Abstract

Postmenopausal period represents a risk condition for UTI (urinary tract infection) in relation to hormonal changes.

The decrease of serum estradiol levels is inversely correlated with age, altering the vaginal flora and pH, which normally prevent the adhesion and development of gram-negative bacteria.

Other pathological conditions related to estrogenic deficiency are urinary incontinence, cystocele and post-void residual (PVR); mechanical factors may also favor UTI, such as the bladder catheter.

The presence of asymptomatic bacteriuria (ABU) is not considered to be a urinary infection because it may play a protective effect against a subsequent infection from uropathogens, such as E. coli.

New strategies have been proposed to reduce the use of antimicrobics for the prevention and treatment of UTIs in elderly women. Although it has been shown that vaginal estrogen cream reduces the pH and restores Lactobacillus flora-decreasing UTI episodes, there is still no strong evidence to support this therapy. Oral estrogens are not recommended in postmenopausal women, they are not useful in the prevention of UTIs. Regarding probiotics and cranberry juice or capsules, many studies bring a positive effect but there is not a conclusive evidence on their possible preventive role for UTIs in postmenopausal age. Surgical correction of cystocele and PVR is a viable option to reduce risk factors for UTIs in this population. The role of new immunostimulant therapies, D-Mannose, ascorbic acid and vaginal vaccines is still to be confirmed.

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Summary of recommendations

Definition of uncomplicated UTIs in postmenopause

• Acute uncomplicated UTIs are infections of the low urinary tract (acute cystitis) and high urinary tract (acute pyelonephritis) affecting postmenopausal women without underlying urologic abnormalities.

Risk factors

• The decrease of circulating estrogens: serum estradiol levels decrease as the woman’s age progresses, reaching a nadir after menopause. Therefore, the vaginal pH increases and vaginal Lactobacilli decrease, favoring the colonization by Enterobacteriaceae.
• Prolapse: the cystocele may lead to some consequences such as incontinence, closely linked to UTIs, and to the post-void residual (PVR), which increases the risk of infection if it is >50 ml.
• Non-secretor status: women who do not produce blood group antigens in secretions and bodily fluids are more prone to UTIs.
• Urinary catheter: one of the main causes of nosocomial UTIs is bladder catheter.
• Hygienic behaviors: intravaginal practices may inhibit or lower the colonisation of beneficial Lactobacilli strains, with detrimental effects on vaginal microbiota.

Antibiotic and non-antibiotic therapy

• The antibiotic treatment of uncomplicated UTIs does not differ between postmenopausal and younger women.
• Vaginal estrogens: treatment with local estrogens reduces pH and increases vaginal contents of Lactobacilli, thus reducing the risk of UTIs.
• Oral estrogens: oral treatment does not reduce UTIs.
• Surgical management: the reduction surgery of prolapse reduces the PVR and incontinence resulting in the reduction of symptomatic UTIs.
• Oral immunostimulant OM-89: extract of 18 different serotypes of heat-killed uropathogenic E. coli.
• Vaginal vaccines: Urovac is a vaginal vaccine which contains 10 heat-killed uropathogenic bacteria, including 6 different serotypes of E. coli, and 1 strain each of Proteus vulgaris, Klebsiella pneumoniae, Morganella morganii and Enterococcus faecalis.
• Prophylaxis with Lactobacilli: specific Lactobacilli strains may interfere with the adhesion, growth and colonization of the urogenital human epithelium by uropathogenic bacteria.
• Cranberry prophylaxis is currently used for years in the treatment and prevention of UTIs, although its mechanism of action is not yet clear. It contains type-A proanthocyanidins that inhibit adhesion to urothelial cell receptors by E. Coli P fimbriae. Although sometimes statistically significant, pooled findings for the other interventions should be considered tentative until corroborated by more research.
• D-mannose: it is part of the molecules that can bind in a competitive way to the superficial ligands of the bacteria, used to adhere to the bladder mucosa.
• Ascorbic acid: vitamin C (ascorbic acid) is also used to prevent cystitis. The results are promising but other studies need to be recommended.

1 Introduction

Urinary tract infections (UTIs) are the most common bacterial infection in the world [1]. The definition of UTIs comprises a set of clinical entities that have in common a culture positivity of urine specimen: uncomplicated, complicated and recurrent UTIs [2], [16].

Acute uncomplicated UTI affects postmenopausal women who are immunocompetent and without underlying urologic abnormalities (such as nephrolithiasis, strictures, stents, or urinary diversions) or poorly controlled diabetes mellitus [3].

Uncomplicated UTIs occur in more than 50% of women during their lifetime. 20–30% of female patients have a recurrent urinary infection (rUTI) [4], [5]; this has an impact on the quality of patients’ lives and on social costs [6].

Many risk factors are present in postmenopause: decreased circulating level of estrogen, incontinence, prolapse, PVR, history of UTI before menopause. Cognitive decline and indwelling catheter have an important impact especially in hospitalized women [7].

Uropathogenic Escherichia coli (UPEC) cause 85% or more of uncomplicated UTI cases, while other gram-negative rods and gram-positive cocci, such as Staphylococcus saprophyticus and Enterococci, are responsible for the remaining 5–15% of cases [8].

In the present chapter, the main risk factors of UTIs and the possible non-antibiotic treatments to reduce urinary infections and their recurrence are described.

2 Methods

A systematic search in PubMed for literature of the last 30 years was performed in PubMed with the following key words: “UTI”, “cystitis”, “pyelonephritis”, “treatment”, “management”, “elderly women”, “post-menopausal women”.

A total of 1,016 publications were identified, which were screened by title, abstract and date, with preference for publications after the year 2000.

A manual search of references from some specific studies was also conducted. Search results were limited to studies written in English. After removing duplicates, a total of 92 publications were included in the present analysis.

3 Risk factors

3.1 Decreased estrogens

Estrogens promote the proliferation of the vaginal microflora that produces hydrogen peroxide, bactericidal proteins and lactic acid, which keep the vaginal pH low [9]. Menopause involves a decrease of vaginal Lactobacilli and increased vaginal pH and therefore a more likely colonization of Enterobacteriaceae [10], [11]. In vitro studies showed that estrogens have an effect of growth and maintenance of the bladder epithelium, due to the presence of beta-estrogenic receptors (Erβ) [12], [13], with a protective effect from pathogens [14].

An increase of cholinergic muscarinic receptors has been shown in rabbits under estrogen therapy, and an increase in autonomic innervation in mouse blisters. Estrogenes also promote vascularization and decrease collagen in the bladder by improving bladder contractility and thus reducing PVR [15].

3.2 Prolapse and incontinence

Menopause involves a decrease in estrogen, implying a worsening of the connective tissue of the pelvic floor and therefore a worsening of the symptoms of prolapse of the pelvic organs (POP)[16], [17].The weak pelvic floor is unable to provide proper support to pelvic organs, leading to the development of POP in older women [18]. The prolapse of the pelvic organs (POP) does not directly correlate with the UTI [19]. However, the anterior prolapse may involve urination disorders, related to an increased risk of UTI [20]. Incontinence is very common in women >60 years. In a multivariate analysis, a strong correlation between incontinence and UTI has been shown, compared to patients without incontinence (41% vs. 9%), even if the mechanism is not entirely known [1].

POP can also be linked to the presence of PVR. A PVR greater than 30 ml results in an increase in the probability of developing UTI [21]. The cut-off level for PVR volume according to American Urological Association Guidelines is 50 ml [22].

3.3 Non-secretor status

Among the genetic risk factors the status of non-secretor has an important impact on the UTI. Two classes of individuals are distinguished: secretor and non-secretor, based on the presence of blood group antigens in secretions and bodily fluids. The risk is probably given by the presence of two glycolipids that promote the adhesion of E. coli in the vaginal seat and hence the infection of the urinary tract [23], [24].

3.4 Urinary catheter

Catheter-associated UTI (CAUTI) can occur, per definition, in a patient with a bladder catheter or one that has had the catheter in the last 24 hours. About 20% of the hospital-acquired bacteriemias come from the urinary tract; the mortality associated with this condition is about 10% [25]. In the United States, CAUTIs are the most common nosocomial infections. They are 30–40% of healthcare-associated infections and count about 1 million new cases per year [26]. However, the only bacteriuria should not be interpreted as an infection and therefore should not be treated. Only in case of symptoms (fever, flank pain, lethargy, hematuria, suprapubic pain) should a urine culture and possibly an antibiotic therapy be performed [27]. Not even the pyuria is indicative of UTI. Urine culture should be performed 24 hours after the bladder catheter removal or immediately after replacing it.

3.5 Hygienic behaviours

Personal hygiene can predispose to bacterial vaginosis and thus lead to urinary infections [28]. In fact, in the Longitudinal Study of Vaginal Flora, especially the vaginal douching is related to bacterial vaginosis [29]. The vaginal microbiota can be damaged by suppository practices that diminish the presence of strains of beneficial lactobacillus strains [30], [31]. Some menopausal women use personal lubricants and moisturizers to relieve pain during sexual intercourses. These products can alter both vaginal osmolality and pH [32]. Irritation of the vaginal mucosa and epithelial damage can be caused by the presence of parabens and microbicides, but also by pH and non-physiological osmolality [32]. This condition of the vagina can promote colonization of the Enterobacteriaceae from the rectum [33]. Therefore, products with characteristics similar to vaginal secretions should be used. For this reason, the World Health Organization recommends an osmolarity that does not exceed 380 mOsm/kg [34].

4 Diagnosis

Symptoms of the lower urinary tract in the absence of vaginal symptoms may be sufficient for the diagnosis of cystitis [35], [36]. However, in elderly women genitourinary symptoms are not necessarily related to cystitis. A number of nonspecific urinary symptoms (such as chronic dysuria or urinary incontinence) mimic symptoms of cystitis, even when there is no evidence of UTI. Acute dysuria (with a duration of less than one week), new or worsening urinary urgency, new incontinence, frequency, gross hematuria, and suprapubic pain or tenderness are discriminating symptoms [37].

Dipstick analysis may increase the likelihood of an uncomplicated cystitis diagnosis if leukocytes and nitrite are positive, only nitrite or nitrite and blood are positive, or leukocytes and blood are positive [38], [39]. A urine culture is recommended in patients with atypical symptoms, as well as those who fail to respond to appropriate antimicrobial therapy [40], [41]. In patients presenting with symptoms of uncomplicated cystitis, a colony count of 10³ cfu/mL of uropathogens confirms the diagnosis microbiologically [42].

The management of uncomplicated UTI in postmenopausal women is resumed in table 1.

Table 1: Management of uncomplicated UTI in postmenopausal women

Symptoms	Acute dysuria, new or worsening urinary urgency, new incontinence, frequency, gross hematuria, suprapubic pain or tenderness
Diagnosis	Dipstick analysis: pyuria, leukocyte esterase, nitrite Urine culture: 103 colony-forming units/mL of uropathogens
Treatment	Antibiotics Vaginal estrogens Surgical Management Further Strategies: oral immunostimulant OM-89, Vaginal vaccines, Lactobacilli prophylaxis, Cranberry prophylaxis
Prophylaxis	Vaginal estrogens Surgical Management Further Strategies: oral immunostimulant OM-89, Vaginal vaccines, Lactobacilli prophylaxis, Cranberry prophylaxis

5 Treatment of UTIs in postmenopausal women

Antibiotic therapy

The treatment of uncomplicated UTIs in post-menopause women, although it is still a matter of debate, does not seem to differ from that used for younger women.

A short course of therapy with ciprofloxacin is appropriate in this category of patients with a similar efficacy as the standard 7-day therapy for treatment of uncomplicated symptomatic UTI in older women and with less adverse event [43].

In a randomized trial, a short-course 3-day regimen of 200 mg of ofloxacin (once a day) achieves better microbiological rates of E. coli eradication than the conventional 7-day treatment of 500 mg cefalexin (four times a day) [44].

However, a growing number of Quinolone resistances should be considered: in methicillin-resistant strains of Staphylococcus aureus and in Pseudomonas aeruginosa, especially in hospitals [45], [46], in enteric bacteria in intensive care units [47], in Neisseria gonorrhoeae (in the United States quinolones are no longer recommended in the treatment of Gonorrhoeae) [48], [48], [50], in Campylobacter jejuni [51], in Streptococcus pneumoniae [52], [53]. A case-control study of nosocomial acquisition of fluoroquinolone-resistant strains of E. coli or K. pneumoniae also confirmed recent fluoroquinolone use as an independent risk factor [54]. Randomized double-blind clinical trials have assessed possible adverse events. The most frequent are those of the gastroenteric tract (anorexia, nausea, vomiting, and abdominal discomfort) and the central nervous system (delirium, impairment of memory, disorientation, naval, and disturbances in attention). Other adverse effects include rashes and other allergic reactions, tendinitis and tendon rupture, QT prolongation, hypoglycemia and hyperglycemia, and hematologic toxicity [55].

6 Non-antibiotic prophylaxis of recurrent UTI

6.1 Estrogens

The hormonal-replacement treatment is the best therapy, with vaginal estrogen replacement improving the vaginal mucosa status and thus preventing UTIs in postmenopausal women. Randomized double-blind trials have shown that estrogen vaginal cream significantly reduces the incidence of UTIs in elderly women compared to placebo cream. Already after 1 month of therapy, estriol cream reduces the pH and increases vaginal colonization with lactobacilli by 60% [7].

The same results were shown in women who received an estradiol-releasing vaginal ring. The cumulative likelihood of remaining free of disease was approximately 45% in the study group compared with approximately 20% in controls [57]. In a systematic review and meta-analysis of trials for the non-antibiotic prophylaxis of rUTIs, vaginal estrogens showed a positive trend in reducing urinary infections but with an insignificant pooled effect (RR 0.42, 95% CI 0.16-1.10) [58].

6.2 Surgical management

Mesh abdominal sacrocolpopexy represents the mainstay of transabdominal repairs as it provides the highest success rates for apical/vaginal vault POP with durable results [59], [60]. The laparoscopic and robotic-assisted techniques have a better post-operative outcome, less pain and quicker recovery [61]. To avoid abdominal surgery, a transvaginal network should be used. The purpose of such techniques is to correct prolapse and thus to improve symptoms such as stress incontinence, urge incontinence, and then rUTIs.

6.3 Oral immunostimulant OM-89

It is an extract of 18 different serotypes of heat-killed uropathogenic E. coli stimulating innate immunity by increasing neutrophils, macrophage phagocytosis, and the upregulation of dendritic cells. 891 patients with recurrent UTI have been selected in four placebo-controlled trials [62], [63], [64], [65].

In the study of Bauer et al., patients received the immunotherapeutic OM-89 or a matching placebo; 1 capsule per day for 90 days, followed by 3 months without treatment, then the first 10 days in months 7, 8 and 9 and were followed during 12 months. The risk ratio for developing at least one UTI was lower in treatment with OM-89 (RR 0.61, 95% CI 0.48–0.78) and the mean number of UTIs was about half compared to placebo [58].

6.4 Vaginal vaccines

Urovac is a vaginal vaccine which contains 10 heat-killed uropathogenic bacteria, including 6 different serotypes of uropathogenic E. coli, and 1 strain each of Proteus vulgaris, Klebsiella pneumoniae, Morganella morganii and Enterococcus faecalis. This vaccine primarily induces immunoglobulin G and immunoglobulin A in the urogenital tract, thereby reducing potential colonization of the vagina and bladder with uropathogens [66].

6.5 Lactobacilli

Specific Lactobacilli strains may interfere with the adhesion, growth and colonization of the urogenital human epithelium by uropathogenic bacteria.

Different lactobacilli strains show different results in the prevention of recurrent UTIs. Intravaginal suppositories with Lactobacillus crispatus in premenopausal women should be considered here, [67], as well as oral capsules with Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 in postmenopausal women [68]. It is considered that strains producing antibacterial compounds, such as biotensioactives and hydrogen peroxide (H₂O₂) – the latter mostly attributable to Lactobacillus crispatus and Lactobacillus jensenii [69], [70] – are important for maintaining normal urogenital flora and preventing infections in women [58]. In fact, it has been demonstrated by multiple culture-based studies that women with recurrent UTI have an increase in vaginal colonization of E. coli and a decrease in H₂O₂-producing lactobacilli [71], [72], [73], [74].

Probiotics can also lower the vaginal pH and induce responses of anti-inflammatory cytokines in epithelial cells, as well as creating steric obstruction. In a review of four randomized controlled trials of Lactobacillus probiotics for bacterial genitourinary infections in women, only one demonstrated a significant reduction in rates of UTI recurrence [75].

A subsequent trial, in which postmenopausal women with a history of recurrent UTI were randomly assigned to take trimethoprim-sulfamethoxazole (n=127) or Lactobacillus tablets (n=125) for 12 months, reported that women in the Lactobacillus group had more frequent clinical recurrences over the year (mean 3.3 vs. 2.9 events) and shorter time until recurrence (3 vs. 6 months) than women in the antibiotic group [76].

The prevention of infections is important to reduce the use of antibiotics, which now have many resistances.

One of the best interventions is to maintain the homeostasis of the vaginal microbiota [77].

6.6 Cranberry

Cranberry prophylaxis is currently used for years in the treatment and prevention of UTI, although its mechanism of action is not known. It contains type-A proanthocyanidins that inhibit adhesion to urothelial cell receptors by E. coli P fimbriae [58].

Clinical studies on the efficacy of cranberry juice have been limited by suboptimal study design (underpowered, not blinded, or limited by other design flaws) and mixed results [78], [79], [80], [81], [82], [83], [84], [85], [86], [87]. In a meta-analysis of nine randomized trials, there was a decreased risk of UTI (RR 0.62, 95% CI 0.49-0.80) [54]. An updated Cochrane meta-analysis included data from recent study and concluded that cranberry products did not significantly reduce the occurrence of symptomatic UTI in women with recurrent UTIs (RR 0.74, 95% CI 0.42-1.31). They also concluded that cranberry juice may be unacceptable to consume over a long period [75].

6.7 D-mannose

D-mannose is a natural sugar that can bind in a competitive way to the superficial ligands of the bacteria, used to adhere to the vesical mucosa [88], [89]. In a recent clinical study, 308 women with recurrent UTIs were randomized to receive daily 2 grams of D-mannose prophylaxis for six months, continuous antibiotic prophylaxis with nitrofurantoin, or no prophylaxis. The rate of recurrent UTI in the D-mannose group was 15%, compared to 20% in the nitrofurantoin group, and 60% in the untreated group. To date, the data on efficacy of D-mannose in rUTI treatment are limited [90].

6.8 Vitamin C (ascorbic acid)

Vitamin C (ascorbic acid) is also used to prevent cystitis. Two studies assessed its efficacy with contradictory results. Castello et al. have evaluated the effect of vitamin C at high doses (500 mg four times daily) on urine pH: they have not shown a significant decrease in urine pH value or any efficacy compared to the placebo group [91]. Ochoa-Brust et al. studied low dosages (100 mg/day) of ascorbic acid in pregnant women with a significant reduction in the incidence of UTIs. The results are promising but other studies are needed [92].

7 Further strategies

The surgical correction of urological risk factors and the antimicrobial treatment of UTI represent, to date, the only therapeutic options in these patients.

Further wide-scale randomized studies are essential to define and establish the exact role of new prevention strategies to reduce the use of antibiotics, especially considering the emerging problem of multidrug-resistant uropathogens.

8 Conclusion

UTI is the most common bacterial infection in women in general and in postmenopausal women, with consequences on social costs. Urological factors and estrogen deficiency play an important role in the development of bacteriuria and UTI in the elderly population.

While asymptomatic bacteriuria should not be treated, for the possible protective role in relation to more pathogenic infections, UTI should be prevented and treated with antibiotic and non-antibiotic therapy.

Despite antibiotic treatment, surgical correction of prolapse and vaginal replacement of estrogens have a sure role in the treatment and prevention of symptomatic UTI in elderly women. The restoration of the normal flora with lactobacilli using probiotics may be helpful in the perspective of alternative therapies in case of antimicrobial resistance, a globally-emerging problem.

Unfortunately, the role of other strategies in preventing UTI in postmenopausal women remains questionable. The development of the oral immunostimulant OM-89 and vaginal vaccines seems promising; this, however, requires further clinical studies.

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