Overcoming challenges in the management of recurrent urinary tract infections

Abstract

Introduction:

Urinary tract infection (UTI) is a major global health concern. While acute UTIs can usually be effectively treated, recurrent UTIs (rUTI) impact patients for years causing significant morbidity and can become refractory to front-line antibiotics.

Areas covered:

This review discusses the risk factors associated with rUTI, current rUTI treatment paradigms, prophylactic strategies, and challenges in rUTI diagnostics. We specifically discuss common risk factors for rUTI, including biological sex, age, menopause status, and diabetes mellitus. We also review recently available evidence for commonly used treatments, from oral antibiotic therapy to intravesical antimicrobials, electrofulguration of chronic cystitis, and the last-resort treatment, cystectomy. We discuss the most current literature evaluating prophylactic strategies for rUTI including long-term antibiotic prophylaxis, estrogen hormone therapy and dietary supplements. Finally, we address the important role of UTI diagnostics in effective rUTI management and review the strengths and limitations of both current and emerging UTI diagnostic platforms as well as their ability to operate at point-of-care.

Expert opinion:

We discuss current challenges faced by clinicians in managing rUTI in women and steps that should be taken so that clinicians, scientists, and patients can work together to better understand this disease and develop better strategies for its management.

Introduction

Urinary tract infection (UTI) is a diagnostic umbrella term referring to infections that occur anywhere within the urinary tract and associated tissues including the urethra, prostate, bladder, or kidneys.[1] UTIs are primarily caused by infection of the bladder (cystitis) and/or infection of the kidney(s) (pyelonephritis). Symptoms of UTI generally include dysuria, urgency, frequency, suprapubic pain, or discomfort, and/or hematuria.[2] A large portion of UTI cases will be classified as uncomplicated UTI.[3] However, additional comorbidities and risk factors will cause some cases to be classified as “complicated”.[4] Complicated UTIs include, but are not limited to, those involving anatomical abnormalities, pregnancy, catheters, stones, urinary obstructions, and pyelonephritis. While complicated UTI is prevalent among certain clinical populations, the confounding nature of their causal comorbidities makes them difficult to address in the context of standard UTI management.

UTIs are considered among the most common bacterial infections in humans with an estimated 50% of women experiencing at least one UTI in their lifetime and over 10% of women experiencing at least one UTI with the past 12 months.[5] However, accurate assessment of UTI incidence remains challenging due to poor diagnostic accuracy.[6] In addition to being common community acquired infections, UTIs account for roughly 30% of all nosocomial infections.[7] Taken together, the high prevalence of UTI results in high financial implications. Individual ($390-$730) and indirect social ($3.5 billion) costs were estimated in 2019 and 2003 respectively.[8,9] Modern direct and indirect costs are likely much higher due to compounding factors of inflating healthcare costs, increasing antibiotic resistance, and an aging population.

UTIs are highly prone to recurrence. Roughly 25% of women who experience UTI will develop recurrent urinary tract infection (rUTI).[10] For postmenopausal women, the frequency of UTI progressing to rUTI increases dramatically to approximately 50%.[11] The current definition of rUTI is ≥3 symptomatic, culture proven UTIs within 12 months, or two or more symptomatic, culture proven UTIs within 6 months.[2,11,12] rUTI is distinguished from chronic UTI by resolution of symptoms and negative intervening urine culture. Generally, the threshold of positive bacterial urine culture in diagnosing UTI is 10⁴ colony forming units per milliliter (CFU/mL) of urine.[13] However, some guidelines recommend a diagnostic positive urine culture threshold as high as 10⁵ CFU/mL while other guidelines suggest a lower threshold of ≥10² CFU/mL of uropathogen in patients with ≥2 symptoms of UTI and a high suspicion of infection.[2,14] It is estimated that uropathogenic Escherichia coli (UPEC) are responsible for 65%−77% of rUTI cases.[15,16] The remaining cases are primarily caused by Klebsiella ssp., Enterococcus faecalis, and Proteus mirabilis.[16] In a study of 86 female patients with rUTI, Malik et al found that UPEC was responsible for rUTI in 55.8% of patients, followed by Enterococcus spp. (18.6%) and Klebsiella pneumoniae (14%) with the remaining 7% being polymicrobial.[17] This review does not address molecular pathogenesis of rUTI as this topic has been discussed in several other excellent reviews. [18–20] The disease progression of rUTI can be defined as a vicious cycle where, due to the interplay between the pathogen and host inflammatory response during the initial infection, the bladder becomes sensitized, or more susceptible to subsequent infections (Figure 1). Bladder sensitization likely encompasses changes in urothelial barrier function, bladder innate and adaptive immune responses, and the resident microbiota as well as the formation of bladder bacterial reservoirs that may seed new infections.[21–26]

Figure 1. The vicious cycle of recurrent urinary tract infection (rUTI).

Recurrent UTI can be characterized as a vicious cycle of infection, inflammation, and sensitization to recurrent infection due to the complex interplay between the pathogen, the host immune response and the urinary microbiota. QIR: quiescent intracellular reservoir, IBC: intracellular bacterial community. Created with BioRender.com.

In addition to being a very common and financially costly infection, rUTI takes a large toll on the quality of life of those who are afflicted.[27] In a popular website, Bladder Health UK, dedicated to supporting people with bladder problems many people (N=5994) complained of rUTI limiting their ability to work, negatively affecting their self-esteem and impairing their personal, social, and intimate relationships.[28] In further demonstration of the disruptive effects of rUTI, a study of rUTI patients in Europe showed that on average, afflicted patients were taking roughly three days of sick leave each year. Additionally, patients visited clinicians to address rUTI an average of three time per year, with 3–8% of patients visiting their doctor more than 10 times per year.[29] Another survey conducted by Chronic UTI Australia found that 90% of chronic or recurrent UTI patients experienced impacts on their quality of life with half reporting an extreme negative impact. The survey also found that the majority of patients were frustrated by the lack of specific knowledge and expertise exhibited by medical professionals in the management of their UTIs. [30] Additional lower urinary tract symptoms (LUTS) associated with rUTI are frequency/urgency of urination and nocturia. These disruptions to daily life and sleep patterns are associated with anxiety and chronic fatigue.[31] Taken together, these studies indicate that rUTI is a major threat to quality of life, and in future studies should include metrics of quality of life for studies which access patient outcomes.[32]

This review summarizes our current understanding of rUTI risk factors, current treatment strategies, existing and emerging methods of prophylaxis, and explores current challenges and future innovations in rUTI diagnostics. The review does not address recent developments in vaccines for the prevention of rUTI as this topic has been recently reviewed in Simoni et al.[33]

1. Risk factors for recurrent urinary tract infection (rUTI)

Biological Sex

While UTI can affect both men and women, there are stark differences between rUTI susceptibility, and severity between sexes and across the lifespan.[34–36] In pediatric cases (<24 months old), males and females exhibit similar susceptibility to rUTI.[37] In adolescence and into adulthood (10–50 years old), males (0.1%) have a much lower susceptibility to UTI than females (5%).[38,39] However, when men develop UTI, the severity and duration tends to be increased with respect to women.[37] Later in life (65–85 years old), the rates of UTI increase in both men (5%) and women (15%).[40] This trend continues for late elderly (>85 years old) individuals of both men (15%) and women (25%).[41] In males, many of these cases are attributed to prostatic hypertrophy which causes urinary retention and may require drainage by catheterization and are thus classified as complicated UTI, while older women can often suffer from both catheter-associated UTI and community-acquired uncomplicated UTI.[34,42] In juxtaposition to their female counterparts, rUTI is rare in adult males (age 15–50).[40] However for both males and females the majority of cases are caused by UPEC.[40] In women, UPEC has been found to colonize the vaginal epithelium and gastrointestinal tract where they may act as reservoirs of infection.[43,44] In addition to UPEC, other common causative agents of UTI in women include K. pneumoniae and Streptococcus agalactiae. However, in men E. faecalis, P. mirabilis, and Pseudomonas aeruginosa can commonly cause UTI.[45,46]

Together, these data suggest there may be differences in the immune response to UTI between males and females. Mechanistic support for this hypothesis has been provided by studies in mouse models of UTI.[36,47] Scharff et al found that female mice had greater immune cell infiltration, resolved UTI more often and more quickly, and had significantly higher secretion IL-17 than male mice.[36] Strikingly, treatment of female mice with testosterone abrogated their ability to quickly resolve UTI.[36] Similarly, Olson et al observed that castration attenuated severe UTI and complementation with testosterone reversed the protective effects of castration.[47]

Age and menopausal status

Amongst females, perhaps the most striking risk factors for rUTI are increased age and menopause. As women enter menopause their risk for UTI rises sharply from 19–36% for premenopausal women to 55% for postmenopausal women.[37,42,46] Decreasing estrogen production has been implicated for the increase in susceptibility to UTI among postmenopausal women. Generally, it has been found that estrogens (e.g. estrone, estradiol, estriol) modulate the immune system to elicit anti-inflammatory effects and are associated with improved immunological function.[48] In nonpregnant, pre-menopausal women estradiol is the most potent and abundant estrogen and is primarily produced in the ovaries.[49] Estradiol has been found to be a particularly robust immunomodulator and two of its 3 known receptors, ERα and GPER1, are known to activate anti-inflammatory pathways.[50] In postmenopausal women, estrogen production of the ovaries diminishes and estriol replaces estradiol as the most abundant estrogen.[49] Though estriol can also have anti-inflammatory properties, it is not as potent or abundant as estradiol, resulting in poor immunoregulation and increased inflammation.[51,52] There are also changes in estrogen receptor (ER) concentration in both the urothelium and vaginal epithelial linings associated with menopause that include a decrease in ER-β and increased concentrations of ER-α which have been linked to stress urinary incontinence.[53,54]

While mouse models have been used to study UTI, there are caveats to the use of animal models to study the impact of menopause on disease outcomes. Although there is a decrease in reproductive success in aged female mice, female mice do not undergo menopause.[55] While ovariectomized (OVX) mouse models address ovary production of estrogen, there is currently no widespread model that accurately recapitulates the gradual decline of estrogen that women endure during menopause.[56] With these caveats, however; murine models have demonstrated significant changes in the bladder immunological landscape with increased age. Notably, the formation of bladder tertiary lymphoid tissues (bTLT) has been observed in aged mice and postmenopausal women.[24] bTLTs are thought to act as germinal centers and sites of inflammation in the lamina propria of the bladder. While the formation of bTLTs in humans remains poorly characterized, more frequent and larger bTLTs have been observed in aged female mice compared to young female mice.[57] Additionally, Ligon et al found that bTLTs were associated with, and dependent on, increased expression and secretion of TNF-α, a pro-inflammatory cytokine.[57] Estradiol has been previously shown to decrease expression of TNF-α.[58,59] When taken together, these observations indicate that age-associated dysregulation of the immune system may be linked with the decreased estrogen levels and menopause,[60] and therefore may contribute to the increased incidence of rUTI in postmenopausal women.

Diabetes mellitus

There are numerous studies indicating that individuals with type I and type II diabetes mellitus face UTIs more frequently than their non-diabetic counterparts.[61–63] Papp et. al combined results from several studies spanning different countries and reported that the recurrence rate of UTIs specifically in diabetic women ranged between 23%−37%.[64] It has been observed in previous studies that having diabetes was significantly associated with the progression of acute cystitis and that other factors like insulin treatment could also impact recurrence of UTI.[65,66] Research consistently shows that diabetes is a significant risk factor for UTI. Specifically, postmenopausal women with diabetes face a higher risk of acute symptomatic UTI with risk being greater in women undergoing pharmacologic treatment for diabetes.[67] Hammar et al. also confirmed a higher incidence of UTIs in patients with T2DM. These findings underscore the importance of managing diabetes to reduce the risk of UTIs.

The pathogenesis of UTI in those with T2DM may be influenced by multiple factors, including immune system deficiencies[68] poor diabetes management[69] and issues with bladder emptying due to autonomic neuropathy.[70] Al-Rubeaan et. al., identified female gender, high BMI, hypertension, insulin therapy, and nephropathy as risk factors for UTIs in diabetic patients.[71] High glucose concentration in the urine may provide a nutritious environment for microorganisms associated with UTI.[72] Similarly, incomplete bladder voiding may lead to accumulation of urine which increases the chances of uropathogens infecting and invading the bladder epithelium.[72] Finally, hyperglycemia inhibits proper functioning of the immune system that is required for the recognition and eradication of infectious microorganisms.[68] Furthermore, diabetic patients with UTI were also found to have higher frequency of bladder catheterization than non-diabetics thereby making UTI eradication difficult.[73]

2. Current treatments for rUTI and their limitations

Antibiotic therapy for treatment of acute rUTI

While non-antibiotic approaches for the treatment of acute rUTI, such as the use of over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), have been explored, their ability to resolve infections are generally inferior to antibiotic approaches. [74] As such, current guidelines from the dictate that first line antibiotic therapy for rUTI should include treatment with antibiotics such as nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), or Fosfomycin.[2] [75] The duration of antibiotic therapy should generally be no longer than seven days.[2] The AUA currently recommends that urine culture, antimicrobial sensitivity testing (AST), and urinalysis should be performed before clinicians initiate treatment of rUTI.[2] While these guidelines are useful, some physicians have found that in practice they fall short for treatment of some patients in a timely manner.[76] The logistical challenge of obtaining bacterial culture results and prescribing the appropriate antibiotics, could, for example, lead to patients seeking treatment at the end of the week going for longer without treatment than their counterparts that had appointments earlier in the week. A 2022 study by Kusin et al explored the use of empirical versus culture-directed prescription of antibiotic regimens and found that at 14 days, the treatment failure rates were 31% and 17% for culture-based and empiric prescriptions, respectively.[77] These results indicate that delaying antimicrobial therapy for culture-based antibiotic selection may lead to increased failure rates, even when accounting for antimicrobial sensitivity. UTI has been shown to cause damage to the urothelial layers of the bladder, and taken together these data lead some to hypothesize that the prolonged time without treatment for rUTI allows bacteria to further damage and invade the bladder wall leading to more recalcitrant infections.[78,79]

Another challenge in the management of rUTI with antibiotics is the interplay between patient antibiotic allergies and antibiotic resistance. When accounting for antibiotic resistance and allergy, the limitations for treatment of rUTI are major hurdles to overcome.[80,81] In 2018 Malik et al analyzed the coincidence of allergy and antibiotic resistance in a group of 86 women with rUTI. They found that allergy and/or resistance was exclusionary for treatment of rUTI with TMP-SMX, fluoroquinolones, and nitrofurantoin in 77%, 56%, and 35% of cases respectively.[17] The same study found that 20% of women were allergic or infected with bacteria that were resistant to all three of the frontline antibiotics discussed.[17]

Intravesical antimicrobial therapies

A strategy for the localized treatment of rUTI is intravesical instillation of antimicrobials directly into the bladder via a urinary catheter. [82] Though intravesical antimicrobial treatment of UTI has been practiced since the 1960s, it is infrequently used and often only recommended as a last line of treatment of rUTI.[83] However, the alarming increase in resistance rates against oral antibiotics may warrant the reevaluation of this treatment modality as a therapy for rUTI that is unresponsive to frontline antimicrobials. There is currently no universally recommended course of intravesical antimicrobial therapies for rUTI.[2] However, several studies have explored the use of gentamicin, colistin, and neomycin/polymyxin for prophylaxis and treatment of rUTI with varying time points and dosages which are outlined by an excellent review by Pietropaolo et al.[84] The safety and efficacy of bladder instillation with the antibiotic gentamicin for treatment of antibiotic-refractory rUTI has been evaluated by multiple studies.[85–89] A recent prospective survey of patients with neurogenic lower urinary tract dysfunction prescribed long-term intravesical gentamicin for UTI prevention indicated that this therapy increased quality of life and decreased UTIs from 3.9 to 1.1 per year.[90] Overall these studies have found that intravesical gentamicin is safe and can reduce UTI recurrence.[82] However, intravesical gentamicin may be limited in its ability to cure rUTI since gentamicin alone cannot penetrate bladder epithelial cells to remove intracellular bacterial communities (IBCs) and quiescent intracellular reservoirs (QIRs).[91] The data regarding the use of gentamicin as well as other intravesical antimicrobials are promising; however, the majority of studies to date have been observational and there is a need for randomized control trials of these important rUTI interventions.

Electrofulguration for antibiotic recalcitrant UTI

One of the major problems posed by rUTI is the ability of uropathogens such as UPEC to invade the bladder wall and establish chronic bacterial niches.[92–94] It is well documented that UPEC is capable of establishing IBCs and then QIRs in mouse models of UTI.[95,96] Furthermore, a 2019 study of bladder biopsies from women with rUTI revealed the presence of bacterial reservoirs throughout the urothelium and sub-epithelial layers like the lamina propria.[25] These bacterial communities have also been observed within cystitis cystica lesions that have been identified as tertiary lymphoid tissues by Ligon et al.[24] These lesions are negatively associated with resolution of rUTI and have been observed in higher frequency in postmenopausal women.[24] Together these data indicate that a potential source of recurrent infections and local inflammation may be these deeply embedded bladder resident bacteria that are shielded from antimicrobial treatments. To target these recalcitrant bacterial niches, some women with antibiotic refractory rUTI elect to undergo electrofulguration of areas of areas of chronic cystitis detected during office cystoscopy. Electrofulguration is a common and minimally invasive procedure frequently used for the treatment of small, superficial bladder tumors but is not yet widely used in the advanced management of rUTI.[97] In 2019 Crivelli et al studied a cohort of 95 women with rUTI undergoing bladder electrofulguration after having failed multiple antibiotic courses and observing cystitis cystica of the trigone.[98] As a result, over a median follow-up period of 4.9 years 15% of patients were cured (no further UTI), 73% were improved (≤2 UTIs/year), and 15% failed (≥3 UTIs/year). Similarly, a study of 73 women with rUTI by Ribeiro-Filho et al found that 96% of patients remained infection-free during the first year after electrofulguration and 57% of women were infection free after 2 years.[99] In both studies, the majority of relapse cases were caused by multiple pathogens, highly antibiotic resistant pathogens, or a combination thereof.[98,99] Finally, a 9-year audit of the efficacy of diathermy, the use of deep heat to ablate tissues, for the treatment of cystitis cystica found that median number of UTIs dropped from three to one during the 12-month follow up period and that 34% of women were UTI free.[100]

Radical cystectomy as a treatment of last resort

Unfortunately, for some individuals with rUTI, conventional treatments and prophylactic strategies are insufficient to prevent UTI recurrence. For patients whose quality of life is extremely affected or are at high risk for urosepsis, radical cystectomy (RC) may be considered as a last resort in the advanced management of antibiotic-refractory rUTI.[101] Though RC is more often performed in the treatment of invasive bladder cancer, 5%−8% of cystectomies in the US are for benign disease, including infectious cystitis.[102] In a study published by Carlton et al in 2024, 24 women underwent radical cystectomy with ileal conduit urinary diversion for treatment of antibiotic recalcitrant rUTI.[101] Following treatment, 25% of patients had postoperative UTI within 14 months following RC. However, RC alleviated complaints of urinary incontinence, low bladder capacity, and lower urinary tract symptoms and thus patients reported a higher quality of life and lower financial burden.[101]

3. Prophylactic strategies to prevent UTI recurrence

Antimicrobial prophylaxis

One of the primary forms of rUTI prophylaxis is long-term, low-dose antibiotic therapy. In a study of 699 women experiencing rUTI from diverse populations in 7 countries, Renard et al found that with effective prophylaxis across a 180 day time span, quality of life scores improved and reports of anxiety and depression among the sampling population decreased by 59.3%.[103] According to the AUA and IDSA guidelines, Nitrofurantoin is the first-line antibiotic of choice for long term rUTI prophylaxis.[2,104] One of the benefits of nitrofurantoin is the limited effect on the gut microbiome. Nitrofurantoin is concentrated in the urine, and thus is hypothesized to have very little impact on the flora of the gastrointestinal tract, and to not contribute to the selection of antimicrobial resistant pathogens.[104] While for many women, it has proven effective for the management or rUTI, in some cases nitrofurantoin has been associated with negative side effects such as pulmonary, neurological and hepatic toxicities. The overall rate of negative side effects of long-term nitrofurantoin treatment was 0.001%. More specifically, the rates of pulmonary, neurological, and hepatic damage were 0.0002%, 0.0003%, and 0.0007% respectively.[105] While these adverse reactions are rare, they warrant physician and patient education so that symptoms can be quickly recognized and addressed.[106]

In women whose rUTI episodes are associated with coitus prior to active infection, postcoital antibiotic therapy is recommended as a prophylactic measure. [107] In a randomized, double-blind, placebo-controlled study, postcoital administration of trimethoprim-sulfamethoxazole was associated with a decrease in recurrence.[108] Another antibiotic sparing option for long term prophylaxis against rUTI is methenamine hippurate, a urinary antiseptic that produces formaldehyde in acidic environments like urine resulting in a non-specific antimicrobial activity.[109,110] A randomized clinical trial of 240 rUTI patients by Harding et al. found that methenamine hippurate reduced UTIs to 1.38 episodes per person per year while antibiotics reduced UTI episodes to 0.89 per person per year. [109] While the difference between these two treatments does not exceed the pre-established threshold of non-inferiority (1 UTI/year), additional studies are needed to determine long-term efficacy and impact on quality of life. [109]

Estrogen Hormone Therapy

Estrogen depletion during menopause alters the urogenital epithelium and mucosal environment reducing cervicovaginal secretions, epithelial barrier function, and changing the microbial (i.e. loss of Lactobacillus predominance) and metabolic environments, thereby creating favorable conditions for uropathogen colonization.[111] Estrogen hormone therapy (EHT) is a widely available but underutilized treatment that can reduce the incidence of rUTI in some PM women.[112–114] The 2019 AUA guideline for uncomplicated rUTI recommends vaginal EHT for both peri- and post-menopausal women to reduce the risk of rUTI.[2] EHT is widely hypothesized to reduce rUTI by encouraging a transition to a Lactobacillus (Lb)-dominated female urogenital microbiome (FUM)[26,115], consistent with known roles of lactobacilli in prevention of bacterial vaginosis (BV) and STIs.[116] Vaginally delivered EHT (vEHT) has been the most widely investigated EHT modality for rUTI prophylaxis. In 1993, a landmark study by Raz and Stamm showed that vEHT significantly reduced the incidence of rUTI compared to placebo (0.5 vs. 5.9 episodes per year).[112] A more recent study by Ferrante et al found that fewer women taking vEHT had UTI within 6 months compared to placebo. Interestingly, in both studies about half of the women taking vEHT still experienced rUTI and non-inferiority to antibiotic prophylaxis has yet to be demonstrated.[117]

Dietary Supplements

In addition to the physician-prescribed treatments for rUTI, there are also proposed strategies for non-pharmacological prophylaxis. One of the most popular is cranberry juice.[118,119] Though current data are insufficient to draw definitive conclusions of clinical efficacy, cranberry is hypothesized to be effective in preventing adherence of uropathogens in the bladder.[120] Cranberries are high in proanthocyanidins, a type of tannin, which, in vitro, prevents the adhesion of P-fimbriated uropathogens such as UPEC to the surface of cells containing α-Gal.[121] To test the efficacy of a cranberry beverage as a prophylactic for UTI, Maki et al conducted a double-blind, randomized, placebo-controlled clinical trial on a total of 346 women with a history of UTI over a span of 24 weeks. They found that daily servings of cranberry beverage (250 mL) produced a 39% reduction in UTI episodes.[122]

Another non-pharmacological strategy for the management of rUTI is D-mannose. D-mannose is a naturally occurring sugar, which similar to cranberry, is hypothesized to inhibit the binding of bacteria to the urothelial cells that compose the luminal surface of the bladder.[123] UPEC, the most common causative pathogen of rUTI express type 1 fimbriae with a terminal adhesion protein, FimH.[124] UPEC utilizes FimH to bind mannosylated glycans which are conjugated to Uroplakin 1a, a receptor on the luminal surface of urothelial cells.[125] Some have hypothesized that by binding D-mannose instead of the mannosylated glycans of Uroplakin 1a, bacterial adhesion to the bladder lumen can be prevented and the pathogens can be flushed out during urination.[123] However, a recent double-blind, randomized, placebo-controlled clinical trial published by Hayward et al rebuffed this hypothesis. They found that prophylaxis with orally administered D-mannose did not significantly prevent the onset of UTI, and when patients did contract UTI D-mannose failed to reduce the frequency of severe symptoms.[126]

4. Addressing current challenges in rUTI diagnostics

Clinical guidelines for UTI diagnosis call for documented UTI symptoms (i.e. dysuria, urgency and frequency, hematuria, incontinence) and a positive urine culture (UC), which has a diagnostic window of 24–72 hours.[2,127] Both symptoms and causative pathogen are required for accurate UTI diagnosis because antibiotics are not recommended for asymptomatic bacteriuria (ASB), where bacteria are present but do not provoke inflammation (i.e. symptoms),[128] and because UTI symptoms can overlap with other urologic disorders.[129] The AUA has described a set of guidelines for diagnosing rUTI in women. According to these guidelines, clinicians should obtain a complete patient history, perform a pelvic examination, perform urinalysis, and obtain a urine culture.[2] Standard clinical urine culture employs a limited set of culture conditions to determine the presence, type and number of bacteria present within a urine sample. AUA guidelines also recommend antibiotic susceptibility testing (AST) to determine effective antibiotics against infecting pathogens for enhanced antimicrobial stewardship. However, the current turnaround time for AST is 2–3 days and waiting for these results would require delaying treatment of the UTI.[130] Following these diagnostic guidelines can be especially difficult in rUTI patients who experience UTI symptoms frequently and may prefer telemedicine to an office visit. Although documented symptoms and positive UC is the current gold-standard for UTI diagnosis, available point-of-care (POC) methods are often used to rapidly diagnose UTI and broad-spectrum antibiotics are then empirically prescribed.[127] However, empiric prescription of antibiotics without accurate, confirmed UTI diagnosis is a major contributor to antibiotic overuse.[128] rUTI management is not only currently limited by the lack of accurate point-of-care (POC) diagnostics, but also by the inability to determine rUTI prognosis.

Current UTI diagnostic methods

Qualitative measurement of leukocyte esterase (LE) and nitrites (Ni) by urine dipstick is the most commonly used POC UTI test but suffers from poor specificity and a high false-positive rate (Table 1).[131] Additional available diagnostic methods are either not POC, technically difficult, do not detect symptoms (i.e. inflammation), or are not sufficiently selective.[132–134] To improve UTI diagnosis and reduce the overuse of antibiotics, new POC UTI diagnostic methods must be developed. The higher prevalence of issues like dementia, delirium and the use of indwelling catheters make it difficult to assess symptoms accurately in elderly populations.[135] Symptoms such as urgency, frequency, and urinary incontinence are common and hard to differentiate from non-infectious conditions like genitourinary syndrome of menopause and overactive bladder.[136] The prevalence of ASB in older women also complicates UTI diagnosis. Studies have found that up to 50% of non-catheterized older women have ASB, with 90% also having pyuria.[137] These factors may reduce the specificity of common UTI diagnostic markers, such as leukocyte esterase or nitrite, and urine culture for rUTI diagnosis, especially among older women.[135]

Table 1.

Overview of the clinical utility of available UTI diagnostic methods.

Diagnostic Method	Diagnostic window	Sensitivity/Specificity	POC	Advantage	Disadvantage
Symptoms + Clinical Urine Culture	24 – 72 hrs	100% / 100%[126]	No	High accuracy and targeted treatment	Not translatable to POC, cannot detect fastidious uropathogens
Microscopic Urinalysis	10 min – 1 hr	96% / 63%[139]	Yes	Direct observation of immune cells and bacteria in urine	Poor specificity, requires clinical laboratory
Urine Dipstick (Ni and LE)	2 min	85% / 53%[130]	Yes	Rapid results, cost-effective, easy to use	Poor specificity and high false-positive rate
Lateral flow immunoassay (RapidBac)	20 min	86% / 94%#[133]	Yes	Offers broad detection range of pathogens	Only diagnoses bacteriuria, only in use by veterinarians
Enzymatic Assay (UriScreen)	2 min	88% / 68%[131]	Yes	Rapid, easy to use test	Only detects catalase (+) bacteria
ELISA Test (Uristat)	1–2 hrs	77% / 56%[132]	No	Detects seven common uropathogens	Can produce false positives/negatives, less reliable than UC
Multiplex PCR	5–6 hrs	80% / 60%[143]	No	Quick identification of common UTI pathogens	Loss of information on antibiotic sensitivity
Next generation sequencing	24–48 hrs	100% / 50%[147]	No	Can identify fastidious pathogens not cultivable by clinical urine culture	Complex sample preparation, high cost, and extended diagnostic window

POC: point-of-care,

^#sensitivity and specificity to detect bacteriuria, not symptomatic UTI reported.

Microscopy, while seldom used as the sole diagnostic method, can play a valuable role in the initial screening and interpretation of urine culture results. Urine microscopy can be used to analyze various urinary components to diagnose UTIs like white (pyuria) and red blood cells (hematuria), squamous epithelial cells and bacteria.[138] Point-of-care urine microscopy can be performed using a simple inverted microscope with either stained or unstained samples. The diagnostic utility of microscopy has been debated due to the subjectivity of results. A systematic review of the use of urine microscopy in UTI diagnosis found that the sensitivity ranged from 47%−97% and the specificity ranged from 27%−100% depending on the study.[139] For example, one study found the sensitivity of an automated microscopy sediment analyzer to be 93% and 63%, respectively.[140] While light microscopy with oil immersion has been found to have the highest sensitivity and specificity, it is considerably more time-consuming than phase contrast microscopy, potentially limiting its utility as a POC diagnostic method.[139] Evidence suggests that microscopy may be combined with other POC methods for more accurate results. For example, Werneburg et. al report that negative urinalysis (Nitrites, leukocyte esterase) and absence of white blood cells (WBCs) in urine is highly predictive (97.4%) for the absence of culture-proven UTI in premenopausal women.[141,142]

Emerging UTI diagnostic methods

In order to balance patient care with the increasing need for antimicrobial stewardship, improved rapid diagnostic methods for UTI and rUTI must be developed and integrated into clinical practice. Existing POC methods like the urine dipstick are mainly qualitative, have poor precision and lack pathogen identification and AST capabilities.[143] The ideal POC UTI diagnostic platform would not only accurately distinguish UTI from ASB and non-infectious LUTS but would also perform rapid AST. New POC UTI diagnostic platforms currently in development are testing the application of Multiplex PCR, microfluidics, biosensing, and next generation sequencing for rapid UTI diagnosis. Multiplex PCR platforms in development for POC UTI diagnosis include the Roche SeptiFast^®, a multiplex real-time PCR test for pathogens in blood[144] and the BioMérieux FilmArray, an integrated PCR platform for pathogen identification and AST.[130]

Biosensor platforms offer direct urine analysis and compact device integration. Key focus areas include developing biosensors for rapid, POC UTI diagnosis, adhering to the WHO’s ASSURED criteria: Affordable, Sensitive, Specific, User-Friendly, Rapid, Equipment-Free, and Delivered diagnostics. Infection detection via biosensors can use either label-free or labeled methods. Aptamers, which are highly specific oligonucleotides, are commonly used in these platforms for detecting biomarkers and genetic signatures.[145] Ganguly et al. have reported on a novel urine electrochemical biosensor for Prostaglandin E2 (PGE2) to detect early inflammatory responses associated with UTI.[146] They have further described an electrochemical biosensor platform capable of evaluating a panel of three biomarkers like PGE2, IL-6 and CRP for UTI diagnosis.[147] Similarly, Altobelli et. al have designed a biosensor integrated with a modified process of AST that can rapidly detect Enterobacteriaceae as well as ciprofloxacin minimum inhibitory concentration (MIC).[143]

Next Generation Sequencing (NGS) revolutionized genomics by enabling the simultaneous sequencing of vast amounts of genetic material. For example, MicrogenDX uses amplicon NGS to identify bacteria present in urine.[138] While this method has high sensitivity for detection of potential pathogens in urine, it typically only provides relative abundance information, can be confounded by contaminating environmental DNA, and results take 24–48 hour thus limiting its translation to POC.[148] Wang et. al reported using MinION as a metagenomic NGS platform for decreasing the time to pathogen detection with a reported turnaround time of four hours; however, the reported method does not allow sample multiplexing, which would significantly increase turnaround time, and minimizes sequencing depth limiting analysis of encoded antibiotic resistance.[149] Recently, Szlachta-McGinn et. al compared 9 studies that utilized NGS for UTI diagnosis to papers with conventional urine culture processes and found that NGS is more sensitive and detects higher species diversity.[150] In addition to its high cost and lengthy turnaround time, the use of NGS for UTI diagnosis is significantly complicated by the discovery of a urinary microbiome in healthy men and women that refutes the dogma of urinary tract sterility.[151] Given our current limited knowledge of the function of many urinary microbiome species in maintaining or disrupting urinary tract health, care must be taken when interpreting urine NGS results as the presence of bacteria alone is not indicative of UTI.

Conclusion

rUTI afflicts millions of people every year, especially postmenopausal women, and is the source of a great deal of suffering. rUTI is often recalcitrant to available front-line antibiotics and as the prevalence of antibiotic resistance continues to increase, so too will the number of patients desperate to find a solution to this complicated disease. Currently there exist several strategies for rUTI treatment and prophylaxis. However, many facets of current technology remain insufficient to meet the needs of many patients, warranting the need for improving existing management strategies and the continued search for novel therapies. Furthermore, the current limitations of available methods for POC diagnosis of UTI, result in the imprecise or delayed prescription of antibiotics, the misuse of antibiotics to treat ASB or non-infective LUTS, which exacerbate the current challenges in the clinical management of rUTI and negatively impact patient outcomes. Therefore, to improve patient care and antibiotic stewardship, new diagnostic platform should aim to accurately distinguish UTI from ASB and non-infectious LUTS and perform AST during the office visit, at the point of care.

Expert Opinion

As the US population ages, the rate of women referred for management of rUTI is rapidly growing in our practices. At the same time, the limited treatment options revolving primarily around antibiotic therapy are painfully witnessed by everyone worried about the looming threat of antibiotic resistance and a post-antibiotic era, and therefore represent a wake-up call for both patients and physicians that innovation in rUTI management is desperately needed.

What do patients read about rUTI? The internet abounds in websites, chats, group discussions with a variety of advice on how best to prevent UTIs ranging from techniques to wipe after voiding as well as what to do before and after intercourse, all the way to douching, soaps, intravaginal suppositories, a long list of OTC supplements for “urinary health”, countless recommendations on diet adjustments, etc. Although this information may be helpful to some women, many of us ask “Where is the real science behind these remedies?” How do we respond to a woman asking: “Why does my UTIs keep recurring?”; “How much D-mannose should I take?”; “I have been doing so well on my daily antibiotic prophylaxis, but how safe is it long-term?”; “What can I do to avoid another infection every time I have intimacy with my husband? This is affecting our relationship.”; “Despite taking antibiotics for a long time, I still get UTIs. Why?”; “I am so anxious to travel because my UTIs come on so quickly that I fear another septic episode. I have already been hospitalized several times. What should I do?”; “Is there something wrong with my immune system?”; and “What will I do if I become resistant to all antibiotics; Will my bladder have to be removed?”.

The list of questions is long and unending, and the answers are not always there. That is our challenge for the years to come. We need to come up with a better way to stage the rUTI condition as some patients will experience a few events in their lifetime whereas others suffer from rapid recurrences with devastating effects on their life and overall health. We will also need tools to detect UTI episodes early, at point of care, to allow rapid treatment with less antibiotics. We will have to develop more elaborate testing approaches to refine our understanding of these bacteria and their chances to survive in the host. We all know that each strain of E. coli, the most common bacterial species involved in rUTI, is genetically different, but these bacteria are not routinely sequenced in clinical practice. We are not sure of what host defense mechanisms are present and could be better activated. Clearly, not all women get infected. In fact, nearly half of the population never gets an infection which is fortunate for them but begs the question as to what are their protective defense mechanisms? We are discovering the world of the urogenital microbiome and hope to harness this new knowledge to develop better probiotics to naturally defend against infections and prevent antibiotic resistance. We are advancing in metabolomics and diet research to comprehend the nutrients used by bacteria to grow so rapidly and the role of urinary pH in mitigating their growth. We are developing better intravesical therapies and technologies so that some infections can be treated directly in the bladder and bypass the need for systemic oral or intravenous antibiotic therapies.

On the treatment side, it is regrettable that the pipeline for new antibiotics has dried up in the last decade but with directed effort and investment newer antibiotics may become available in the future. Gepotidacin, a new antibiotic targeting DNA gyrase and topoisomerase, has recently demonstrated non-inferiority to nitrofurantoin for uncomplicated UTI in adolescents and adults in EAGLE-2 and EAGLE-3 trials. However, given the trial period was 28 days, its efficacy for rUTI is still to be demonstrated. Phage therapy has been contemplated, but no real breakthrough has happened in its application to managing rUTI in the past years. Our group has championed electrofulguration of areas of chronic cystitis detected on office cystoscopy during the evaluation of women with antibiotic-refractory rUTI and have proven by biopsy that these lesions harbor deeply embedded bacteria, but level I evidence with randomized clinical trial is still needed to endorse this approach as part of our current rUTI guidelines. UTI vaccines are being developed but their long-term efficacy is still unknown. The hope comes from the ever-increasing passionate interaction between clinicians, scientists, and patients all over the world to move this field forward since so few efforts have been devoted to this disease that has too long been reliant on antibiotic therapies.

As with many diseases primarily impacting women, the funding support is often times lacking for this “benign” condition even though it can have such a devastating impact on the health of millions. However, recent Women Health initiatives, if backed by dedicated funding, may turn the tide and provide the necessary resources for the development of innovations needed to better manage rUTI by the end of this decade. If these resources are allocated, for the five-year view, it is realistic to expect a more rapid diagnostic process to quantitate accurate diagnostic biomarkers of UTI, identify diverse uropathogenic bacteria and their antibiotic susceptibilities, which will directly improve the clinical management of UTI and antibiotic stewardship efforts. In the next five years, if clinical trials continue to progress positively, we may have new tools, like the UROMUNE vaccine and Gepotidacin to help prevent UTI recurrence. The next five years should also see the completion of additional randomized controlled trials to better delineate the ideal candidates and treatment regimens for non-antibiotic preventive approaches using cranberry, D-mannose, estrogen or methenamine hippurate, or other treatment approaches such as electrofulguration, intravesical agents, or phage therapies in the management of rUTI in women. With an increased evidenced-based understanding of the mechanism and efficacy of these interventions, clinicians will be better equipped to effectively manage and permanently end the vicious cycle of rUTI. Bacteria beware!

Article Highlights.

• Roughly 25% of women who experience UTI will develop recurrent urinary tract infection (rUTI) and the frequency increases to 50% in postmenopausal women

• The disease progression of rUTI can be defined as a vicious cycle where, due to the interplay between the pathogen and host inflammatory response, the bladder becomes sensitized to subsequent UTI episodes

• While females are more susceptible to rUTI, UTIs are generally severe in males and these differences in susceptibility and severity between sexes and across the lifespan can largely be attributed to the modulation of immune responses and the urogenital microbiome by sex hormones.

• Although diabetes is major risk factor for rUTI, our mechanistic knowledge of how this disease increases rUTI susceptibility is limited.

• There is a need for randomized, controlled trials to evaluate intravesical therapies and electrofulguration for the advanced management of antibiotic-refractory rUTI.

• Nitrofurantoin is the first-line antibiotic of choice for long term rUTI prophylaxis, but other non-antibiotic prophylactic strategies, like estrogen hormone therapies, should be utilized and improved so that patients can be offered a more sustainable solution.

• In light of the diagnostic windows of available technologies, guidelines recommending urine culture, antimicrobial sensitivity testing (AST), and urinalysis be completed before treatment is initiated, significantly delays treatment which can negatively impact patient outcomes.

• Point-of-care diagnostic platforms capable of accurately differentiating UTI from asymptomatic bacteriuria and rapidly providing antibiotic susceptibility predictions are urgently needed for clinicians to more effectively manage both acute UTI and rUTI.