of adults, urine sample collection should be carefully considered in pediatric cohorts. Furthermore, the nature of urine as a low microbial biomass sample provides methodological challenges to evaluate urinary microbiome [21,22]. For nontoilet-trained children, noninvasive sampling (midstream urine, adhesive bags, or nappy pads) showed a high prevalence of contamination in urine cultures [23]. Therefore, there are 3 techniques to obtain urine samples in current research on pediatric urinary microbiome; clean-catch midstream urine, transurethral catheterization and suprapubic aspiration. Although suprapubic aspiration provides the “cleanest” urine sample, it has not been recommended in pediatric cohorts due to its invasiveness and ethical considerations, especially in healthy children [22]. Therefore, clean-catch midstream urine and transurethral catheterizations account for approximately equal proportions of current urine sampling techniques cohorts [24].

In toilet-trained children with urinary continence, midstream voided urine is usually sufficient, recognized as the dominating urine sampling technique in infant [23]. Meanwhile, either first voided or midstream urine samples showed no significant differences regarding 16S ribosomal RNA analysis [25].

URINARY MICROBIOME IN “HEALTHY” CHILDREN

Using 16S ribosomal RNA sequencing analysis, up to 200 difference genera of urinary microbiome have been detected, including previously unidentified microbial taxa [26-29]. Several studies which examined urinary microbiome in pediatric cohorts, defined “healthy” children as those who are asymptomatic for UTI and have urinary continence. Approximately 83.0%–90.5% of healthy children have urinary microbiome, but there is no consensus regarding the taxonomy of healthy urine microbiome [24].

The origin of urinary microbiome is still not entirely elucidated. Kinneman et al. [27] demonstrated that even the urine samples from infants and young children younger than 48 months contain urinary microbiome. The most common species identified in urine samples were tissierellaceae, prevotellaeae, veillonellaceae, enterobacteriaceae, and comamonadaceae, while the 5 most common genera were Prevotella, Peptoniphilus, Escherichia, Veillonella, and Finegoldia [27]. Robertson et al. [30] suggested that the composition and function of human microbiome in the first 1,000 days are primarily determined by birth mode, maternal microbiome, exposure to antibiotics, and feeding practices in early life. Indeed, the fetus is considered to be sterile during normal pregnancy, gaining bacteria through maternal transmission at delivery [31]. The composition of infant microbiome matures within 2–3 years after birth [30,31].

There are several studies evaluating the microbiome of prepubertal “healthy” children after toilet training [32-35]. Kassiri et al. [32] revealed that the predominant genera from urine sample in prepubertal “healthy” boys were different with those in adults, suggesting that the development of the urinary microbiome starts in early life and becomes more stable in adulthood. Recently, Kelly et al. [33] demonstrated that the predominant taxa of urinary microbiomes in prepubertal children do not include taxa which are common in adults (e.g. Lactobacillus in females and Staphylococcus in males) and the diversity of urinary microbiome increased with age, mainly in boys.

According to sex, the composition of urine microbiome differed significantly, probably due to differences in sex-specific anatomy and sex hormones levels in the prepubertal period [34]. Recently, Kelly et al. [33] showed that alpha diversity of urinary microbiome was significantly higher in prepubertal girls compared to boys. Another case-control pilot study which included toilet-trained prepubertal female showed that the composition of urinary microbiome did not differ according to bladder and bowel syndrome [35].

URINARY MICROBIOME IN CHILDREN WITH URINARY TRACT INFECTION

To date, there are few studies are on the urinary microbiome in children with UTI. Kinneman et al. [27] demonstrated that the episode of UTI significantly decreased alpha diversity of urinary microbiome in not toilet-trained children. They also showed that the usage of antibiotics within 2 weeks prior to urine sampling significantly reduced the diversity of urinary microbiome. In contrast, Forster et al. [36] suggested that alpha diversity was higher in febrile children with UTI. Although there were differences in the predominant microbial taxa between children with and without UTI, there was no significant difference in beta diversity between the 2 groups. A recent pilot study conducted showed that the recurrence of UTI reduced urinary microbiome diversity. When comparing the diversities of urinary microbiome according to the numbers of UTIs, the diversity was significantly reduced in patients who experienced 3 and more episodes of UTIs. Meanwhile, prophylactic use of antibiotics did not result in the elimination of the urinary microbiome [33].

DYSBIOSIS OF URINARY MICROBIOME AND URINARY TRACT INFECTION

While the advantages of bacteria from the host are rather clear, including nutrient supply, pH and oxygen, it is still unclear what benefits the urinary microbiome provide to the host. However, several roles of urinary microbiome in the homeostasis of the urinary tract have been suggested. For instance, commensal microbiome might compete with uropathogens for common resource, enhance immune system of the host and create a barrier [37].

Although there is no consensus how to define ‘healthy’ urinary microbiome, the imbalance of urinary microbiome might be associated with the presence of UTI. Indeed, the imbalance or disruption of the host microbiome, termed dysbiosis may result in disease susceptibility and pathophysiology of skin, respiratory tract, or gastrointestinal disease in children [38].

In urologic field, dysbiosis of the urinary microbiome is suggested to be related to an increased risk of UTI [39], nephrolithiasis [40], and lower urinary tract symptoms/benign prostatic hyperplasia [41]. For pediatric cohort, dysbiosis of microbiome is also reported to be associated with urinary diseases [42-45].

Conventionally, Escherichia coli was recognized as the most predominant pathogen of primary UTI (approximately 80%) in pediatric cohort [46], followed by Klebsiella, Enterobacter, Proteus and Citrobacter [2,47]. However, whole-genome sequencing revealed that there were no differences in the genomic content of virulence factors genes between strains isolated from patients and healthy individuals. Therefore, E. coli is suggested to be part of the commensal urinary microbiome, and their uropathogenicity might be the result of an imbalance in urinary microbiome composition [48]. Kinneman et al. [27] showed that pediatric patients with UTI showed significantly reduction of alpha diversity compared with children without UTI.

MODIFICATION OF THE URINARY MICROBIOME TO PREVENT PEDIATRIC URINARY TRACT INFECTION

Considering that dysbiosis of urinary microbiome is related with UTI [43,44], the strategies of modifying urinary microbiome could be a potential option for prophylaxis against UTI in children. Those strategies could be divided into 2 classes; antibiotic prophylaxis and non-antibiotic prophylaxis [43,49].

1. Antibiotics Prophylaxis for Pediatric UTI

Although low-dose continuous antibiotic prophylaxis has been attempted to prevent recurrent UTI and subsequent complications [50], its efficacy is controversial. Storm et al. [51] suggested that long-term antibiotic prophylaxis failed to decrease the frequency of UTI or prevent renal scarring, but increased the risk of antibiotic resistance, impacted the microbiome, and induced potential long-term side effects. The updated Cochrane Systematic Review in 2019 demonstrated that antibiotics may provide limited or no significant benefit to reduce recurrent UTI compared to placebo or no treatment, but causing the risk of antibiotic resistance of approximately 2.5 times higher [50].

Another systematic review concluded that continuous antibiotic prophylaxis in children is not recommended due to its limited efficacy and the risk of antimicrobial resistance, but could be suggested for those with significant obstructive uropathies until surgical correction [52]. Meanwhile, another multicenter randomized trial demonstrated that continuous antibiotic prophylaxis presents a small but significant advantage in prevent a first event of UTI in UTI-naïve infants with grade III or severe vesicoureteral reflux. However, the authors also reported that continuous antibiotic prophylaxis showed an increased prevalence of non-E. coli organisms and antimicrobial resistance [53].

Considering the controversial efficacy of antibiotic prophylaxis and the probability of antibiotic resistance, a variety of novel strategies have been tried to prevent UTI in pediatric population [43,54].

2. Nonantibiotics Prophylaxis for Pediatric UTI

Table 1 summarized the concurrent studies which evaluated the therapeutic effect of nonantibiotics prophylaxis, comparing that of conventional antibiotic prophylaxis in pediatric population [55-69].

Table 1.

Summary of studies on the therapeutic effect of nonantibiotics prophylaxis

1) Human breast milk

Breastfeeding is suggested to play a key role in the induction and education of pediatric immune system, protecting children [70]. Indeed, breastfeeding might be a cost-free, natural prophylaxis against pediatric UTI, particularly during the first 6 months of life [71]. Breastfeeding during this period is known to affect the diversity of the gut microbiome, with greater Bacteroides and Bifidobacterium [30]. Furthermore, as human breast milk contains high level of immunoglobulins [72], human breast milk could provide antibacterial effect by preventing bacterial adherence to the gastrointestinal mucosa and urothelium [73].

The presence of the human milk oligosaccharides (HMOs) might explain how breastfeeding could prevent pediatric UTI. HMOs are the third most important component in human breast milk, improving the gastrointestinal barrier and promoting a Bifidobacterium-rich gastrointestinal microbiome, which provides protection against infection [74]. Moreover, HMOs act as soluble decoy receptors for surface adhesins of a variety of pathogens, blocking uropathogens from urothelium [75].

However, the protective effect of human breast milk against UTI in vivo remains rather controversial. Lin et al. [76] suggested that HMOs could protect bladder epithelial cells from cytotoxicity and proinflammatory effects by uropathogenic E. coli (UPEC). In contrast, a prospective study in 2018 failed to show any correlation of breastfeeding with the number of UTI episodes within 5 years [77].

2) Cranberry products

Oral intake of cranberry products, primarily in juices, have been used as a folk medicine for centuries to prevent and treat UTI [78]. Although no definitive mechanism how cranberries prevent UTI has been established, several hypotheses have been proposed. Recently, anthocyanidins and proanthocyanidins, which are tannins (polyphenols) are suggested to explain the antimicrobial mechanisms of cranberries [54]. The isolated A-type proanthocyanidin oligomers purified from cranberries inhibited adhesion of P-fimbriated UPEC adhesion to uroepithelial cells [79], depending on the concentration of cranberry products and the number of cultures the bacteria were exposed to cranberry products [80]. In addition to proanthocyanidins, other phenolic components such as myricetin and quercetin [81], or xyloglucan oligosaccharides [82] are also suggested as potential inhibitor against the adhesion of P-fimbriated UPEC to bladder epithelium. Moreover, cranberry products could also modulate human gut microbiome [83] and probably preventing dysbiosis of gut microbiome, which could partially explain the mechanisms how cranberries prevent UTI [84].

To the best of our knowledge, there are 2 meta-analyses evaluating the efficacy of cranberries to prevent UTI recurrences in the pediatric cohort. A meta-analysis including 23 studies with 3,979 patients showed that cranberry products as adjuvant therapy could substantially decrease the recurrence rate of UTI in susceptible population, including children [85]. Another meta-analysis concluded that cranberry products could reduce the risk of UTI recurrence in children with a normal urinary tract, which was as effective as antibiotic prophylaxis [86]. In terms of safety issue, cranberry is very safe for most children, but intaking large amounts could cause diarrhea [87].

3) Probiotics

Probiotics are defined as “live microorganisms which could provide a health benefit on the host when administered in adequate amounts, confer” [88]. Probiotics, mostly containing Lactobacilli, is also recognized as a potential prophylaxis against symptomatic UTI recurrence [89]. A multicenter randomized trial showed that cow’s skim milk fermented with Lactobacillus paracasei CBA L74 could prevent common pediatric infectious diseases, such as acute rhinitis, tracheitis, laryngitis, pharyngitis and otitis media [90,91]. Indeed, Lactobacilli are prevalent in the healthy vaginal flora, performing anti-biofilm, antioxidant, pathogen-inhibition, and immunomodulation activities against vaginal infection and further UTI [92].

Several articles demonstrated the effectiveness of probiotics to prevent UTI recurrence in children. For children with normal urinary tract, probiotics were more effective than placebo at decreasing the risk of recurrent UTI after their first episode of febrile UTI [64]. Another recent randomized controlled trial showed that probiotics containing Lactobacillus rhamnosus PL1 and Lactobacillus plantarum PM1 decreased UTI of almost 50% compared to the placebo group [93].

However, the prophylactic effect of probiotics against recurrent UTI is rather controversial. According to the Cochrane Systematic Review, probiotics failed to show significant benefit in the prevention of pediatric UTI compared to with placebo or no treatment. However, as the evidence level was limited, the potential benefit of probiotics was not entirely denied [94]. Another meta-analysis also demonstrated that monotherapy of probiotics did not reduce the prevalence or recurrence of UTI in children, but showed a moderate efficacy when used as adjuvant therapy to antibiotics [95]. Meanwhile, Meena et al. [86] found that probiotics provide more beneficial effect to reduce the recurrence of UTI in children with normal urinary tract. Compared to antibiotics, probiotics failed to show significant benefit in preventing UTI, but reduced the risk of antibiotic-resistant bacteria.

There is no consensus with regard to the selection of probiotic strains, accurate dosage, mode of administration, or proper duration of therapy. Moreover, a variety of factors influencing the viability of probiotic bacteria during production, storage, and delivery until consumption time, including temperature, pH, molecular oxygen, and additives may affect the clinical outcomes of probiotics. In addition, the effects of probiotics are strain-specific, and may not be in other strains of the same bacteria [43]. In terms of safety, probiotics are considered to be safe and well-tolerated. The most frequent side effects of oral probiotics included diarrhea, nausea, vomiting, constipation, and vaginal symptoms [94].

Although probiotics are mainly administered orally in children, probiotics could be administered vaginally or as intravesical instillation. The vagina serves as a potential reservoir for uropathogens, resulting in UTI [96]. Indeed, vulvovaginitis is reported to result in UTI by modifying the perineal microbiome and increased colonization of uropathogens [97], while the loss of vaginal Lactobacilli raises the risk of colonization with uropathogenic microbes [89]. In addition, probiotics maintain vagina’s characteristic low pH, by producing lactic acid [43]. Therefore, it would be reasonable to suggest that vaginal probiotics as an efficient method to prevent recurrent UTI. Although the preliminary observational studies have shown promising results in adults, there is a lack of studies on the efficacy of vaginal probiotics in children.

Stapleton [96] reported that vaginal probiotics containing Lactobacillus crispatus (Lactin-V; Osel) significantly prevented UTI recurrence in premenopausal women. The side effects included vaginal discharge, itching, or moderate abdominal discomfort. Gupta and colleagues [89] also demonstrated that either vaginal probiotics or in combination with oral probiotics could effectively prevent recurrent symptomatic UTI episodes in premenopausal women, without no serious adverse events.

Regarding intravesical instillation of probiotics, Forster et al. [98] suggested that intravesical instillation of Lactobacillus rhamnosus GG (LGG) could be safe route of administration, with self-resolved symptoms within one week. Groah et al. [99] also showed that intravesical LGG could be safe and well-tolerated in adult and pediatric patients with neurogenic lower urinary tract dysfunction under clean intermittent catheterization. The same authors reported that intravesical LGG alters the composition and diversity of urinary microbiome [100].

4) Intravesical instillation of glycosaminoglycan

The glycosaminoglycan (GAG) layer, which covers the urothelial epithelium of bladder, forms a barrier to prevent the adherence of uropathogens [101]. Recently, the GAG replacement therapy with intravesical instillation of combined hyaluronic acid and chondroitin sulfate is tried in the patients with recurrent cystitis, post-radiation cystitis and bladder pain syndrome, suggested as a potential prophylaxis against UTI [102,103].

However, there are only 2 studies on the effectiveness of intravesical GAG replacement therapy in children with recurrent UTI [104,105]. In 2015, a case-series first reported the efficacy of intravesical hyaluronic acid instillation in children with recurrent UTI, demonstrating that 86.7% experienced overall complete or partial response within 24 months [104]. Cicek et al. [105] showed that intravesical hyaluronic acid instillation significantly decreased mean UTIs per patient-month during a follow-up period of 16 months, among the pediatric patients with spina bifida and neurogenic bladder who undergo clean intermittent catheterization.

5) Immunostimulants and autologous bacterial lysates

Since the oral vaccine, Uro-Vaxom/OM-89 was first approved in Europe, immunostimulants have become a promising prophylaxis against recurrent UTI, providing UTI-free rates of 55%–90% [106]. A recent meta-analysis suggested that vaccines could be effective in the short term (6–12 months) at reducing recurrent UTI for adult females, but the evidence level was limited [107]. Another systemic review also showed that immunostimulants could decrease the risk of UTI recurrence compared to placebo [108].

However, a majority of previous studies on the efficacy of immunostimulants included only adult population. Only a few studies assessed the effectiveness of immunostimulants in children. A recent meta-analysis reported that immunostimulants could reduce the risk of acute upper respiratory tract infections by 39% in children, despite limited quality of evidence [109]. To the best of our knowledge, there is no previous studies on the efficacy of immunostimulants for prevention of pediatric UTI.

Autologous bacterial lysates are manufactured with the isolated bacteria from the infected site, inactivated by heat, and homogenized in a suspension, favoring immunoglobulin (Ig) G and IgM production and T-lymphocyte activation [110,111]. In adult, autologous bacterial lysates were reported to reduce UTI recurrence [112]. A prospective study also showed a promising result in children with recurrent UTI due to congenital anomalies of the urinary tract after surgical intervention, showing insufficient response to antimicrobial therapy. The autologous bacterial lysates reduced the presence of E. coli in the urine culture from 92.5% of patients at the beginning of the study, to 55.5% and 34% for the second and third months, respectively [113].

CONCLUSIONS

With advanced techniques such as EQUC and high-throughput molecular gene sequencing analysis, the presence of urinary microbiome is now well-known. Recently, the urinary microbiome has been recognized to play an important role in maintaining homeostasis and health of urinary tract. In childhood, starts to mature and changes with age, stabilizing in the adulthood. The imbalance or dysbiosis of the urinary microbiomes may cause a variety of pediatric urinary tract disease, including UTI. Indeed, the potential effect of manipulating urinary microbiome on the prevention of UTI seems promising. Further larger scale, well-designed, prospective studies are required to elucidate the association between the urinary microbiome and the common risk factors of pediatric UTI, including vesicoureteral reflux, obstructive uropathy, overactive bladder, or neurogenic bladder. This will enable the development of novel microbiome-based prophylactic strategies to control recurrent UTI in children.

Notes

Funding/Support

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of Interest

The authors have nothing to disclose.

Author Contribution

Byeongdo Song is the single author of this article.

References

1. Gupta K, Trautner BW. Diagnosis and management of recurrent urinary tract infections in non-pregnant women. BMJ 2013;346:f3140.

2. Yoo YM, Park BS, Lee SY, Park KJ, Jung HU, Pai KS. An epidemiologic study on hosts and pathogens of urinary tract infection in urban children of Korea (2012-2017). Child Kidney Dis 2019;23:29–35.

3. Spencer JD, Schwaderer A, McHugh K, Hains DS. Pediatric urinary tract infections: an analysis of hospitalizations, charges, and costs in the USA. Pediatr Nephrol 2010;25:2469–75.

4. Shaikh N, Morone NE, Bost JE, Farrell MH. Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr Infect Dis J 2008;27:302–8.

5. Conway PH, Cnaan A, Zaoutis T, Henry BV, Grundmeier RW, Keren R. Recurrent urinary tract infections in children: risk factors and association with prophylactic antimicrobials. JAMA 2007;298:179–86.

6. Dai B, Liu Y, Jia J, Mei C. Long-term antibiotics for the prevention of recurrent urinary tract infection in children: a systematic review and meta-analysis. Arch Dis Child 2010;95:499–508.

7. Petcu CT, Stehr E, Isaac JP, Desai D. Management of paediatric recurrent urinary tract infections and challenges in special patient populations. Aust J Gen Pract 2021;50:458–64.

8. Becknell B, Schober M, Korbel L, Spencer JD. The diagnosis, evaluation and treatment of acute and recurrent pediatric urinary tract infections. Expert Rev Anti Infect Ther 2015;13:81–90.

9. Lederberg J, McCray AT. 'Ome sweet 'omics -- a genealogical treasury of words. Scientist 2001;15:8.

10. Jones-Freeman B, Chonwerawong M, Marcelino VR, Deshpande AV, Forster SC, Starkey MR. The microbiome and host mucosal interactions in urinary tract diseases. Mucosal Immunol 2021;14:779–92.

11. Zorc JJ, Kiddoo DA, Shaw KN. Diagnosis and management of pediatric urinary tract infections. Clin Microbiol Rev 2005;18:417–22.

12. Hilt EE, McKinley K, Pearce MM, Rosenfeld AB, Zilliox MJ, Mueller ER, et al. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol 2014;52:871–6.

13. Sathiananthamoorthy S, Malone-Lee J, Gill K, Tymon A, Nguyen TK, Gurung S, et al. Reassessment of routine midstream culture in diagnosis of urinary tract infection. J Clin Microbiol 2019;57:e01452–18.

14. Wolfe AJ, Toh E, Shibata N, Rong R, Kenton K, Fitzgerald M, et al. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol 2012;50:1376–83.

15. Xu R, Deebel N, Casals R, Dutta R, Mirzazadeh M. A new gold rush: a review of current and developing diagnostic tools for urinary tract infections. Diagnostics (Basel) 2021;11:479.

16. Thomas-White K, Brady M, Wolfe AJ, Mueller ER. The bladder is not sterile: History and current discoveries on the urinary microbiome. Curr Bladder Dysfunct Rep 2016;11:18–24.

17. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature 2007;449:804–10.

18. Marshall CW, Kurs-Lasky M, McElheny CL, Bridwell S, Liu H, Shaikh N. Performance of conventional urine culture compared to 16S rRNA gene amplicon sequencing in children with suspected urinary tract infection. Microbiol Spectr 2021;9:e0186121.

19. Gerber D, Forster CS, Hsieh M. The role of the genitourinary microbiome in pediatric urology: a review. Curr Urol Rep 2018;19:13.

20. Price TK, Dune T, Hilt EE, Thomas-White KJ, Kliethermes S, Brincat C, et al. The clinical urine culture: enhanced techniques improve detection of clinically relevant microorganisms. J Clin Microbiol 2016;54:1216–22.

21. Karstens L, Asquith M, Caruso V, Rosenbaum JT, Fair DA, Braun J, et al. Community profiling of the urinary microbiota: considerations for low-biomass samples. Nat Rev Urol 2018;15:735–49.

22. Brubaker L, Gourdine JF, Siddiqui NY, Holland A, Halverson T, Limeria R, et al. Forming consensus to advance urobiome research. mSystems 2021;6:e0137120.

23. Brandström P, Hansson S. Urinary tract infection in children. Pediatr Clin North Am 2022;69:1099–114.

24. Jeries LM, Sysoeva TA, Karstens L, Kelly MS. Synthesis of current pediatric urinary microbiome research. Front Pediatr 2024;12:1396408.

25. Ozer MS, Yildiz HA, Incir C, Deger MD, Bozkurt O, Ergor G, et al. Urinary microbiota; which non-ınvasive urine collection method should we use? Int J Clin Pract 2021;75:e14193.

26. Hoffman C, Siddiqui NY, Fields I, Gregory WT, Simon HM, Mooney MA, et al. Species-level resolution of female bladder microbiota from 16S rRNA amplicon sequencing. mSystems 2021;6:e0051821.

27. Kinneman L, Zhu W, Wong WS, Clemency N, Provenzano M, Vilboux T, et al. Assessment of the urinary microbiome in children younger than 48 months. Pediatr Infect Dis J 2020;39:565–70.

28. Kispal ZF, Vajda P, Kardos D, Klymiuk I, Moissl-Eichinger C, Castellani C, et al. The local microbiome after pediatric bladder augmentation: intestinal segments and the native urinary bladder host similar mucosal microbiota. J Pediatr Urol 2019;15:30.e1–30.e7.

29. Moustafa A, Li W, Singh H, Moncera KJ, Torralba MG, Yu Y, et al. Microbial metagenome of urinary tract infection. Sci Rep 2018;8:4333.

30. Robertson RC, Manges AR, Finlay BB, Prendergast AJ. The human microbiome and child growth - first 1000 days and beyond. Trends Microbiol 2019;27:131–47.

31. Roswall J, Olsson LM, Kovatcheva-Datchary P, Nilsson S, Tremaroli V, Simon MC, et al. Developmental trajectory of the healthy human gut microbiota during the first 5 years of life. Cell Host Microbe 2021;29:765–76.e3.

32. Kassiri B, Shrestha E, Kasprenski M, Antonescu C, Florea LD, Sfanos KS, et al. A prospective study of the urinary and gastrointestinal microbiome in prepubertal males. Urology 2019;131:204–10.

33. Kelly MS, Dahl EM, Jeries L, Sysoeva TA, Karstens L. Characterization of pediatric urinary microbiome at species-level resolution indicates variation due to sex, age, and urologic history. medRxiv. J Pediatr Urol 2024;20:884–93.

34. Fredsgaard L, Thorsteinsson K, Bundgaard-Nielsen C, Ammitzbøll N, Leutscher P, Chai Q, et al. Description of the voided urinary microbiota in asymptomatic prepubertal children - a pilot study. J Pediatr Urol 2021;17:545.e1–545.e8.

35. Cole EB, Khemmani M, Liu H, Halverson TM, Noronha MF, Forster CS, et al. Urogenital urobiome of healthy children does not differ from that of children with bladder and bowel dysfunction. J Pediatr Urol 2023;19:368.e1–368.e8.

36. S Forster C, Liu H, Kurs-Lasky M, Ullmer W, Krumbeck JA, Shaikh N. Uromycobiome in infants and toddlers with and without urinary tract infections. Pediatr Nephrol 2023;38:2117–23.

37. Whiteside SA, Razvi H, Dave S, Reid G, Burton JP. The microbiome of the urinary tract--a role beyond infection. Nat Rev Urol 2015;12:81–90.

38. Johnson CL, Versalovic J. The human microbiome and its potential importance to pediatrics. Pediatrics 2012;129:950–60.

39. Saenz CN, Neugent ML, De Nisco NJ. The Human Urinary Microbiome and Its Potential Role in Urinary Tract Infections. Eur Urol Focus 2024;10:889–92.

40. Wang Z, Zhang Y, Zhang J, Deng Q, Liang H. Recent advances on the mechanisms of kidney stone formation (Review). Int J Mol Med 2021;48:149.

41. Pina-Vaz T, Silva AC, Silva C, Miranda I, Cruz F, Silva JA. The urinary and prostatic microbiome in non-neurogenic male LUTS/BPH: a systematic review. Neurourol Urodyn 2024;43:1938–47.

42. Kusumi K, Islam MS, Banker H, Safadi FF, Raina R. Navigating the microbial maze: unraveling the connection between gut microbiome and pediatric kidney and urinary tract disease. Pediatr Nephrol 2025;40:339–53.

43. Kawalec A, Zwolińska D. Emerging role of microbiome in the prevention of urinary tract infections in children. Int J Mol Sci 2022;23:870.

44. Lemberger U, Quhal F, Bruchbacher A, Shariat SF, Hiess M. The microbiome in urinary tract infections in children - an update. Curr Opin Urol 2021;31:147–54.

45. Curley T, Forster CS. Recurrent UTIs in girls: what is the role of the microbiome? Urology 2021;151:94–7.

46. Marsh MC, Junquera GY, Stonebrook E, Spencer JD, Watson JR. Urinary tract infections in children. Pediatr Rev 2024;45:260–70.

47. Gökçe İ, Çiçek N, Güven S, Altuntaş Ü, Bıyıklı N, Yıldız N, et al. Changes in bacterial resistance patterns of pediatric urinary tract infections and rationale for empirical antibiotic therapy. Balkan Med J 2017;34:432–5.

48. Garretto A, Miller-Ensminger T, Ene A, Merchant Z, Shah A, Gerodias A, et al. Genomic survey of E. coli from the bladders of women with and without lower urinary tract symptoms. Front Microbiol 2020;11:2094.

49. Kwok M, McGeorge S, Mayer-Coverdale J, Graves B, Paterson DL, Harris PN, et al. Guideline of guidelines: management of recurrent urinary tract infections in women. BJU Int 2022;130 Suppl 3(Suppl 3):11–22.

50. Williams G, Craig JC. Long-term antibiotics for preventing recurrent urinary tract infection in children. Cochrane Database Syst Rev 2019;4:CD001534.

51. Storm DW, Braga LH, Cooper CS. Continuous antibiotic prophylaxis in pediatric urology. Urol Clin North Am 2018;45:525–38.

52. Autore G, Bernardi L, Ghidini F, La Scola C, Berardi A, Biasucci G, et al. Antibiotic prophylaxis for the prevention of urinary tract infections in children: guideline and recommendations from the emilia-romagna pediatric urinary tract infections (UTI-Ped-ER) study group. Antibiotics (Basel) 2023;12:1040.

53. Morello W, Baskin E, Jankauskiene A, Yalcinkaya F, Zurowska A, Puccio G, et al. Antibiotic prophylaxis in infants with grade III, IV, or V vesicoureteral reflux. N Engl J Med 2023;389:987–97.

54. Sihra N, Goodman A, Zakri R, Sahai A, Malde S. Nonantibiotic prevention and management of recurrent urinary tract infection. Nat Rev Urol 2018;15:750–76.

55. Foda MM, Middlebrook PF, Gatfield CT, Potvin G, Wells G, Schillinger JF. Efficacy of cranberry in prevention of urinary tract infection in a susceptible pediatric population. Can J Urol 1995;2:98–102.

56. Schlager TA, Anderson S, Trudell J, Hendley JO. Effect of cranberry juice on bacteriuria in children with neurogenic bladder receiving intermittent catheterization. J Pediatr 1999;135:698–702.

57. Ferrara P, Romaniello L, Vitelli O, Gatto A, Serva M, Cataldi L. Cranberry juice for the prevention of recurrent urinary tract infections: a randomized controlled trial in children. Scand J Urol Nephrol 2009;43:369–72.

58. Afshar K, Stothers L, Scott H, MacNeily AE. Cranberry juice for the prevention of pediatric urinary tract infection: a randomized controlled trial. J Urol 2012;188:1584–7.

59. Salo J, Uhari M, Helminen M, Korppi M, Nieminen T, Pokka T, et al. Cranberry juice for the prevention of recurrences of urinary tract infections in children: a randomized placebo-controlled trial. Clin Infect Dis 2012;54:340–6.

60. Wan KS, Liu CK, Lee WK, Ko MC, Huang CS. Cranberries for preventing recurrent urinary tract infections in uncircumcised boys. Altern Ther Health Med 2016;22:20–3.

61. Dotis J, Stabouli S, Pavlaki A, Papachristou F, Printza N. Cranberry standardized capsules may prevent recurrences of urinary tract infections in children. Clin Pediatr 2018;1:1007.

62. Uberos J, Nogueras Ocana M, Fernandez-Puentes V, Rodriguez-Belmonte R, Narbona-López E, Molina Carballo A, et al. Cranberry syrup vs trimethoprim in the prophylaxis of recurrent urinary tract infections among children: a controlled trial. Open Access J Clin Trials 2012;4:31–8.

63. Dani C, Biadaioli R, Bertini G, Martelli E, Rubaltelli FF. Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infants. A prospective double-blind study. Biol Neonate 2002;82:103–8.

64. Sadeghi-Bojd S, Naghshizadian R, Mazaheri M, Ghane Sharbaf F, Assadi F. Efficacy of probiotic prophylaxis after the first febrile urinary tract infection in children with normal urinary tracts. J Pediatric Infect Dis Soc 2020;9:305–10.

65. Lee SJ, Cha J, Lee JW. Probiotics prophylaxis in pyelonephritis infants with normal urinary tracts. World J Pediatr 2016;12:425–9.

66. Lee SJ, Shim YH, Cho SJ, Lee JW. Probiotics prophylaxis in children with persistent primary vesicoureteral reflux. Pediatr Nephrol Berl Ger 2007;22:1315–20.

67. Lee SJ, Lee JW. Probiotics prophylaxis in infants with primary vesicoureteral reflux. Pediatr Nephrol Berl Ger 2015;30:609–13.

68. Mohseni MJ, Aryan Z, Emamzadeh-Fard S, Paydary K, Mofid V, Joudaki H, et al. Combination of probiotics and antibiotics in the prevention of recurrent urinary tract infection in children. Iran J Pediatr 2013;23:430–8.

69. Madden-Fuentes RJ, Arshad M, Ross SS, Seed PC. Efficacy of fluoroquinolone/probiotic combination therapy for recurrent urinary tract infection in children: a retrospective analysis. Clin Ther 2015;37:2143–7.

70. Verhasselt V. Breastfeeding, a personalized medicine with influence on short- and long-term immune health. Nestle Nutr Inst Workshop Ser 2020;94:48–58.

71. Mårild S, Hansson S, Jodal U, Odén A, Svedberg K. Protective effect of breastfeeding against urinary tract infection. Acta Paediatr 2004;93:164–8.

72. Rio-Aige K, Azagra-Boronat I, Castell M, Selma-Royo M, Collado MC, Rodríguez-Lagunas MJ, et al. The breast milk immunoglobulinome. Nutrients 2021;13:1810.

73. Levy I, Comarsca J, Davidovits M, Klinger G, Sirota L, Linder N. Urinary tract infection in preterm infants: the protective role of breastfeeding. Pediatr Nephrol 2009;24:527–31.

74. Dinleyici M, Barbieur J, Dinleyici EC, Vandenplas Y. Functional effects of human milk oligosaccharides (HMOs). Gut Microbes 2023;15:2186115.

75. Donovan SM, Comstock SS. Human Milk Oligosaccharides influence neonatal mucosal and systemic immunity. Ann Nutr Metab 2016;69 Suppl 2(Suppl 2):42–51.

76. Lin AE, Autran CA, Espanola SD, Bode L, Nizet V. Human milk oligosaccharides protect bladder epithelial cells against uropathogenic Escherichia coli invasion and cytotoxicity. J Infect Dis 2014;209:389–98.

77. Ardiç C, Yavuz E. Effect of breastfeeding on common pediatric infections: a 5-year prospective cohort study. Arch Argent Pediatr 2018;116:126–32.

78. Jepson R, Craig J, Williams G. Cranberry products and prevention of urinary tract infections. JAMA 2013;310:1395–6.

79. Howell AB, Reed JD, Krueger CG, Winterbottom R, Cunningham DG, Leahy M. A-type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry 2005;66:2281–91.

80. Pinzón-Arango PA, Liu Y, Camesano TA. Role of cranberry on bacterial adhesion forces and implications for Escherichia coli-uroepithelial cell attachment. J Med Food 2009;12:259–70.

81. Kimble LL, Mathison BD, Kaspar KL, Khoo C, Chew BP. Development of a fluorometric microplate antiadhesion assay using uropathogenic Escherichia coli and human uroepithelial cells. J Nat Prod 2014;77:1102–10.

82. Hotchkiss AT Jr, Nuñez A, Strahan GD, Chau HK, White AK, Marais JP, et al. Cranberry Xyloglucan structure and inhibition of Escherichia coli adhesion to epithelial cells. J Agric Food Chem 2015;63:5622–33.

83. Lessard-Lord J, Roussel C, Lupien-Meilleur J, Généreux P, Richard V, Guay V, et al. Short term supplementation with cranberry extract modulates gut microbiota in human and displays a bifidogenic effect. NPJ Biofilms Microbiomes 2024;10:18.

84. González de Llano D, Moreno-Arribas MV, Bartolomé B. Cranberry polyphenols and prevention against urinary tract infections: relevant considerations. Molecules 2020;25:3523.

85. Xia JY, Yang C, Xu DF, Xia H, Yang LG, Sun GJ. Consumption of cranberry as adjuvant therapy for urinary tract infections in susceptible populations: a systematic review and meta-analysis with trial sequential analysis. PLoS One 2021;16:e0256992.

86. Meena J, Thomas CC, Kumar J, Raut S, Hari P. Non-antibiotic interventions for prevention of urinary tract infections in children: a systematic review and meta-analysis of randomized controlled trials. Eur J Pediatr 2021;180:3535–45.

87. Goldman RD. Cranberry juice for urinary tract infection in children. Can Fam Physician 2012;58:398–401.

88. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11:506–14.

89. Gupta V, Mastromarino P, Garg R. Effectiveness of prophylactic oral and/or vaginal probiotic supplementation in the prevention of recurrent urinary tract infections: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2024;78:1154–61.

90. Corsello G, Carta M, Marinello R, Picca M, De Marco G, Micillo M, et al. Preventive effect of cow's milk fermented with Lactobacillus paracasei CBA L74 on common infectious diseases in children: a multicenter randomized controlled trial. Nutrients 2017;9:669.

91. Nocerino R, Paparo L, Terrin G, Pezzella V, Amoroso A, Cosenza L, et al. Cow's milk and rice fermented with Lactobacillus paracasei CBA L74 prevent infectious diseases in children: a randomized controlled trial. Clin Nutr 2017;36:118–25.

92. Chee WJY, Chew SY, Than LTL. Vaginal microbiota and the potential of Lactobacillus derivatives in maintaining vaginal health. Microb Cell Fact 2020;19:203.

93. Daniel M, Szymanik-Grzelak H, Sierdziński J, Pańczyk-Tomaszewska M. Lactobacillus rhamnosus PL1 and Lactobacillus plantarum PM1 versus Placebo as prophylaxis for recurrence of urinary tract infections in children. Microorganisms 2024;12:1037.

94. Schwenger EM, Tejani AM, Loewen PS. Probiotics for preventing urinary tract infections in adults and children. Cochrane Database Syst Rev 2015;2015:CD008772.

95. Hosseini M, Yousefifard M, Ataei N, Oraii A, Mirzay Razaz J, Izadi A. The efficacy of probiotics in prevention of urinary tract infection in children: a systematic review and meta-analysis. J Pediatr Urol 2017;13:581–91.

96. Stapleton AE. The vaginal microbiota and urinary tract infection. Microbiol Spectr 2016;4:10.1128/microbiolspec.UTI-0025-2016.

97. Gorbachinsky I, Sherertz R, Russell G, Krane LS, Hodges SJ. Altered perineal microbiome is associated with vulvovaginitis and urinary tract infection in preadolescent girls. Ther Adv Urol 2014;6:224–9.

98. Forster CS, Hsieh MH, Pérez-Losada M, Caldovic L, Pohl H, Ljungberg I, et al. A single intravesical instillation of Lactobacillus rhamnosus GG is safe in children and adults with neuropathic bladder: a phase Ia clinical trial. J Spinal Cord Med 2021;44:62–9.

99. Groah SL, Rounds AK, Ljungberg IH, Sprague BM, Frost JK, Tractenberg RE. Intravesical Lactobacillus rhamnosus GG is safe and well tolerated in adults and children with neurogenic lower urinary tract dysfunction: first-in-human trial. Ther Adv Urol 2019;11:1756287219875594.

100. Groah SL, Rounds AK, Pérez-Losada M. Intravesical Lactobacillus rhamnosus GG alters urobiome composition and diversity among people with neurogenic lower urinary tract dysfunction. Top Spinal Cord Inj Rehabil 2023;29:44–57.

101. Poggi MM, Johnstone PA, Conner RJ. Glycosaminoglycan content of human bladders. a method of analysis using cold-cup biopsies. Urol Oncol 2000;5:234–7.

102. Parsons CL. Epithelial coating techniques in the treatment of interstitial cystitis. Urology 1997;49(5A Suppl):100–4.

103. Poletajew S, Brzózka MM, Krajewski W, Kamecki H, Nyk Ł, Kryst P. Glycosaminoglycan replacement therapy with intravesical instillations of combined hyaluronic acid and chondroitin sulfate in patients with recurrent cystitis, post-radiation cystitis and bladder pain syndrome: a narrative review. Pain Ther 2024;13:1–22.

104. Fidan K, Büyükkaragöz B, Özen O, Demirogullari B, Söylemezoglu O. The use of intravesical hyaluronic acid for recurrent urinary tract infections in children: a case-series study. Ren Fail 2015;37:354–8.

105. Cicek N, Yildiz N, Alpay H. Intravesical hyaluronic acid treatment in recurrent urinary tract infections in children with spina bifida and neurogenic bladder. J Pediatr Urol 2020;16:366.e1–366.e5.

106. Prattley S, Geraghty R, Moore M, Somani BK. Role of vaccines for recurrent urinary tract infections: a systematic review. Eur Urol Focus 2020;6:593–604.

107. Mak Q, Greig J, Dasgupta P, Malde S, Raison N. Bacterial vaccines for the management of recurrent urinary tract infections: a systematic review and meta-analysis. Eur Urol Focus 2024;10:761–9.

108. Aziminia N, Hadjipavlou M, Philippou Y, Pandian SS, Malde S, Hammadeh MY. Vaccines for the prevention of recurrent urinary tract infections: a systematic review. BJU Int 2019;123:753–68.

109. Berber A, Del-Río-Navarro BE, Reyes-Noriega N, Sienra-Monge JJL. Immunostimulants for preventing respiratory tract infection in children: a systematic review and meta-analysis. World Allergy Organ J 2022;15:100684.

110. Taha Neto KA, Nogueira Castilho L, Reis LO. Oral vaccine (OM-89) in the recurrent urinary tract infection prophylaxis: a realistic systematic review with meta-analysis. Actas Urol Esp 2016;40:203–8.

111. Brumbaugh AR, Mobley HL. Preventing urinary tract infection: progress toward an effective Escherichia coli vaccine. Expert Rev Vaccines 2012;11:663–76.

112. Ahumada-Cota RE, Hernandez-Chiñas U, Milián-Suazo F, Chávez-Berrocal ME, Navarro-Ocaña A, Martínez-Gómez D, et al. Effect and analysis of bacterial lysates for the treatment of recurrent urinary tract infections in adults. Pathogens 2020;9:102.

113. Hernández-Chiñas U, Chávez-Berrocal ME, Ahumada-Cota RE, Navarro-Ocaña A, Rocha-Ramírez LM, Pérez-Del Mazo Y, et al. Prospective study in children with complicated urinary tract infection treated with autologous bacterial lysates. Microorganisms 2021;9:1811.

Article information Continued

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Study	Patients’characteristics	No. of patients	Intervention	Control	Duration of follow-up (mo)	Significant findings
Cranberry products versus placebo
Foda et al. [55] (1995)	Children aged 1–18 yr with neuropathic bladder requiring CIC	40	15 mL/kg/day of cranberry cocktail (30% cranberry concentrate)	Placebo	12	No significant difference in the rate of UTI.
Schlager et al. [56] (1999)	Children aged 2–18 yr with neuropathic bladder requiring CIC	15	60 mL of cranberry concentrate (300 ml juice)	Placebo	3	No significant difference in the rate of bacteriuria.
Ferrara et al. [57] (2009)	Girls aged 3–14 yr	28 vs. 29	7.5 g of cranberry concentrate + 1.7 g of lingonberry concentrate in 50-mL water - daily	Control	6	Cranberry group showed fewer rate of symptomatic UTI (18.5% vs. 48.1%, p<0.05)
Afshar et al. [58] (2012)	Children aged with 5–18 yr	20 vs. 20	2 mL/kg of cranberry juice every day	Placebo	12	Cranberry group showed 65% reduction in the risk of UTI (p=0.045)
Salo et al. [59] (2012)	Children aged with 1–16 yr	129 vs. 134	5-mL/kg cranberry juice up to 500 mL for 6 mo	Placebo	12	No significant difference in the recurrence of UTI (p=0.21)
Salo et al. [59] (2012)	Children aged with 1–16 yr	129 vs. 134	5-mL/kg cranberry juice up to 500 mL for 6 mo	Placebo	12	Cranberry group showed significantly fewer days of microbials (-6 days per patient-year, p<0.001)
Wan et al. [60] (2016)	Boys aged with 6–18 yr	28 vs. 39	120 mL of cranberry juice once daily	Placebo	6	Cranberry group showed lower incidence of UTI. (25% vs. 35.9%)
Dotis et al. [61] (2018)	Children aged with 2–18 yr	30 vs. 35	Cranberry extract 250 mg every day	Routine care	12	Cranberry group showed 1ower percentage of UTIs, fewer days/year on antibiotic treatment and lower percentage of initiation of antimicrobial prophylaxis (p<0.05)
Cranberry products versus antibiotics prophylaxis
Uberos et al. [62] (2012)	Children aged with 1 mo–13 yr	75 vs. 117	Cranberry 0.2 mL/kg	TMP 0.2 mL/kg/day	12	No significant difference in the recurrence of UTI.
Uberos et al. [62] (2012)	Children aged with 1 mo–13 yr	75 vs. 117	Cranberry 0.2 mL/kg	TMP 0.2 mL/kg/day	12	No significant difference in the rate of antimicrobial resistance.
Probiotics versus placebo
Dani et al. [63] (2002)	Newborn infants with a gestational age <33 wk or birthweight <1,500 g	295 vs. 290	7 Days of Lactobacillus GG supplementation starting with the first feed	Placebo	2	Probiotics group showed a fewer rate of UTI (3.4% vs. 5.8%), but not significantly.
Sadeghi-Bojd [64] et al. (2019)	Children aged with 4 mo–5 yr	91 vs. 90	Probiotic mixture (Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifdobacterium bifidum, and Bifdobacterium lactis)	Placebo	18	Probiotics group showed a superior UTI-free rate at 18 mo to placebo group (96.7% vs. 83.3%)
Lee et al. [65] (2016)	Children aged with 1–24 mo	73 vs. 50	Lactobacillus acidophilus (10⁸ CFU/g bid)	TMP/SMX (2/10 mg/kg qhs)	6	Probiotics group showed lower rate of recurrent UTI (8.2% vs. 20.6%, p=0.035)
Ferrara et al. [57] (2009)	Girls aged with 3–14 yr	28 vs. 29	100 mL of Lactobacillus GG drink on 5 days a month	Control	6	No significant difference in the rate of symptomatic UTI (42.3% vs. 48.1%, p>0.05)
Probiotics versus antibiotics prophylaxis
Lee et al. [66] (2007)	Persistent primary VUR (all grades) after TMP-SMX prophylaxis for 1 yr	60 vs. 60	Lactobacillus acidophilus (10⁸ CFU/g bid)	TMP/SMX (2/10 mg/kg qhs)	12	No significant difference in the recurrence of UTI (18.3% vs. 21.6%, p=0.926)
Lee et al. [67] (2015)	Children aged with 1 wk–1 yr	64 vs. 64	Lactobacillus acidophilus (10⁸ CFU/g bid)	TMP/SMX (2/10 mg/kg qhs)	12	Probiotics group showed a slightly lower rate of recurrent UTI (32.8% vs. 40.6%) but not significantly (p=0.348)
Lee et al. [65] (2016)	Children aged with 1–24 mo	73 vs. 50	Lactobacillus acidophilus (10⁸ CFU/g bid)	TMP/SMX (2/10 mg/kg qhs)	6	No significant difference in the rate of recurrent UTI (8.2% vs. 10.0%, p=0.532)
Probiotics plus antibiotics versus antibiotics alone
Mohseni et al. [68] (2013)	Children aged 3–15 yr with recurrent UTI and VUR (all grades)	41 vs. 41	Probiotic yoghurt (0.25 mL/kg from 100 ml yoghurt containing 10⁷ CFU/mL of Lactobacillus acidophilus and Bifidobacterium lactis)+nitrofurantoin 1 mg/kg/day	Nitrofurantoin 1 mg/kg/day	36	No significant difference in the recurrence of UTI (39% vs. 50%, p=0.4)
Mohseni et al. [68] (2013)		41 vs. 41		Nitrofurantoin 1 mg/kg/day	36	Probiotics + antibiotics groups showed a lower rate of febrile UTI (0.00±0.00 vs. 0.13±0.40, p=0.03)
Madden-Fuentes et al. [69] (2015)	Children aged 4–13 yr	10 (retrospective)	Ciprofloxacin (20 mg/kg bid) + 250 mg of Saccharomyces boulardii daily for 1 yr	NA	9	Number of UTI decreased after therapy
Madden-Fuentes et al. [69] (2015)	Children aged 4–13 yr	10 (retrospective)		NA	9	Of the 8 patients with known compliance, 7 (88%) were free of recurrent UTIs.