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Abstract

Recurrent urinary infections are a common problem for women of all ages. Risk factors for urinary infection differ for pre- and postmenopausal women. Management strategies are well established, and include treatment of the acute symptomatic episode, and decreasing the frequency of subsequent episodes. This update focuses on the management of acute uncomplicated urinary infection, the most common bacterial infection in women.

Keywords

cystitis estrogen prevention treatment uncomplicated urinary infection urinary infection vaccines women

Urinary tract infection is bacterial infection of the bladder or kidneys. Acute uncomplicated urinary infection, also commonly called acute cystitis, is symptomatic bladder infection which occurs in women with a normal genitourinary tract [1]. Common symptoms are dysuria, frequency, urgency, and supra-pubic discomfort. Acute nonobstructive pyelonephritis is kidney infection, usually presenting with costovertebral angle pain and tenderness, often with accompanying fever or lower-tract irritative symptoms. Complicated urinary tract infection is urinary infection which occurs in a functionally or structurally abnormal urinary tract. Urinary infection may be asymptomatic, also known as asymptomatic bacteriuria, when the urine culture meets quantitative criteria for bacteriuria with no symptoms or signs attributable to infection. This update focuses on the management of acute uncomplicated urinary infection, the most common bacterial infection in women.

Recurrent urinary infection may either be relapse or reinfection. Relapse is recurrent infection caused by an organism which has persisted within the genitourinary tract and re-emerges following antimicrobial therapy. Reinfection is recurrent infection with an infecting organism which has ascended into the bladder from the normal flora of the genitourinary mucosa. Relapse is characterized by isolation of the same strain prior to and following therapy, whereas reinfection is generally characterized by isolation of distinct strains. For women with acute uncomplicated cystitis, however, the same strain is isolated from 30–50% of early post-treatment reinfections. Presumably, this strain has persisted in the colonizing flora [2,3].

Incidence & morbidity

Acute uncomplicated urinary infection is the most common bacterial infection that occurs in healthy young women. Most women experience at least one episode of urinary infection in their lifetime, and as many as 15% of sexually active women have an infection in a given year [4]. A substantial proportion of these women have recurrent infection. The frequency of recurrent infection varies widely among different women, or for the same woman at different times [5]. Ikaheimo followed 179 women from 17 to 82 years old who initially presented to a family physician with acute cystitis; 88 (43%) had at least one episode of urinary infection during 12 months follow-up, 13% of subjects had two episodes, and 5% had three or more episodes [6]. The infection rate was 0.73/patient-year. Foxman and colleagues followed 224 university students for 6 months after a first episode of acute cystitis; 53 (24%) had culture-confirmed infection during follow-up [7]. Stamm and colleagues described 51 women with recurrent infection followed for 1–15 years (mean age 46 years) at a specialty ambulatory clinic [5]. The rate of infection during observation was 2.6 episodes per patient-year (range 0.3–7.6/year). In a group of 799 postmenopausal women in a Seattle Health Maintenance Organization (HMO) followed for 1 year, 0.07 episodes of cystitis/person-year were reported, with 7% of women experiencing one infection, 1.6% two, and 1% three or more [8].

A woman with frequent recurrent urinary infection may experience substantial social and professional disruption attributable to symptomatic episodes [9]. Recurrent episodes of acute cystitis are not, however, associated with long-term morbidity such as renal failure, genitourinary cancer, or increased mortality. Women who experience acute uncomplicated urinary infection are also at risk for acute nonobstructive pyelonephritis [10]. The frequency of pyelonephritis compared with cystitis was estimated to be 18 to 1 in an American study [5] and 29 to 1 from Finland [6].

Pathogenesis

Host factors

Recurrent urinary infection is attributable to both genetic and behavioral factors (Table 1). The individual propensity to recurrent infection is lifelong, and any history of prior urinary infection is highly predictive of subsequent infection [11,12,16,17]. Many women experience their first infection as a girl, although the peak onset is during the young sexually active age [11]. Women with recurrent urinary infection are more likely to have first-degree female relatives – sisters, mothers, daughters – who also experience recurrent urinary infection, than women without infection [11]. Some of this genetic propensity is explained by women with recurrent infection being more likely to be nonsecretors of the blood group substances, leading to altered binding of Escherichia coli to epithelial cells [15,16]. There must be additional genetic attributes not yet characterized that also promote urinary infection.

Table 1.

Risk factors associated with recurrent acute uncomplicated urinary infection in adult women.

Risk factor	Cystitis [7,9,11 –15]	Pyelonephritis [10]	Postmenopausal [8,16 –18]
Genetic
Prior urinary infection	++	++	++
Family history	+	+	+
Non-secretor	+/−	?	+
Sexual activity
Frequency	++	++	+/−
Spermicide use	++	+	NA
New sexual partner	+	+	?
Diaphragm use	+	?	NA
Other
Diabetes	+	++	+
Incontinence	−	+	+/−
Vaginal estrogen use	NA	NA	+/−
Systemic estrogen use	NA	NA	+/−
Not associated
Postcoital voiding	−	?	−
Cranberry juice or tablets	−	?	−
Postvoid residual	?	?	−
Birth control pill	−	−	NA
Clothing type	−	?	?

++ strongly associated

+ moderately associated

+/− variable association

NA: not applicable

?: unknown

Sexual activity and the use of spermicides for birth control are the two most important behavioral factors [9,12] (Table 1). Together, these account for most episodes of recurrent acute uncomplicated urinary infection in premenopausal women. Women who have been sexually active within the past month are six-times more likely to present with infection compared with women who are not sexually active [11]. There is a dose–response relationship between sexual activity and frequency of urinary infection among young women [12,14]. Sexual intercourse appears to facilitate the ascension of colonizing periurethral organisms into the bladder − 30% of women have at least a one log increase in bacteria in the bladder immediately following intercourse [19]. These organisms are usually rapidly removed by voiding, but some will persist and cause symptomatic infection. A woman with a new sexual partner also has an increased risk of infection [10,11]. This association has been attributed to acquisition of new uropathogens, but increased frequency of intercourse likely also contributes.

The normal flora of the vagina is lactobacillus predominant. These organisms produce hydrogen peroxide and maintain an acidic milieu in the vagina, which prevents colonization by potential uropathogens. Spermicides deplete this normal flora. Women who use spermicides for birth control have an increased vaginal pH and increased colonization with potential uropathogens, particularly E. coli [20]. Sexually active young women who use spermicide for birth control have a five-times greater rate of infection compared with nonspermicide users [12]. There is a dose–response relationship between frequency of spermicide use and infection [12]. Diaphragm use may also contribute to infection, irrespective of concomitant spermicide use, but as most diaphragm users also use spermicide it is difficult to quantify the additional risk attributable to the diaphragm [7]. The birth control pill or condom without spermicide are not associated with increased urinary infection [12,21]. Many other behavioral factors have been said to contribute to recurrent urinary infection, including taking baths rather than showers, type of underwear, perineal wiping habits after voiding, voiding habits, and type of menstrual protection. Case–control studies which have explored these putative risk factors, however, have consistently found no association with urinary infection [7,11,13,14].

The strongest association of recurrent infection in postmenopausal women is a prior history of urinary infection. Sexual intercourse does not persist as a strong association for recurrent urinary infection in postmenopausal women [8,18]. Other associations include diabetes, the presence of a cystocele, incontinence, and increased postvoid residual urine volume, all of which suggest voiding abnormalities and are more consistent with complicated urinary infection [8,16 –18].

Microbiology

Organisms

E. coli is isolated from 80 to 85% of infections worldwide, for both initial and recurrent infection [22] (Table 2). A necessary virulence factor of E. coli is fimH, a surface adhesin which binds to uro-plakin on the bladder surface [26]. This adhesin is widespread in E. coli resident in the normal flora as well as infecting strains. The papG fimbria is a less common virulence factor, and highly associated with acute nonobstructive pyelonephritis. A variety of other E. coli virulence factors potentially contributing to urinary infection have been identified; however, the association of any of these with acute cystitis is minor, and inconsistent among different studies [26]. Multiple virulence factors may be necessary. The second most common organism is a coagulase-negative staphylococcus, Staphylococcus saprophyticus [22]. This is isolated in 5–10% of episodes, and is relatively specific to acute cystitis. It has a seasonal predisposition, and is isolated more commonly in the fall. Other organisms that may be isolated are enterobacteriaceae such as Klebsiella pneumoniae and, particularly in diabetic or pregnant women, group B streptococcus. Proteus mirabilis may occur, but underlying urolithiasis needs to be considered when it is isolated.

Table 2.

Organisms isolated from women with acute uncomplicated urinary infection.

		% of isolates
Reference	[23]	[24]	[25]
E. coli	80%	81%	81%
K. pneumoniae	12.7%	2.6%	4%
Other Gram-negative	3.7%	5.3%	6.2%
S. saprophyticus	3.6%	3.6%	7%
Other Gram-positive			2.5%

Antimicrobial susceptibility

The antimicrobial susceptibility of E. coli strains isolated from women with acute uncomplicated urinary infection has evolved continually since antimicrobials were introduced. Currently, 30–50% of E. coli are ampicillin resistant, and 20–30% are cephalosporin resistant [27]. There is substantial geographic variation in antimicrobial susceptibility. Current concerns relevant to E. coli susceptibility are the relatively recent increase in resistance to trimethoprim/sulfamethoxazole (TMP/SMX), reaching 10–20% in North America [23,28], and the still low but increasing flouroquinolone resistance [23]. Extended-spectrum β-lactamase (ESBL)-producing E. coli are also being isolated more frequently from women with acute cystitis [29]. Recent prior antimicrobial use is a consistent association with isolation of more resistant E. coli from women presenting with acute cystitis [30].

Diagnosis

Clinical

The clinical presentation of acute cystitis is characteristic. Women with recurrent urinary infection are highly accurate in self-diagnosis [31 –33]. Symptoms include acute onset of dysuria, often associated with frequency, urgency, and suprapubic discomfort. Gross hematuria occurs in 10–20% of women. Fever is uncommon and, if present, suggests an alternate diagnosis. The major differential diagnosis for dysuria is urethritis due to sexually transmitted infections including Chlamydia trachomatis, Neisseria gonorrhea, and Trichomonas vaginalis. These infections are usually accompanied by vaginal discharge or irritation, which are not clinical features of acute cystitis [34]. The presence of dysuria and frequency, together with the absence of vaginal discharge, predicts acute cystitis 67–77% of the time [34]. Vulvovaginal candidiasis also presents with dysuria, characterized as external rather than internal, and is often accompanied by pruritus. Vulvovaginal candidiasis is common in women who receive repeated antimicrobial courses, and women with recurrent acute cystitis may have concurrent yeast infection [2]. Women with pyelonephritis may also have lower tract symptoms, but costovertebral angle pain or tenderness is also present, often accompanied by fever.

Urine culture

Isolation of a uropathogen in a quantitative count of ≥10² colony-forming units (cfu)/ml from a urine specimen obtained from a woman with consistent symptoms meets the microbiologic criteria for diagnosis of acute cystitis [34]. Between 50 and 70% of women have an organism isolated in a quantitative count of ≥10⁵cfu/ml, and 20–30% have lower quantitative counts. A small proportion of symptomatic women, 10–20%, have pyuria but negative urine cultures. The clinical response to antimicrobial therapy is similar for women with consistent symptoms and pyuria, irrespective of quantitative counts of organisms [24,35].

The characteristic clinical presentation, predictable microbiology, limitations in interpretation of the quantitative urine culture, and delay in reporting urine culture results for 48 to 72 h have supported a recommendation that a urine culture not be routinely obtained prior to antimicrobial treatment [36]. Most episodes of infection respond to empiric therapy initiated on the basis of presenting symptoms, with or without a test for pyuria [37]. As the current standard antimicrobial regimen is 3 days therapy, the therapeutic course is usually complete before urine culture results are available. A urine specimen for culture prior to antimicrobial therapy is, however, recommended for women with a clinical presentation suggesting acute pyelonephritis, complicated urinary infection, or who are pregnant [37]. Urine specimens for culture should also be obtained if there is diagnostic uncertainty, and from women with failure of therapy or early recurrence (within 4 weeks), when a resistant organism is more likely.

Recommendations to limit pre-therapy urine cultures are, however, controversial. Not obtaining a urine culture may result in overdiagnosis and unnecessary antimicrobial treatment [38]. In addition, if urine cultures are not obtained uniformly from all women presenting with uncomplicated infection, urine cultures which are obtained will over-represent women with complicated urinary infection or treatment failure. These women are more likely to have infection with organisms of increased antimicrobial resistance. The prevalence of resistance may then be overestimated in laboratory-based surveillance of urinary isolates, promoting the use of empiric therapy with more costly or broad-spectrum agents [39].

Urinalysis

Pyuria is universally present with symptomatic infection. The presence of pyuria supports the diagnosis of acute uncomplicated cystitis. A rapid screening test for pyuria, with or without concomitant screening for nitrites, is often used to support institution of empiric antimicrobial therapy for symptomatic women [34 –38]. Patients presenting with symptoms consistent with acute cystitis but without pyuria should have urine specimens obtained for culture.

Treatment

Empiric therapy

The goals in management of women with recurrent acute uncomplicated urinary infection are to treat symptomatic episodes promptly, and to limit social and professional disruption by limiting the frequency of episodes. Obviously, any management strategy must be acceptable to the patient and cost effective.

The natural history of untreated acute uncomplicated cystitis is resolution of symptoms and bacteriuria. By 6 weeks following the onset of symptoms, at least 50% of untreated women are asymptomatic, and 47% are free of bacteriuria [35,40]. Treatment of symptomatic infection will, however, lead to a more rapid resolution of symptoms.

Current antimicrobials recommended for empiric treatment of acute episodes of cystitis are listed in Table 3. A specific regimen is selected considering patient tolerance and local antimicrobial resistance prevalence. Short-course therapy of 3 days is preferred. The relatively short course is associated with fewer adverse effects, lower costs and, possibly, less emergence of resistance in normal flora. However, for women with prolonged symptoms prior to treatment (> 7 days) or recent previous infection, a longer duration of at least 7 days therapy may be required. It has been suggested that postmenopausal women also require more prolonged antimicrobial therapy, but a recent clinical trial reported similar outcomes with 3 or 7 days ciprofloxacin for postmenopausal women presenting with acute cystitis and no complicating genitourinary factors [41].

Table 3.

Antimicrobial regimens effective for empiric treatment of acute uncomplicated cystitis.

Agent	Recommended regimen	Pregnancy
Trimethoprim/sulfamethoxazole	160/800 mg b.i.d. × 3 days	Avoid in first trimester
Trimethoprim	100 mg b.i.d. × 3 days	Avoid in first trimester
Nitrofurantoin macrocrystals	100 mg q.i.d. × 7 days	Safe; avoid at term
Monohydrate/macrocrystals	100 mg b.i.d. × 7 days	Safe; avoid at term
Norfloxacin	400 mg b.i.d. × 3 days	Contraindicated
Ciprofloxacin	250–500 mg b.i.d. × 3 days	Contraindicated
extended-release	500 mg o.d. × 3 days
Levofloxacin	500 mg o.d. × 3 days	Contraindicated
Gatifloxacin	400 mg o.d × 3days	Contraindicated
Pivmecillinam	400 mg b.i.d. × 3 days or 200 mg b.i.d. × 7days	Safe
Fosfomycin	1g	Safe
Cephalexin	250–500 mg q.i.d. × 7 days	Safe

b.i.d.: Twice-daily; o.d.: Once daily; q.i.d.: Four times daily

Antimicrobials

Trimethoprim/sulfamethoxazole (TMP/SMX) or trimethoprim (TMP) alone were the mainstay of acute cystitis treatment for several decades. Cure rates are 90–95% for susceptible E. coli with 3 days therapy [25,36], similar to cure rates with flouroquinolone antimicrobials [25]. Some countries, including the UK and Sweden, restrict use of TMP/SMX because of concerns about adverse effects from the sulfa. These agents are also considered second line for treatment of pregnant women, and should be avoided in the first trimester [42]. The major limitation with empiric treatment with TMP/SMX or TMP is the increasing worldwide prevalence of E. coli resistance to these agents [23]. It is recommended that if the local prevalence of resistance in E. coli is greater than 20%, an alternate agent should be considered for empiric therapy [36].

Flouroquinolones are extensively used for the treatment of urinary infection. The most common are norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, and gatifloxacin. All flouroquinolones appear to be effective for the treatment of acute cystitis, with cure rates of 90–95% with 3 days therapy [25,36]. Single-dose therapy with flouroquinolones is effective for cystitis caused by E. coli [43 –46]. However, the relatively slow killing of S. saprophyticus in the urine by these agents means single-dose therapy is not reliable for treating infection with this second most common infecting organism [43 –46]. Recent clinical trials have reported single-dose gatifloxacin to be equivalent to 3 days therapy, but these studies have limited information addressing efficacy with S. saprophyticus [47]. Flouroquinolones are well tolerated, but must be avoided in pregnancy. The major concern with widespread empiric use is the potential to promote resistance, which may limit subsequent treatment not only of urinary infection but also other significant infections [39]. Increasing flouroquinolone resistance in community-acquired E. coli is being reported, particularly in Southern Europe [23]. The prevalence of resistance remains low in Northern Europe and North America, but has increased over recent years [28].

Three antimicrobials which can be considered ‘urospecific’ agents are of particular interest. These are nitrofurantoin, pivmecillinam, and fosfomycin. All three have indications largely restricted to acute cystitis, and little resistance has emerged in E. coli despite prolonged use in at least some parts of the world [23,28]. As resistance to TMP/SMX and flouroquinolones increases, these agents may become more attractive for empiric first-line therapy. Some of these agents also appear to be effective for ESBL-producing E. coli.

Nitrofurantoin is effective for the treatment of acute cystitis, but 7 days therapy is required to achieve cure rates of 90% [36,40]. Cure with 3 days therapy is lower, only about 70–80%, and the efficacy of intermediate durations such as 5 days, is not yet known. Current formulations of nitrofurantoin are well tolerated. This agent is safe in pregnancy, but avoided at term because of a theoretical risk of increased hemolysis of fetal hemoglobin. Nitrofurantoin is not effective for infections with K. pneumoniae or P. mirabilis. Potential explanations for the failure of nitrofurantoin resistance to develop despite prolonged use of the agent include the limited systemic absorption, lack of impact on colonizing gut or vaginal flora, use restricted to lower urinary tract infection, and the necessity for multiple mutations in the bacteria for resistance to develop.

Pivmecillinam is a β-lactam antimicrobial with a unique target, the cell wall Type II peptidoglycan. It is marketed in a limited number of countries, primarily in Northern Europe, and is not licensed in the USA [48]. This agent is effective for empiric treatment of acute cystitis as 3 days of therapy at 400 mg twice daily or 7 days at 200 mg twice daily [24,49]. It is well tolerated, and safe for use in pregnancy. Fosfomycin is also a unique antimicrobial agent which inhibits the cell wall [50]. It has been used for around 20 years, primarily in Mediterranean countries, and is given as a single dose. Repeated dosing results in a fairly rapid emergence of resistant organisms within the colonizing flora. This agent is somewhat less effective than other regimens, with about 70- 80% cure after a single dose, but is safe for use in pregnant women.

β-lactam antibiotics including amoxicillin, amoxicillin/clavulanic acid, and cephalosporins have been used in the treatment of acute cystitis but have lower cure rates than first-line antibiotics [36,49]. They are not generally recommended for empiric treatment. Where the infecting organism is known to be susceptible, and antimicrobial choices are limited because of resistance or patient intolerance, they may be appropriate, given as a 7-day course. These agents are particularly useful for the treatment of pregnant women, as they are safe for the fetus.

Self-treatment

Women with recurrent infection are highly accurate in self-diagnosis based on symptoms, and patient-initiated self-treatment is an effective strategy [31 –33] (Table 4). This approach is preferred by some women because it gives an element of personal control in management, and more rapid access to treatment, limiting disruption to daily activities. Studies have consistently reported this strategy is highly effective, with 90–95% cure [31 –33] (Table 4). A 3-day treatment regimen is usually provided. Women are advised to contact their physician if there is no response to treatment or rapid recurrence after therapy. This approach is particularly useful for women with relatively infrequent recurrences, or who are concerned about developing infection while traveling.

Table 4.

Self treatment of acute uncomplicated urinary infection.

Study	Number patients	Number infections; incidence rate	Antimicrobial regimen	Bacteriologically documented	Cure	Ref.
Wong et al.	34	42; 2.2/ patient-year	TMP/SMX 80/400 mg × 4 as single dose	90%	92%	[33]
Shaeffer and Stuppy	34	84; 2.8/patient-year	Norfloxacin 400 mg b.i.d. × 3 days	80%	92%	[32]
Gupta et al.	172	172	Ofloxacin or 200 mg b.i.d. or Levofloxacin 250 mg o.d. × 3 days	84%	92%	[31]

b.i.d.: Twice-daily; o.d.: Once daily; q.i.d.: Four-times daily; TMP/SMX: Trimethoprim/sulfamethoxazole.

Asymptomatic bacteriuria

Women with asymptomatic bacteriuria in early pregnancy have a 30% likelihood of experiencing acute pyelonephritis later in pregnancy. This usually occurs at the end of the second or early third trimester, when hormonal effects on the genitourinary smooth muscle are maximal, and obstruction of the ureters from pressure of the fetal head on the pelvic brim may also occur. Acute pyelonephritis at this gestational age carries a high risk of premature labor and neonatal death. Treatment of asymptomatic bacteriuria identified early in pregnancy will prevent about 90% of episodes of pyelonephritis, substantially reducing the risk of premature labor and delivery and other adverse fetal outcomes [51].

Asymptomatic bacteriuria is not an indication for antimicrobial treatment of women who are not pregnant. Women with asymptomatic bacteriuria experience recurrent acute uncomplicated urinary infection more frequently than women without asymptomatic bacteriuria [29]. However, the symptomatic infection is not directly attributed to the asymptomatic infection, and treatment of asymptomatic bacteriuria does not decrease the frequency of symptomatic infection [51]. In fact, antimicrobial treatment of asymptomatic women may increase the short-term risk of symptomatic urinary infection [52]. This may occur because of disruption to the normal vaginal flora with antimicrobial therapy, or by eradication of bacteria which interfere with receptor sites or nutrients in the urinary tract, enabling replacement by more pathogenic organisms.

Urologic investigation

Women who present with characteristic symptoms and signs of acute uncomplicated urinary infection and respond promptly to empiric therapy do not require further genitourinary investigations. These women virtually never have genitourinary abnormalities which require intervention [53]. Investigations to search for underlying genitourinary abnormalities should be considered for women with infection with a susceptible organism who have failed to respond to therapy, or with repeated early recurrence post-therapy. The clinical presentation should direct the diagnostic strategy, which may include renal ultrasound, computed tomography, cystoscopy or urodynamic studies.

Prevention

Treatment of a single episode of acute cystitis is generally straightforward. The major management challenge is prevention of recurrent urinary infection in women experiencing frequent recurrences. An initial behavioral modification which may be recommended is to avoid spermicide use. Limiting sexual activity is seldom a realistic intervention. There are, however, several effective strategies which may be recommended, and several other approaches being evaluated.

Antimicrobial prophylaxis

The effectiveness of low-dose prophylactic antimicrobials in preventing recurrent acute uncomplicated urinary infection is well established (Table 5). While most clinical trials which support this approach were reported some time ago [54], one recent publication confirms the continuing efficacy of nitrofurantoin for prophylaxis [55]. Long-term low-dose prophylaxis is 95% effective in preventing symptomatic episodes [56]. Antimicrobials such as TMP/SMX and flouroquinolones eradicate potential uropathogens from the gut and vaginal flora – the reservoir for infecting organisms. A second mechanism of action appears to be intermittent sterilization of the urine, as nitrofurantoin has no impact on colonizing flora but is as effective as TMP/SMX for prophylaxis [56].

Table 5.

Effective prophylactic antimicrobial regimens for prevention of recurrent acute uncomplicated urinary infection.

Antimicrobial	Regimen
	Long-term low dose	Post-intercourse
TMP/SMX	40/200 mg × o.d. or every other day	40/200 mg
Trimethoprim	100 mg ohs	100 mg
Nitrofurantoin*	50–100 mg o.d.	50 mg
Norfloxacin	200 mg every other day	200 mg
Ciprofloxacin	125 mg o.d.	125 mg
Ofloxacin	NA**	100 mg
Levofloxacin	NA	200 mg
Cephalexin*	500 mg o.d.	250 mg

Recommended for pregnant women

NA: Not applicable

o.d.: Once daily; TMP/SMX: Trimethoprim/sulfamethoxazole.

Antimicrobial prophylaxis may be given daily or on alternate days, usually at bedtime. The initial duration of therapy is generally 6 months to 1 year. Low-dose prophylaxis has continued efficacy when given as long as 2–5 years in selected patients [57,58]. Postcoital prophylaxis, given as a low dose immediately post intercourse, is also effective. The choice of long-term low-dose or postcoital prophylaxis is determined by individual preference and patient lifestyle. If a woman is taking prophylaxis and experiences a symptomatic episode, the infecting organism is likely resistant to the prophylactic antimicrobial [58]. An antimicrobial from a different class should be selected for empiric therapy in this setting. When prophylaxis is discontinued, the frequency of recurrent urinary tract infection is similar to that of the preprophylaxis period [54]. Thus, prophylaxis does not alter the long-term natural history of recurrent urinary infection. The goal is to manage a woman through a period of frequent recurrent infection, until a period of less frequent infection is achieved.

Cranberry products

The use of cranberry juice to treat or prevent urinary infection has been a popular recommendation for many years. Proposed mechanisms of efficacy include an antiseptic effect of hippuric acid, blocking of urothelial E. coli receptors, or decreased bacterial fimbrial production [59]. In two studies of women with frequent recurrent urinary infection, cranberry products as juice or tablets decreased the frequency of recurrent infection by about 30% [60,61]. However, a more recent prospective study reported no decrease in frequency of infection with cranberry juice [62], and a case–control study also found no decrease in infection for women with increased use of cranberry products [7]. A recent comprehensive review concluded that while there is some suggestion of a preventive effect with cranberry products, the optimum dose or method of administration is not known, and there may be problems with long-term tolerability [63]. This review concluded that further studies are needed before this approach can be recommended. Thus, the role of cranberry products in the management of recurrent urinary infection remains unclear.

Probiotics

Recurrent acute uncomplicated urinary infection is associated with disruption of the normal vaginal flora. The hydrogen-peroxide-producing lactobacilli which maintain an acidic environment are depleted, allowing overgrowth of potential uropathogens, including E. coli and yeast species [54]. A proposed approach to management of recurrent urinary infection is to reconstitute the normal vaginal lactobacillus flora through a probiotic [59]. There has been substantial popular enthusiasm for this approach as a ‘natural’ method which avoids antimicrobial therapy. Despite this enthusiasm, and substantial work in this field, there is currently no evidence that this approach is effective. Orally administered Lactobacillus rhamnosus GG does not effectively colonize the vagina [64]. A prospective, randomized placebo-controlled trial which evaluated this product found no benefit in preventing urinary infection [60]. Further clinical trials with alternate candidate Lactobacilli spp., exploring oral or vaginal administration, may be appropriate.

Estrogen therapy

The postmenopausal period is associated with estrogen deficiency of the genitourinary mucosa. The vaginal flora is altered in the presence of estrogen deficiency, with a decline in lactobacilli, increased pH, and an increase in colonization with potential uropathogens such as E. coli [65]. Estrogen replacement has been proposed to lead to a more ‘premenopausal flora’, and protect postmenopausal women from recurrent urinary infection. The clinical evidence to support an efficacy of estrogen replacement is, however, conflicting. Two prospective, randomized trials of topical vaginal estrogen, one with estriol and the other with estradiol, have reported efficacy in preventing urinary infection in postmenopausal women with frequent recurrent infection [66,67]. The efficacy of estrogen therapy, however, was less than achieved with antimicrobial prophylaxis. A randomized trial using an estriol-containing vaginal pessary [55], and a prospective observational study of topical estrogen [8], both reported no benefit. Studies evaluating systemic estrogen, including comparative clinical trials [68 –70], prospective observational studies [8,69] and case–control studies [71], have consistently reported no reduced frequency of urinary infection in women receiving estrogen. In fact, some studies report an increased frequency of infection, potentially attributable to an increased frequency of sexual intercourse in women taking estrogen [8,71]. Currently, use of topical estrogen solely to prevent urinary infection cannot be recommended. Further long-term studies in selected, well-characterized, postmenopausal women are necessary to characterize the benefits, if any, of vaginal estrogen in preventing urinary infection.

Vaccines

There has been substantial interest in vaccine strategies to prevent recurrent urinary infection in women [59,72]. Vaccines which have been developed include a whole-cell heat-killed mixture of ten uropathogens administered as a vaginal suppository (Urovac®) [73], oral immunostimulating fractions of 18 uropathogenic E. coli [74], and a fimH vaccine [75]. In Phase II trials of the whole-cell heat-killed vaccine, infection was prevented in 50% of women with vaccination and continuing boosters for a 6-month period, compared to 25% in women who received placebo or only three initial doses of vaccine without boosters [73]. The study numbers in this trial were small, and actual infection rates in the three groups were not reported. Clinical trials with other candidate vaccines are limited [72]. Currently, vaccination is not an option for preventing recurrent acute uncomplicated urinary infection, but continuing studies may clarify the potential role of this approach.

Conclusion

Recurrent acute cystitis is an important women's health problem. Frequent reinfections are frustrating and disruptive for many women, although there are no long-term negative outcomes. Management includes appropriate treatment of each symptomatic episode, and institution of strategies to decrease the frequency of infection over the long term. Currently, the most appropriate long-term strategy is antimicrobial prophylaxis for women with frequent infections, or self-treatment for women with less frequent infections. Any management approach should be developed in consultation with the individual woman who experiences recurrent infections.

Future perspective

Antimicrobial resistance will continue to evolve in community E. coli, requiring continuing re-evaluation and alteration of empiric antimicrobial therapy and prophylactic regimens. Urospecific antimicrobials including nitrofurantoin, pivmecillinam and fosfomycin may have a larger role in empiric therapy of symptomatic episodes because of limited development of resistance and lack of cross-resistance for other antimicrobial classes. Evaluation of non-antimicrobial approaches to controlling urinary infection will continue. None of the current suggested approaches, however, seem likely to provide a major advance in management. Fuller characterization of the genetic associations of recurrent urinary infection could lead to identification of additional targets, which may be explored to develop alternate approaches for managing frequent recurrent infection.

Executive summary

Pathogenesis & host factors

Recurrent urinary tract infection is a distressing problem for many women. Factors which promote recurrent acute uncomplicated urinary infection include:

Genetic propensity, as evidenced by a lifelong predilection to develop infection in many women, and increased frequency in nonsecretors and first-degree female relatives.

For premenopausal women, major behavioral factors are sexual intercourse and use of spermicide for birth control.

For postmenopausal women, a history of prior urinary infection is the most important association. Diabetes, voiding abnormalities, and presence of a cystocele, all of which suggest complicated urinary infection, are also associated with recurrent infection.

Escherichia coli is isolated in over 80% of episodes. Staphylococcus saprophyticus is the second most common organism. Increasing prevalence of antimicrobial resistance in community acquired E. coli requires continual reassessment of antimicrobial management.

Treatment

The usual approach to management is empiric antimicrobial therapy:

Treatment is initiated based on symptoms, and a urine culture is not uniformly obtained. Urine culture prior to antimicrobial therapy is recommended for women presenting with symptoms of acute pyelonephritis, complicated urinary infection, who are pregnant, when the diagnosis is uncertain, or when there has been a recent failure of therapy.

The natural history of untreated acute uncomplicated urinary infection is usually resolution of symptoms and bacteriuria, but symptoms are abbreviated by antimicrobial courses.

Many antimicrobials are effective. First-line agents include trimethoprim/sulfamethoxazole, trimethoprim, flouroquinolones, nitrofurantoin, pivmecillinam and fosfomycin.

An effective and acceptable approach for many women is short course self-initiated treatment based on recognition of their own symptoms.

Asymptomatic bacteriuria should be screened for and treated in pregnant women. In nonpregnant women, asymptomatic bacteriuria is benign and should not be treated.

Women who present with a characteristic clinical presentation and respond promptly to empiric therapy do not require further urologic investigations.

For women with frequent recurrent urinary infection, the major therapeutic challenge is to decrease morbidity due to frequent symptomatic episodes. Current approaches include:

Long-term low-dose or postcoital antimicrobial prophylaxis.

Interventions being evaluated, but with uncertain efficacy including the use of cranberry products, probiotics, estrogen therapy for postmenopausal women, and vaccines.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

Rubin

Shapiro

Andriole

Davis

Stamm

: Evaluation of new anti-infective drugs for the treatment of urinary tract infection. Clin. Infect. Dis. 15(Suppl. 1), S216–S227 (1992).

Fihn

Johnson

Roberts

Running

Stamm

: Trimethoprim-sulfamethoxazole for acute dysuria in women: A single dose or 10-day course. Ann. Intern. Med. 108, 350–357 (1988).

Karkkainen

W-M

Ikaheimo

Katila

M-L

Siitonen

: Recurrence of urinary tract infections in adult patients with community-acquired pyelonephritis caused by E. coli: A 1-year follow-up. Scand. J. Infect. Dis. 32, 495–499 (2000).

Foxman

Braun

: Epidemiology of urinary tract infections: Transmission and risk factors, incidence and costs. Infect. Dis. Clin. North Am. 17, 227–242 (2003).

Stamm

McKevitt

Roberts

White

: Natural history of recurrent urinary tract infections in women. Rev. Infect. Dis. 13, 77–84 (1991).

Ikaheimo

Siitonen

Heiskanen

: Recurrence of urinary tract infection in a primary care setting: Analysis of a one-year follow-up of 179 women. Clin. Infect. Dis. 22, 91–99 (1996).

Foxman

Gillespie

Koopman

: Risk factors for second urinary tract infection among college women. Am. J. Epidemiol. 151, 1194–1205 (2000).

Jackson

Boyko

Scholes

Abraham

Gupta

Fihn

: Predictors of urinary tract infection after menopause: a prospective study. Am. J. Med. 117, 903–911 (2004).

10.

Foxman

Frericks

: Epidemiology of urinary tract infection: 1. Diaphragm use and sexual intercourse. Am. J. Public Health 75, 1308–1313 (1985).

11.

Scholes

Hooton

Roberts

Gupta

Stapleton

Stamm

: Risk factors associated with acute pyelonephritis in healthy women. Ann. Intern. Med. 142, 20–27 (2005).

12.

Scholes

Hooton

Roberts

Stapleton

Gupta

Stamm

: Risk factors for recurrent urinary tract infection in young women. J. Infect. Dis. 182, 1177–1182 (2000).

13.

Hooton

Scholes

Hughes

: A prospective study of risk factors for symptomatic urinary infection in young women. N. Engl. J. Med. 335, 468–474 (1996).

14.

Foxman

Frericks

: Epidemiology of urinary tract infection: II. Diet, clothing, and urination habits. Am. J. Public Health 75, 1314–1317 (1985).

15.

Remis

Gurwith

Hargrett-Bean

Layde

: Rick factors for urinary tract infection. Am. J. Epidemiol. 126, 685–694 (1987).

16.

Sheinfeld

Schaeffer

Cordon-Cardo

Rogatko

Fair

: Association of the Lewis blood-group phenotype with recurrent urinary tract infections in women. N. Engl. J. Med. 320, 773–777 (1989).

17.

Raz

Gennesin

Wasser

: Recurrent urinary tract infections in postmenopausal women. Clin. Infect. Dis. 30, 152–156 (2000).

18.

Boyko

Scholes

: Risk factors for urinary tract infections in postmenopausal women. Arch. Intern. Med. 164, 989–93 (2004).

19.

Foxman

Somel

Tallman

: Urinary tract infection among women aged 40 to 65: behavioral and sexual risk factors. J. Clin. Epidemiol. 54, 710–718 (2001).

20.

Buckley

McGuckin

MacGregor

: Urine bacterial counts after sexual intercourse. N. Engl. J. Med. 298, 321–324 (1978).

21.

Gupta

Hillier

Hooton

Roberts

Stamm

: Effects of contraceptive method on the vaginal microbial flora: a prospective evaluation. J. Infect. Dis. 181, 595–601 (2000).

22.

Hooton

Roberts

Stamm

: Effects of recent sexual activity and use of a diaphragm on the vaginal microflora. Clin. Infect. Dis. 19, 274–278 (1994).

23.

Ronald

: The etiology of urinary tract infection: Traditional and emerging pathogens. Am. J. Med. 113(1A), 14S–19S (2002).

24.

Kahlmeter

, ECO.SENS: An international survey of the antimicrobial susceptibility of pathogens from uncomplicated urinary tract infections: the ECO.SENS project. J. Antimicrob. Chemother. 51, 69–76 (2003).

25.

This multi-center European and Canadian study describes the prevalence of antimicrobial resistance in E. coli isolated from women with acute uncomplicated urinary tract infection for common antimicrobials used for treating urinary infection.

26.

Nicolle

Madsen

KeBeeck

: Three days pivmecillinam or norfloxacin urinary infection in women. Scand. J. Infect. Dis. 34, 487–492 (2002).

27.

McCarty

Richard

Huck

: A randomized trial of short-course ciprofloxacin, ofloxacin, or trimethoprim/sulfamethoxazole for the treatment of acute urinary tract infection in women. Am. J. Med. 106, 292–299 (1999).

28.

Johnson

Russo

: Extraintestinal pathogenic Escherichia coli: “The other bad E. coli“. J. Lab. Clin. Med. 139, 155–162 (2002).

29.

Gupta

: Addressing antibiotic resistance. Amer. J. Med. 113(Suppl. 1A), 29S–34S (2002).

30.

Gupta

Scholes

Stamm

: Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. JAMA 281, 736–738 (1999).

31.

Colodner

Rock

Chazan

: Risk factors for the development of extended-spectrum β-lactamase producing bacteria in non-hospitalized patients. Eur. J. Clin. Microbiol. Infect. Dis. 23, 163–167 (2004).

32.

Brown

Freeman

Foxman

: Prevalence and predictors of trimethoprim-sulfamethoxazole resistance among uropathogenic isolates in Michigan. Clin. Infect. Dis. 34, 1061–1066 (2002).

33.

Gupta

Hooton

Roberts

Stamm

: Patient-initiated treatment of uncomplicated recurrent urinary tract infections in young women. Ann. Intern. Med. 135, 9–16 (2001).

34.

Schaefer

Stuppy

: Efficacy and safety of self-start therapy in women with recurrent urinary tract infections. J. Urol. 161, 207–211 (1999).

35.

Wong

McKevitt

Running

Counts

Turck

Stamm

: Management of recurrent urinary tract infections with patient-administered single dose therapy. Ann. Intern. Med. 102, 302–307 (1985).

36.

Bent

Saint

: The optimal use of diagnostic testing in women with acute uncomplicated cystitis. Am. J. Med. 113(1A), 20S–28S (2002).

37.

Ferry

Holm

LSE

Stenlund

Lundholm

Monsen

: The natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study. Scand. J. Infect. Dis. 36, 296–301 (2004).

38.

Warren

Abrutyn

Hebel

: Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Clin. Infect. Dis. 29, 745–758 (1999).

39.

This evidence-based review summarizes recommendations for treatment of acute uncomplicated urinary-tract infection.

40.

Hooton

: The current management strategies for community-acquired urinary tract infection. Infect. Dis. Clin. North Am. 17, 303–332 (2003).

41.

A comprehensive review of approaches to the management of acute uncomplicated urinary-tract infection in women.

42.

McIssac

Low

Biringer

Pimlott

Evans

Glazier

: The impact of empirical management of acute cystitis on unnecessary antibiotic use. Arch. Intern. Med. 162, 600–605 (2002).

43.

Hooton

Besser

Foxman

Fritsche

Nicolle

: Acute uncomplicated cystitis in an era of increasing antibiotic resistance. A proposed approach to empirical therapy. Clin. Infect. Dis. 39, 75–80 (2004).

44.

Christiaens

De Meyere

Versctiraegen

: Randomized controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Br. J. Gen. Pract. 52, 729–734 (2002).

45.

Vogel

Verreault

Gourdeau

Morin

Grenier-Gosselin

Rochette

: Optimal duration of antibiotic therapy for uncomplicated urinary tract infection in older women: a double-blind randomized controlled trial. Can. Med. Assoc. J. 170, 469–463 (2004).

46.

Hernandez-Diaz

Werler

Walker

Mitchell

: Folic acid antagonists during pregnancy and the risk of birth defects. N Engl. J. Med. 343, 1608–1614 (2000).

47.

Saginur

Nicolle

, Canadian Infectious Diseases Society Clinical Trials Study Group: Single-dose compared with 3-day norfloxacin treatment of uncomplicated urinary tract infection in women. Arch. Intern. Med. 152, 1233–1237 (1992).

48.

Iravani

: Multicenter study of single-dose and multiple dose fleroxacin versus ciprofloxacin in the treatment of uncomplicated urinary tract infections. Am. J. Med. 94(Suppl. 3A), 895–965 (1993).

49.

Garlando

Rietiker

Tauber

Flepp

Meier

Luthy

: Single-dose ciprofloxacin at 100 versus 250 mg for treatment of uncomplicated urinary tract infections in women. Antimicrob. Agents Chemother. 31, 354–356 (1987).

50.

Backhouse

Matthews

: Single-dose enoxacin compared with 3-day treatment for urinary tract infection. Antimicrob. Agents Chemother. 33, 877–880 (1989).

51.

Naber

Allin

Clarysse

: Gatifloxacin 400 mg as a single shot or 200 mg once daily for 3 days is as effective as ciprofloxacin 250 mg twice daily for the treatment of patients with uncomplicated urinary tract infections. Int J. Antimicrob Agents 23, 596–605 (2004).

52.

Nicolle

: Pivmecillinam in the treatment of urinary tract infections. J. Antimicrob. Chemother. 46(Suppl. S1), 35–40 (2000).

53.

Nicolle

: Empiric treatment of acute cystitis in women. Int J. Antimicrob Agents 22, 1–6 (2003).

54.

Patel

Balfour

Bryson

: Fosfomycin tromethamine. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single dose treatment for acute uncomplicated lower urinary tract infections. Drugs 53, 637–656 (1997).

55.

Nicolle

: Asymptomatic bacteriuria. When to screen and when to treat. Infect. Dis. Clin. North Am. 17, 367–394 (2003).

56.

Reviews current knowledge and management of asymptomatic bacteriuria including recommendations for screening and treatment in specific populations.

57.

Smith

Hughes

Hooton

: Antecedent antimicrobial use increases the risk of uncomplicated cystitis in young women. Clin. Infect. Dis. 25, 63–66 (1997).

58.

Hooton

Stamm

: Diagnosis and treatment of uncomplicated urinary tract infection. Infect. Dis. Clin. North Am. 11, 551–581 (1997).

59.

Stapleton

Stamm

: Prevention of urinary tract infection. Infect. Dis. Clin. North Am. 11, 719–733 (1997).

60.

Raz

Colodner

Rohana

Rottensterich

Wasser

Stamm

: Effectiveness of estriol containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of recurrent urinary tract infection in postmenopausal women. Clin. Infect. Dis. 36, 1362–1368 (2003).

61.

Nicolle

Ronald

. Recurrent urinary tract infection in adult women: Diagnosis and treatment. Infect. Dis. Clin. North Am. 1, 793–806 (1987).

62.

Harding

GKM

Ronald

Nicolle

Thomson

Gray

. Long-term antimicrobial prophylaxis for recurrent urinary infection in females. Rev. Infect. Dis. 4, 438–443 (1982).

63.

Nicolle

Harding

GKM

Thomson

Kennedy

Urias

Ronald

. Efficacy of five years of continuous low dose cotrimoxazole prophylaxis for prevention of urinary tract infection. J. Infect. Dis. 157, 1239–1242. (1988).

64.

Stapleton

: Novel approaches to prevention of urinary tract infections. Infect. Dis. Clin. N. Amer. 17, 457–471 (2003).

65.

Addresses proposed novel management strategies for recurrent urinary tract infection.

66.

Kontiokari

Sundqvist

Nuutinen

Pokka

Koskela

Uhari

: Randomized trial of cranberry lingonberry juice or Lactobacillus GG drink for the prevention of urinary tract infections in women. Br. Med. J. 322, 1571 (2001).

67.

Stothers

: A randomized trial to evaluate effectiveness and cost-effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection. Can. J. Urol. 9, 1558–1562 (2002).

68.

Dan

Colodner

Hazan

Raz

: A double-blind, randomized study of cranberry juice versus placebo for preventing recurrent urinary tract infection in healthy, premenopausal women. Abstract L-1000, 44th Interscience Conference on Antimicrobial Agents and Chemotheapyr, Washington Oct 30-Nov 2 (2004).

69.

Jepson

Mihaljevic

Craig

: Cranberries for preventing urinary tract infections. Cochrane Database Syst. Rev. 2, CD001321 (2004).

70.

Colodner

Edelstein

Chazan

Raz

: Vaginal colonization of orally administered Lactobacillus rhamnosus GG. Isr. Med. Assoc. J. 5, 767–769 (2003).

71.

Pabich

Fihn

Stamm

Scholes

Boyko

Gupta

: Prevalence and determinants of vaginal flora alterations in postmenopausal women. J. Infect. Dis. 188, 1054–1058 (2003).

72.

Raz

Stamm

: A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J. Med. 329, 753–756 (1993).

73.

Erikson

: A randomized, open, parallel group study on the preventive effect of an estradiol-releasing vaginal ring on recurrent urinary tract infections in postmenopausal women. Am. J. Obstet. Gynecol. 180, 1072–1079 (1999).

74.

Brown

Vittinghoff

Kanaga

Agarwal

Hulley

Foxman

: Urinary tract infections in postmenopausal women: effect of hormone therapy and risk factors. Obstet. Gynecol. 98, 1045–1052 (2001).

75.

Ouslander

Greendale

Uman

Lee

Paul

Schnelle

: Effects of oral estrogen and progestin on the lower urinary tract among female nursing home residents. J. Am. Geriatr. Soc. 49, 803–807 (2001).

76.

Cardozo

Bennes

Abbott

: Low dose oestrogen prophylaxis for recurrent urinary tract infections in elderly women. Br. J. Obstet. Gynaecol. 105, 403–407 (1998).

77.

Orlander

Jick

Dean

Jick

: Urinary tract infections and estrogen use in older women. J. Am. Geriatr. Soc. 40, 817–820 (1992).

78.

Hopkins

Uehling

: Vaccine development for the prevention of urinary tract infections. Curr. Infect. Dis. Rep. 4, 509–513 (2002).

79.

Uehling

Hopkins

Elkahwaji

Schmidt

Leverson

: Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections. J. Urol. 170, 867–869 (2003).

80.

Schmidhammer

Ramoner

Holtl

Bartsch

Thurnher

Zelle-Rieser

: An Escherichia coli based oral vaccine against urinary tract infections potently activates human dendritic cells. Urology 60, 521–526 (2002).

81.

Langermann

Burlein

Palaszynski

: Prevention of mucosal. Vaccination with FimH^∗adhesin protects cynomolgus monkeys from colonization and infection by uropathogenic Escherichia coli. J. Infect. Dis. 181, 774–778 (2000).

Managing Recurrent Urinary Tract Infections in Women

Abstract

Keywords

Incidence & morbidity

Pathogenesis

Host factors

Microbiology

Organisms

Antimicrobial susceptibility

Diagnosis

Clinical

Urine culture

Urinalysis

Treatment

Empiric therapy

Antimicrobials

Self-treatment

Asymptomatic bacteriuria

Urologic investigation

Prevention

Antimicrobial prophylaxis

Cranberry products

Probiotics

Estrogen therapy

Vaccines

Conclusion

Future perspective

References