Recurrent Urinary Tract Infections in Female Patients—A Clinical Review

Abstract

Worldwide, urinary tract infections (UTIs) have an increased incidence, especially in women. Recurrent UTIs (rUTIs) appear in less than three months in 80% of the cases, being associated with age, sexual activity, or diabetes mellitus. Antibiotics represent the first line of treatment for rUTIs after the diagnosis based on a positive mid-stream urine (MSU) culture. Alternative therapies including low-dose antibiotic treatment, immunoprophylaxis, cranberry extracts, probiotics, D-mannose, intravesical instillations, methenamine, and estrogens may reduce the recurrence of UTIs in female patients. Multimodal therapy seems to be the future in preventing and treating rUTIs. The main aim of this narrative review is to present the actual therapeutic challenges and the most efficient prophylaxis options in women diagnosed with rUTIs.

1. Introduction

Every year, urinary tract infections (UTIs) affect more than 400 million people [1]. UTI episodes are associated with significant short-term morbidity, on average causing about six symptomatic days, of which at least two will affect the patient’s work or study, and even social interactions. UTIs are the most frequent infections in women, representing about 25% of all cases. About 60% of women will have at least one UTI [2]. Reinfections happen in less than 3 months after the initial infection, accounting for about 80% of the cases [3]. Their incidence increases with age, sexual activity, and comorbidities like diabetes mellitus [4,5]. Recently published studies have reported a prevalence of bacteriuria of 2–4% among sexually active young women, a percentage that increases to 6–8% in women aged between 60 and 80 years and up to 20% in age groups over 80 years [1,3].

Multiple uropathogens are involved in the genesis of cystitis [5].

The uropathogenic E. coli strain can cause cystitis [6,7]. Other germs include Proteus, Staphylococcus epidermidis, and saprophytic Klebsiella, commonly in patients with diabetes, and Pseudomonas in patients who are on long-term catheters is also involved in complicated UTI pathogenesis [8,9]. Proteus mirabilis not only determines the infection but also produces urease, an enzyme that hydrolyzes urea into ammonia and carbon dioxide. The resulting ammonia increases urinary pH, favoring the crystallization of the salts that are present in the urine and determining struvite stone formation [10].

Recurrent UTIs (rUTIs), characterized by repeated episodes of UTI, are often associated with lower urinary tract symptoms, which can significantly affect the patient’s quality of life. rUTIs, which are defined as two or more UTIs in 6 months or three or more in 1 year, are common in female patients, where the risk of recurrence about 1 year after the initial infection varies between 24% and 50% [3,4]. Studies have demonstrated that not all cases of UTIs/rUTIs with bacteriuria can be confirmed by mid-stream urine (MSU) culture [2,11]. Recent publications regarding rUTIs recommend that doctors consider a patient-centered perspective, where patients’ expectations and choices play an essential role [8,12].

rUTIs also have a significant socioeconomic impact, representing around 1–3% of all primary care consultations and about 13.7% of community-based antibiotic prescriptions [3]. Dysuria, frequency, micturition urgency, poor flow, suprapubic pain, and hematuria are the symptoms at presentation. Diagnosis is based on the specific signs and symptoms, medical history, and the presence of three positive MSU cultures within the last year [8,13]. Up to 30% of women with cystitis have frequency, dysuria, and micturition urgency [14]. Gupta K and co-workers conducted a cross-sectional study including women with acute uncomplicated cystitis, with E. coli and Staphylococcus saprophyticus infection presenting multiple drug resistance [15].

It is of paramount importance in clinical practice to differentiate between the clinical symptoms of an rUTI and an overactive bladder or interstitial cystitis [16]. The appropriate diagnosis determines the appropriate treatment, and therefore unnecessary antibiotic prescription is avoided [16].

The clinical diagnosis includes history-taking, clinical and pelvic examination, and urinalysis [9,17]. A post-void bladder scan could reveal high residual urine. Urinalysis and MSU with culture and sensitivity are valuable tests [18,19]. MSU plays an essential role, determining the pathogenic cause and the effective antibiotics that need to be prescribed [20,21].

A urine culture that shows more than 100,000 colony-forming units (cfu/mL) reflects the presence of UTIs. MSU is mandatory only in rUTIs or complicated UTIs, and is not recommended in women with uncomplicated UTIs [5].

Studies showed that MSU remains positive even after antibiotic therapy for about 10 days to 2 weeks. Urinalysis, either by dipstick or microscopy, is sensitive in 80–90% of cases and is specific in about 50%, as it only detects a limited number of bacteria that reduce the nitrates. Dipstick analysis detects the presence of leukocyte esterase from various pathogens with a sensitivity of 72–97% and a specificity of 41–86% [13].

Therefore, in the case of women over the age of 50, other investigations such as cystoscopy to rule out urethral or bladder pathology, or ultrasound of the abdomen and pelvis or computed tomography (CT) to diagnose potential obstructive causes or urologic pathology, can be helpful [12].

Improving diagnosis and decreasing antibiotic use involves frequent patient follow-up, identification of risk factors that maintain urinary tract infections, and a differential diagnosis with urethritis and vaginitis. It is important to perform urine cultures in patients with persistent symptoms who do not respond to appropriate antimicrobial therapy [22,23]. Therefore, it is important to evaluate all the UTI maintenance factors according to the patient’s age [24,25].

2. Antimicrobial Therapy in UTIs

UTI is a common indication for antibiotic prescriptions. The cost of antibiotic prescriptions for UTIs/rUTIs in primary care has significantly increased, especially considering their prevalence as well as the significant incidence of antibiotic-resistant bacteria [8,9]. Given the rising rates of antibiotic resistance among uropathogenic microorganisms, antimicrobial stewardship is critically needed to improve the efficiency of antibiotic use, especially in primary care, outpatient clinics, and emergency departments [8,9].

The antimicrobial stewardship for UTIs focuses on the “five Ds” represented by accurate Diagnosis, right Drug choice, appropriate Dose, appropriate Duration of treatment, and timely De-escalation. Some of the most important challenges which make it difficult to achieve the antimicrobial stewardship objectives for UTIs/rUTIs are the diagnostic uncertainty, the increasing antibiotic resistance, the limitations of guidelines, and the time constraints of the medical and nursing staff [8,9,10,11,12].

Antimicrobial therapy is the main option for rUTIs, aiming to sterilize urinary tract bacterial growth through an effective, safe, and cost-effective treatment. This can be achieved only if the antibiotic concentration in the urine is over the minimum bactericidal concentration [8,9,10,11,12].

To ensure the patient’s compliance and to prevent acquired bacterial resistance, medication should be given only for a short time, but at levels sufficient to kill the microbes that colonized the urinary tract [8,9,10,11,12].

The treatment should be prescribed based on the susceptibility of the pathogenic agent, its minimal bacteriostatic or bactericidal concentration, and the severity of the patient’s symptoms. The appropriate antibiotic choice and dosage are required for patients with chronic kidney disease and need to take into account the patient’s age, as well as their co-morbidities [8,9,10,11,12].

Studies have shown that chronic kidney disease is a risk factor for infection and reinfection with multi-resistant organisms [11].

A large number of antibiotics are used for the prophylaxis and treatment of rUTIs. The criteria for selecting the best antibiotic to be prescribed in a specific patient are dependent on the patient’s co-morbidities, previous allergies, possible adverse effects, current medication and interactions with other medication, and, finally, the cost [17,18].

Reviews of antibiotics-versus-placebo studies have shown that antibiotics are more effective in preventing infections and recurrences in both pre- and postmenopausal females. Even if oral antibiotic therapy has proved to be effective in the vast majority of uncomplicated UTIs, recurrence is observed quite frequently. The most common clinical practice guideline recommendations for the antibiotic treatment of acute cystitis are the associations between Trimethoprim and Sulfamethoxazole on one hand (TMP-SMX) and Nitrofurantoin on the other hand. Both are used as first-line therapy in managing uncomplicated urinary infections based on a treatment length of 3–5 days. Studies have shown different mechanisms of action: TMP-SMX and fluoroquinolones prevent rUTIs by inhibiting uropathogen recovery (like E. coli), while Nitrofurantoin sterilizes urine and inhibits the bacterial attachments [17,18].

Single-dose Fosfomycin is also an effective option for the treatment of urinary tract infections but is less effective than the previously mentioned alternatives [18]. Pivmecillinam administered on a 3- or 7-day course is a useful choice in some patients [19].

The administration of beta-lactams, such as cephalosporins, or the association between Amoxicillin and Clavulanic Acid is considered appropriate when the so-called first-line therapy cannot be used. The clinical experience confirmed by multiple studies reports that Nitrofurantoin and its association with Amoxicillin/Clavulanic Acid remain the most effective choices [19].

In some countries, about 5% of E. coli strains are resistant to Nitrofurantoin, and around 20–30% are resistant to fluoroquinolones. Currently, fluoroquinolones can be used in selected patients who have low tolerance to antibiotics or have experienced allergic reactions after empiric therapy [5].

In pregnant women, penicillin and cephalosporins are recommended, but Trimethoprim, sulfonamides, and fluoroquinolones must be avoided [5].

Up to now, several studies have shown that Amoxicillin and Ampicillin have a low efficacy and must not be used for empiric treatment due to the presence of antibiotic resistance in about 15–20% of rUTIs with E. coli [19].

Of course, an assessment of microbial resistance in a hospital or in a stability area would optimize antibiotic therapy and help us analyze and re-prioritize antibiotic administration according to the model applied in 2019, when fluoroquinolones were withdrawn as a first-line antibiotic in lower UTI, based on the assessment of antimicrobial resistance [25].

3. Therapeutic Alternatives in rUTI Prophylaxis

Antibiotic prophylaxis in patients with UTIs/rUTIs increases the risk of developing antibiotic resistance. However, prophylactic anti-biotherapy with low-dose antibiotics for 3 to 6 months or more, post-sexual intercourse antibiotic prophylaxis, and acute on-demand antibiotic treatment are effective therapeutic choices in preventing rUTIs [17,18,19,20,21].

Prophylactic daily low-dose antibiotics for 3 to 6 months or more represent the most common choice in preventing rUTIs. They assure a constant antibiotic concentration in the urine with a bactericidal or bacteriostatic effect. To decrease the risk of antibiotic resistance, a rotating antibiotic regimen seems to be a very good option [17,18,19,20,21,25].

After intercourse, a single dose of Nitrofurantoin, Trimethoprim, or TMP-SMX can be used to prevent rUTIs, or in particular cases, even fluoroquinolones can represent an option [17,18,19,20,21,25].

Self-management (on-demand) of antibiotic treatment represents another option. It involves the appropriate teaching of patients in order for them to understand which antibiotics are recommended and what their side effects are. Subsequently, it reduces the use of antibiotics in patients and determines a decreased risk of antibiotic resistance [17,18,19,20,21,25].

The use of estrogens in rUTIs determines the Lactobacillus proliferation on the vaginal epithelium, decreases the pH, and inhibits the colonization of the vaginal mucosa with uropathogens. In postmenopausal women, the level of estrogens and the number of lactobacilli decrease, resulting in vaginal atrophy, which makes postmenopausal women more susceptible to UTIs. Vaginal estrogen cream or rings can reduce rUTI incidence by approximately 36–50% with minimal systemic absorption. Studies have demonstrated a better effect of estrogens administered intra-vaginally versus estrogens administered orally [26,27].

Cranberry extract tablets contain proanthocyanidins that are thought to prevent UTIs by inhibiting the adhesion of E. coli fimbriae to the urothelial mucosa [12,28]. Several studies and meta-analyses have shown that cranberry extracts can reduce the rate of recurrence of urinary tract infections, especially in young women [28].

Alternative medicine (acupuncture) may prevent rUTIs in healthy adult women based on the results of some clinical studies [29,30]. Studies have shown that acupuncture not only reduced the recurrence rate among cystitis-prone women to half the rate among untreated women but also determined a decrease in post-voiding residual urine, by an unknown mechanism [29,30].

Probiotics, especially Lactobacillus and Bifidobacterium, are widely used in the prophylaxis of UTIs/rUTIs, and their mechanism of action is based on the production of lactic acid that lowers urinary pH, thus preventing the development of uropathogens, improving the local immune response, and finally reducing the risk of recurrent infections [31]. It seems that vaginal probiotic prophylaxis has a beneficial clinical impact in preventing rUTIs. The available data are too few or of too low a quality to allow recommendations on the optimal dose and duration of treatment for probiotic prophylaxis [25].

Immunoprophylaxis has demonstrated benefits in reducing the recurrence of UTIs in women [25,32,33,34]. Uro-Vaxom^®, a lyophilized extract of E. coli, has been confirmed in various studies to reduce the rate of recurrence. Other options such as the StroVac vaccine contain antigens from several bacterial species, including E. coli, Proteus, and Klebsiella, and have been reported to determine favorable results in various therapeutic regimens [32,33,34].

In 2012, the European Association of Urology (EAU) recommended, for the first time, with level 1a scientific evidence, the use of vaccines to prevent uncomplicated rUTIs. Additionally, the EAU advised Uro-Vaxom^® tablets with a grade B recommendation and intramuscular StroVac^® and parenteral Solco-Urovac^® vaccines with a grade C recommendation to prevent rUTIs [32].

Uromune^®, as a polybacterial sublingual vaccine, was also recognized as it proved not only to be well tolerated, but also to be effective in reducing the incidence of rUTIs. Uromune^® is used sublingually and acts on the mucous membranes, activating the local immunity via dendritic cells, natural killer cells, and macrophages, with a consecutive increase in immunoglobulin A (IgA) secretion. IgA inhibits bacterial adhesion to the mucous membranes. Additionally, it seems that Uromune^® increases the levels of specific antibodies and B and T lymphocytes [35,36,37,38,39].

Methenamine can be used for both the treatment and prophylaxis of rUTIs. Methenamine acts as a bactericide for some strains of bacteria, and the treatment always needs to be accompanied by adequate hydration. A Cochrane review reported that in patients with no urinary tract abnormalities, the use of methenamine hippurate has short-term effects in the prevention of rUTIs [40].

D-mannose is a monosaccharide that is involved in human metabolism and determines the glycosylation of glycoproteins and secretory proteins [41].

It seems that D-mannose is excreted in the urine, where it prevents bacterial adherence to uroepithelial cells by attaching to the bacterial receptors. Therefore, D-mannose reduces the risk of rUTIs [42]. Studies showed that D-mannose can block the uropathogenic E. coli adhesion and invasion of the urothelium, thus preventing urinary tract infection [41,42,43]. However, a Cochrane systematic review that included 719 patients could not determine whether D-mannose compared to other treatments, other supplements, or antibiotics significantly reduced the number of rUTI episodes [42].

The administration of various compounds with a prophylactic role may have bactericidal or bacteriostatic effects on uropathogens, significantly reducing UTI incidence (

Table 1. Therapeutic prophylaxis in women with recurrent urinary tract infections.

Therapeutic Prophylaxis in Women with Recurrent Urinary Tract Infections	Effects	References
Low-dose antibiotic therapy	Bacteriostatic Bactericidal	[17,18,19,20,21,25]
Immunoprophylaxis	Bacteriostatic	[35,36,37,38,39]
Probiotics	Bacteriostatic	[31]
Methenamine	Bactericidal	[40]
D-mannose	Bacteriostatic	[41,42,43]
Cranberry extract	Bacteriostatic	[12,28]

).

Intravesical instillations of hyaluronic acid (HA) or chondroitin sulfate (CS) temporarily replace the deficient glycosaminoglycan (GAG) layer and have proved to be effective in the treatment of interstitial cystitis, overactive bladder, and post-radiation cystitis, as well as in rUTI prevention. A meta-analysis of two randomized control trials (RCTs) and six non-RCTs including 800 patients showed that intravesical treatment with HA, associated or not with CS, determined a low incidence of rUTIs and a significantly longer disease-free interval of time between the episodes of infection [44].

Therefore, the high recurrence rate of rUTIs can be reduced according to the age at which patients present for re-evaluation, whether the same types of germs persist or not, and lifestyle. All of these should be evaluated according to the recommendations of the guidelines, both those of urology and those of infectious diseases [24,25] (Figure 1).

4. Conclusions

rUTIs represent a significant challenge in clinical practice. That is why they require an accurate diagnosis and early detection of the pathological causes that can determine the recurrence. Clinicians always need to remember that rUTIs bring an increased risk of acquired antimicrobial resistance. Investigations are carried out according to a well-established medical protocol that includes both serum and urine tests as well as ultrasound and radiological investigations. Antibiotic therapy represents the gold standard, where Amoxicillin/Clavulanic Acid administration is one of the most effective choices. Prophylaxis with the help of different treatment options including low-dose antibiotics, consumption of probiotics, methenamine, D-mannose, immunotherapy, and intravesical anti-biotherapy must not only target the pathologic bacteria but also improve the host’s immune system.

Taking all these aspects into consideration, women diagnosed with rUTIs can have a decreased incidence if all the doctor’s recommendations are followed.