Management and Prevention of Recurrent Urinary Tract Infections in Women

Author:
Bryan Farford, DO

Citation:
Farford B. Management and prevention of recurrent urinary tract infections in women. Consultant. 2018;58(3):99-103.

An estimated 150 million urinary tract infections (UTIs) occur worldwide each year, approximately 80% of which occur in women, making UTIs one of the most common causes of bacterial infection in women of all ages.¹ UTIs have a significant impact on morbidity and account for more than $6 billion in annual direct health care costs in the United States.¹

Approximately 20% to 30% of women who develop a UTI will have a recurrence.^1,2 Recurrent UTIs lead to increases in the number of office visits, time off from work, the number of urologic evaluations, and the use of antimicrobials.³ Although the evaluation and management of recurrent UTIs are similar to that of single-episode UTIs, there are a number of effective strategies to consider when managing recurrent UTIs.

Definitions

An uncomplicated UTI is one that presents in a patient who has no predisposing structural or functional abnormalities of the genitourinary tract and is otherwise in good health. Three or more uncomplicated UTIs in 12 months is used to define recurrent uncomplicated UTI. Recurrent UTIs may be due to bacterial reinfection or bacterial relapse. A relapse occurs when the same organism is not eradicated from the urine after 2 weeks despite appropriate antimicrobial treatment. Reinfection occurs when recurrence presents with a different organism, or with the same organism greater than 2 weeks after the initial infection, or if a sterile culture is documented between the 2 UTIs in a patient who is no longer taking antibiotics.⁴

A UTI is generally considered complicated if the patient has an anatomic abnormality, a voiding dysfunction, or an obstructed urinary tract, or if the infection is iatrogenic. Pregnancy, urolithiasis, diabetes, and immunosuppression are also associated with complicated UTIs.⁴

Pathogenesis

The most common organisms causing UTIs are the gram-negative bacteria Escherichia coli and Klebsiella pneumoniae. It is estimated that E coli causes 70% to 95% of upper and lower UTIs.^5,6 The pathogenesis for recurrent UTIs in women is assumed to be identical to that of a sporadic infection and appears  to result from infecting E coli strains interacting with epithelial cells.⁷ In healthy women, most uropathogens originate in the rectal flora, colonize the urethra and periurethral area, and subsequently invade the bladder.⁷ Women with recurrent UTIs are more susceptible to colonization of the vaginal flora with uropathogens than are those without a history of recurrent UTIs.⁷

Risk Factors

Risk factors for recurrent UTIs in premenopausal women include sexual intercourse, the use of a diaphragm, exposure to spermicide (including from spermicide-coated condoms), a personal history of previous UTI, a maternal history of UTI, and recent use of antibiotics (Table 1).^1,3,7 A large case-control study of women with and without a history of recurrent UTIs identified any lifetime sexual activity and any sexual activity during the past year as conferring the highest risk for recurrent UTI in university women and women enrolled in a health maintenance organization. This study also found that precoital and postcoital voiding, delays in urination, frequency of urination, wiping patterns, tampon use, douching, hot tub use, and wearing tight-fitting undergarments were not associated with recurrent UTIs.³

The behavioral risk factors of postmenopausal women differ from those of younger women. A case-control study comparing 149 postmenopausal women with a history of recurrent UTI to 53 age-matched women without a history of UTI found that urinary incontinence (41% of case patients vs 9% of control patients), the presence of a cystocele (19% vs 0%), and postvoid residual urine (28% vs 2%) were strongly associated with recurrent UTI.¹ Other risk factors for recurrent UTI in postmenopausal women are listed in Table 1.

Diagnosis

Taking a detailed history in women presenting with symptoms indicative of a UTI is essential in the diagnosis, evaluation, and management of recurrent UTIs. This history should include factors that predispose to recurrent UTI in women, including spermicide use, sexual activity, menopause status, recent antimicrobial use, and family history. In order to rule out structural or functional abnormalities of the urinary tract, a physical examination, including a pelvic examination, should be performed on women with recurrent UTIs.⁴

Symptoms of an uncomplicated UTI include dysuria, hematuria, urinary frequency, and urgency. The presence or absence of symptoms is a valuable clue in diagnosing UTI. Women presenting with at least 1 symptom of an uncomplicated UTI increases the pretest probability of an uncomplicated UTI from 5% to 50%. The use of urinary dipsticks in conjunction with patient symptoms also improves the precision of a UTI diagnosis.^4,8 Conversely, the risk for an uncomplicated UTI decreases in women presenting with vaginal discharge or irritation.⁸

When evaluating women for recurrent uncomplicated UTIs, culture and sensitivity tests should be performed while the patient is symptomatic. Isolation of at least 10⁵ colony-forming units (CFU) of a single uropathogen per mL in a clean-catch or catheterized specimen is the standard reference for making a diagnosis of UTI; however, more recently, a threshold between 10² and 10³ CFU/mL has been used.^4,8

Diagnostic imaging studies are generally unnecessary in women with uncomplicated recurrent UTIs. However, if clinical suspicion warrants further evaluation, computed tomography scanning of the abdomen and pelvis with and without contrast is the ideal imaging study for determining the causes of complicated UTI. Ultrasonography of the genitourinary tract and abdominal radiography may also be used if radiation exposure is a concern.⁴

Most women with recurrent UTIs have a normal urinary tract and do not require cystoscopy or specialty referral. In one evaluation of 118 women with recurrent UTI, 9 patients (8%) had significant abnormalities on cystoscopy. Urethral stricture was the most common abnormality (6 patients), followed by bladder calculi, bladder diverticulum, and colovesical fistula (1 patient each).⁹ Only 2 women with abnormalities were younger than 50 years.⁹ Women with risk factors for complicated UTI or with a surgically correctable cause of recurrent UTIs should be referred for further evaluation.⁴

Treatment

The treatment for recurrent UTI is the same as the treatment for acute uncomplicated cystitis. According to recent guidelines published by the Infectious Diseases Society of America (IDSA), nitrofurantoin monohydrate/macrocrystals (100 mg twice daily for 5 days) is an appropriate choice for therapy due to minimal resistance and efficacy compared with 3 days of trimethoprim-sulfamethoxazole (TMP-SMX).¹⁰ Results of recent clinical trials suggest that a 5-day course is as effective as the traditionally recommended 7-day regimen.

TMP-SMX (160 mg trimethoprim and 800 mg sulfamethoxazole [1 double-strength tablet] twice daily for 3 days) remains a highly effective treatment for acute uncomplicated cystitis; however, rates of resistance among uropathogens, especially outside the United States, have resulted in a revision of the use of TMP-SMX as recommended in the IDSA guidelines. TMP-SMX should be considered if the infecting strain is known to be susceptible or if the local resistance rates of uropathogens that cause acute uncomplicated cystitis are less than 20%.¹⁰

Fosfomycin trometamol, administered as a 3-g single dose, is also an appropriate choice for therapy. One study found that the clinical efficacy of fosfomycin was comparable with other first-line agents, but the bacterial efficacy of fosfomycin is lower. As the resistance rates of uropathogens increases, fosfomycin may be a more useful treatment option.¹⁰

The fluoroquinolones levofloxacin, ciprofloxacin, and ofloxacin are highly efficacious in 3-day regimens but should be considered alternative antimicrobials for acute cystitis due to their propensity for collateral damage (the ecological adverse effects of antimicrobial therapy) and resistance. These agents should be reserved for important uses other than acute cystitis and for women who have a known or suspected history of resistant uropathogens, who are allergic to or do not tolerate the first-line agents, or who live in areas where resistance to conventional treatment is greater than 20%.^7,10

Prevention

Several strategies have been used to attempt to prevent UTIs in women. Given the rising rate of antibiotic resistance, alternatives to antibiotic management have been considered. Additionally, patients are becoming more interested in alternative methods of prevention and treatment of recurrent UTIs.²

Behavioral modification. Currently, no good evidence supports the use of behavioral modification in the prevention of recurrent UTIs. These techniques include voiding before and after intercourse, avoiding hot baths, having good wiping habits, and drinking a certain amount of water daily. Despite the lack of evidence of efficacy, these practices are unlikely to cause harm.^3,4 Patients should be educated on predisposing risk factors for recurrent UTIs, including multiple sexual partners and the use of a diaphragm and spermicide.^2-4,7

Continuous antimicrobial prophylaxis. It has been well documented that the use of continuous antibiotic prophylaxis is effective in the prevention of UTIs.^11,12 Ten trials involving 430 healthy nonpregnant women were evaluated in a 2004 meta-analysis from the Cochrane Database of Systematic Reviews.13 The women in the trials had 2 or more UTIs during the previous 12 months and had been treated with continuous antibiotic prophylaxis, postcoital antibiotics, or placebo for 6 to 12 months. During active prophylaxis, the rate range of microbiologic recurrence per person-year was significantly lower (0-0.9 person-years in the antibiotic group vs 0.8-3.6 person-years in the placebo group), and the relative risk of having 1 microbiologic recurrence was 0.21 (95% CI, 0.13-0.33). The number needed to treat in order to prevent 1 recurrence in 12 months was 1.85. Adverse effects from antibiotic use included oral and vaginal candidiasis and gastrointestinal tract symptoms. The relative risk for severe adverse effects (most commonly skin rash and nausea) was 1.58 (95% CI, 0.47-5.28), and for other adverse effects, the relative risk was 1.78 (CI 1.06-3.00).¹³

The optimal prophylactic antibiotic and ideal duration for prophylaxis is currently unknown. Table 2 summarizes the antimicrobial options for continuous prophylaxis of UTIs. A recent systematic review and meta-analysis found no significant differences in prophylactic antibiotic treatment with nitrofurantoin and norfloxacin, trimethoprim, TMP-SMX, methenamine hippurate, estriol, or cefaclor in clinical or microbiologic cure in adult nonpregnant women with recurrent UTIs.¹⁴ However, nitrofurantoin was associated with a greater number of adverse effects compared with other prophylactic agents.¹⁴

The antibiotic choice should be based on allergies, local resistance patterns, prior susceptibility, adverse effects, and costs.4 Most experts recommend administering the prophylaxis nightly for a 6-month period, and then discontinuing the medication and observing for further infection.7 Some authorities suggest that antimicrobial prophylaxis is highly effective in preventing acute cystitis, asymptomatic bacteriuria, and acute pyelonephritis, even when used for as long as 5 years.^4,7,15 It does appear that most women revert to their previous rate of recurrence once prophylaxis has been discontinued.¹³

Postcoital antibiotic prophylaxis. For women whose recurrent UTIs are related to sexual intercourse, postcoital prophylaxis may be a more efficient method of preventing UTIs. Table 3 summarizes the antimicrobial options for postcoital prophylaxis of UTIs. In one randomized, double-blind, placebo-controlled trial, 16 women were randomly assigned to postcoital administration of TMP-SMX, while 11 received postcoital placebo.¹⁶ After 6 months of observation, postcoital administration of TMP-SMX was highly effective in preventing recurrent UTIs. The treatment group had an infection rate of 0.3 per patient-year compared with 3.6 per patient-year in the placebo group.¹⁶ Other antimicrobials including ciprofloxacin, nitrofurantoin, and cephalexin also have been found to be effective for postcoital prophylaxis of UTIs.^17,18 In one randomized trial of sexually active women, postcoital ciprofloxacin was found to be as effective as daily prophylactic ciprofloxacin and required a third of the amount of the drug.¹⁸

Self-treatment. Although it is not classified as a true prevention strategy, self-administered treatment is an effective, safe, and economical way for women to manage recurrent UTIs. Studies have shown that women are able to accurately self-diagnose a UTI in 85% to 95% of cases and that a short course of antibiotic therapy is a highly effective treatment.^19-21 Experts recommend that patients be given a 3-day course of antibiotics and instructed to follow up with a health care professional if the symptoms do not improve after 48 hours.^4,7 A urine dipstick test for the presence of leukocytes and nitrites is commercially available for home use, but to date, no clinical trial has evaluated its effectiveness.

Topical estrogen. A decrease in the estrogen level is associated with vesical prolapse, cystocele, postvoid residual volume, and urinary incontinence, all of which are common factors associated with recurrent UTIs in postmenopausal women.² As a result, estrogen therapy has been proposed as a method for preventing UTIs in postmenopausal women. A double-blind, placebo-controlled study of 93 postmenopausal women with a history of recurrent UTIs found that topically applied intravaginal estrogen markedly reduced the incidence of recurrent UTIs compared with placebo (0.5 vs 5.9 episodes per patient year).²² Possible adverse effects of topical estrogen include vaginal irritation, burning, and pruritus.²² Topical vaginal estrogen appears to be an effective method for prevention of UTIs in postmenopausal women who are not taking oral estrogen.²³ Patient preference is the determining factor in choosing the type of topical estrogen.⁴

Cranberry products. The use of cranberry products for the prevention of recurrent UTIs has been in practice for decades. Evidence suggests that cranberries contain potent anti-adhesion compounds (anthocyanidins and proanthocyanidins) that prevent the adhesion of type 1- and P-fimbriated uropathogens (such as E coli) to the uroepithelium, thus impairing colonization.²⁴ Cranberry juice and cranberry tablets both have been studied and have been found to reduce the recurrence of UTIs. The challenge for research on the prophylactic use of cranberry products is the inability to determine a standardized dose to prevent UTIs.² Even though the authors of a Cochrane meta-analysis concluded that cranberry products have the potential to prevent recurrent UTIs in young and middle-aged women, they recommended against their prophylactic use, given the diversity of clinical study designs and the lack of agreement regarding the dosage and formula to use.²⁵

Probiotics. The use of probiotics to restore the vaginal flora of depleted Lactobacillus species as a nonantimicrobial approach to the prevention of recurrent UTIs has been considered. A 2011 placebo-controlled trial evaluated the benefits of Lactobacillus crispatus vaginal suppositories, administered daily for 5 days then once-weekly for 10 weeks, in 100 premenopausal women with a history of recurrent UTIs.²⁶ The 50 women in the treatment group had a lower rate of recurrent UTIs (15% vs 27%) than the 50 women in the placebo group and had minimal adverse effects.²⁶ Although the use of Lactobacillus probiotics shows promise for the prevention of recurrent UTIs in women, further studies are needed before it can be recommended for clinical use.

Acupuncture. The use of acupuncture for the prevention of recurrent UTIs has shown promise. Two open trials showed that the use of acupuncture compared with a sham approach reduced the rate of recurrent UTI in women.^27,28 These studies were relatively small, and further investigation would be beneficial. Additionally, acupuncture is dependent on several factors including needle placement, manipulation, and the use of herbs and should be cautiously considered as an option for prevention of recurrent UTIs.

d-mannose. The natural sugar d-mannose mimics the host uroepithelial receptor and may compete with the binding of bacteria to the mucosa. d-mannose has long been used in animals for the treatment of UTIs, and it is also marketed for the prevention of cystitis in humans online and in health food stores despite limited evidence to support its use. One study evaluated 308 women with acute UTI and a history of recurrent UTIs.²⁹ After initial antibiotic treatment with ciprofloxacin, 500 mg twice daily for 1 week, the women were randomly assigned to 1 of 3 groups: prophylaxis with 2 g of d-mannose powder daily for 6 months, prophylaxis with 50 mg of nitrofurantoin once a day, or no prophylaxis. The rate of recurrent UTI in the 6-month study was significantly higher in the group that did not receive prophylaxis (60%) compared with the groups receiving d-mannose (15%) or nitrofurantoin (20%), which did not differ significantly.²⁹ Despite the limited evidence and the amount needed to be taken orally to achieve effective levels, d-mannose could be considered an option for women seeking nonantimicrobial options for the prevention of recurrent UTIs.

Methenamine hippurate. Methenamine salts are converted to formaldehyde when they are exposed to acidified urine, and they have general antibacterial potential. As a result, the use of methenamine hippurate as prophylaxis for UTIs has been proposed. A recent Cochrane review found that methenamine hippurate might be effective for preventing UTIs in patients without renal tract abnormalities, particularly when used for short-term prophylaxis.³⁰ More randomized controlled trials are needed to determine the benefits of methenamine hippurate for longer-term prophylaxis before it can be recommended as a prophylactic agent.³⁰

Oral immunostimulants. OM-89 is an extract of 18 different serotypes of heat-killed uropathogenic E coli that increases macrophage phagocytosis and neutrophils, thus stimulating immunity when taken orally. In a meta-analysis of 4 studies with 891 total participants, OM-89 significantly reduced the rate of UTI recurrence (relative risk, 0.61; 95% CI, 0.48-0.78), and the mean number of UTIs in women taking OM-89 was approximately 50% lower than the number in women in the placebo group.² The adverse effects were similar to those reported in the placebo group.² OM-89 has not been approved for use in the United States but is commercially available under the trade name Uro-Vaxom in a number of countries.

Vaccinations. A vaginal vaccine, Urovac, contains 10 heat-killed uropathogenic bacteria, including 6 strains of E coli and 1 strain each of Proteus vulgaris, K pneumoniae, Morganella morganii, and Enterococcus faecalis. A meta-analysis of 3 studies with 195 total participants found that Urovac slightly reduced the rate of recurrent UTI (relative risk, 0.81; 95% CI, 0.68-0.96).² Urovac is not currently available in the United States, and further studies are needed to support its clinical use.

Conclusion

Recurrent UTIs remain a common health problem for women. The use of daily or postcoital antimicrobials is an effective way to prevent recurrent UTIs. In responsible patients, the use of self-administered antimicrobials is a safe and cost-effective way to manage recurrent UTIs. In postmenopausal women, the use of topical estrogen appears to be a safe and effective prophylactic method.

The use of cranberry products is currently not recommended for prevention of recurrent UTIs. Lactobacillus probiotics, acupuncture, and d-mannose appear to have some benefit in the prevention of recurrent UTIs, but further investigation is needed before they can be routinely recommended. Future developments, including oral immunostimulants and vaccines, may offer additional methods of nonantimicrobial prophylaxis of recurrent UTIs. 

Bryan Farford, DO, is a physician at Mayo Clinic Florida in Jacksonville, Florida.

References:

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