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PELVIC FLOOR DYSFUNCTION How to prevent recurrent urinary tract infection in sexually active premenopausal women, postmenopausal patients, and women undergoing pelvic surgery

›› Autumn L. Edenfield, MD ›› Cindy L. Amundsen, MD Dr. Edenfield is a Fellow in Female Dr. Amundsen is Professor and Pelvic Medicine and Reconstructive Fellowship Director in Female Surgery and Clinical Instructor Pelvic Medicine and Reconstructive of Obstetrics and Gynecology at Surgery, Department of Obstetrics Duke University Medical Center in and Gynecology, at Duke University Durham, North Carolina. Medical Center in Durham, North Carolina.

The authors report no financial relationships relevant to this article.

rinary tract infections (UTIs) are preva- TABLE 1 Risk factors for urinary Ulent among women, afflicting as many tract infection in women as 60% of women during their lifetime.1 Symptoms include urgency, frequency, and Premenopausal women dysuria. Although the diagnosis can be made • History of urinary tract infection (UTI) In this on the basis of symptoms alone in many cases, • Frequent or recent sexual activity Article urinalysis and urine cultures often are help- • Use of diaphragm as contraception ful in confirming it.2 The differential diagnosis • Use of spermicidal agents Summary of includes infectious or atrophic , ure- • Increasing parity therapeutic strategies thritis from a sexually transmitted infection, • Diabetes mellitus for recurrent UTI urethral diverticulum, painful bladder syn- • Obesity page 48 drome, urinary tract calculi, and urinary tract • Sickle cell trait neoplasms. Common risk factors for UTIs are • Anatomic congenital abnormalities listed in TABLE 1.3 • Urinary tract calculi Antibiotic prophylaxis Recurrent UTIs are defined as three • Neurologic disorders or medical conditions after pelvic surgery? infections in 12 months or two infections in that require an indwelling catheter or repetitive page 50 bladder catheterization 6 months. In this Update, we explore strate- gies to prevent recurrent UTIs in three groups Postmenopausal women Vaginal estrogen of women: • Vaginal atrophy prevents recurrent UTI • sexually active premenopausal women • Incomplete bladder emptying in postmenopausal • postmenopausal women • Poor perineal hygiene women • women undergoing pelvic surgery. • , , urethrocele, uterovaginal In the process, we summarize the results of prolapse page 52 five trials that explore treatment modali- • History of UTI ties such as prophylactic antibiotics, vaginal • Type 1 diabetes mellitus estrogen therapy, cranberry supplementa- SOURCE: Adapted from ACOG3 tion, and probiotics (TABLE 2, page 48).

On the Dr. Cindy Amundsen describes a novel strategy to prevent recurrent UTI Web in premenopausal women, at obgmanagement.com continued on page 48

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TABLE 2 Summary of therapeutic strategies for prevention of recurrent urinary tract infections

Strategy Dose Advantages Disadvantages Prophylactic Trimethoprim-sulfamethoxazole Highly effective Potential for future microbial antibiotics (Bactrim): 1 double-strength tablet* resistance Inexpensive OR Nitrofurantoin: 50 or 100 mg Caution with nitrofurantoin, partic- ularly in older patients or women Either drug can be given daily who have renal insufficiency for 6 months or as one dose ­postcoitally In pregnancy, nitrofurantoin is ­better studied

Vaginal Conjugated estrogens (0.625 mg Highly effective in postmenopaus- Can be expensive estrogen** conjugated estrogens/1 g cream al women, who can be difficult to [Premarin]). Give 0.5–2.0 g cream treat Compliance may be an issue twice weekly. Few true contraindications Estradiol (100 µg estradiol/1 g cream [Estrace]). Give 1–4 g cream

Cranberry Dosing varies among products. Generally well-tolerated Can be expensive supplement Unsweetened natural cranberry juice or cranberry tablets, 1–3 times Few side effects or Compliance may be an issue contraindications daily. May not be as effective in post- menopausal patients

Probiotics Dosing varies among products and Few side effects or Limited data local availability contraindications Can be expensive

* Consider trimethoprim (100 mg) alone if the patient has an allergy to sulfa. ** Creams are preferred to the vaginal ring or tablets because they can be applied to periurethral tissues.

Postcoital antibiotic prophylaxis prevents some cases of recurrent UTI

Melekos MD, Asbach HW, Gerharz E, Zarakovitis IE, recurrent UTIs in premenopausal women are Weingaertner K, Naber KG. Post-intercourse versus often postcoital in temporal pattern. daily ciprofloxacin prophylaxis for recurrent urinary Daily antibiotic prophylaxis for 6 to tract infections in premenopausal women. J Urol. 12 months has proved to be effective in the 1997;157(3):935–939. prevention of recurrent UTIs, reducing the risk of recurrence by 95%, compared with placebo.4 In this trial by Melekos and colleagues, TIs typically involve fecal flora that col- sexually active premenopausal women who U onize the vagina and perineum, most had a history of three or more documented commonly Escherichia coli, Staphylococcus UTIs in the preceding 12 months were ran- saprophyticus, Klebsiella pneumonia, and domly assigned to: Proteus mirabilis. These pathogens ascend • oral ciprofloxacin, one dose daily, or to the bladder via the urethra. Sexual inter- • oral ciprofloxacin, one dose immediately course is thought to facilitate this process, and after intercourse.

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A total of 135 patients (65 in the daily group What this evidence means and 70 in the postcoital group) were followed for practice for 12 months. The regimens were equally effective at preventing UTIs. The mean num- Postcoital antibiotic prophylaxis is an ber of UTIs in 12 months decreased signifi- effective strategy for the prevention of cantly in both groups—from 3.74 to 0.031 in UTIs associated with the daily group and from 3.67 to 0.043 in the in premenopausal women. Although the postcoital group. optimal duration of such a regimen was not addressed in this study, it would be The best antibiotic? Nitrofurantoin or appropriate to revisit the need for prophy- trimethoprim-sulfamethoxazole laxis after 1 year. This randomized, controlled trial was rigor- ous and well-executed and included only and the Infectious Disease ­Society of healthy premenopausal women. However, ­America ­recommend that fluoroquinolones given the emergence of antibiotic resistance be avoided, if possible, in the treatment of since this trial was conducted, ciprofloxacin uncomplicated UTIs.5 A better therapeutic is not an ideal antibiotic for prophylaxis. choice would be nitrofurantoin or trime- Both the American Urological Association thoprim-sulfamethoxazole.

Is there a role for antibiotic prophylaxis among patients who are catheterized Catheterization remained an following pelvic surgery? independent risk factor for UTI after adjusting for other Dieter AA, Amundsen CL, Visco AG, Siddiqui NY. Catheterization increased Treatment for urinary tract infection after midurethral the risk of UTI confounding factors sling: a retrospective study comparing patients who Fifty-eight percent of women required place- receive short-term postoperative catheterization and ment of a catheter postoperatively—either patients who pass a void trial on the day of surgery. an indwelling Foley or intermittent self- Female Pelvic Med Reconstr Surg. 2012;18(3):175–178. catheterization. The duration of catheteriza- tion ranged from 1 to 14 days, with a mean of 4 days. The incidence of UTI was significantly rinary tract catheterization and urogy- higher in the group that was catheterized Unecologic surgery are associated with postoperatively, compared with the group an increased risk for UTI. The risk of UTI that was not (30.0% vs 5.2%), and catheter- following a midurethral sling procedure, in ization remained an independent risk factor particular, ranges from 4.1% to 33.6% in the for UTI after adjusting for other confounding literature.6,7 To further explore the risk of factors. UTI after placement of a midurethral sling, Dieter and colleagues followed 138 women Data may not be applicable to other who had undergone the procedure with and types of surgery without concomitant pelvic surgery. The pri- This large retrospective cohort study of a mary outcome was treatment of UTI within well-characterized population was based the first 3 weeks postoperatively. on consistent postoperative data related to

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­catheterization and UTI treatment. Because What this evidence means the study focused on patients who had for practice undergone placement of a midurethral sling, its findings may not be applicable to women The risk of UTI is increased with short- undergoing other types of pelvic surgery, term catheterization following placement including general gynecologic procedures. of a midurethral sling. There may be a role However, given the significant difference in for antibiotic prophylaxis in the setting the rate of UTI between the two groups, the of short-term postoperative catheteriza- increased risk of UTI may be at least partially tion; however, a prospective, randomized, placebo-controlled study is needed to attributable to short-term postoperative determine whether the rate of UTI would catheterization rather than urinary tract be reduced. instrumentation during the procedure.

Vaginal estrogen prevents recurrent UTIs among postmenopausal women

Raz R, Stamm WE. A controlled trial of intravaginal es- a significantly reduced risk of UTI (0.5 vs 5.9 triol in postmenopausal women with recurrent urinary infections per patient-year), increased lac- tract infections. N Engl J Med. 1993;329(11):753–756. tobacilli on vaginal cultures (61% vs 0%), decreased vaginal pH, and a lower rate of 28% of participants colonization with Enterobacteriaceae species. discontinued vaginal he tissues of the vagina, urethra, bladder, Although this rigorous double-blind, estrogen; mild local Tand pelvic floor musculature all express randomized, placebo-controlled trial was 8 reactions were the estrogen receptors. In postmenopausal published 20 years ago, its findings remain reason women, the effects of decreased estrogen on significant—and have been corroborated in the urinary tract include a rise in the vaginal other studies.9 pH level and decreased colonization with Lactobacillus. These effects predispose this Pros and cons of vaginal estrogen population to an increased risk for UTI.3 The replacement literature does not support the use of oral Raz and Stamm utilized vaginal estriol; the estrogen replacement as a therapy for recur- preparations used most commonly today rent UTI; however, data suggest that vaginal are conjugated estrogens (Premarin) and estrogen replacement may be helpful.9 estradiol (Estrace). Vaginal estrogen formu- Raz and Stamm conducted their random- lations can be expensive. Compliance also ized trial of 93 postmenopausal women with can wane over time. This study, in particular, a history of recurrent UTIs to elucidate the showed a discontinuation rate of 28%; mild effects of vaginal estrogen on the risk of UTI. Fifty women were randomly assigned to treat- What this evidence means ment with intravaginal estriol cream (0.5 mg for practice nightly for 2 weeks, followed by 0.5 mg twice weekly for 8 months), and 43 women were Vaginal estrogen is an effective therapy for randomly assigned to placebo (equivalent the prevention of UTIs in postmenopausal regimen). Compared with the placebo group, women. the women treated with estriol ­experienced

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local ­reactions were the reason. Although the with infrequent dosing (twice weekly), has women who discontinued treatment in this few contraindications. In fact, local estrogen study were included in the final analysis, no replacement is one of the most highly effec- subanalysis of these patients was published. tive regimens for UTI prevention among Despite these challenges, local estrogen postmenopausal women, who can otherwise replacement is generally well-tolerated and, be difficult to treat for recurrent UTIs.

Cranberry supplementation may prevent UTIs, but products vary widely

Stothers L. A randomized trial to evaluate effectiveness those ­taking a cranberry tablet and 32% of and cost-effectiveness of naturopathic cranberry prod- those in the placebo group (P<.05). In this ucts as prophylaxis against urinary tract infection in study, the annual cost of prophylaxis with women. Can J Urol. 2002;9(3):1558–1562. cranberry juice was $1,400 per woman, and it was $624 per woman for the cranberry tab- lets. Compliance was lowest among women ranberries have been used for many consuming cranberry juice, decreasing at Cyears in various formulations to prevent times to less than 80%. UTI, but no definitive mechanism has been established. In theory, cranberries keep bac- Findings are difficult to extrapolate teria from adhering to the urothelium.10 In This randomized, double-blind study dem- vitro studies have revealed that Escherichia onstrated a significant reduction in the rate of The risk of UTI coli is prevented from adhering to uroepithe- UTI with cranberry supplementation, com- during treatment was lial cells by two components of cranberry— pared with placebo, among women with a reduced significantly 10 fructose and proanthocyanidins. mean age of 40 to 44 years. However, because in the groups In this trial of 150 sexually active women cranberry preparations, juice, and tablets are taking a cranberry (ages 21–72 years) who had experienced at not regulated as to the amount and bioavail- formulation, least two UTIs in the past calendar year, Sto- ability of the active ingredient, it is difficult to compared with thers randomly assigned participants to one compare one to another and extrapolate to a placebo of three arms for 12 months: particular type of preparation. • placebo tablets and cranberry juice (n = 50) This study does highlight the higher rate • cranberry tablets and placebo juice (n = 50) of noncompliance and cost with cranberry • placebo tablets and placebo juice (n = 50). juice, although it was as effective at reducing Tablets were taken twice daily, and juice was UTIs as cranberry tablets. consumed three times daily. All cranberry juice was organic, unsweetened, and unfil- tered and taken in 250-mL servings; cran- What this evidence means berry tablets were 1:30 parts concentrated for practice cranberry juice. Cranberry supplementation reduced the The risk of UTI during treatment was risk of UTIs in sexually active women; reduced significantly in the groups taking placebo did not. Cranberry use may be an a cranberry formulation, compared with alternative to postcoital antibiotic prophy- placebo. Twenty percent of patients con- laxis; a randomized comparison of these suming cranberry juice experienced a UTI therapies is needed. during treatment, compared with 18% of continued on page 56

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continued from page 55 Can nonhormonal therapy alter vaginal flora?

Stapleton AE, Au-Yeung M, Hooton TM, et al. Random- Vaginal probiotic formulations may be ized, placebo-controlled phase 2 trial of a Lactobacillus hard to obtain crispatus probiotic given intravaginally for prevention The use of probiotics to prevent recurrent of recurrent urinary tract infection. Clin Infect Dis. UTIs is new and innovative. However, vagi- 2011;52(10):1212–1217. nal probiotic formulations are not widely available, and most commercially available oral probiotic formulations are marketed for robiotics have been used recently in digestive health—an area where the effects Pattempts to prevent recurrent UTI, albeit have been studied widely. with very little evidence in the literature. In this study, the mean age was 21 years. Their effectiveness is plausible due to pro- Given that hypoestrogenization is associated motion of healthy vaginal flora. with decreased vaginal colonization with This study by Stapleton and colleagues Lactobacillus, an interesting area of future enrolled premenopausal women (ages study would be the use of probiotics in post- 18–40) with a history of one UTI within the menopausal women. past calendar year and a current, active, Continued investigation of probiotics is uncomplicated UTI. Ninety-nine percent of warranted, as this approach could help in the participants were sexually active. All women treatment of women who have intolerance to were treated with a standard antibiotic antibiotics and is generally considered safe regimen for UTI. Seven to 10 days later, par- and well-tolerated. ticipants were randomly assigned to: The risk of UTI was • Lactobacillus crispatus vaginal suppository 15% among women [Lactin-V (Osel)], daily for 5 days and then What this evidence means in the probiotic weekly for 10 weeks (n = 50), or for practice group, compared • placebo (same regimen) (n = 50). with 27% in the The risk of UTI was 15% among women Intravaginal probiotic prophylaxis placebo group in the probiotic group, compared with 27% in may ­reduce the risk of recurrent UTIs. the placebo group—but this difference was ­However, further studies are needed to only statistically significant for women who confirm early enthusiasm and delineate had a higher level of Lactobacillus crispatus ideal populations. vaginal colonization in the treatment group.

References 6. Sutkin G, Alperin M, Meyn L, Wiesenfeld HC, Ellison R, 1. Foxman B, Barolow R, D’Arcy H, Gillespie B, Sobel JD. Uri- Zyczynski HM. Symptomatic urinary tract infections after nary tract infection: self-reported incidence and associated surgery for prolapse and/or incontinence. Int Urogynecol J. costs. Ann Epidemiol. 2000;10(8):509–515. 2010;21(8):955–961. 2. Bent S, Nallamothu BK, Simel DL, Fihn SD, Saint S. Does this 7. Dieter AA, Amundsen CL, Visco AG, Siddiqui NY. Treatment woman have an acute uncomplicated urinary tract infection? for urinary tract infection after midurethral sling: a retro- JAMA. 2002;287(20):2701–2710. spective study comparing patients who receive short-term 3. ACOG Practice Bulletin #91: Treatment of urinary tract postoperative catheterization and patients who pass a void infections in nonpregnant women. Obstet Gynecol. trial on the day of surgery. Female Pelvic Med Reconstr Surg. 2008;111(3):785–794. 2012;18(3):175–178. 4. Hooton TM. Recurrent urinary tract infection in women. Int J 8. Robinson D, Cardozo L. Estrogens and the lower urinary Antimicrob Agents. 2001;17(4):259–268. tract. Neurourol Urodyn. 2011;30(5):754–757. 5. Gupta K, Hooton TM, Naber KG, et al. International clinical 9. Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestro- practice guidelines for the treatment of acute uncomplicated gens for preventing recurrent urinary tract infection in cystitis and pyelonephritis in women: a 2010 update by the postmenopausal women. Cochrane Database Syst Rev. Infectious Disease Society of America and the European 2008;(2):CD005131. Society for Microbiology and Infectious Diseases. Clin Infect 10. Jepson RG, Craig JC. Cranberries for preventing urinary tract Dis. 2011;52(5):e103–120. infections. Cochrane Database Syst Rev. 2008;(1):CD001321.

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