Antibiotic regimens are the current standard of care treatment for acute and RUTIs, including asymptomatic bacteriuria, in pregnant women (Nicolle 2015; Nicolle et al., 2019; Smaill and Vazquez 2019). The choice of antibiotic regimen depends on gestational age, the target pathogen, pathogen resistance, the recurrence of infection, and clinical judgment (Tamma et al., 2017). Additional considerations include the increased risk of passing on resistant bacteria to a neonate and the potential teratogenic effects of antimicrobial treatment on the fetus (Ghouri et al., 2019). Some of the most common antibiotics include cephalosporins (first, second, and third-generation), penicillins, β-lactam antibiotics in combination with β-lactamase inhibitors, and nitrofurantoin (Rac et al., 2019). The recommended therapies for asymptomatic bacteriuria in pregnant women include nitrofurantoin after the first trimester and β-lactam antibiotics (e.g., cephalexin and ampicillin) given over a 4–7-days course (Gupta et al., 2011; Nicolle et al., 2019). These antimicrobial drugs are preferred because of their safety profile in pregnant women (Nicolle et al., 2019). However, nitrofurantoin is not recommended during the first trimester due to associated congenital disabilities. The treatment of symptomatic bacteriuria/cystitis is similar to asymptomatic bacteriuria; however, nitrofurantoin and β-lactam antibiotics (e.g., cephalexin and ampicillin) demonstrate less short-course effectiveness for acute cystitis (Gupta et al., 2011; Nicolle et al., 2019). The Infectious Diseases Society of America (IDSA) currently has no recommendations regarding further periodic screening after the antibiotic treatment course (Nicolle et al., 2019).

For example, other clinically prescribed antimicrobial drugs include amoxicillin, amoxicillin-clavulanate, and trimethoprim-sulfamethoxazole (TMP-SMX) after the first trimester through early to mid-second trimester (Vazquez and Abalos 2011; Nicolle et al., 2019; Habak and Griggs 2022). Fosfomycin administered as a single dose is also a potential therapy (Rac et al., 2019). First-line oral antimicrobial drugs for acute pyelonephritis include β-lactam antibiotics. Cephalexin and ampicillin are preferred because of the known safety profiles. Nitrofurantoin and fosfomycin are ineffective in treating pyelonephritis (Rac et al., 2019). Third-generation cephalosporins (e.g., ceftriaxone) may be recommended. When urine culture is available, first-generation cephalosporins and penicillins (e.g., ampicillin and ampicillin-sulbactam) may be recommended (Denoble et al., 2021). For severe pyelonephritis cases, carbapenems may be prescribed. For life-threatening infections, aminoglycosides may be prescribed. There are no consistent recommendations for the duration, but they are currently in the range of 10–14 days (Matuszkiewicz-Rowinska et al., 2015).

Generally, acute mild to moderate pyelonephritis is initially treated empirically based on resistance patterns and previous patient antimicrobial exposure until susceptibility testing is available (Nicolle et al., 2005; Jolley and Wing 2010; Vazquez and Abalos 2011; Matuszkiewicz-Rowinska et al., 2015; Rac et al., 2019). Parenteral administration of fluids and antibiotics should occur while the patient is febrile (≥48 h), after which the patient transitions to oral antimicrobial drugs for an extended period. In the first 48 h, ceftriaxone, cefepime, amoxicillin/clavulanic acid, and aztreonam are typically prescribed in less severe cases (Nicolle et al., 2005; Matuszkiewicz-Rowinska et al., 2015; Rac et al., 2019). For more severe cases, penicillin combinations (e.g., ticarcillin with clavulanic acid, piperacillin with tazobactam) and carbapenems (e.g., meropenem, ertapenem, doripenem) are more common (Nicolle et al., 2005; Matuszkiewicz-Rowinska et al., 2015; Rac et al., 2019).

Approximately 6–8% of pregnant women will have recurrent pyelonephritis. In these cases, prophylactic treatment (e.g., nitrofurantoin, cephalexin) may be initiated with typical treatment reinitiated when bacteriuria is detected (Matuszkiewicz-Rowinska et al., 2015). In addition, intrapartum prophylaxis is recommended by the CDC in women testing positive for GBS infection. GBS infection is associated with significant morbidity and mortality in infants (Verani et al., 2010).

The rapid development of antimicrobial resistance is considered a serious threat to individual health and life expectancy (Solomon and Oliver 2014). In 2019, it was estimated that microbial resistance resulted in over 2.8 million infections and over 35,000 deaths per year in the United States alone (CDC, 2019). Resistance development is particularly concerning for both mother and infant outcomes; however, there are limited studies in pregnant women for both gram-positive and gram-negative bacteria. According to a 2019 CDC report (CDC, 2019), gram-positive GBS is present in one-fourth of pregnant women and often treated with penicillin before delivery to prevent transmission to the baby. Clindamycin and erythromycin can be used in women allergic to penicillin; however, over 40% of GBS infections are resistant to clindamycin, and over 50% are resistant to erythromycin (CDC, 2019). A recent retrospective cohort study of 334 women with gram-negative bacteriuria found that antibiotic-resistant organisms were most often (>50%) responsible for bacteriuria in pregnant women; these women were 2–3x as likely to develop pyelonephritis (Denoble et al., 2021).

Minimizing the development of microbial resistance to antimicrobial agents is the foundation for stewardship programs. Part of stewardship programs includes tracking local or regional resistance patterns. These patterns often vary. For example, Chelkeba et al. (Chelkeba et al., 2022) recently performed a systematic review of antimicrobial resistance patterns in Ethiopia. In pregnant women with bacteriuria, 83% of E. coli were multidrug-resistant. Kaye et al. (Kaye et al., 2021) performed a retrospective study of 1.5 million Escherichia coli isolates from the United States. They found that 14.36% of E. coli isolates in urine samples in adult and adolescent females showed a non-susceptible phenotype to multiple drugs. Resistance and development of resistance to specific drugs showed significant variation throughout regions, states, and counties. For example, observations showed that the New England region had an average increase in multidrug resistance of 7.0% (6.5–7.5), whereas the East South-Central region had an average increase of 16.7% (16.1–17.3). Understanding these patterns and trends is vital to maximizing mother and baby outcomes as a recurrent infection is common in pregnant women (Schneeberger et al., 2015).

Resistance to antimicrobial drugs often occurs rapidly. For example, E. coli showed resistance to cefotaxime, an extended-spectrum beta-lactam, 3 years after it was introduced (CDC, 2019). Kim et al. recently studied 265 infants (<1 year of age) and found that antibiotic use by mothers during pregnancy was associated with isolation of the extended-spectrum beta-lactamase (ESBL)-producing bacteria from specimens of infants with UTIs (Kim et al., 2022). Currently, there are very few therapeutic options available for the treatment of ESBL-positive infections, mainly due to ESBL-producing bacterium ability to hydrolyze third-generation cephalosporins (Pana and Zaoutis 2018). Carbapenem treatment has been set as the preferred treatment for infections with ESBL-producing bacteria (Pana and Zaoutis 2018). Fosfomycin has been recommended specifically for the treatment of UTIs with ESBL-producing bacteria. Efforts are being made to develop new antimicrobial drugs; however, the development of antimicrobial drugs is being outpaced by the development of resistance (CDC, 2019).

Antimicrobial regimens are critical components for treating symptomatic UTIs; however, the benefits of using antimicrobial agents to treat uncomplicated UTI and asymptomatic bacteriuria are not entirely understood. In general, the need to treat asymptomatic UTIs is considered questionable. Current issues associated with antimicrobial use include patient compliance, the development of resistance, potential adverse effects for both mother and baby, and the overall treatment effectiveness. Additionally, current testing methods of UTIs appear to have low sensitivity and specificity for screening bacteriuria, leukocyte esterase, and nitrite (Jido 2014; Gehani et al., 2019). These issues complicate the development of effective antimicrobial treatments for UTI and RUTI treatments. Additional therapies with the potential to reduce infection and exposure to antimicrobial drugs should be explored.

Traditional first-line antibiotic treatment of UTIs in young children has typically included oral amoxicillin, a sulfonamide-containing antimicrobial, or a cephalosporin (Beetz and Westenfelder 2011; Porter and Kaplan 2011; Subcommittee on Urinary Tract Infection et al., 2011; White 2011; Balighian and Burke 2018). The antibiotic of choice should ideally be patient-specific and tailored to individual bacterial susceptibility patterns (Nickavar and Sotoudeh 2011; Balighian and Burke 2018; Kaufman et al., 2019). Currently, the vast majority of bacteria that cause UTIs are sensitive to third-generation cephalosporins (Shaikh et al., 2016b; Mattoo et al., 2021). A first-generation cephalosporin, TMP-SMX, or nitrofurantoin may be a more reasonable choice of antibiotic in non-febrile pediatric patients diagnosed with a UTI (Shaikh et al., 2016b; Mattoo et al., 2021). Amoxicillin should be currently avoided, as most bacteria are resistant to this antibiotic (Mattoo et al., 2021).

The reported duration of oral antibiotic treatment can vary between a shorter duration (6–9 days) and a longer duration (>10 days). A review carried out from the Cochrane Database that analyzed 2–4 days (short duration) versus 7–14 days (standard duration) of oral antibiotic treatment among children diagnosed with lower UTIs found no differences in positive urine culture samples between therapy durations immediately following treatment (Michael et al., 2003). In addition, no significant differences existed between the short and standard treatment durations for the development of resistant organisms (Michael et al., 2003). Nonetheless, despite comparable outcomes observed for shorter and longer durations of treatment, the typical length of oral antibiotics prescribed to pediatric patients diagnosed with a UTI is 14 days (Michael et al., 2003; Fitzgerald et al., 2012; Fusco et al., 2020; Mattoo et al., 2021).

While the majority of children with a diagnosed UTI can be treated with an oral antibiotic (Hoberman et al., 1999; Bloomfield et al., 2005; Hodson et al., 2007), patients unable to receive oral medication should be administered an antimicrobial agent via the parenteral route (Subcommittee on Urinary Tract Infection et al., 2011). Parenteral administration should continue until the patient exhibits clinical improvement and can retain oral fluids and medications (Subcommittee on Urinary Tract Infection et al., 2011; Balighian and Burke 2018). Both oral and parenteral antibiotic therapy appears to have similar effective rates for UTIs among children (Hoberman et al., 1999; Hodson et al., 2007). Antibiotic treatment should be started within the first 48 h of fever onset in children with a febrile UTI to decrease the risk of renal scaring (Oh et al., 2012; Shaikh et al., 2016c; Karavanaki et al., 2017; Mattoo et al., 2021) with an expectant resolution of fever in 68% of patients by 24 h and 92% by 72 h (Bachur 2000).

Parenteral antibiotic treatment durations show a similar trend. A recent study from 2019 reported that ≤7 days of parenteral antibiotic therapy in infants older than 60 days diagnosed with a bacteremia UTI appears to be as safe and effective as the conventional, longer-duration treatment (Desai et al., 2019). Overall, oral antibiotics with low resistance patterns for 7–10 days for upper UTI and 3 days for lower UTI are recommended for pediatric patients older than 3 months (Baumer and Jones 2007). In addition, the regimen 2–4 days of parenteral antibiotics followed by a switch to oral antibiotics for 10 days has been recommended for vomiting patients unable to receive oral antibiotics (Baumer and Jones 2007). Following treatment and resolution of UTI symptoms, follow-up urinalysis and cultures are not required unless clinically indicated (Currie et al., 2003; Oreskovic and Sembrano 2007; Mattoo et al., 2021).

In addition to first-line antibiotic treatment, preventive treatment with antibiotic prophylaxis is a commonly used practice to deter RUTIs in patients who experience two or more infections during a 6-month period (Nickavar and Sotoudeh 2011; Kaufman et al., 2019). Among children diagnosed with a UTI, over 30% will undergo recurrent infection, which supports prophylactic antimicrobial administration (Keren et al., 2015; Kaufman et al., 2019). Several studies have explored the effectiveness of antibiotic prophylaxis for preventing UTI recurrence among children; however, results remain unclear and contradictory. Nitrofurantoin and TMP-SMX are the most common antibiotics used for UTI prophylaxis in children, and the long-term use of these low-dose antibiotics are mostly safe with minimal related adverse effects (Coraggio et al., 1989; Uhari et al., 1996; Song and Kim 2008). Whereas the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR), Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteral Reflux and Normal Renal Tracts (PRIVENT), and Careful Urinary Tract Infection Evaluation (CUTIE) trials suggest fewer infections in children receiving prophylactic antibiotics with significant benefits in children diagnosed with vesicoureteral reflux (VUR) and bladder-bowel dysfunction (Craig et al., 2009; Investigators et al., 2014; Shaikh et al., 2016a), majority of trials have shown no beneficial effect of antibiotic prophylaxis (Garin et al., 2006; Montini et al., 2008; Pennesi et al., 2008; Roussey-Kesler et al., 2008). A trial exploring prophylactic administration of TMP-SMX showed that children had a 3-times higher chance of recurrent infections than children who received a placebo (Hari et al., 2015). From these results, it may be plausible to conclude that young children with high-grade VUR are likely to benefit most from antibiotic prophylaxis (Uhari et al., 1996). Variations in trial results could be attributable to differences in patient age and inclusion and exclusion criteria. Nonetheless, prophylactic prevention practices remain controversial as they have been shown to contribute significantly to antibiotic resistance from increased dosing and exhibit inconsistent results (Conway et al., 2007; Beetz and Westenfelder 2011; Nickavar and Sotoudeh 2011; Porter and Kaplan 2011; White 2011; Balighian and Burke 2018; Kaufman et al., 2019).

The efficacy of commonly prescribed antibiotics to treat UTIs in children has been negatively altered in recent years due to increased pathogen resistance rates. Inappropriate antibiotic treatment and dose selection can result in treatment failure and contributes to increased resistance (Samanci et al., 2020). Specifically, the broad use of antibiotics and low-dose prophylactic antibiotic use has been blamed for the development of resistance. While there are regional differences, pathogenic resistance rates to antibiotics chosen for UTI treatment in children exhibit a steady increase worldwide (Pena et al., 1995; Ladhani and Gransden 2003; Prais et al., 2003; Lutter et al., 2005; Budnik and Bevzenko 2020; Samanci et al., 2020). Within the United States, amoxicillin and TMP-SMX have traditionally been chosen as first-line antibiotics for UTI in children; however, increased rates of E. coli resistance have made these antibiotics less ideal (Lutter et al., 2005; White 2011; Samanci et al., 2020). A recent study investigating the prevalence of antibiotic resistance among children with UTI over the past 10 years, specifically the sensitivity of E. coli to commonly prescribed antibiotics, revealed alarming increases in resistance rates since 2009 (Budnik and Bevzenko 2020). Specifically, ampicillin and amoxicillin showed a low sensitivity level (3.5 ± 32.14%) (Budnik and Bevzenko 2020). Common oral therapy options incorporate sulfisoxazole, ciprofloxacin, and cephalosporins, including ceftazidime, cefixime, cefpodoxime, cefprozil, cephalexin (Alper and Curry 2005; Lutter et al., 2005; Beetz and Westenfelder 2011; Nguyen and Whitehill 2011; Porter and Kaplan 2011; White 2011; Budnik and Bevzenko 2020). Among these, ceftazidime and ciprofloxacin have shown a relatively high sensitivity level, 77.4 ± 3.34% and 83 ± 2.81%; however, the use of these antibiotics have subsequently caused a rapid increase in E. coli resistance rates such that they have almost doubled over the past 5 years (Budnik and Bevzenko 2020). Due to the developing resistance of urinary tract pathogens to antibiotics, it may be advantageous to explore complementary medicine options among children who experience RUTIs to improve patient outcomes.

Women experience higher UTI incidence during pregnancy. During pregnancy, the urinary tract changes, including ureteral dilation and hormonal effects, predisposing pregnant women to infection (Habak and Griggs 2019). Ingestion of cranberry during pregnancy is considered safe, and there is scientific evidence that cranberry is of minimal risk to pregnant mothers and the fetus (Dugoua et al., 2008). A survey that included 400 pregnant women detected no adverse events when regularly consuming cranberry (Dugoua et al., 2008). This is particularly important as there are limited therapeutic options available to treat UTIs during pregnancy. A few clinical trials have evaluated the effectiveness of cranberry against UTI in pregnant women. Among these, a pilot study that evaluated the compliance of cranberry capsules during pregnancy showed that consumption of cranberry capsules was tolerable in pregnant women with an 82% compliance rate over 6 months (Wing et al., 2015). An additional randomized control trial was carried out to compare the effectiveness of cranberry juice versus placebo in preventing asymptomatic bacteriuria associated with UTI in women under 16 weeks of pregnancy. Of the 188 pregnant women included women who received multiple cranberry doses each day had a 57% reduction in asymptomatic bacteriuria and a 41% reduction in symptomatic UTIs; however, while others have reported daily ingestion of cranberry to be tolerable for women during pregnancy, this study reported a high incidence of withdrawal (38.8%) due to gastrointestinal intolerability (Wing et al., 2008).

Nonetheless, the UTI frequency reduction rates from this trial are supported by an additional randomized controlled trial such that 70.5% of pregnant participants who consumed cranberry juice reported a reduction in UTI frequency compared to 32.16% of pregnant participants who consumed water (Essadi and Elmehashi 2010). In addition, a pilot study evaluating the in vivo cytokine profiles of urinary samples from pregnant women ingested cranberry juice reported significantly low levels of interleukin-6, a cytokine involved in the early phase of inflammation, in women who ingested cranberry multiple times a day versus the placebo (Wing et al., 2010). However, pregnant women who took cranberry juice once or twice a day did not demonstrate any differences in cytokine profiles versus the placebo. Studies in pregnant women were primarily focused on utilizing cranberry as prophylaxis to prevent RUTIs rather than treatment of primary UTI.

The use of cranberry has been confirmed to be safe in both infants and children (Fernández-Puentes et al., 2015). Several clinical trials that explored the effects of cranberry supplementation among pediatric patients have demonstrated reduced UTI incidence in children with recurrent episodes, both male and female (Ferrara et al., 2009; Afshar et al., 2012; Mutlu and Ekinci 2012; Salo et al., 2012; Fernández-Puentes et al., 2015; Wan et al., 2016). In a randomized placebo-controlled study that evaluated the effectiveness of cranberry juice with high concentrations of proanthocyanidins and had a mean patient age of 9.5 years, ingestion of cranberry juice reduced UTI risk by 65% (Afshar et al., 2012). An additional study that explored cranberry juice consumption in children treated for UTI exhibited that cranberry juice reduced related antimicrobial use by significantly decreasing the number of days on antimicrobial drugs from 17.6 to 11.6 days (Salo et al., 2012). In a study that evaluated the benefits of a highly concentrated cranberry juice for the prevention of RUTIs in uncircumcised boys, cranberry juice decreased the incidence of bacteria (urine cultures greater than or equal to 1 × 10⁵ were 25% for cranberry, 37% for placebo), mainly E. coli, and resulted in fewer RUTI episodes (Wan et al., 2016). While these studies explored and assumed daily consumption of cranberry juice versus placebo, Ferrara et al. demonstrated differences in daily consumption versus non-daily consumption of cranberry juice versus placebo. Among female children, cranberry juice resulted in fewer UTIs when ingested daily rather than 5 days a month (18.5 versus 42.3%) (Ferrara et al., 2009). In a study that observed effects of cranberry capsules instead of juice in children with neurogenic bladder (NB) caused by myelomeningocele, cranberry supplementation significantly decreased infection rate and frequency of pyuria (Mutlu and Ekinci 2012). Prophylactic comparison with a cranberry cocktail versus an antibiotic (trimethoprim) in a controlled, double-blind Phase III clinical trial demonstrated cranberry cocktail prophylaxis was not inferior to antibiotic prophylaxis (cumulative rate of UTI: 26 versus 35%) in children older than 1 year of age (Fernández-Puentes et al., 2015). However, the same study showed that the cranberry cocktail was inferior to antibiotic prophylaxis in children younger than 1 year (cumulative rate of UTI: 35 versus 28%) (Fernández-Puentes et al., 2015). This suggests that age may play a role in pediatric patient outcomes when utilizing cranberry prophylaxis for UTI prevention. An additional study that explored the effects of a cranberry cocktail prophylaxis versus placebo (water) with a cross-over design in pediatric patients presented no differences in cranberry versus placebo (Foda et al., 1995), which contradicts previous studies. These dissimilarities could be attributable to differences in age, total cranberry content consumption, and gender among studies. In general, cranberry supplementation appears to aid in RUTI prevention when administered as prophylaxis in the form of juice, capsule, or cocktail and gains potential to decrease antibiotic use in pediatric patients for overcoming antibiotic resistance rates.

Exploration of HA for complementary therapy in pregnant women has not been thoroughly explored; however, the results from a case presentation where HA treatment was given to a woman at 27.2 weeks of gestation to treat interstitial cystitis, a syndrome associated with urinary symptoms, were significantly improved following puerperium (Arguelles Rojas et al., 2021). Although a UTI does not always accompany interstitial cystitis, patients diagnosed with this syndrome have reported UTI at interstitial initiation (Held et al., 1990; Driscoll and Teichman 2001; Porru et al., 2004; Warren et al., 2008). Nonetheless, HA treatment caused partial improvement of urinary symptoms during gestation with complete eradication of symptoms 6 months after pregnancy when HA doses were continued (Arguelles Rojas et al., 2021). Following 6 months, the patient was asymptomatic. The use of HA treatment during pregnancy for UTI may also be supported by the findings from a study that evaluated the concentrations of HA in various urogenital organs of pregnant and non-pregnant rats (Laurent et al., 1995). In addition, high levels of HA content were observed in the vagina, and urinary bladder of both pregnant and non-pregnant rats, with the highest level of HA, observed in the vagina for the pregnant rats (Laurent et al., 1995). Finally, the high HA content in the urinary bladder, even observed during pregnancy, supports its protective properties in UTI treatment and prevention. Regardless, administration of HA during pregnancy for UTI treatment is warranted and needs to be more thoroughly studied in a clinical setting.

Pediatric patients experience a high prevalence (2–8%) of UTIs with increased risk amid patients with underlying VUR and bladder instability such as NB (Saadeh and Mattoo 2011; Fidan et al., 2015). A clinical study that evaluated the use of intravesical HA in conjunction with TMP-SMX antibiotic prophylaxis in complicated (including patients with VUR or NB) and uncomplicated pediatric males and females found that patients who received HA administration resulted in complete response with sterile urine cultures of 53% for complicated patients and 71.4% for uncomplicated patients following a 2-years monthly follow-up period (Fidan et al., 2015). In addition, 25% of complicated patients and 14.3% of uncomplicated patients reported a partial response, and RUTI frequencies were less than half compared to the period prior to HA therapy (Fidan et al., 2015). Another clinical study assessed the effectiveness and safety of intravesical HA ability to reduce RUTIs in complicated pediatric patients who had spina bifida (SB) and NB versus a control group when antibiotic prophylaxis was given (Cicek et al., 2020). The mean UTIs per patient month were significantly decreased (p < 0.001) for the HA-treated patients compared to the control group (Cicek et al., 2020). Both studies suggest intravesical HA as an applicable treatment option for RUTIs in pediatric patients with and without complications. An additional study assessed the frequency of postoperative UTIs following Deflux® treatment in 75 pediatric patients (mean age of 6.59 years) with primary VUR. Deflux® is an endoscopically injected drug comprised of dextranomer and hyaluronic acid. The study demonstrated a 100% success rate in patients with grade I and II VUR, 91% in patients with grade III, and 82.6% in patients with grade IV (Ure et al., 2016). A retrospective study conducted earlier investigated the effectiveness of Deflux® for the prevention of UTIs in children with VUR (Traxel et al., 2009). In this study, 13% of treated patients developed a postoperative UTI and 3.5% febrile UTI (Traxel et al., 2009). It has been determined that patients with pre-operative UTIs and bladder dysfunctions may be at risk of developing post-operative UTIs. The overall results are promising and support the administration of Deflux® as an option for HA treatment in pediatric patients with VUR to prevent UTIs.

Prophylactic administration of ascorbic acid in pregnant women suggests favorable outcomes for UTI prevention. A single-blinded clinical trial compared an oral treatment with 200 mg ferrous sulfate, 5 mg folic acid, and 100 mg ascorbic acid and treatment with ferrous sulfate and folic acid only of pregnant women (Ochoa-Brust et al., 2007). The addition of ascorbic acid to the formulation appeared to result in lower overall UTIs. Specifically, the treatment group supplemented with ferrous sulfate, folic acid, and ascorbic acid had a UTI frequency of 12.7% compared to 29.1% of pregnant women who received ferrous sulfate and folic acid (p = 0.03). Patients who acquired a UTI during the study were given treatment according to positive urine cultures, but antibiotics were not given otherwise. This study suggests that daily intake of ascorbic acid may play a role in reducing UTIs and potentially could be used for RUTI prophylaxis.

Interestingly, three infants from the group of pregnant women who did not receive ascorbic acid had low birth weights, while no infants in the ascorbic acid-treated group were born with low birth weights. These results further support ascorbic acid supplementation in pregnant women for overall improved health of both mother and infant (Ochoa-Brust et al., 2007). Therefore, investigation of ascorbic acid as a monotherapy prophylactic agent in pregnant women is necessary and should be considered for future exploration.

Ascorbic acid supplementation as a possible tool to relieve UTI symptoms in children has been evaluated. One clinical trial included 152 female children who tested positive for UTI in a hospital setting and were assigned to either an ascorbic acid supplemented treatment group or a placebo control (Yousefichaijan et al., 2018). These pediatric patients were also given routine parenteral ceftriaxone for admitted patients followed by oral cefixime antibiotics following patient discharge in conjunction with ascorbic acid or placebo. The trial found that ascorbic acid supplementation resulted in controlled symptoms associated with UTIs, including fever, dysuria, urinary urgency, and dribbling urine with decreased frequency of these symptoms in the treatment group (Yousefichaijan et al., 2018). These results suggest that ascorbic acid plays a role in reducing UTI symptoms among pediatric females when given intravenous and oral antibiotics; however, additional exploration is needed to confirm these results.

Animal studies conducted by Reid et al., in 1985 demonstrated that inserting Lactobacillus casei into the bladder of rats previously infected with uropathogenic bacteria could prevent the development of bladder infection in 84% of treated animals (Reid et al., 1985). The randomized placebo-controlled clinical trial conducted by Stapleton et al. found that prophylactic treatment of pre-menopausal women with RUTIs daily for 5 days and then weekly for 10 weeks with vaginal suppositories containing Lactobacillus crispatus resulted in a significant reduction of recurrent infections (Stapleton et al., 2011). This study determined that the high level of colonization in the vagina with Lactobacillus crispatus was associated with reducing RUTIs. The single intravaginal administration of Lactobacillus rhamnosus GR-1 to a woman with RUTIs resulted in up to 8 weeks of survival of Lactobacillus in the vagina (Reid et al., 1994). In addition, the treatment of bacterial vaginosis with an oral suspension of Lactobacillus rhamnosus GR-1 and Lactobacillus fermentum RC-14 for 14 days improved overall well-being and relief vaginosis symptoms (Reid et al., 2001).

The meta-analysis of five studies conducted by Grin et al. questioned the effectiveness of Lactobacillus strains for the treatment and prophylaxis of RUTIs in adult women (Grin et al., 2013). The authors concluded that Lactobacillus strains prevent recurrent infections and are safe to use. A recent meta-analysis that evaluated the effectiveness of probiotics for prophylaxis of UTIs in premenopausal women concluded that probiotics do not prevent recurrent infections compared to placebo (Abdullatif et al., 2021). A potential difference in the result of these two meta-analyses was that Grin’s study excluded studies “using ineffective strains.” In contrast, Abdullatif’s study used a variety of Lactobacillus strains administered via the oral route and intravaginally. These meta-analyses collectively concluded that only a few strains of Lactobacillus could effectively treat or prevent RUTIs in women.

Unfortunately, little evidence exists about the effectiveness of probiotic treatments of UTIs or asymptomatic bacteriuria in pregnant women. Up to 15 percent of pregnant women would have asymptomatic bacteriuria, and ∼30% of them can develop cystitis and acute pyelonephritis (Kass 1970; Smaill and Vazquez 2019). About 2–10% of pregnant women carry GBS (Mead and Harris 1978; Matuszkiewicz-Rowinska et al., 2015; Szweda and Jozwik 2016; Abou Heidar et al., 2019). The GBS colonization may lead to intrauterine fetal death and neonatal sepsis (Wood and Dillon 1981). However, past GBS infections or inflammation induced by anti-GBS antibodies may be associated with premature labor (Møller et al., 1984; McKenzie et al., 1994). Therefore, screening for and eliminating GBS vaginal colonization is essential for preventing pregnancy complications. A randomized clinical study conducted in 2016 by Ho et al. investigated oral Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 treatment on vaginal colonization with GBS in pregnant women (Ho et al., 2016). About 43% of pregnant women previously positive for vaginal and rectal GBS taking oral probiotics were tested negative for GBS. It appears that this study has initiated another randomized clinical trial (Gutierrez 2017). This randomized clinical trial carried out by Gutierrez in 2017 had an intent to investigate the effectiveness of probiotics Lactobacillus reuteri DSM 16666/ATCC 55845 and Lactobacillus reuteri DSM 17938 for the treatment of bacteriuria and cystitis in pregnant women. The study’s primary outcomes were reducing symptoms and bacteriuria after 7-days treatment. Unfortunately, the results of this study were not published. An additional study conducted by Lui et al. investigated the effects of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 on GBS levels in the vagina of women in the third trimester of pregnancy who had GBS- positive vaginal cultures (Liu et al., 2020). The authors also investigated the effects of probiotics on pregnancy outcomes. The probiotic treatment decreased the percent of women with GBS-positive cultures and premature rupture of membranes.

A few clinical trials have investigated the effectiveness of various probiotics for treating UTIs in children with normal development of urinary tract and children with primary VUR. A small retrospective study investigated the effectiveness of therapy combining fluoroquinolone for 14 days and probiotic (S. boulardii) for 1 year in children with RUTIs (Madden-Fuentes et al., 2015). The study has shown a significant reduction in UTI episodes after treatment initiation. Seventy percent of children (7/10) were free of UTIs during the follow-up period (3–15 months).

The effectiveness of probiotic prophylaxis of RUTIs in infants with pyelonephritis was compared with antibiotic therapy or no-prophylaxis (Lee et al., 2016). Only 8.2% of infants had RUTIs during a 6-month follow-up period. However, probiotic therapy was more effective than no-prophylaxis; however, the effectiveness of probiotics was comparable to antibiotic treatment.

The vast majority of children with an anatomically normal urinary tract recovered from their first febrile UTI who were treated with a probiotic formulation containing Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium bifidum, and Bifidobacterium lactis and were subsequently free of UTI recurrence for 18 months (Sadeghi-bojd et al., 2019). A randomized, double-blind placebo-controlled clinical trial was initiated by Daniel et al. that investigated the effectiveness of probiotics Lactobacillus rhamnosus PL1 and Lactobacillus plantarum PM1 in preventing UTI in children (Daniel et al., 2020). The primary outcomes of this study were the frequency of RUTIs during the intervention and the follow-up period (9 months after the intervention). Unfortunately, no results were reported.

The ability of Lactobacillus acidophilus probiotic to prevent RUTIs in children with persistent primary VUR was compared to an antibiotic treatment (TMP-SMX) (Lee et al., 2007). It has been determined that both treatments could effectively prevent RUTIs in these patients. The effectiveness of a combinational therapy of probiotics Lactobacillus acidophilus and Bifidobacterium lactis with nitrofurantoin in preventing RUTIs was compared with nitrofurantoin alone in children with unilateral VUR and RUTIs (Mohseni et al., 2013). The combinational treatment reduced the number of RUTIs in treated patients. The difference between the probiotic plus antibiotic group and the antibiotic group was not statistically significant.

A meta-analysis of randomized clinical trials analyzing the effectiveness of probiotics in children with RUTIs concluded that probiotics are more effective than placebo, and the effectiveness of probiotics was comparable to antibiotic treatment (Meena et al., 2021). However, another meta-analysis has shown that probiotic therapy for treating RUTIs in children is effective only when combined with antibiotics (Hosseini et al., 2017).

The review of available evidence on the effectiveness of probiotics led us to conclude that the most effective in preventing RUTIs in pregnant women and children appear to be Lactobacillus strains. Altogether, probiotics can better prevent RUTIs than a placebo; they are comparable in effectiveness to antibiotic treatments. Potentially, a combination of probiotics with antibiotics may be most beneficial in preventing RUTIs.

Canephron® N is a well-known registered multi-component herbal remedy containing centaury powder (Centaurium erythraea Rafn), lovage roots (Levisticum officinale Koch), and rosemary leaves (Rosmarinus officinalis Linné) (Naber 2013). According to a Bionorica leaflet information, the remedy (phytodrug) is recommended as a supportive therapy of conditions associated with “inflammatory diseases of the efferent urinary tract; to flush out the urinary tract in order to prevent the deposition of renal sand” in patients older than 12 years (Bionorica 2016).

Due to the presence of three medicinal herbs, the remedy demonstrates diuretic, anti-nociceptive, anti-spasmodic, and anti-adhesive effects (Höller et al., 2021). A retrospective analysis of the effectiveness of Canephron® N conducted by Höller et al. has concluded that Canephron® N treatment was associated with less sporadic RUTIs within 1 year after treatment compared to antibiotic therapies as well as fewer follow-up antibiotic prescriptions (Höller et al., 2021). The authors suggested that Canephron® N can treat UTIs and acute cystitis as an alternative symptomatic treatment. A phase III double-blind randomized clinical trial reported that 83% of women, age 18–70, with acute UTIs receiving Canephron® N had no additional antibiotic prescriptions between days 1 and 38 (Wagenlehner et al., 2018). Similar results were seen in the group receiving Fosfomycin. The effectiveness of Canephron® N treatment of UTIs was tested in pregnant women and children.

Cystenium II (aka, Cistenium II) tablets/lozenges are dietary supplements intended to support adults’ and children’s urinary tract health (Vidal 2021). The supplement contains cranberry fruit extract standardized by proanthocyanidins A, D-mannose, and vitamin C. Cranberry-driven polyphenols may prevent UTI-causing bacteria from adhering to epithelial cells of the urinary tract (González de Llano et al., 2020). D-mannose prevents bacteria from binding to epithelial cells by attaching to bacterial type 1 pili, specifically adhesin FimH (Bouckaert et al., 2005). D-mannose may also act as an immunomodulator stimulating TGF-β production and regulatory T cell differentiation (Zhang et al., 2017).

Cystenium II is recommended for children older than 7 years of age to consume one lozenge twice per day for 2 weeks (Vidal, 2021). Pregnant women should take this remedy under physician supervision. A clinical trial evaluated the effectiveness of Cystenium II for the treatment of asymptomatic bacteriuria, acute cystitis, or exacerbation of chronic cystitis in pregnant women (Nashivochnikova and Leanovich 2020). One group of women received fosfomycin trometamol (3 g/day/14 days) and Cystenium II (1 lozenge/day). Another group was treated with fosfomycin trometamol only. The combined treatment with fosfomycin trometamol and Cystenium II effectively eliminated bacteria from the urinary tract in ≥70% of treated women by day 14 of treatment, and monotherapy with fosfomycin trometamol led to the elimination of pathogenic bacteria in 61% of women. Overall clinical effectiveness, measured by recurrency of asymptomatic bacteriuria or exacerbation of chronic cystitis in the combined therapy group, was 82–90%, and in the monotherapy group was only 56.5%.

We could not find any published clinical trial data investigating the effectiveness of this dietary supplement in children. However, Kotov and Petrov, in their article discussing the prophylaxis of RUTIs, stated that based on the safety profile of herbal remedies, Cystenium II can be used for the treatment of lower UTIs in children 7 years of age and older (Kotov and Perov 2020).