What Is Recurrent Urinary Tract Infection?

The American Urologic Association, the Canadian Urologic Association, and the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (AUA/CUA/SUFU) guidelines for “Recurrent uncomplicated Urinary Tract Infections in Women” acknowledge that even though there are multiple definitions for rUTI, the 2 most commonly used are: 2 episodes of acute bacterial cystitis within 6 months or 3 episodes within 1 year. These episodes are expected to be separate infections with resolution of symptoms between episodes. ^, It is important to note that this definition applies largely to women with uncomplicated UTIs. Given that the SCI/D population is predominately male and that a UTI in someone with NLUTD is, by definition, “complicated”, this definition of rUTI may not apply directly to the population with NLUTD. However, in the absence of a rUTI definition specific for individuals with NLUTD, 2 UTIs in 6 months or 3 UTIs in 1 year will be utilized. Using these parameters, the majority of individuals with NLUTD will have complicated UTIs that also qualify as rUTI, as the average frequency for UTIs within individuals with NLUTD is 2.5 episodes of infection per patient per year. For simplicity, we will utilize rUTI and UTI interchangeably throughout the article, given the caveats noted earleir.

Diagnostic Inconsistencies and Challenges

The conventional diagnostic framework (for people without NLUTD) relies on a combination of (1) symptoms, (2) inflammatory reaction (typically white blood cells), and (3) bacterial load. However, when this framework is applied to people with NLUTD (who often utilize urinary catheters), application is encumbered by differences in the experience of symptoms among people with NLUTD, and the frequent presence of pyuria and bacteriuria in the absence of symptoms, which is evidenced in inconsistencies amongst authoritative guidelines. Table 1 demonstrates the discordance in diagnostic criteria by symptoms, inflammation, and bacterial load across authoritative guidelines and recent works focused on the SCI or spina bifida (SB) populations (see Table 1 ). This discordance contributes to subjectivity in diagnosis which leads to overdiagnosis and overuse of antibiotics. Given the high prevalence of rUTI combined with diagnostic subjectivity, we propose that advancing care of rUTI among people with NLUTD due to SCI/D requires a reconceptualization of our understanding of UTI, diagnosis, management, and prevention.

Reconceptualization of the Pathophysiology of Urinary Tract Infection Among People with Spinal Cord Injury and Disease

Reconceptualizing UTI diagnosis and rUTI among people with NLUTD requires an understanding of the pathophysiology among individuals with SCI/D. Individuals with anatomic or functional abnormality of the urinary tract, or with the presence of an indwelling catheter are considered to have a complicated UTI (cUTI). Vasudeva and Madersbacher (2014) describe the multifactorial nature of the pathophysiology of cUTI among individuals with NLUTD ( Fig. 1 ). Notably, the risk of UTI is dynamic and related to catheterization practices, both local and systemic immune responses, fluctuations in the uroepithelium, and the process of bacterial washout, collectively highlighting the complexity of infection susceptibility.

Simplified overview of the multifactorial etiology of UTI in NB.

( From Vasudeva P, Madersbacher H. Factors implicated in pathogenesis of injury tract infections in neurogenic bladders: some revered, few forgotten, others ignored. Neurourol Urodyn. 2014;33(1):95-100. doi:10.1002/nau.22378; with permission.)

A Urobiome Exists and Healthy Urine Is Not Sterile

Next generation sequencing and omics technologies have advanced our understanding of the urobiome and there is now more than a decade of research indicating that urine is not sterile Using 16S rRNA sequencing, work done independently by Fouts and Groah and colleagues and Wolfe and colleagues verified the existence of the urobiome in distinct populations more than 10 years ago. However, the current UTI diagnosis, treatment, and antibiotic resistance paradigms do not account for the urobiome—the “newly” discovered communities of microbes (bacteria, archaea, protists, fungi, and viruses) that inhabit the urinary bladder. The microbial ecosystem balance that helps to maintain health is called eubiosis, and is characterized by a preponderance of commensal or potentially beneficial species over pathogenic species. When an imbalance between pathogens and protective species in the urobiome occurs, ^, the disruption of this equilibrium is termed dysbiosis. ^,

Characterization of the healthy urobiome within the general population is evolving and reveals distinct sex differences and correlations with urinary symptoms. In women without NLUTD, Lactobacillus, and Gardnerella are the most frequently detected genera, verified both through sequencing and culture, with transurethral catheter-collected urine samples confirming urinary tract sources rather than vaginal contamination. ^{, , ,} Similarly, in a study comparing asymptomatic urine samples from individuals with and without NLUTD, samples from individuals without NLUTD are distinguished by a predominance of Lactobacillus in females, and Corynebacterium, Staphylococcus, and Streptococcus in males. When species level analyses were performed, the non-NLUTD female urine Lactobacillus community was characterized by Lactobacillus crispatus and Lactobacillus iners. Genus level analyses revealed a predominance of Streptococcaceae among non-NLUTD males. Others have shown that a predominance of Lactobacillaceae (which includes species formerly belonging to the genera Lactobacillus) in the urine is associated with reduced urinary symptoms. ^, In the vagina, L crispatus and L iners vaginal microbiomes are considered the healthiest and less likely to be associated with disease states. ^{, ,}

We have shown that NLUTD urobiomes vary by catheterization status, sex, and there is the suggestion of increasingly abnormal findings with increased exposure to a urinary catheter. Broadly, the urine microbiome of individuals with NLUTD is characterized by the predominance of known uropathogens, such as Escherichia coli, Escherichia faecalis, P. aeruginosa, and K. pneumoniae . In a study by Fouts and Groah, urine samples from individuals with NLUTD exhibited urobiome composition with a statistically significant greater presence of Enterococcus, Escherichia, Salmonella, Klebsiella sp, Aerococcus, and Proteus species compared with non-NLUTD controls. Interestingly, compared with non-NLUTD female urobiomes, Lactobacillaceae species predominance is reduced in women with NLUTD and is characterized by the presence of L iners , while L crispatus was absent in all NLUTD samples. Furthermore, NLUTD females demonstrated a significantly higher proportion of Lactobacillus, Gardnerella , and Enterobacter compared to NLUTD males. Individuals with NLUTD using indwelling and intermittent catheterization had a significantly greater abundance of the family Enterobacteriaceae than those without an NLUTD; however, this trend was not observed for people with NLUTD who were voiders. The observed dysbiosis in the urobiome among those with NLUTD due to SCI/D, is postulated to arise from factors such as bacterial translocation from the gut during neurogenic bowel care, translocation related to urinary catheter use, and/or changes in bladder wall integrity due to urine retention (among other potential causes).

Of note, we have explored the impact of sampling methods (void vs intermittent catheterization) on urobiome composition among healthy controls. Our findings revealed notable within-subject variations in bacterial genera between samples collected by voiding and by intermittent catheterization within 1 hour of collection. Urethral samples exhibited the highest abundance of Veillonella, Staphylococcus , and Neisseria , while bladder samples displayed a prevalence of Lactobacillus, Streptococcus , and Gardenerella . This work demonstrated urethral and bladder urobiomes.

Urobiome Discoveries Will Positively Disrupt our Diagnostic and Treatment Paradigms

The growing evidence base around the urobiome, eubiosis, and dysbiosis, will transform diagnosis and treatment of UTI. For example, given that we now know that a urobiome exists, the term asymptomatic bacteriuria can be considered antiquated given the ubiquitous presence of bacteria in healthy urine. We now know that healthy urine is synonymous with asymptomatic bacteriuria; however, asymptomatic bacteriuria carries a connotation of abnormality.

To date and currently, we treat a single “uropathogen” based on antibiotic susceptibilities. We now need to consider the entire urobiome in our treatment approaches, and the functioning of bacteria in their bladder ecosystem. The bacteria that grow most predominately on an agar plate may not be the bacteria causing dysbiosis (and there may be multiple interactions in play). Next generation sequencing (NGS) and omics approaches, which have allowed the identification of bacterial RNA and DNA, are and will be critical in determining not only what bacteria, viruses, fungi, etc, are present in the bladder and urine, but will provide information on the functioning of these members of the urine ecosystem. We are now on the precipice of a much deeper understanding of the roles of various urobiome constituents in bladder-host interactions that are key to health and disease and inform the spectrum of eubiosis and dysbiosis.

Emerging Concepts Around Urinary Tract Infection Diagnosis Among People with Spinal Cord Injury and Disease

The long-held dogma that a UTI represents an invasion of a sterile environment by a single uropathogen that causes urinary symptoms is now known to be a myth, overturned in the last decade by the discovery of the urobiome. ^, To advance UTI diagnostics for people with SCI, it is necessary to examine the pillars of diagnosis (symptoms, inflammation, bacterial load) more closely, recognizing that this non-NLUTD model may be found to be suboptimal among people with NLUTD in the future.

The first diagnostic criterion is urinary symptoms. Uncomplicated UTI symptoms are typically dysuria, frequency, hesitancy, urgency, suprapubic pain or discomfort, bladder spasms, and hematuria. However, among people with NLUTD, these may not be accessible (due to sensory and/or motor impairment, or catheterization status), and therefore may not be applicable. Addressing this problem, our group has developed 3 instruments specific to bladder management (one each for voiders, and people who use intermittent or indwelling catheters) to measure and track urinary symptoms indicative of UTI specific to people with NLUTD due to SCI/D and other causes. ^, These patient- centered patient-reported outcomes (PC-PROs) were developed to not only monitor symptoms, but to aide decision-making in response to urinary symptoms among individuals with NLUTD. The instruments include 4 categories of symptoms: actionable symptoms (A), bladder-related (B1), urine quality (B2), and constitutional (C) ( Tables 2–4 ). ^, A decision-making tool based on symptoms and symptom combinations has been developed and is currently in testing. It is important to consider that symptoms may differ by individual, that not all symptoms should be considered equal (would a clinician consider “fever” to be of equal significance as “cloudy urine”?), and that future algorithms may go beyond presence/absence of symptoms and incorporate severity, impact, change from baseline, and/or other factors. Therefore, diagnostic information around symptoms is evolving.

The second diagnostic criterion is bladder inflammation, which is quantified by white blood cells (WBC) in the urine on urinalysis (or “pyuria”). However, it is widely known that this criterion is not ideal among people with NLUTD and SCI due to the persistent presence of WBC in the absence of symptoms. ^, This underlying bladder inflammation and pyuria complicates the use of WBC or leukocyte esterase, limiting their use as reliable inflammatory biomarkers for UTI in NLUTD. ^, In fact, the IDSA states that WBC in the urine should not be used as a diagnostic criterion among this population. Of note, it has been proposed by us ^, and Devillé that absence of pyuria conveys important information about a lack of inflammation. Similarly, nitrites provide only limited information, as their presence only indicates specific organisms. Because of this there are numerous inflammatory biomarkers currently under investigation.

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  uNGAL: Urinary neutrophil gelatinase-associated lipocalin is a 24 kDa protein expressed and secreted by the genitourinary epithelium in response to a variety of injurious stimuli, including infection. The most promising clinical use of uNGAL is as a marker of acute kidney injury. There is ongoing exploration as to uNGAL as a biomarker for UTI. There are some data suggesting that NGAL can differentiate between eubiosis and dysbiosis. ^,

  
  
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  Serum Procalcitonin: Procalcitonin is a serum biomarker for the early detection of systemic bacterial infections. However, procalcitonin levels can also become elevated during noninfectious conditions (trauma, burns, certain carcinomas, immunomodulator therapy, cardiogenic shock, and others), limiting its use. Further limiting use is that it requires a blood draw, which can be inconvenient and add discomfort to the individual. The utility of this test is still limited and requires further research for its implementation.

  
  
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  Urine Leukocyte esterase (LE): Used as a fast approach to determine the presence of WBC in urine via dipstick. Our team conducted a prospective observational study to assess the utility of leukocyte esterase measured by dipstick, and found that the LE levels did not correlate with the presence or absence of urinary symptoms among people with NLUTD and SCI/D who used either indwelling catheters or voided. ^, In the future, LE levels may prove useful for other purposes.

  
  
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  Other biomarkers: Other serum and urine biomarkers under study include C-reactive protein, interleukins, elastase alpha (1)-proteinase inhibitor, lactofferin, secretory immunoglobulin A, heparin-binding protein, xanthine oxidase, myeloperoxidase, soluble triggering receptor expressed on myeloid cells-1, α-1 microglobulin, tetrazolium nitroblue test, and key inflammatory genes measured in rats bladder tissue (ie, slc11a1, il1b and il6). Some of these are still under study, and further research will be needed to determine their clinical utility.

The third UTI diagnostic criterion is bacterial load, currently determined by standard urine culture (SUC), which was originally designed and intended to be used to culture E coli for diagnosis of pyelonephritis. Use of SUC presumes that UTI represents the growth of a single uropathogen in a sterile environment, which has been disproven. ^{, ,} Several problems exist with reliance on SUC, include taking 48 to 72 hours to complete (therefore leading to empiric (over-) use of antibiotics and unnecessary patient suffering) and high false negative results (not detecting 90% of all bacterial species and 50% of known uropathogens). For more information on this the reader is encouraged to access “Tarnished gold—the “standard” urine culture: reassessing the characteristics of a criterion standard for detecting urinary microbes”. In the future, diagnostics will need to incorporate the urobiome and dysbiosis. Several techniques are being investigated.

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  16S rRNA sequencing: Has demonstrated that the bladder is not a sterile environment, contrary to previous beliefs. 16s identifies bacterial RNA but does not identify to the species level nor does it provide information on bacterial function, interactions, or information on antibiotic resistance genes. Despite this breakthrough, the clinical utility of these tests has not been established. While its cost has decreased in recent years, it remains relatively expensive and does not allow for real time clinical use.

  
  
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  Metagenomics: Is a large-scale analysis of microbial communities. This is a broad sequencing of bacterial populations. Metagenomics analysis in clinical trials necessitates detailed information at individual taxonomic levels to inform future experiments and treatments. However, this process is time-consuming and again cannot be conducted in real time.

  
  
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  Metaproteomics: Basic metaproteomics offers valuable insights into microbiomes, encompassing information on the composition, abundance dynamics, as well as metabolism, and physiology of individual members, including the host. Additionally, it enables the examination of gene expression responses to varying conditions, identification of potential host-microbe interaction proteins within a host-microbe system, and assessment of substrate uptake labeled with heavy carbon or nitrogen. However, it is important to note that metaproteomics analysis, like other methods mentioned earlier, are expensive and cannot be conducted in real time.

  
  
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  PCR: A technique used to identify DNA-based microorganisms, PCR primers are used for sequencing and amplification. Different PCR primer pairs target different regions of the 16S rRNA gene sequences, which can result in variable microbiome profiles for the same sample. PCR analyses are also time-dependent.

  
  
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  Expanded quantitative urine culture (EQUC): The use of EQUC involves plating a significantly larger volume of urine, 100x more urine than SUC, on various growth media, and incubating it for twice as long (48h), under diverse atmospheric conditions. ^, This comprehensive tool has emerged as a valuable diagnostic method, providing a more thorough assessment of urinary pathogens than SUC, although the processing of EQUC requires additional time and is resource-intensive compared with SUC.

  
  
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  Nicotinamide adenine dinucleotide hydrogen (NADH): A metabolite currently under investigation holds potential as a biomarker for assessing the urobiome bacterial activity. Bacteria release autofluorescent NADH during their metabolic processes, and its fluorescence intensity, indicating NADH concentration, is quantified in relative fluorescent units (RFUs). This measure has the potential to serve as a real-time indicator of urobiome bacterial metabolic activity.

A paradigm shift is necessary beyond traditional pathophysiology and diagnostic approaches. In the future, diagnostic methods will need to assess the entire urobiome community, including bacteria-bacteria and bacteria-host interactions that impact health and disease. As such, the use of newer techniques that provide an assessment of the bacterial community of the bladder (and urethra) as well as host response, is critical. While technologies noted earlier remain largely in the research arena as most are resource intensive, we anticipate rapid technologic advances in the future making these more accessible (and useful) clinically.

Emerging Treatment Approaches

Treatment of UTIs in people with SCI/D is highly subjective, reliant on slow and unreliable diagnostic techniques, which leads to overtreatment with systemic antibiotics. This approach has not improved UTI prevalence and has had the unwanted consequence of multidrug-resistant infections, frequently requiring subsequent re-treatment with broad-spectrum antibiotics. The implications of fostering the growth of “Super Microbes” cannot be overlooked. The emergence of antibiotic-resistant strains highlights the urgency to reevaluate established antibiotic treatments, improve patient outcomes, reduce adverse consequences, reduce or prevent an increase in antimicrobial resistance, and deliver cost-effective therapy.

Treatment of UTI is typically with narrow spectrum oral or IV antibiotics, based on culture results, once available. Treatment should only be started after a urine specimen has been obtained for microbiologic testing, to choose the appropriate antibiotic and to avoid bacterial resistance. ^, The recommendation from IDSA for catheter-associated UTIs (CA-UTI) in people with NLUTD, is to give 7 to 10 days of antimicrobial treatment for individuals with a prompt resolution of symptoms (without fever), and 10 to 14 days for those with fever. ^, In individuals with long-term indwelling catheters, the catheter should be changed before treatment, and the urine culture should be obtained from the freshly placed catheter. In persons with uncomplicated cystitis and mild clinical symptoms, nitrofurantoin is a preferred option if sensitive, because of the low resistance rate and marginal alteration of the bowel or vaginal flora. In hospitalized individuals with severe infection suspicious of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin is an option. In individuals with MRSA in an outpatient setting, trimethoprim-sulfamethoxazole is often recommended

Systemic antimicrobial prophylaxis should not be routinely used in people with short-term or long-term catheterization, ^, or those without a catheter. The AUA/SUFU Guideline on Adult NLUTD (2021), supports the critical need to avoid unnecessary antibiotic use, such as for treating asymptomatic bacteriuria (which we now know is synonymous with healthy urine). The effectiveness of antibiotic prophylaxis should be weighed against concern for resistance selection, and adverse effects of long-term antibiotic use. Indiscriminate antibiotic use impacts the equilibrium of the microbiome, with potential alterations that have an impact on the urobiome, and microbial antibiotic resistance. The exception to treat asymptomatic bacteriuria in pregnant women and prior to urologic procedures in which the urothelial disruption or upper tract manipulation is anticipated. While pharmaceutical companies continue to develop stronger antibiotics due to the worldwide epidemic of antibiotic resistance, other options are in development.

Bacteriophage (Phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics. Phages are viruses that infect bacteria. They can evolve to efficiently target specific bacteria and have been used to treat complex drug-resistant bacterial infections in a procedure termed phage therapy. Phage therapy is being studied as a potential treatment for antibiotic-resistant infections. Phages were discovered over a century ago, however, the advent of chemical antibiotics led to the virtual abandonment of phage therapy in most of the world. The development of phages for use against human infections has been described as following 2 pipelines: the “ prêt à porter ” (ready to wear), and the “ sur mesure” (custom made). The first is more expensive and time-consuming but can be licensed, whereas the second is inexpensive but currently has not been licensed. With phage, 2 therapeutic options are available, either the person can be treated with the phage alone, or phage plus antibiotic. Studies on this are still at an early stage, there is a phase I/II clinical trial (active/not recruiting, ClinicalTrial.gov Identifier: NCT05537519), that aims to evaluate the potential of bacteriophage therapy to treat and prevent the recurrence of a drug-resistant urinary tract infection. The phage therapy in this study consists of oral, topical (opening of the urethra), and bladder installations. Also, a Phase 1b study to assess bladder instillation safety, tolerability, pharmacokinetics, and pharmacodynamics of bacteriophage therapy in SCI with bacteriuria is in the process of being submitted for the Food and Drug Administration (FDA) approval (unpublished data). Phage therapy is not without limitations, as they have a similar mutation rate to bacteria; the organisms reproduce so rapidly that the high numbers lead to large mutant populations on which selection can operate to enrich selected phenotypes, and bacteria can develop resistance to phage.

Antibiotic-Sparing Intravesical Instillations

Another option that will likely become more widespread in the near future is treatment using intravesical therapeutics. Treatment of UTI and other lower urinary tract symptoms with intravesical instillation of various therapeutics is an accepted clinical option (in many cases as off-label treatment), yet these are typically recommended only as a last resort, after multiple infections and exposures of the body and its microbiome to antimicrobials. Intravesical instillation of therapeutic agents for UTI started in the 1960s and has been an accepted clinical practice since the late 1980s, however use seems to be more prevalent among children with NLUTD due to spina bifida. Some options include ( Table 5 ).

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  Bladder washes: Normal saline solution (and/or mixed with citric acid), acts to enable the physiologic process of bacterial washout, and is FDA-approved for bladder catheter encrustation. Advantages of this approach include its low cost, and that people with NLUTD can be taught to do this themselves (self-management).

  
  
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  Oxybutynin: Intravesical oxybutynin is an effective treatment option for bladder spasms and overactive bladder symptoms among people with NLUTD due to SCI/D. In a study with children and NLUTD, 1.25 mg/5 mL Oxybutynin was administered intravesically after catheterization, twice daily, and the results suggest that this intervention is an effective and relatively safe long-term therapeutic option for children with neurogenic bladder. In a systematic review that included children and adults, it was concluded that the use of intravesical oxybutynin could be an effective treatment for detrusor overactivity due to NLUTD with fewer side effects. In sum, it has been demonstrated to have fewer adverse effects than oral medication, with the disadvantage of the time required to prepare and perform the instillation.

  
  
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  Lactobacillus rhamnosus GG (LGG): This is a live biotherapeutic product (LBP) and the specific mechanisms underlying the protective activity of Lactobacilli in the bladder has only been partially explored. Lactobacillus species have been showing to decrease uropathogen adherence to the urothelial cells (in vitro), produce antimicrobials peptides (AMP), ^{, ,} produce killing proteins against uropathogenes, compete with uropathogenes for nutrients and attachment sites, and disrupt bacterial biofilm. These effects are active against a limited range of uropathogens, but their potency against antimicrobial-resistant pathogens remains untested. Use of intravesical LGG is currently experimental under an Investigational New Drug (IND) approval from the FDA. Groah and colleagues have demonstrated that intravesical instillation of LGG is a promising approach for urinary symptoms. ^, Specifically, in a previous study from our group, intravesical LGG self-instilled in response to urine that is more cloudy or foul-smelling, demonstrated to be safe and well tolerated among adults and children with NLUTD who manage their bladders with IC. Ultimately, the goal is to determine if intravesical L. rhamnosus can restore a dysbiotic urobiome to eubiosis, improve symptoms, and reduce UTI.

  
  
  
  
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    Intravesical LGG and Lactobacillus crispatus ( ClinicalTrials.gov Identifier:NCT04323735; NCT04373512;NCT05230511) are currently under investigation through INDs from the FDA.

  
  
  
  
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  Hyaluronic acid and chondroitin sulfate: It is hypothesized that deficiency of the uroepithelial glycosaminoglycan (GAG) layer of the bladder facilitates bacterial adherence leading to recurrent UTIs. The GAG layer, composed of hyaluronic acid (HA), heparin sulfate, dermatan sulfate, chondroitin sulfate(CA), and keratan sulfate covers the bladder epithelium and forms a biofilm functioning essentially as an impermeable barrier to solutes. In a limited number of studies, intravesical instillation of HA has been considered as a treatment to reduce the prevalence of recurrent UTIs in children with SB and NLUTD. There is another study done on female participants as a prophylaxis option for recurrent UTI, utilizing intravesical HA and CA. The clinical use of HA has been tested in a small number of adult studies and children, but the efficacy of this therapy in individuals who require IC has not been addressed with randomized controlled trials.

  
  
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  Intravesical acetic acid : Dilute acetic acid, hypothesized to be bactericidal, is an inexpensive, FDA approved, option for bladder instillations. A case report using an irrigation with 0.25% acetic acid, showed a decrease in bacteriuria, but further assessment of the safety of this technique has not been studied. Its potential to cause bladder irritation and autonomic dysreflexia should be considered.

  
  
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  Chlorhexidine : Initial reports by Paterson in 1960, using 0.02% chlorhexidine solution in women with urinary retention following gynecologic surgery to reduce the incidence of bacteriuria after transurethral operations were encouraging. Further analysis showed an unacceptable rate of hematuria in patients with long-term use and a study of rat models revealed erosive cystitis. This approach is no longer being used.

  
  
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  Non-pathogenic E coli : A review of non-pathogenic E coli for preventing urinary tract infections in adults and children was published in 2017 and included 3 RCTs (total of 110 participants) during the period from 2005 to 2011 (Darouiche 2005; Sunden 2010; Darouiche 2011). All the studies examined intravesical instillation of a low virulence E coli strain. The overall quality of the studies was considered poor and there was a high risk of reporting bias. In one study the pre-inoculation, plus catheter manipulation were precipitating symptomatic severe UTIs. For that reason, the approach was halted. No recent studies in humans have been published with E coli , and this is not currently approved by the FDA.

Table 5

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