**2. Prevention of UTIS in the outpatient setting**

Given the increasing emergence of multidrug resistant bacteria in UTIs, every effort should be made to use non-pharmacologic measures as first line preventive strategies in patient who have recurrent UTIs.

ation between onset of overactive bladder and weekly consumption of carbonated drinks. (P=. 03). These findings did not apply to men in the survey [7]. There are also several studies linking

Prevention of Urinary Tract Infections in the Outpatient and Inpatient Settings

http://dx.doi.org/10.5772/56709

5

Although these data don't indicate that dietary factors actually cause UTIS, women who have frequent UTIs often mistake the frequency and urgency caused by a dietary bladder irritant for an infection. This could lead to calls to their provider requesting therapy and the chance of overtreatment. Thus it would seem prudent for these women who are plagued with frequent UTIS to avoid an excessive amount of carbonated beverages and caffeine. There may well be other dietary bladder irritants, such as citrus and other acidic fruits that can cause urgency. It is helpful for women with frequent UTIS to keep a food diary for a short time and see if they

Although there are no contraceptive methods that prevent UTIs, there are several that may increase the risk, primarily diaphragms and spermicides. Diaphragms were widely used in the 1950s through the early 1980s, but are not often used now that there are more effective methods of contraception that are easier to use. Diaphragm users have been shown to have a two to threefold increased risk of UTI compared to non-users [10], [11]. This is due to partial urethral compression by the rim of the diaphragm and also is likely related to the spermicide

Spermicides contain nonoxynol-9 which can cause a chemical irritation to the vaginal and urethral mucosa as well as changes in the normal flora. This in turn predisposes to colonization by coliforms as well as Staph saprophyticus [12]. Patients with recurrent UTIs should avoid diaphragms and spermicide coated condoms, as well as other barrier agents containing

After menopause, the vulvar skin atrophies and thins. There is decreased blood flow to this area and decreased mucous production. The periurethral mucosa is lubricated by the Skene's glands and these also atrophy, thus causing loss of mucous that is the first line of defense against bacteria. In addition, vaginal ph increases after menopause and lactobacilli counts decrease. These conditions set up the postmenopausal woman for higher risk of UTIs, particularly after intercourse. In addition, urinary incontinence, the presence of a cystocele and incomplete emptying and have been found to be highly associated with recurrent UTI, and

Systemic estrogen replacement therapy in the prevention of UTI has not been shown to be of help in preventing recurrent UTIs in postmenopausal women. However, there is strong evidence that *topical vaginal* estrogen replacement does protect against recurrent UTIs. Raz and Stamm in 1993 conducted a randomized controlled trial in postmenopausal women and found a significant decrease in rate of urinary tract infections in the treated group which used intravaginal estrogen twice weekly, versus placebo., (0.5 vs. 5.9 episodes per patient-year,

caffeine to lower urinary tract symptoms, but not infection [8], [9].

can link certain foods to irritative voiding symptoms.

nonoxynol-9 such as foam, suppositories, and sponges.

these are problems that increase with age as well [13].

**2.4. Vaginal estrogen replacement for postmenopausal women**

**2.3. Contraception**

that is used on the rim.

### **2.1. Hygiene**

There are many "old wives" tales about causes of UTIs, and many of these beliefs are ingrained in women. Women are told by other women to wear cotton underwear, avoid drinking sodas, and even to avoid strong laundry detergent in an effort to prevent UTIS.

Studies have not been done to evaluate most of these measures. A search of PubMed using the terms "urinary tract infection" and "sodas, carbonated beverages, hygiene, wiping patterns" did not reveal any studies. However, it is intuitive that girls and women should always wipe from front to back after a bowel movement to avoid brining fecal bacteria towards the vagina and the urethra. If a woman is predisposed to urinary tract infections, she should carefully watch hygiene. It is helpful to show these women a picture of the vulvar anatomy, explaining the close proximity of the urethra to the anal area and that an infection occurs when intestinal bacteria enter the urethra. These women should be encouraged to clean with a moist wipe (such as a baby wipe or other hygienic cleansing wipe) after a bowel movement. It is the author's opinion that it is helpful to wash the perineum and perianal area with antibacterial soap prior to intercourse. Patients should also be instructed to avoid any sexual practices that might bring colonic bacteria forward towards the vagina, such as touching the perianal area and then the vaginal area. Voiding after intercourse has been shown to protect against UTI [5]. There is no evidence that vaginal douching after intercourse decreases UTI incidence and in fact, it may increase the risk of vaginal infections. As such, it is not a recommended practice.

It is also the author's opinion that patient with recurrent UTIs should avoid tub baths. This recommendation comes from repeated observations over years of practice that many women who present UTIs give a history of taking frequent tub baths. It is plausible that the hot water washes away some of the protective mucous coating the urethral and vaginal introitus, making the mucosa drier and more susceptible to bacterial colonization. There were no studies on this found during a literature search on PupMed and OVID using the search terms "tub bath" "bathing" and "urinary tract infection". There were interestingly a few papers in the 70s linking Pseudomonas infections, including UTIs, to whirlpools and hot tubs, and this led the Centers for Disease Control (CDC) in the United States to establish standards for chlorination and filtration of these tubs [6]. Patient with UTIs should likely avoid these public tubs as well. Even if the water is correctly chlorinated and filtered, it is extremely hot and drying to the skin.

### **2.2. Diet**

There is evidence that links overactive bladder but not UTI to regular consumption of carbonated beverages. A large study that examined the prevalence and incidence of irritative voiding symptoms in men and women over a 12 months period showed a significant associ‐ ation between onset of overactive bladder and weekly consumption of carbonated drinks. (P=. 03). These findings did not apply to men in the survey [7]. There are also several studies linking caffeine to lower urinary tract symptoms, but not infection [8], [9].

Although these data don't indicate that dietary factors actually cause UTIS, women who have frequent UTIs often mistake the frequency and urgency caused by a dietary bladder irritant for an infection. This could lead to calls to their provider requesting therapy and the chance of overtreatment. Thus it would seem prudent for these women who are plagued with frequent UTIS to avoid an excessive amount of carbonated beverages and caffeine. There may well be other dietary bladder irritants, such as citrus and other acidic fruits that can cause urgency. It is helpful for women with frequent UTIS to keep a food diary for a short time and see if they can link certain foods to irritative voiding symptoms.

### **2.3. Contraception**

**2. Prevention of UTIS in the outpatient setting**

4 Recent Advances in the Field of Urinary Tract Infections

have recurrent UTIs.

**2.1. Hygiene**

**2.2. Diet**

Given the increasing emergence of multidrug resistant bacteria in UTIs, every effort should be made to use non-pharmacologic measures as first line preventive strategies in patient who

There are many "old wives" tales about causes of UTIs, and many of these beliefs are ingrained in women. Women are told by other women to wear cotton underwear, avoid drinking sodas,

Studies have not been done to evaluate most of these measures. A search of PubMed using the terms "urinary tract infection" and "sodas, carbonated beverages, hygiene, wiping patterns" did not reveal any studies. However, it is intuitive that girls and women should always wipe from front to back after a bowel movement to avoid brining fecal bacteria towards the vagina and the urethra. If a woman is predisposed to urinary tract infections, she should carefully watch hygiene. It is helpful to show these women a picture of the vulvar anatomy, explaining the close proximity of the urethra to the anal area and that an infection occurs when intestinal bacteria enter the urethra. These women should be encouraged to clean with a moist wipe (such as a baby wipe or other hygienic cleansing wipe) after a bowel movement. It is the author's opinion that it is helpful to wash the perineum and perianal area with antibacterial soap prior to intercourse. Patients should also be instructed to avoid any sexual practices that might bring colonic bacteria forward towards the vagina, such as touching the perianal area and then the vaginal area. Voiding after intercourse has been shown to protect against UTI [5]. There is no evidence that vaginal douching after intercourse decreases UTI incidence and in fact, it may increase the risk of vaginal infections. As such, it is not a recommended practice.

It is also the author's opinion that patient with recurrent UTIs should avoid tub baths. This recommendation comes from repeated observations over years of practice that many women who present UTIs give a history of taking frequent tub baths. It is plausible that the hot water washes away some of the protective mucous coating the urethral and vaginal introitus, making the mucosa drier and more susceptible to bacterial colonization. There were no studies on this found during a literature search on PupMed and OVID using the search terms "tub bath" "bathing" and "urinary tract infection". There were interestingly a few papers in the 70s linking Pseudomonas infections, including UTIs, to whirlpools and hot tubs, and this led the Centers for Disease Control (CDC) in the United States to establish standards for chlorination and filtration of these tubs [6]. Patient with UTIs should likely avoid these public tubs as well. Even if the water is correctly chlorinated and filtered, it is extremely hot and drying to the skin.

There is evidence that links overactive bladder but not UTI to regular consumption of carbonated beverages. A large study that examined the prevalence and incidence of irritative voiding symptoms in men and women over a 12 months period showed a significant associ‐

and even to avoid strong laundry detergent in an effort to prevent UTIS.

Although there are no contraceptive methods that prevent UTIs, there are several that may increase the risk, primarily diaphragms and spermicides. Diaphragms were widely used in the 1950s through the early 1980s, but are not often used now that there are more effective methods of contraception that are easier to use. Diaphragm users have been shown to have a two to threefold increased risk of UTI compared to non-users [10], [11]. This is due to partial urethral compression by the rim of the diaphragm and also is likely related to the spermicide that is used on the rim.

Spermicides contain nonoxynol-9 which can cause a chemical irritation to the vaginal and urethral mucosa as well as changes in the normal flora. This in turn predisposes to colonization by coliforms as well as Staph saprophyticus [12]. Patients with recurrent UTIs should avoid diaphragms and spermicide coated condoms, as well as other barrier agents containing nonoxynol-9 such as foam, suppositories, and sponges.

### **2.4. Vaginal estrogen replacement for postmenopausal women**

After menopause, the vulvar skin atrophies and thins. There is decreased blood flow to this area and decreased mucous production. The periurethral mucosa is lubricated by the Skene's glands and these also atrophy, thus causing loss of mucous that is the first line of defense against bacteria. In addition, vaginal ph increases after menopause and lactobacilli counts decrease. These conditions set up the postmenopausal woman for higher risk of UTIs, particularly after intercourse. In addition, urinary incontinence, the presence of a cystocele and incomplete emptying and have been found to be highly associated with recurrent UTI, and these are problems that increase with age as well [13].

Systemic estrogen replacement therapy in the prevention of UTI has not been shown to be of help in preventing recurrent UTIs in postmenopausal women. However, there is strong evidence that *topical vaginal* estrogen replacement does protect against recurrent UTIs. Raz and Stamm in 1993 conducted a randomized controlled trial in postmenopausal women and found a significant decrease in rate of urinary tract infections in the treated group which used intravaginal estrogen twice weekly, versus placebo., (0.5 vs. 5.9 episodes per patient-year, P<0.001. They demonstrated a return of lactobacilli to the vaginal flora and normalization of vaginal ph. In addition, vaginal colonization with Enterobacteriaceae fell from 67 percent to 31% in the treated group [13].

**2.5. Natural remedies**

cranberry products more than twice daily [16].

warrants further large scale studies [17].

significant. No side effects were noted [19].

as compliance will be higher.

Cranberries and their juice have long been touted for both treatment and prevention of UTI. This was previously thought to be due to acidification of the urine, but more recent research has shown that substances (proanthocyanadins) in the cranberry prevent adhesion of E. coli strains to the uroepithelium, including multidrug resistant strains [15]. Studies of cranberry prophylaxis are mixed, but several recent studies have shown that there is benefit from this simple remedy. Wang et al did a meta-analysis of randomized controlled trials comparing prevention of UTIs in users of cranberry products versus placebo or non-placebo controls. They found a risk ratio for cranberry users versus nonusers was 0.62 and statistically signifi‐ cant, leading them to conclude that cranberry products are associated with protection against UTIs. Further, cranberry products were more effective in certain subgroups including women with recurrent UTIs, children, cranberry juice users (as opposed to tablets) and those who used

Prevention of Urinary Tract Infections in the Outpatient and Inpatient Settings

http://dx.doi.org/10.5772/56709

7

A recent RCT examined women with recurrent UTIs, randomizing them to either cranberry juice or placebo for 6 months. Those in the cranberry juice did have lower incidence of recurrent UTIS, but it did not reach statistical significance. However, they did have significantly decreased counts of P-fimbriated E. coli in their urine during the study periods. These are uropathogenic strains with fimbriae capable of attaching to the uroepethelium. The authors concluded that though the cranberry juice didn't significant reduce the number of recurrent UTIs, the reduction in adherent E. coli lends plausibility to a protective effect of cranberry and

Within the pediatric population, several new cranberry studies have emerged. A RCT from Finland randomized 263 children with a prior history of UTI to 6 months of cranberry juice versus placebo. Their findings: the juice did not significantly reduce the number of children who experienced a recurrence of UTI, but it was effective in reducing the actual number of recurrences and related antimicrobial use [18]. Another recent randomized controlled pro‐ spective study found cranberry capsules effective in the prevention of UTI in children with neurogenic bladder caused by myelomeningocele who required chronic intermittent cathe‐ terization. The median UTI rate in this small cohort of 20 children was 0.5 UTI/year during placebo usage and 0/year with cranberry capsule usage. This decrease was statistically

Cranberry juice is safe in pregnancy and there is data from a small study to suggest that it may be efficacious in preventing asyptomatic bacteruria and symptomatic UTI. However in this same study, the juice was poorly tolerated by the pregnant women, and there was a high rate of withdrawal [20]. If used in pregnancy, use of cranberry pill form will likely be more effective

Propolis is a resinous material collected by bees from exudates and buds of plants, then mixed with wax and bee enzymes. It has well documented antibacterial activity. Lavigne et al added propolis to proanthocyanidins from the cranberry and studied its effect on human volunteer subjects. They found that once daily ingestion offers some protection against bacterial

adhesion, bacterial multiplication and virulence in the urinary tract [21].

Vaginal estrogen therapy is available in three forms in the United States. These are listed in decreasing order of systemic absorption:


An exact dosage for vaginal estrogen therapy for UTI prevention hasn't been established. Raz's landmark study used 0.5 mg estriol cream intravaginally once daily for 2 weeks, then twice weekly. Estriol cream is not commercially available in the United States and most prescribers use one to two grams of Estrace or Premarin cream per vagina twice weekly. Dosage should be individualized based on patient weight and degree of atrophy present. In an obese woman with higher levels of endogenous estrogen, 0.5 mg of estrogen cream twice weekly will likely be adequate, whereas in a thin woman who is very atrophic, a higher dose will be needed, especially in the initial months of treatment. Of note, progesterone does not need to be prescribed with topical vaginal estrogen in women with a uterus. In the recommended dosages, vaginal estrogen therapy does not cause endometrial hyperplasia as the amount of systemic absorption of estrogen is quite low. Progesterone therapy does NOT need to be given in a woman with a uterus who is using vaginal estrogen on a long term basis.

Despite strong evidence of benefit, topical estrogen is underutilized as a preventive strategy. In a study of nursing home residents in Norway who were on preventive therapy for UTI, only about 10% were prescribed vaginal estrogen [14]. Many women have a fear of estrogen containing products due to fear of breast or uterine cancer. There is no evidence that vaginal estrogen therapy causes uterine cancer or even endometrial hyperplasia. The same holds true for breast cancer. Patients often need reassurance that vaginal estrogen is safe and doesn't have the risk of systemic ERT, which uses much higher dosages. Vaginal estrogen therapy can be used safely in women with a prior history of breast cancer or thrombosis. The estrogen ring has the lowest amount of systemic absorption, followed by the vaginal estrogen tablets, then cream.

Cost is also significant obstacle in the United States, as many health insurance plans don't cover these products well, and after age 65 there is variable coverage of these with Medicare. One solution for women who cannot afford these products is to have a compounding pharmacist make an equivalent substitute. Estradiol 0.1 mg/gm can be added to a pluronic gel base that has excellent adherence to the vaginal mucosa. Cost is approximately \$50.00 for a two to three month supply.

### **2.5. Natural remedies**

P<0.001. They demonstrated a return of lactobacilli to the vaginal flora and normalization of vaginal ph. In addition, vaginal colonization with Enterobacteriaceae fell from 67 percent to

Vaginal estrogen therapy is available in three forms in the United States. These are listed in

**1.** Estradiol vaginal cream: Premarin Vaginal cream = 0.625 mg/gm and Estrace vaginal cream = 0.1 mg/gm. Dosage varies from 0.5 mg to 2 mg/vagina twice weekly. Retail cost

**2.** Estradiol vaginal tablets: Vagifem = 10 mcg estrogen per tablet. Dosage is one tablet

**3.** Estradiol 2 mg vaginal ring. One ring is placed intravaginally and changed every 3

An exact dosage for vaginal estrogen therapy for UTI prevention hasn't been established. Raz's landmark study used 0.5 mg estriol cream intravaginally once daily for 2 weeks, then twice weekly. Estriol cream is not commercially available in the United States and most prescribers use one to two grams of Estrace or Premarin cream per vagina twice weekly. Dosage should be individualized based on patient weight and degree of atrophy present. In an obese woman with higher levels of endogenous estrogen, 0.5 mg of estrogen cream twice weekly will likely be adequate, whereas in a thin woman who is very atrophic, a higher dose will be needed, especially in the initial months of treatment. Of note, progesterone does not need to be prescribed with topical vaginal estrogen in women with a uterus. In the recommended dosages, vaginal estrogen therapy does not cause endometrial hyperplasia as the amount of systemic absorption of estrogen is quite low. Progesterone therapy does NOT need to be given

Despite strong evidence of benefit, topical estrogen is underutilized as a preventive strategy. In a study of nursing home residents in Norway who were on preventive therapy for UTI, only about 10% were prescribed vaginal estrogen [14]. Many women have a fear of estrogen containing products due to fear of breast or uterine cancer. There is no evidence that vaginal estrogen therapy causes uterine cancer or even endometrial hyperplasia. The same holds true for breast cancer. Patients often need reassurance that vaginal estrogen is safe and doesn't have the risk of systemic ERT, which uses much higher dosages. Vaginal estrogen therapy can be used safely in women with a prior history of breast cancer or thrombosis. The estrogen ring has the lowest amount of systemic absorption, followed by the vaginal estrogen tablets, then

Cost is also significant obstacle in the United States, as many health insurance plans don't cover these products well, and after age 65 there is variable coverage of these with Medicare. One solution for women who cannot afford these products is to have a compounding pharmacist make an equivalent substitute. Estradiol 0.1 mg/gm can be added to a pluronic gel base that has excellent adherence to the vaginal mucosa. Cost is approximately \$50.00 for a two to three

is \$140/tube for both of these products (www.drugstore.com)

inserted vaginally twice weekly. Retail cost is \$64.00/month

in a woman with a uterus who is using vaginal estrogen on a long term basis.

months. Retail cost is \$216.00 per ring (3 months).

31% in the treated group [13].

cream.

month supply.

decreasing order of systemic absorption:

6 Recent Advances in the Field of Urinary Tract Infections

Cranberries and their juice have long been touted for both treatment and prevention of UTI. This was previously thought to be due to acidification of the urine, but more recent research has shown that substances (proanthocyanadins) in the cranberry prevent adhesion of E. coli strains to the uroepithelium, including multidrug resistant strains [15]. Studies of cranberry prophylaxis are mixed, but several recent studies have shown that there is benefit from this simple remedy. Wang et al did a meta-analysis of randomized controlled trials comparing prevention of UTIs in users of cranberry products versus placebo or non-placebo controls. They found a risk ratio for cranberry users versus nonusers was 0.62 and statistically signifi‐ cant, leading them to conclude that cranberry products are associated with protection against UTIs. Further, cranberry products were more effective in certain subgroups including women with recurrent UTIs, children, cranberry juice users (as opposed to tablets) and those who used cranberry products more than twice daily [16].

A recent RCT examined women with recurrent UTIs, randomizing them to either cranberry juice or placebo for 6 months. Those in the cranberry juice did have lower incidence of recurrent UTIS, but it did not reach statistical significance. However, they did have significantly decreased counts of P-fimbriated E. coli in their urine during the study periods. These are uropathogenic strains with fimbriae capable of attaching to the uroepethelium. The authors concluded that though the cranberry juice didn't significant reduce the number of recurrent UTIs, the reduction in adherent E. coli lends plausibility to a protective effect of cranberry and warrants further large scale studies [17].

Within the pediatric population, several new cranberry studies have emerged. A RCT from Finland randomized 263 children with a prior history of UTI to 6 months of cranberry juice versus placebo. Their findings: the juice did not significantly reduce the number of children who experienced a recurrence of UTI, but it was effective in reducing the actual number of recurrences and related antimicrobial use [18]. Another recent randomized controlled pro‐ spective study found cranberry capsules effective in the prevention of UTI in children with neurogenic bladder caused by myelomeningocele who required chronic intermittent cathe‐ terization. The median UTI rate in this small cohort of 20 children was 0.5 UTI/year during placebo usage and 0/year with cranberry capsule usage. This decrease was statistically significant. No side effects were noted [19].

Cranberry juice is safe in pregnancy and there is data from a small study to suggest that it may be efficacious in preventing asyptomatic bacteruria and symptomatic UTI. However in this same study, the juice was poorly tolerated by the pregnant women, and there was a high rate of withdrawal [20]. If used in pregnancy, use of cranberry pill form will likely be more effective as compliance will be higher.

Propolis is a resinous material collected by bees from exudates and buds of plants, then mixed with wax and bee enzymes. It has well documented antibacterial activity. Lavigne et al added propolis to proanthocyanidins from the cranberry and studied its effect on human volunteer subjects. They found that once daily ingestion offers some protection against bacterial adhesion, bacterial multiplication and virulence in the urinary tract [21].

Blueberries and blackberries are widely touted on the internet as effective prevention for UTIs but there are no trials of these foods found on PubMed or Ovid. Bearberry leaves are another folk remedy believed to be helpful in treating mild UTIs, but likewise, no studies of effective‐ ness have been undertaken. The same hold true for Vitamin C. There are no studies of this alone for prevention of UTI. However when Vitamin C was added to cranberry extract, Dmannose, fructo-oligosaccharides, and bromelain, this mixture was effective in reducing recurrent UTIs and improving quality of life in both pre and postmenopausal women [22]. More studies are needed on efficacy of these nutraceuticals.

**2.7. Pharmacologic suppressive treatments: Antibacterial**

term use for patients without renal tract abnormalities [26].

**2.8. Pharmacologic suppressive treatments: Antimicrobials**

Methenamine hippurate is not an antibiotic, but is a urinary antibacterial agent used for prevention of recurrent UTI when long term therapy is needed. It exhibits antibacterial activity by conversion of methenamine to formaldehyde in the presence of acidic urine. The hippuric acid component acidifies the urine and also has some antibacterial activity. This drug is often used in combination with a urinary acidifier such as sodium phosphate (Uroqid acid#2). The dose for suppression is 1 gram orally twice daily. It is safe for both adult and pediatric patients, but is contraindicated in patients with renal or hepatic insufficiency. Methenamine is Preg‐ nancy Category C, and there are no adequate and well controlled studies of its use in preg‐ nancy. It is excreted in breast milk and the amount excreted does not appear to adversely affect

Prevention of Urinary Tract Infections in the Outpatient and Inpatient Settings

http://dx.doi.org/10.5772/56709

9

Methenamine is effective in the prevention of recurrent UTIs in both adult and pediatric patients, but should only be used following eradication of the infection by antibiotics. It is not as effective as nitrofurantoin or trimethoprim/sulfamethoxazole as prophylactic treatment, but also does not cause antimicrobial resistance. Per Micromedex, it has shown to be effective in reducing bacteruria in gynecological surgical patients with short term foley catheter placement up to 3 days, but was not effective in prophylaxis for patients with long term indwelling

Most of the studies of efficacy of methenamine were done in the 1960s and 70's. Lee et al undertook a meta-analysis of all studies in 2007. There were 13 studies included, 6 of which reported on symptomatic UTI and eight for bacteruria. The overall estimates were difficult to interpret due to heterogeneity of the studies. Subgroup analysis did show that methenamine likely has benefit in patients without renal tract abnormalities for both symptomatic UTI and bacteruria but not in patients with known renal tract abnormalities. The authors concluded that methenamine may be effective for preventing UTI in patients without rental tract abnormalities, especially when used for short-term prophylaxis. It doesn't appear to work in patients with neurogenic bladder or those who have renal tract abnormalities. The rate of adverse events is low. There is a need for further large well RCT to clarify the value of its longer

There are 3 strategies commonly used today for prevention for patients with recurrent UTI: **1.** Post coital therapy: The patient takes a single dose of an antibiotic immediately after

**2.** Patient initiated therapy: The patient takes a single antibiotic tablet on first noticing

**3.** Continuous daily suppression: The patient takes a daily dose of suppressive antibiotic for

*2.7.1. Methenamine hippurate*

the nursing infant.

catheters.

intercourse

symptoms of infection

3 to 6 months or sometimes longer.

In summary, there is emerging evidence that cranberries are effective in the prevention of UTI in women and children, including children with neurogenic bladder. Both the juice and the capsules seem to be effective, the juice possibly more so, but it should be unsweet‐ ened juice to prevent high intake of unnecessary sugars. The capsules may be better tolerated however, particularly in pregnancy. Whichever form is used, it seems that it should be ingested three or more times daily for maximal effectiveness. The optimal dose of cranberry is not known and was studied in only one of the studies included in Wang's meta-analysis [23]. He concluded that the cranberry juice provides the most benefit, and it should be ingested three times daily at a dose of 4 to 6 ounces [24]. Most over the counter cranberry preperations contain 400 to 500 mg of cranberry extract and are likely also more effective if taken three times/daily. More studies are needed in this area to determine the optimal dose and type of cranberry. Cranberries should be used with caution in patients on blood thinners and those with kidney stones.

### **2.6. Vaccines**

Attempts have been underway to create an oral or parental immunoprophylaxis or vaccination for patients with recurrent UTIs for some time, but these efforts have been frustrated by the short lived nature of immunity created. The premise of a vaccine is inactivated bacteria or bacterial components presented to a host's mucosal surface to boost immunity. Intransal sprays, sublingual preparations, vaginal suppositories and IM injec‐ tions have been developed thus far. Recent publications show promise in this area. Currently, a vaccine has been developed by Immunotek in Spain called Uromune® a sublingual preparation which contains an inactivated bacterial cell suspension of selected strains of *Escherichia coli, Klebsiella pneumoniae*, *Proteus vulgaris,* and *Enterococcus faecalis*. A multicenter observational study was conducted by Lorenzo-Gomez et al in which a group of 319 women with a history of recurrent UTIs were divided into two groups. Group A was treated with 3 months of this vaccine and Group B with 6 months of prophylactic antibiotic treatment with sulfamethoxazole/trimethoprim 200/40 mg/day. These women were then followed for 15 months. The authors found that patients in Group A had a highly statistically significant decrease in number of UTI's that persisted for up to 15 months. The numbers of patients who did not have any UTI at 3, 9, and 15 months were 101, 90, and 55 in group A versus 9, 4, and 0 in group B (P < 0.0001) [25].

### **2.7. Pharmacologic suppressive treatments: Antibacterial**

### *2.7.1. Methenamine hippurate*

Blueberries and blackberries are widely touted on the internet as effective prevention for UTIs but there are no trials of these foods found on PubMed or Ovid. Bearberry leaves are another folk remedy believed to be helpful in treating mild UTIs, but likewise, no studies of effective‐ ness have been undertaken. The same hold true for Vitamin C. There are no studies of this alone for prevention of UTI. However when Vitamin C was added to cranberry extract, Dmannose, fructo-oligosaccharides, and bromelain, this mixture was effective in reducing recurrent UTIs and improving quality of life in both pre and postmenopausal women [22].

In summary, there is emerging evidence that cranberries are effective in the prevention of UTI in women and children, including children with neurogenic bladder. Both the juice and the capsules seem to be effective, the juice possibly more so, but it should be unsweet‐ ened juice to prevent high intake of unnecessary sugars. The capsules may be better tolerated however, particularly in pregnancy. Whichever form is used, it seems that it should be ingested three or more times daily for maximal effectiveness. The optimal dose of cranberry is not known and was studied in only one of the studies included in Wang's meta-analysis [23]. He concluded that the cranberry juice provides the most benefit, and it should be ingested three times daily at a dose of 4 to 6 ounces [24]. Most over the counter cranberry preperations contain 400 to 500 mg of cranberry extract and are likely also more effective if taken three times/daily. More studies are needed in this area to determine the optimal dose and type of cranberry. Cranberries should be used with caution in patients

Attempts have been underway to create an oral or parental immunoprophylaxis or vaccination for patients with recurrent UTIs for some time, but these efforts have been frustrated by the short lived nature of immunity created. The premise of a vaccine is inactivated bacteria or bacterial components presented to a host's mucosal surface to boost immunity. Intransal sprays, sublingual preparations, vaginal suppositories and IM injec‐ tions have been developed thus far. Recent publications show promise in this area. Currently, a vaccine has been developed by Immunotek in Spain called Uromune® a sublingual preparation which contains an inactivated bacterial cell suspension of selected strains of *Escherichia coli, Klebsiella pneumoniae*, *Proteus vulgaris,* and *Enterococcus faecalis*. A multicenter observational study was conducted by Lorenzo-Gomez et al in which a group of 319 women with a history of recurrent UTIs were divided into two groups. Group A was treated with 3 months of this vaccine and Group B with 6 months of prophylactic antibiotic treatment with sulfamethoxazole/trimethoprim 200/40 mg/day. These women were then followed for 15 months. The authors found that patients in Group A had a highly statistically significant decrease in number of UTI's that persisted for up to 15 months. The numbers of patients who did not have any UTI at 3, 9, and 15 months were 101, 90, and

More studies are needed on efficacy of these nutraceuticals.

8 Recent Advances in the Field of Urinary Tract Infections

on blood thinners and those with kidney stones.

55 in group A versus 9, 4, and 0 in group B (P < 0.0001) [25].

**2.6. Vaccines**

Methenamine hippurate is not an antibiotic, but is a urinary antibacterial agent used for prevention of recurrent UTI when long term therapy is needed. It exhibits antibacterial activity by conversion of methenamine to formaldehyde in the presence of acidic urine. The hippuric acid component acidifies the urine and also has some antibacterial activity. This drug is often used in combination with a urinary acidifier such as sodium phosphate (Uroqid acid#2). The dose for suppression is 1 gram orally twice daily. It is safe for both adult and pediatric patients, but is contraindicated in patients with renal or hepatic insufficiency. Methenamine is Preg‐ nancy Category C, and there are no adequate and well controlled studies of its use in preg‐ nancy. It is excreted in breast milk and the amount excreted does not appear to adversely affect the nursing infant.

Methenamine is effective in the prevention of recurrent UTIs in both adult and pediatric patients, but should only be used following eradication of the infection by antibiotics. It is not as effective as nitrofurantoin or trimethoprim/sulfamethoxazole as prophylactic treatment, but also does not cause antimicrobial resistance. Per Micromedex, it has shown to be effective in reducing bacteruria in gynecological surgical patients with short term foley catheter placement up to 3 days, but was not effective in prophylaxis for patients with long term indwelling catheters.

Most of the studies of efficacy of methenamine were done in the 1960s and 70's. Lee et al undertook a meta-analysis of all studies in 2007. There were 13 studies included, 6 of which reported on symptomatic UTI and eight for bacteruria. The overall estimates were difficult to interpret due to heterogeneity of the studies. Subgroup analysis did show that methenamine likely has benefit in patients without renal tract abnormalities for both symptomatic UTI and bacteruria but not in patients with known renal tract abnormalities. The authors concluded that methenamine may be effective for preventing UTI in patients without rental tract abnormalities, especially when used for short-term prophylaxis. It doesn't appear to work in patients with neurogenic bladder or those who have renal tract abnormalities. The rate of adverse events is low. There is a need for further large well RCT to clarify the value of its longer term use for patients without renal tract abnormalities [26].

#### **2.8. Pharmacologic suppressive treatments: Antimicrobials**

There are 3 strategies commonly used today for prevention for patients with recurrent UTI:


Choosing an effective preventive strategy should be individualized and keep in mind the ultimate goal to minimize exposure to long term antibiotics. Regardless, it should be noted that a patient will improve during any of these types of suppressive therapy, but once therapy is discontinued, the patient's risk of recurrent UTIs increases back to baseline. This again underscores the need for more effective long-term preventive strategies.

Fosfomycin tromethamine is a powder mixed with four ounces of water and drank. It is supplied in a sachet containing 3 grams. The dose is 3 gram as a one-time treatment of uncomplicated UTI. It has also been shown to be highly effective in prophylaxis of UTI recurrence at a dose of 3 grams every 10 days [30]. There is no data on its use as post-coital therapy. It inhibits bacterial cell wall synthesis and also decreases bacterial adherence of to the urothelium. It is most active against Staphylococci (including *S. Saprophiticus*) and *E. coli*, as well as some strains of *Pseudomonas* and *Proteus*. It is less active against enterococci, *Klebsiella spp, Enterobacter* and *Proteus mirabilis*. Good in vitro activity is reported against methicillinresistant *S. aureus* (MRSA). It is Pregnancy Category B and is safe in pregnancy and breast‐ feeding. Side effects are mostly minor, including rash, nausea and diarrhea, headache, and

Prevention of Urinary Tract Infections in the Outpatient and Inpatient Settings

http://dx.doi.org/10.5772/56709

11

TMP-SMX has long been used as suppressive therapy and is effective. There is not much data on the effectiveness of Trimethoprim alone. The dose is trimethoprim 40 mg/sulfamethoxazole 200 mg either after intercourse, three times weekly, or daily. It is Pregnancy Category C but is considered safe to use in pregnancy, though if alternatives are available, another agent is recommended in the first trimester due to the folic acid anatagonist activity of trimethoprim. It is also considered safe to use during breastfeeding. Increasing resistance to this agent should be noted. In the recent Antimicrobial Resistance Epidemiology in Females with Cystitis (ARSEC) study in nine European countries and Brazil, 30-50% of all isolated urinary pathogens were resistant to TMP-SMX [31]. Side effects of TMP-SMX are common and primary gastro‐ intestinal: nausea, emesis and anorexia. Rash is also common. Rarely, more serious side effects occur such as Stevens-Johnson syndrome, toxic epidermal necrolysis or aplastic anemia.

**3. Prevention of UTIS in the inpatient and institutional setting**

2.66 billion dollars in 2007 US dollars [32].

clinical trials.

UTIS are the most common nosocomial infection worldwide, accounting for about 40% of these. The great majority of these infections are due to the presence of an indwelling urethral catheter in hospitals and long-term care facilities (LTCF) and are commonly referred to as catheter-associated UTI (CAUTI). These infections add significantly to morbidity and some‐ times even mortality for the patient. The cost of these infections is substantial, estimated at

More than 1.5 million people in the United States live in nursing homes. Within the last decade, the severity of illness of nursing home residents has increased such that these residents (average age 80) have a risk of developing health care-associated infection (HAI) that ap‐ proaches that seen hospital inpatients. The use of indwelling foley catheters has decreased in this setting and is currently about 5 to 10%, but UTI remains the leading infection in long term care facilities (LTCFs). Guidelines for prevention of CA-UTI applies to both these settings [33]. Of note, the catheter literature commonly reports on catheter-associated asymptomatic bacteruria (CA-ASB) and catheter associated bacteruria if no distinction is made between CA-ASB and CA-UTI. CA-bacteruria is the predominant outcome measure reported in most

back pain. There are rare reports in Drugdex of hepatic toxicity.

For those women who find sexual intercourse to commonly trigger an infection, post-coital therapy would be the easiest and safest option. Patient initiated therapy has been used for many years and is most beneficial for women who have infrequent or clustered recurrent UTIs. Adherent and motivated patients have been shown to be able to accurately self diagnose UTIs 95% of the time and successfully self treat with a short course of antibiotics taken at onset of symptoms [27]. Zhong et al found that patient-initiated single-dose intermittent antibiotic prophylaxis was as effective as low-dose daily antibiotic prophylaxis in the treatment of recurrent UTIs in post menopausal women and was associated with fewer gastrointestinal side effects [28].

Finally, continuous daily suppression has been shown in numerous studies to effectively reduce the incidence of recurrent UTIs by up to 95%. However, in an effort to decrease development of resistance, the first two options are recommended as initial therapy. This option should be reserved for those patients who don't respond to intermittent therapy or are unable to be compliant with it. Most clinicians treat for a 6 month period, but in patients who continue to have frequent episodes, longer periods varying from 2 to 5 years have been used.

The antibiotics most commonly used in suppressive therapies are nitrofurantoin, trimethoprim (TMP), trimethoprim with sulfamethoxazole (TMP/SMX), and fosfomycin. Quinolones or first generation cephalosporins were also used in some trials, but given their broader spectrum of action, they should NOT be used as prophylactic therapy. None of these antibiotics has shown superior effectiveness in UTI prophylaxis.

Nitrofurantoin is an attractive first choice as its bactericidal action is limited to the urinary tract. The dose most often used for prophylaxis is 50 to 100 mg/day, taken after intercourse or at bedtime with food. Once ingested, it has a very short half life in serum (about 30 minutes) and is excreted into the urine. It is effective against *Escherichia coli, Enterococcus*, *Staphylococ‐ cus aureus*, as well as some strains of *Klebsiella* and *Enterobacter*. Due to multiple sites of action, resistance has not been a problem despite over 55 years of use. Nitrofurantoin is not associated with impaired fertility or teratogenicity and is considered safe in pregnancy and breastfeeding. It has few drug interactions, making it an attractive choice for treating elderly patients on multiple medications. It should not be used in patients with impaired renal function. Primary side effects are nausea, emesis and anorexia [29].

Despite its overall safety, rare but serious adverse effects are reported. The most widely known is pulmonary toxicity [29]. Reports also exist of toxic hepatitis and blood dyscrasias [29]. Neurotoxicity from nitrofurantoin is less recognized, and is estimated to occur in 0.0007 percent of courses of therapy [29]. *All of these toxicities can be severe or even fatal, and their occurrence is independent of the length of time the drug is taken. Because these side effects are rare, practitioners who prescribe suppressive therapy with nitrofurantoin must be aware of these.*

Fosfomycin tromethamine is a powder mixed with four ounces of water and drank. It is supplied in a sachet containing 3 grams. The dose is 3 gram as a one-time treatment of uncomplicated UTI. It has also been shown to be highly effective in prophylaxis of UTI recurrence at a dose of 3 grams every 10 days [30]. There is no data on its use as post-coital therapy. It inhibits bacterial cell wall synthesis and also decreases bacterial adherence of to the urothelium. It is most active against Staphylococci (including *S. Saprophiticus*) and *E. coli*, as well as some strains of *Pseudomonas* and *Proteus*. It is less active against enterococci, *Klebsiella spp, Enterobacter* and *Proteus mirabilis*. Good in vitro activity is reported against methicillinresistant *S. aureus* (MRSA). It is Pregnancy Category B and is safe in pregnancy and breast‐ feeding. Side effects are mostly minor, including rash, nausea and diarrhea, headache, and back pain. There are rare reports in Drugdex of hepatic toxicity.

Choosing an effective preventive strategy should be individualized and keep in mind the ultimate goal to minimize exposure to long term antibiotics. Regardless, it should be noted that a patient will improve during any of these types of suppressive therapy, but once therapy is discontinued, the patient's risk of recurrent UTIs increases back to baseline. This again

For those women who find sexual intercourse to commonly trigger an infection, post-coital therapy would be the easiest and safest option. Patient initiated therapy has been used for many years and is most beneficial for women who have infrequent or clustered recurrent UTIs. Adherent and motivated patients have been shown to be able to accurately self diagnose UTIs 95% of the time and successfully self treat with a short course of antibiotics taken at onset of symptoms [27]. Zhong et al found that patient-initiated single-dose intermittent antibiotic prophylaxis was as effective as low-dose daily antibiotic prophylaxis in the treatment of recurrent UTIs in post menopausal women and was associated with fewer gastrointestinal side

Finally, continuous daily suppression has been shown in numerous studies to effectively reduce the incidence of recurrent UTIs by up to 95%. However, in an effort to decrease development of resistance, the first two options are recommended as initial therapy. This option should be reserved for those patients who don't respond to intermittent therapy or are unable to be compliant with it. Most clinicians treat for a 6 month period, but in patients who continue to have frequent episodes, longer periods varying from 2 to 5 years have been used.

The antibiotics most commonly used in suppressive therapies are nitrofurantoin, trimethoprim (TMP), trimethoprim with sulfamethoxazole (TMP/SMX), and fosfomycin. Quinolones or first generation cephalosporins were also used in some trials, but given their broader spectrum of action, they should NOT be used as prophylactic therapy. None of these antibiotics has shown

Nitrofurantoin is an attractive first choice as its bactericidal action is limited to the urinary tract. The dose most often used for prophylaxis is 50 to 100 mg/day, taken after intercourse or at bedtime with food. Once ingested, it has a very short half life in serum (about 30 minutes) and is excreted into the urine. It is effective against *Escherichia coli, Enterococcus*, *Staphylococ‐ cus aureus*, as well as some strains of *Klebsiella* and *Enterobacter*. Due to multiple sites of action, resistance has not been a problem despite over 55 years of use. Nitrofurantoin is not associated with impaired fertility or teratogenicity and is considered safe in pregnancy and breastfeeding. It has few drug interactions, making it an attractive choice for treating elderly patients on multiple medications. It should not be used in patients with impaired renal function. Primary

Despite its overall safety, rare but serious adverse effects are reported. The most widely known is pulmonary toxicity [29]. Reports also exist of toxic hepatitis and blood dyscrasias [29]. Neurotoxicity from nitrofurantoin is less recognized, and is estimated to occur in 0.0007 percent of courses of therapy [29]. *All of these toxicities can be severe or even fatal, and their occurrence is independent of the length of time the drug is taken. Because these side effects are rare,*

*practitioners who prescribe suppressive therapy with nitrofurantoin must be aware of these.*

underscores the need for more effective long-term preventive strategies.

effects [28].

superior effectiveness in UTI prophylaxis.

10 Recent Advances in the Field of Urinary Tract Infections

side effects are nausea, emesis and anorexia [29].

TMP-SMX has long been used as suppressive therapy and is effective. There is not much data on the effectiveness of Trimethoprim alone. The dose is trimethoprim 40 mg/sulfamethoxazole 200 mg either after intercourse, three times weekly, or daily. It is Pregnancy Category C but is considered safe to use in pregnancy, though if alternatives are available, another agent is recommended in the first trimester due to the folic acid anatagonist activity of trimethoprim. It is also considered safe to use during breastfeeding. Increasing resistance to this agent should be noted. In the recent Antimicrobial Resistance Epidemiology in Females with Cystitis (ARSEC) study in nine European countries and Brazil, 30-50% of all isolated urinary pathogens were resistant to TMP-SMX [31]. Side effects of TMP-SMX are common and primary gastro‐ intestinal: nausea, emesis and anorexia. Rash is also common. Rarely, more serious side effects occur such as Stevens-Johnson syndrome, toxic epidermal necrolysis or aplastic anemia.
