Management of urinary tract infections in the era of antimicrobial resistance

Classification and diagnosis

UTIs can be classified differently, but a system developed by the EAU Section of Infections in Urology and the European Society for Infections in Urology (ESIU) and adopted by the EAU provides a valuable classification tool. The EAU/ESIU system classifies UTIs according to the prevalence of risk factors (uncomplicated and complicated UTIs), localization (lower and upper UTIs), the frequency of occurrence (rare and recurrent), relapse or reinfection, and in women and men (8). That is, the system is based on the clinical presentation of the UTI, the anatomical level of the UTI, the grade of severity of the infection, the categorization of risk factors, the frequency of occurrence, and the availability of appropriate antimicrobial therapy (10).

For example, a young, premenopausal, nonpregnant woman with no known relevant anatomical and functional abnormalities within the urinary tract or comorbidities presenting with the typical symptoms of a UTI can be considered to have an uncomplicated UTI. By definition, all other UTIs are complicated UTIs, with a higher risk of developing a complicated course. This classification system for UTIs is summarized in Table I.

Even an uncomplicated UTI is not just a simple infection, as it involves symptoms and restricted activity and may necessitate sick leave or bed rest. A UTI occurring at least three times a year or twice in the previous 6 months is defined as an rUTI. However, contrary to historical practice, it is strongly recommended not to treat cases of asymptomatic bacteriuria, where the presence of bacteria is found in a urine culture taken as part of a routine clinical visit in a patient without symptoms (8). In fact, there is evidence that asymptomatic bacteriuria is a common commensal colonization that may have a protective function against superinfecting symptomatic UTI, and treating it may be harmful in some cases (8,11).

UTI is strongly gender biased, exhibiting one of the most prominent sex disparities among infectious diseases. Premenopausal women are 20-40 times more likely to have a UTI than men of the same age (12-15). Anatomical differences may account for some of this disparity. For instance, men have a longer urethra, and the distance between the anus and urethral opening is shorter in females. However, anatomical differences do not explain why young males and females have similar rates of rUTIs, and the rates of UTIs in males over 65 years increase substantially until they are nearly equivalent to those in older women (12,16). Changes in the incidence of UTIs in older men may, instead, be due to urodynamic changes such as prostatic hypertrophy or other factors, for example, biological or immunological changes occurring over time (16-19). Indeed, the differences in UTI susceptibility by gender are most evident in postpubescent adults younger than 50 years, a time when estrogen and testosterone are at their highest levels in females and males, respectively (12,14).

Zychlinsky Scharff and colleagues hypothesized that sex-based differences in immunity influence response to UTI, which they explored in an animal model designed to bypass anatomical differences, enabling innate and adaptive immune responses in infected female and male mice to be directly compared (19). They identified a cytokine pathway essential for bacterial clearance after infection with uropathogenic E. coli (UPEC), demonstrating that interleukin 17 (IL-17) specifically influenced the innate immune response to bacterial infection in a sex-dependent manner (19). Whether this finding is directly relatable to human infection outcomes remains to be demonstrated. However, it provides a possible explanation for the similarly high frequency of infection in older men and women and the increased severity associated with UTI in men, suggesting hormone-mediated suppression of the innate immune response. This is supported by significant sex differences in the expression of immune-mediating genes induced during UTI, including in the IL-17/IL-33 axis (19). The authors concluded that a better understanding of the immune system’s role in UTIs might contribute to developing nonantibiotic-based stratified therapies targeting sex-specific immune pathways in managing women and men (19).

In conclusion, while multiple factors, including genetics, age, and access to care, contribute to the gender differences in the incidence of UTIs, sex hormones have a powerful influence on the onset, severity, and patient outcomes (12,14).

UTI is a syndrome. The symptoms of urgency, frequency, fever, suprapubic pain, or dysuria, combined with the presence of bacteria in the urine, constitute a UTI. When a patient has symptoms without bacteriuria, other syndromes should be considered, such as overactive bladder (OAB) syndrome or interstitial cystitis/bladder pain syndrome (IC/BPS), which should not routinely be treated with antibiotics (20,21). Point-of-care testing by dipstick may help to clarify a diagnosis, but such analysis has drawbacks, and the characteristic clinical presentation is reliable for the diagnosis. A complete medical history and a short physical examination should still be taken. However, the diagnosis of a first episode of uncomplicated UTI can be symptom based, and there is usually no requirement for further diagnostic workup in women under 40 without other risk factors. Taking a urine culture is not recommended for the first episode but should be considered if presenting symptoms are not characteristic or when there is a failure to respond to antibiotics or the infection recurs within 1 month of antimicrobial therapy (8). A voided urine specimen, collected using a method to minimize contamination, is usually appropriate. An in-and-out catheter specimen is recommended if a voided specimen cannot be obtained. Any gram-negative organism isolated in counts ≥10² colony-forming units (CFU)/mL is considered relevant for this presentation in these patients. Of note, true bacteriuria is considered to be a count >10⁵ CFU/mL, both for pyelonephritis and cystitis, and the cut-off of 10⁵ bacteria/mL remains the benchmark in many laboratories.

Data from international surveillance studies suggest that the most common pathogens associated with uncomplicated UTI are UPEC, which accounted for 76.7% of uncomplicated cystitis, Enterococcus faecalis (4.0%), Staphylococcus saprophyticus (3.6%), Klebsiella pneumoniae (3.5%), Proteus mirabilis (3.5%), and other bacteria (8.7%) (22,23). UPEC is also the most prevalent pathogen identified in complicated cystitis (43%), but to a much smaller extent than in uncomplicated UTI, and many other pathogens, including Klebsiella spp. (13%), Enterococcus spp. (10%), Pseudomonas aeruginosa (9%), Enterobacter spp. (7%), Proteus spp. (6%), S. aureus (3%), fungi (1%), and other bacteria, become important, as does the issue of AMR (22,24).

Treatment strategies

There are a variety of antibiotic strategies and antibiotic-sparing approaches to treating an episode of uncomplicated UTI (Fig. 2A).

A recent systematic review of randomized controlled trials of analgesics (nonsteroidal anti-inflammatory drugs [NSAIDs]/nonsteroidal antirheumatic drugs [NSARs]), herbal formulations, delayed prescription of antibiotics, and placebo therapy to prevent the overuse of antibiotics in women with uncomplicated UTIs found that antibiotic-sparing strategies can reduce antibiotic use by 60-70% (25). However, they may result in higher rates of incomplete recovery or therapy failure compared with immediate antibiotic use, and a higher incidence of secondary outcomes, such as pyelonephritis or febrile UTI (25-27). The use of antibiotic-sparing and other strategies in the treatment and prevention of rUTIs will be developed in the following sections.

The EAU Guidelines for antimicrobial therapy in uncomplicated UTI recommend first-line therapy with fosfomycin trometamol, different formulations of nitrofurantoin, or pivmecillinam. Table II summarizes the regimens and details the doses and duration of therapy. Of note, fluoroquinolone and quinolone antibiotics are no longer included in the treatment of uncomplicated UTIs, having been banned from use by the European Commission from 2019 because of serious disabling and potentially permanent side effects (28).

To guide the choice of antibiotic for uncomplicated UTI, it is important to be aware of the local resistance data. For example, surveillance study conducted in Europe and Brazil in the Antimicrobial Resistance Epidemiology in Females with Cystitis (ARESC) study identified E. coli as by far the most frequent uropathogen identified, present in 74.6% of urine cultures, followed by E. faecalis, S. saprophyticus, K. pneumoniae, and P. mirabilis, all at less than 5% and found that, although susceptibility rates varied considerably from country to country, rates for fosfomycin, pivmecillinam, and nitrofurantoin approached 100% overall (98.1%, 95.8%, and 95.2%, respectively) (23). Susceptibility to cotrimoxazole was lower (70.5%), which is why cotrimoxazole is not recommended as a first-line treatment in uncomplicated UTI.

In contrast, a recent study of the prevalence and resistance patterns of uropathogens in different regions of India found that, while E. coli was still the most prevalent pathogen identified (68.3% overall), there was a much higher prevalence of K. pneumoniae (17.7%) than in Europe, and resistance to nitrofurantoin was higher for both pathogens (5.8% and 45.4%, respectively) (29). Of note, none of the UPEC were resistant to fosfomycin. These differences emphasize the importance of local prevalence and resistance patterns to guide the choice of antibiotic.

Non-antimicrobial prophylaxis

In following a step-by-step approach to prophylaxis for rUTIs, avoidance of risk factors and behavioral modifications (increasing fluid intake, pre- or postcoital urination, and hygiene procedures) can be considered the first step. However, evidence for their benefits in reducing episodes of rUTI is limited. A recent study showed that increasing the daily water intake by about 1.5 L reduced cystitis episodes and antibiotic usage in premenopausal women with rUTIs (31). During 12 months of follow-up, the mean number of cystitis episodes in the 70 women randomized to the increased water intake group was 1.7 (95% confidence interval [CI], 1.5 to 1.8) vs 3.2 (95% CI, 3.0 to 3.4) in the 70 women in the control group who did not increase their usual water intake, a difference in means of 1.5 (95% CI, 1.2 to 1.8; p < 0.001). Over that time, the mean number of antibiotic regimens required to treat cystitis episodes was 1.9 vs 3.6, respectively (p < 0.001) (31).

Non-antimicrobial strategies avoid the risk of AMR and are the next step to consider before antimicrobial therapy is used. These strategies include hormonal replacement therapy, immunoactive prophylaxis, probiotics, cranberry, D-mannose, methenamine hippurate, and intravesical instillations of GAGs (8,32-34).

Hormonal replacement using topical (but not oral) estrogen therapy in postmenopausal women, intended to enhance vaginal and urethral flora, has been shown to have some beneficial effects in reducing rUTIs without systematic side effects, although local irritation and minor bleeding can occur (8,34-36). Topical estrogen administration by vaginal cream or pessary is more effective than placebo but less effective than antimicrobial prophylaxis.

A number of different immune cells are present in the bladder, including macrophages, dendritic cells, lymphocytes, monocytes, neutrophils, and eosinophils, suggesting a role for prophylaxis with immunoactive agents in UTIs (8,34). Immunoactive agents are understood to stimulate both the innate and adaptive immune systems to increase the production of bacteria-specific antibodies. OM-89 (Uro-Vaxom) is perhaps the most widely studied immunostimulant, consisting of an extract for oral administration of 18 strains of heat-killed UPEC. OM-89-S is a newer formulation prepared by a different lysis process. OM-89 (but not OM-89S) has shown significant efficacy in the prophylaxis of rUTIs and is included in the EAU guidelines as an option with a high level of evidence for preventing rUTI in women (8,33,34,37,38). A systematic review of the role of vaccines in the treatment of rUTIs concluded that OM-89 (usually at a dose of one oral tablet once daily for 3 months, and/or a booster of one tablet daily for the first 10 days of months 6-9) had a short-term role in preventing rUTIs, significantly reducing the risk of recurrence compared with placebo, with only mild side effects (33). However, vaccination therapies remain under-reviewed, and further research is needed.

When the balanced ecosystem of normal flora in the vagina is disturbed through repeated antibiotic use, spermicide use, or in postmenopausal women, the vagina may become a reservoir for uropathogenic bacteria (12,34,39). Probiotics may help to prevent rUTIs through many mechanisms, including restoration of the natural vaginal microbiota by increasing the level of protective Lactobacillus species, altering the pH of the vagina, inhibiting bacterial biofilm formation, downregulating inflammatory cytokines, and inhibiting the uptake of E. coli by vaginal epithelial receptors. While there are some contradictory findings, oral or vaginal administration of the lactobacillus strains L. rhamnosus GR-1, L. reuteri B-54 and RC-14, L. casei shirota, or L. crispatus CTV-05 have been shown to be effective for vaginal flora restoration and a beneficial effect in preventing rUTIs (8,12,34,36,39,40). However, the level of evidence is insufficient to allow definitive recommendations on the route of admission, optimal dosage, or treatment duration (8,35).

A number of meta-analyses and systematic reviews that have investigated the efficacy of cranberry-containing products have found a favorable benefit-to-harm ratio but limited evidence for their efficacy in protection against UTIs. However, a recent Cochrane Database systematic review of 50 randomized or quasi-randomized controlled trials (8,857 patients) of cranberry products vs placebo, no specific treatment, or other interventions for the prevention of UTIs supports their use to reduce the risk of symptomatic, culture-verified UTIs in women with rUTIs, children, and people susceptible to UTIs following interventions (41). Currently, the level of evidence for cranberry products compared to antibiotics or probiotics alone is very low, and the available evidence does not support their use in older patients, patients with bladder emptying problems, or pregnant women.

The monosaccharide isomer of glucose, D-mannose, is thought to act in the bladder by inhibiting the adhesion of UPEC to uroepithelial cells (34,36). Again, the overall level of evidence for efficacy in the prevention of rUTI is weak and contradictory, and, as with cranberry products, a good patient history to identify what has already been tried and to determine what triggers the UTI should first be taken. The patient should be informed that further studies are needed before D-mannose can be fully recommended (8). A recent Cochrane systematic review of randomized controlled trials also concluded that there is currently little to no evidence for or against D-mannose use in preventing rUTIs (42).

The urinary antiseptic methenamine hippurate (hexamine hippurate) has bacteriostatic activity via the production of formaldehyde from hexamine in an acid environment (34,36). The most recent Cochrane review of methenamine hippurate for preventing UTIs dates back to 2012 when it was concluded that methenamine hippurate might be effective short-term prophylaxis in patients without renal tract abnormalities (43). There was a 76% reduction in the incidence of UTIs (risk ratio 0.24; 95% CI, 0.07 to 0.89), comparable to antibiotic prophylaxis, but the quality of studies included in the analysis was mixed, and the data were heterogeneous. More recent studies have shown that long-term (6-12 months) methenamine hippurate is not inferior to daily low-dose antibiotics to prevent rUTI (26,44). In a study conducted at eight centers in the United Kingdom, 240 women with rUTIs were randomized to methenamine hippurate twice daily (n = 120) or daily low-dose antibiotics (nitrofurantoin, trimethoprim, or cefalexin; n = 120) for 12 months (26). During the 12-month treatment period, the incidence of UTIs requiring antibiotic treatment was 1.38 (95% CI, 1.05 to 1.72) episodes per person-year in the methenamine hippurate group and 0.89 (95% CI, 0.65 to 1.12) in the antibiotics group. The absolute difference of 0.49 (90% CI, 0.15 to 0.84) indicated noninferiority between the two strategies. Therefore, the current recommendations support using methenamine hippurate to prevent rUTIs in women without urinary tract abnormalities (8).

As disruption of the bladder lining (urothelium) and resultant loss of the protective GAG layer is considered to be a key factor promoting rUTIs, GAG therapy with intravesical instillations of hyaluronic acid (HA) or HA in combination with chondroitin sulfate (CS) has been suggested as an option to prevent rUTIs, particularly in patients where less invasive preventive approaches have been unsuccessful (8). The quality of evidence for the benefits of combination therapy is highest, as randomized controlled trials of the instillation of single-agent HA or CS are lacking. In a randomized trial in 57 women with rUTI, intravesical administration of 50 mL of HA 1.6% plus CS 2.0% (Ialuril®, IBSA) for 6 months, the decrease in mean UTI rate per patient-year at the end of the 12-month study was 86.6% ± 47.6 compared with 9.6% ± 24.6 for placebo (intravesical saline), a mean difference of 77% (95% CI, 72.3 to 80.8, p = 0.0002) (45). The mean time to UTI recurrence was also significantly shorter in the placebo group. Given the issue of antibiotic resistance, the instillation of GAGs may become a recommended prophylactic option to antibiotic prophylaxis when more data are available.

Another, retrospective, case-control study in 276 women treated for rUTIs at seven European centers compared intravesical administration of combination HA+CS with EAU-recommended standard of care (continuous or postcoital antimicrobial prophylaxis, immunoactive prophylaxis, prophylaxis with probiotics or cranberry, or a combination of these) (46). In this real-world setting, bladder instillation of combined HA and CS reduced the risk of UTI recurrences, compared with standard management (55.7% vs 62.1%, respectively), although the difference did not reach statistical significance (p = 0.313). However, when the adjusted odds ratio (OR) for developing a bacteriologically confirmed rUTI within 12 months was calculated, there was a 49% reduced risk of developing a recurrence in women treated with HA+CS compared with standard care (OR 0.51, 95% CI, 0.27 to 0.96) (46). Treatment adherence (≥5 instillations) was associated with improved benefits of HA+CS therapy.

Data from a systematic review and meta-analysis of randomized and nonrandomized trials found that HA plus CS decreased the rate of rUTI per patient-year by a pooled mean difference of 2.56 compared with controls (95% CI, 3.86, −1.26, p < 0.001) (47). The time to a first recurrence of a UTI was also increased by a mean of 130.05 days. However, patients should be informed that further studies are needed to confirm the results of existing trials (8). An oral formulation of HA, CS, quercetin, and curcumin (Ialuril® Soft Gels, IBSA) is available and may be appropriate in patients with pelvic pain, although hard data on usefulness in the prevention of rUTIs are limited.

Many other non-antimicrobial options have been investigated or are already in use as strategies to prevent rUTIs. A detailed review of these approaches is beyond the scope of this article. However, a comprehensive review by Paul Loubet and colleagues provides a useful overview of alternative therapeutic options to antibiotics (40). Among the approaches are small compounds, often molecules that are by-products of or mimic bacterial substrates, designed to occupy binding sites to prevent adherence of pathogens to the uroepithelium, directly target the protective capsule of bacteria, inhibit enzymes essential to UPEC, or reduce biofilm formation (40). The formation of biofilms, either directly on the urothelial surface or formed around indwelling catheters, is a common strategy adopted by UPEC, providing a favorable environment for bacterial colonization and a persistent source for bacterial access to the urinary tract, thus facilitating rUTIs (16,22). Vitamin C, Chinese medical herbs, and various vaccine approaches that target microbial adhesion, the bacterial capsule, toxins secreted by UPEC that act as virulence factors, or iron metabolism processes essential for bacterial growth and colonization are also alternative nonantibiotic therapeutic options for UTIs (34,40). Finally, although not commonly utilized in the West, bacteriophages, viruses that cause lysis of bacterial cells, including antibiotic-resistant UPEC, have been used in eastern European countries for decades (36).

Antibiotic prophylaxis

When non-antimicrobial interventions have failed, continuous low-dose antimicrobials and postcoital antimicrobial prophylaxis have been shown to reduce the rate of rUTIs (8,36) and are recommended for use (8). There is no significant difference between the two strategies. In both approaches, patients should be counseled on possible side effects. The optimal duration of continuous antimicrobial prophylaxis is uncertain, with studies reporting durations of from 3 to as long as 12 months; between 3 and 6 months is typical (8).

Intermittent self-start treatment (self-diagnosis and self-treatment) with a short course of antibiotic therapy is also effective and safe in women with rUTIs who have shown good compliance and motivation and can be an economical approach to preventing rUTIs (8,36).

The choice of antimicrobial agent is the same as that for acute uncomplicated UTI and should be based on local resistance patterns. Patients on antimicrobial prophylaxis may have been advised to increase the dose of the same antibiotic if they have a breakthrough infection. However, a more appropriate course of action would be for a culture to be taken to determine if switching to an antibiotic more helpful in the setting is indicated. If the patient has severe symptoms and wishes to start empirical treatment immediately, the recommended first-line antibiotics (i.e., fosfomycin trometamol, nitrofurantoin, or pivmecillinam) should be chosen (8).