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Urinary tract infections in women
European Journal of Obstetrics & Gynecology and Reproductive Biology, Volume 156, Issue 2, June 2011, Pages 131 - 136
Urinary tract infections (UTIs) are conditions frequently complained by women both in the general population and in the hospital setting. Indeed it has been estimated that one woman out of three will experience at least an episode of UTI during lifetime. A comprehensive literature review of published experimental and clinical studies of UTI was carried out at the University of Insubria electronic library (SFX Bicocca-Insubria) with cross-search of seven different medical databases (AMED, BIOSIS Previews on Web of Knowledge, Cochrane Library, Embase and Medline on Web of Knowledge, OvidSP and PubMed). We aimed to draw a clinical guideline addressed to the management of UTI, based on the most recent evidence.
Keywords: Urine infections, Bacteriuria, Cystitis, Management, Review.
In routine gynecological practice it is very common to be consulted for symptoms suggestive of urinary tract infection (UTI). Indeed UTI is the first and the second infection recorded in the hospital setting and in the social community, respectively. It has been estimated that over one third of the female population experiences at least one episode of UTI during their lifetime. Therefore we decided to review the available international literature in order to provide a practical clinical guideline for the management of UTI. For this purpose we decided to track the contents of this document through a schematic academic division.
2.1. Review criteria
A comprehensive literature review of published experimental and clinical studies on UTI was carried out at the University of Insubria with cross-search of seven different medical databases (Allied and Complementary Medicine Database (AMED), BIOSIS Previews on Web of Knowledge, Cochrane Library, Embase and Medline on Web of Knowledge, OvidSP and PubMed). Search temporal limits included papers published between January 1999 and October 2010 with the purpose of providing the most recent evidence regarding this issue. Studies were queried using the following keywords in various combinations: “urinary/urinary tract/urine”; “infection/infections/bacteriuria/cystitis”; and “treatment/recurrence/recurrent/children/female/women/pregnant/pregnancy/elderly/menopause/asymptomatic”.
Among the thousands of articles identified, we retrieved those manuscripts that were more relevant for the purpose of this review and provided results from case series and/or conceptual findings. If manuscripts were comparable for aim, their clinical relevance was scaled according to: originality, study design (meta-analyses vs. randomized vs. prospective vs. retrospective studies), the method used, the evidence level and the sample size. The journal relevance based on the actual impact factor score was used as ultimate criterion of choice, if needed. When the same authors published more than one paper on the same population only one study was included (the first or the most specific).
A further manual cross-search of the references of each selected article was finally performed in order to further identify studies not captured by the online search but potentially relevant for this review. Only articles published in English language were considered.
UTI are among the most common bacterial infections in women: it is estimated that the lifetime possibility of each woman developing a UTI is above 40–60%. UTI can involve the lower and/or the upper urinary tract . UTI can be schematically divided into different groups according to their characteristics, as follows:
- Asymptomatic bacteriuria: the presence of 100,000 colony-forming units (CFU)/mL in a woman without symptoms; if the patient is symptomatic, the presence of 100 CFU/mL is enough to diagnose bacteriuria.
- Acute urethral syndrome: symptoms of dysuria, frequency and/or pyuria without evidence of significant bacteriuria, often in association with vaginitis or urethritis.
- Cystitis: symptoms of dysuria, frequency and urgency and, sometimes, supraubic tenderness.
- Acute pyelonephritis: infection of renal parenchyma and pelvicalyceal system with bacteriuria, usually accompanied by fever and flank pain.
- Recurrent UTI (RUTI): symptomatic UTI that follows the resolution of a previous one. Also if the same bacteria of the first infection are isolated after adequate antibiotic therapy, it can be defined as relapse and is usually drug resistant. Otherwise a reinfection is diagnosed when a second infection is found after effective antibiotic therapy with a subsequent negative urine culture; it can be caused by the same bacteria during the first two weeks after treatment or by a different one  and is usually drug-susceptible. Most recurring episodes of cystourethritis are due to reinfection.
UTI is considered complicated when it is associated with symptoms of upper urinary tract infection or if it affects patients with compromised general conditions (including structural abnormalities of the urinary tract, previous pyelonephritis, symptoms lasting more than 14 days, diabetes, pregnancy, or immunosuppression). Episodes may be refractory to therapy, often resulting in relapses and occasionally leading to significant sequelae such as sepsis, metastatic abscesses and rarely acute renal failure.
4. Prevalence, epidemiology and costs
The prevalence of UTI is higher in women than in men: about 81% of UTI occurs in women, with a peak between 16 and 35 years. Approximately 27% of women with a first episode of UTI record a recurrence within 6 months, and 48% within the first year. Such infection causes about 6 days of disability per episode, with an increasing morbidity in the USA. UTI is responsible for about 15% of all antibiotic prescriptions in the community with more than 1.6 billion dollars spent every year. UTI results in nearly 7 million office visits, with additional 1 million visits to emergency rooms which result in over 100,000 hospitalizations every year in the USA alone  and .
5. Pathophysiology and microbiology
UTI usually arises from ascending infection from the urethra to the bladder, but occasionally it develops with haematogenous or lymphatic spread. Evidence suggests a sort of genetic predisposition to develop UTI; non-secretors of ABH blood-group antigens, especially in premenopausal women, are genetically determined factors which may predispose to the development of UTI  and . Similarly, a study conducted on mice evidenced the role of innate immunity which is modulated by variable expression of the chemokine receptor CXCR1, involved in the activation of neutrophils .
About 80–90% of UTI is caused by Escherichia coli. A randomized control trial showed that 77% of patients with RUTI had a relapse with the primary infecting E. coli strain and 23% had a reinfection with a different E. coli strain; a burgeoning opinion suggests that E. coli strains originate from a reservoir in the gastrointestinal flora with the hypothesis of a faecal–vaginal–periurethral route of infection; the phylogenetic groups B2 and D of E. coli derive predominantly from faecal strain and the virulence of B2 group is closely associated with faecal abundance, dominance and pauciclonality . The main mechanism of invasion of the uroepithelium seems to be related to the adhesion process mediated by the bacterial fimbria which allows E. coli to penetrate into the bladder epithelium cells. During the replication phase, bacteria produce intracellular niches, known as bacterial factories, that constitute a stable reservoir for bladder colonization. In this particular condition bacteria produce also a bio-film which provides an effective protection against the surrounding inflammatory agents  and . Experiments in vitro and in mice confirmed that treatment with mecillinam can eradicate E. coli in the urine without affecting the bladder reservoir, which can re-start the infection .
About 5–10% of UTI are caused by Staphylococcus saprophyticus, while long-lasting cases are caused by Proteus, Pseudomonas, Klebsiella and Enterobacter: these infections are quite uncommon and are associated with structural abnormalities of the urinary tract, indwelling catheters and renal calculi, whereas Streptococcus of group B is generally associated with fungal infection in hospitalized women  and .
6. Risk factors
Anatomic congenital abnormalities, urinary tract calculi, neurological disorders, diabetes, medical conditions determining indwelling or recurrent bladder catheterizations are the most frequent risk factors. Traumas to the pelvic floor also contribute to the development of UTI, as do multiparity and pelvic organ prolapse. In addition, in young women a number of other important risk factors for recurrent acute cystitis have been recognized, including recent history of UTI, young age at first UTI, frequent or recent sexual intercourse and spermicidal use, especially if in combination with diaphragm. Infrequent voiding, poor fluid intake and functional stool retention are also identified as behavioural abnormalities that facilitate UTI in younger women  and .
Lower UTI generally presents with dysuria, frequent and urgent micturition, sometimes associated with suprapubical pain or pressure and rarely with haematuria. Fever is uncommon and it is usually associated with complicated forms of UTI, as previously mentioned. The likelihood that the underlying condition of a woman presenting with these symptoms is a UTI is about 50% in primary care settings. This possibility rises to 84–92% when women complaining these symptoms have a history of RUTI.
Upper UTI occurs with flank pain radiating to the groin, associated with fever and chills. Upper UTI can be frequently found in association with lower UTI symptoms.
Elderly women with UTI are frequently asymptomatic, complaining only urinary incontinence. Septic shock (urosepsis) is unusual, but it may arise as the onset in the most neglected conditions. In postmenopausal women UTI can increase the urine loss occurrence in the immediate 3-day time period post-UTI .
Imaging studies and/or cystoscopy are mandatory if haematuria persists. However, the diagnosis of UTI, from simple cystitis to complicated pyelonephritis with sepsis, can be established with absolute certainty only by quantitative cultures of urine.
7.1. Laboratory evaluation
Bacteriuria is defined as the presence of 100,000 single isolate bacteria/mL collected by a clean-voided midstream urine sample. In young women with symptoms of cystitis the threshold for a positive urine culture can be lowered to 1000 bacteria/mL, raising the sensitivity and reducing the specificity.
Urine dipstick testing for leukocyte esterase, blood or nitrite is rapid and economic, with a sensitivity of 77% and specificity of 70%; its positive predictive value is 81% and its negative predictive value is 65%. Diagnosis is predicted by three variables independently: nitrite is more predictive for UTI, followed by leucocytes and presence of blood .
The gold standard for symptomatic treatment of uncomplicated acute cystitis is a three-day treatment  with trimethoprim–sulfamethoxazole, with a percentage of eradication rate of 90%. Ciprofloxacin, levofloxacin, norfloxacin and gatifloxacin give comparable eradication rates after 3 days of administration . This short-term treatment option achieves similar results to those obtained by prolonged therapies, and it reduces the number of adverse events and costs. Fosfomycin tromethamine can be used in a single dose, while nitrofurantoin monohydrate macrocrystals are given at seven-day treatment, twice daily.
A one-day therapy cures the 80–100% of young women with acute uncomplicated cystitis in the short-term period, but it results in a higher rate of RUTI in the long term: these data suggest that a single dose in not enough to eradicate completely the vaginal and periurethral reservoir of the infection. A seven-day antibiotic regimen might be used in a minority of women suffering with immunosuppressive conditions or planning pregnancy, prolonged symptoms (more than seven days), recent UTI and age above 65 years in order to achieve a complete bacterial eradication.
The management of acute pyelonephritis requires a 14-day treatment scheme of oral or parental antibiotics, with a percentage of eradication that rises up to 100%. Amoxicillin or amoxicillin combined with clavulanic acid might be useful. Patients who require admission to the hospital, however, should be treated initially with a third-generation cephalosporin or a fluoroquinolone and gentamicin. If no complications ensue, the remaining two-week course can be completed with oral therapy.
During treatment of RUTI, a 3-day therapy allows the relief of symptoms, but prolonged administration (five days or more) is suggested to achieve the complete eradication of the infection. For this reason bacteriological eradication with 7-day antibiotic administration should be considered as the gold standard for the management of RUTI in women .
In postmenopausal women a 3-day regimen has been suggested , as well as a local hormone supplementation.
More than 90% of women have symptom relief within 72 h after the beginning of antibiotic therapy. Resistance rate ranges are based on patient's age: younger women record higher rates of resistance of E. coli toward ampicillin and trimethoprim–sulfamethoxazole than the elderly (namely 45–31% vs. 39–14%). On the contrary the resistance rate for nitrofurantoin and fluoroquinolones is higher in the elderly than in adolescents (1,8–1.7% vs. 16–10%)  and . A resistance rate higher than 15–20% requires the choice of a different antibiotic class . Therefore, assessment of local resistance patterns is needed to guide empirical therapy.
8.1. Specific groups of treatment
UTI affects up to 10% of the childhood population. Compared with adults, young children are more likely to have anatomic abnormalities and/or vesicoureteral reflux predisposing them to have upper UTI. Otherwise, UTI are often identified in preverbal children, who are unable to distinguish and refer symptoms of infections. For these reasons the American Academy of Pediatrics recommended that infants and young children receive a 7- to 14-day antimicrobial course . These data have been also confirmed by a meta-analysis that compared short and long courses of antibiotic therapy for UTI in children, showing that a 7- to 14-day regimen allowed fewer treatment failures without a concomitant increase in reinfections . Moreover, asymptomatic bacteriuria in preschool and school-aged girls may signify underlying vesicoureteral reflux. Therefore, asymptomatic bacteriuria should routinely be detected and treated with follow-up urologic evaluation after six weeks.
8.1.2. Pregnancy and breastfeeding
Bacteriuria in early pregnancy should be regarded as uncomplicated UTI. Later in pregnancy hormonal effects lead to decreased autonomic muscle tone and stasis of the genitourinary tract, and therefore bacteriuria must be considered as complicated UTI. During pregnancy asymptomatic bacteriuria must be treated to reduce the risk of pyelonephritis and preterm delivery. Nitrofurantoin, β-lactam antimicrobials, including both penicillin and cephalosporins, and fosfomycin trometamol are considered safe also during pregnancy .
During breastfeeding trimethoprim and sulfamethoxazole can be used, but with caution in infants with known deficit of G6PD; nitrofurantoin, ciprofloxacin and ofloxacin are allowed during breastfeeding, even though available data in humans are still limited .
Women with diabetes record higher frequency of symptomatic UTI than the general population. Similarly, complicated UTI also with bilateral renal involvement are more frequently reported. Moreover, in diabetic patients under insulin regimen the risk of asymptomatic bacteriuria and UTI is three- and fourfold higher than the healthy counterpart, respectively.
A prospective randomized trial compared antimicrobial therapy with no antimicrobial therapy in women with diabetes and asymptomatic bacteriuria: no benefits were identified in the continuing screening vs. treatment strategy of asymptomatic bacteriuria; specific diabetes variables associated with symptomatic infections are neuropathy and glycosuria . Previous antimicrobial treatment and macrovascular complications are other reported risk factors .
8.1.4. Spinal cord injury (SCI), quadriplegics and high-level spinal cord injuries
Approximately 40% of patients with SCIs die as a consequence of renal-related conditions. E. coli remains a common uropathogen among SCI patients, in addition to Enterococci, Pseudomonas and Proteus mirabilis, which are frequently represented in the retrieved flora. Factors that increase susceptibility to UTI include: over-distension of the bladder, impaired voiding and increased incidence of renal stones. Similarly, quadriplegics and patients with high-level SCI are at higher risk of developing UTI because of the autonomic dysreflexia and the need for indwelling catheterization. Current evidence suggests 14-day of therapy for management of UTI.
UTIs are the most common nosocomial infection in the Intensive Care Unit settings, where patients predominantly need indwelling catheterization. In this particular condition it is extremely difficult differentiate asymptomatic bacteriuria from symptomatic UTIs that require catheter removal and specific antibiotic therapy, since multidrug resistance represents a significant problem. Targeted strategies for preventing catheter-associated UTI include limiting the use and duration of catheterization with particular attention to respecting aseptic technique for insertion . The empiric therapy of these infections is similar to complicated UTIs and patients who rapidly respond to the therapy may be treated only for seven days.
8.1.5. Intermittent catheterization
Intermittent catheterization is a crucial issue for healthcare of individuals with incomplete bladder emptying and it is a well-known cause of UTI. Catheterization is the most common source of nosocomial infection with a risk that proportionally increases with the number and duration of the procedures. Currently, evidence that catheter type, technique or strategy could prevent UTI is still lacking  and .
9.1. Sexual intercourse
For women who describe a clear relationship between sexual intercourse and subsequent cystitis, the use of post-coital prophylaxis can be worthwhile. Postcoital voiding does not prevent cystitis. In sexually active women who use vaginal spermicide or diaphragms with history of RUTI, alternative methods of contraception should be suggested.
9.2. Low-dose antibiotic treatment
In women complaining of ≥2 UTI during a 6-month period or ≥3 infections over a 12-month period, prophylaxis with low-dose antibiotics once a day can be used, reducing 95% of recurrences. Suggested antimicrobial agents are nitrofurantoin, norfloxacin, ciprofloxacin, trimethoprim and trimethoprim–sulfamethoxazole, continued for 6–12 months. Low dose trimethoprim–sulfamethoxazole, as little as half a tablet (trimethoprim 40 mg, sulfamethoxazole 200 mg) three times weekly at bed-time, is associated with an infection frequency of less than 0.2 per patient year  and .
Lactobacilli are probiotics, which are defined as living microorganisms that confer a health benefit to the host. Probiotics seem to prevent the colonization of pathogens of the vagina and bladder. Lactobacilli produce antimicrobial compounds such as lactic acid, bacteriocins and hydrogen peroxide that are toxic to many microorganisms at vaginal concentrations. In addition lactobacilli produce a bio surfactant that inhibits the adhesion of uropathogens to the surface of cells and seems to contribute to a non-specific augmentation of the innate immune response  and .
The use of Lactobacillus in vaginal suppositories has been tested in the prevention of RUTI. A pilot study carried out with suppositories containing Lactobacillus crispatus GAI 98332 demonstrates a significant reduction of RUTI after a 12-month treatment . Otherwise the vaginal instillation of Lactobacilli induces a mild inflammatory response in the bladder and vaginal mucosa, sometimes causing vaginal discharge followed by external genital irritation and vaginal candidiasis . The role of lactobacilli for the prophylaxis of UTI needs further investigations, however, as stated in a recent review .
9.4. Dietary factors, cranberry and lingonberry
Berries such as cranberry and lingonberry contain proanthocyanidins, tannins able to prevent the expression of the P fimbriae of E. coli, inhibiting bacterial cell wall synthesis and cellular expression of adhesion molecules. The block of the E. coli's fimbriae has a key-role for the prevention of colonization although these effects are dose-dependent . A randomized trial concluded that a daily dose of 50 mL of cranberry/lingonberry juice concentrate for six months can significantly reduce the risk of RUTI . Similarly another randomized controlled pilot study compared the effects of daily cranberry juice to those of placebo in pregnant women over 16 weeks of gestation, suggesting a protective effect of cranberry administration against symptomatic UTI and bacteriuria, although the therapy compliance of pregnant women could in part limit these findings .
A Cochrane review of 2008 identified 10 studies on the use of cranberries to prevent UTI and highlighted that cranberries are effective for the prevention of RUTI, especially in young sexually active women .
A randomized control trial including women aged >45 years compared the use of 100 mg of trimethoprim vs. 500 mg of cranberry extract, concluding that antibiotic treatment provided only limited advantages over cranberry extract with more adverse events . Dietary factors can contribute to prevent UTI in fertile women: the consumption of fresh juice, especially berry juice, and fermented milk products containing probiotic bacteria can decrease RUTI. On the contrary neither association was demonstrated with the consumption of coffee, tea or soft drinks nor with vitamins implementation or volume of daily fluid intake .
9.5. Oestrogen deficiency
Oestrogen therapy has been shown to increase vaginal pH and to reverse the microbiological changes that occur in the vaginal environment during the menopausal period. After the menopause oestrogen deficiency causes atrophic changes within the urogenital tract that are usually associated with urinary symptoms, such as frequency, urgency, nocturia, urinary incontinence and RUTI. In a randomized trial, 72 postmenopausal women with RUTI were assigned to oral oestriol vs. placebo; after six months of treatment no differences were found between the groups in terms of frequency of RUTI. Another randomized trial, which included 2763 women, compared the effect of a 4-year treatment with conjugated oestrogens plus medroxypregesterone acetate vs. placebo: this study concluded that hormonal replacement therapy did not affect outcomes in terms of frequency of UTI . On the contrary, a different randomized placebo-controlled trial showed that an estradiol-releasing silicone vaginal ring in postmenopausal women with history of RUTI is an effective option since it decreased the number of annual recurrences of UTI and prolonged intervals between infections episodes . These findings have been confirmed by other papers that recorded reduction of RUTI after the vaginal administration of oestrogen , , and .
9.6. Immunoactive prophylaxis
An increasing number of papers are currently highlighting the advantages offered by bacterial lysates. The biologic rationale of these therapies is that the administration of bacterial lysates should diminish susceptibility toward infections (including RUTI), enhancing the host's defences. A meta-analysis on this subject showed that the administration of an oral immunostimulant (OM-89) reduces the rate of RUTI by 36% . These data have been also confirmed by a double blind randomized study reporting the efficacy of a multivalent bacterial vaccine of mucosal immunogens in women (from late teens to early 70s) in reducing RUTI . Many other vaccines are currently being tested on animals.
Conflicts of interest
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a Department of Obstetrics and Gynecology, University of Insubria, Varese, Italy
b Department of Pediatrics, University of Insubria, Varese, Italy
c Department of Gynecology, IRCCS, Humanitas Clinical Institute, Rozzano, Milano, Italy
d Department of Obstetrics and Gynecology, 2nd Faculty, Naples, Italy
⁎ Corresponding author at: Department of Obstetrics and Gynaecology, University of Insubria, “Del Ponte” Hospital, Piazza Biroldi 1, 21100 Varese, Italy. Tel.: +39 0332 299 309; fax: +39 0332 299 307.
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