Urinary Tract Infections (uncomplicated)  in Women - Diagnosis

INTRODUCTION

Epidemiology of Urinary Tract Infections

               Urinary tract infections (UTIs) are among the most prevalent infectious diseases with a substantial financial burden on society. In the USA, UTIs are responsible for over 7 million physician visits annually, including more than 2 million visits for cystitis. Approximately 15% of all community-prescribed antibiotics in the USA are dispensed for UTI, at an estimated annual cost of over US $1 billion. Furthermore, the direct and indirect costs associated with community-acquired UTIs in the USA alone exceed an estimated US $1.6 billion. Urinary tract infections account for more than 100,000 hospital admissions annually, most often for pyelonephritis. They also account for at least 40% of all hospital-acquired infections and are in the majority of cases catheter-associated. Nosocomial bacteriuria develops in up to 25% of patients requiring a urinary catheter for > 7 days, with a daily risk of 5%. It has been estimated that an episode of nosocomial bacteriuria adds US $500-1,000 to the direct cost of acute-care hospitalization. In addition, the pathogens are fully exposed to the nosocomial environment, including selective pressure by antibiotic or antiseptic substances. Nosocomial UTIs therefore comprise perhaps the largest institutional reservoir of nosocomial antibiotic-resistant pathogens.

Pathogenesis of Urinary Tract Infections

               Micro-organisms can reach the urinary tract by haematogenous or lymphatic spread, but there is abundant clinical and experimental evidence to show that the ascent of micro-organisms from the urethra is the most common pathway leading to a UTI, especially organisms of enteric origin (i.e. Escherichia coli and other Enterobacteriaceae). This provides a logical explanation for the greater frequency of UTIs in women than in men and for the increased risk of infection following bladder catheterization or instrumentation. A single insertion of a catheter into the urinary bladder in ambulatory patients results in urinary infection in 1-2% of cases. Indwelling catheters with open-drainage systems result in bacteriuria in almost 100% of cases within 3-4 days. The use of a closed-drainage system, including a valve preventing retrograde flow, delays the onset of infection, but ultimately does not prevent it. It is thought that bacteria migrate within the mucopurulent space between the urethra and catheter, and that this leads to the development of bacteriuria in almost all patients within about 4 weeks.

               Haematogenous infection of the urinary tract is restricted to a few relatively uncommon microbes, such as Staphylococcus aureus, Candida spp., Salmonella spp. and Mycobacterium tuberculosis, which cause primary infections elsewhere in the body. Candida albicans readily causes a clinical UTI via the haematogenous route, but is also an infrequent cause of an ascending infection if an indwelling catheter is present or following antibiotic therapy. The concept of bacterial virulence or pathogenicity in the urinary tract infers that not all bacterial species are equally capable of inducing infection. The more compromised the natural defence mechanisms (e.g. obstruction, bladder catheterization), the fewer the virulence requirements of any bacterial strain to induce infection. This is supported by the well-documented in-vitro observation that bacteria isolated from patients with a complicated UTI frequently fail to express virulence factors. The virulence concept also suggests that certain bacterial strains within a species are uniquely equipped with specialized virulence factors, e.g. different types of pili, which facilitate the ascent of bacteria from the faecal flora, introitus vaginae or periurethral area up the urethra into the bladder, or, less frequently, allow the organisms to reach the kidneys to induce systemic inflammation.

DIAGNOSIS

General Microbiological and Other Laboratory Findings (seeTable below)

               The number of bacteria is considered relevant for the diagnosis of a UTI. In 1960, Kass developed the concept of ’significant‘ bacteriuria (≥ 105 cfu) in the context of pyelonephritis in pregnancy. Although this concept introduced quantitative microbiology into the diagnostics of infectious diseases and is therefore still of general importance, it has recently become clear that there is no fixed number of significant bacteriuria, which can be applied to all kinds of UTIs and in all circumstances. The following bacterial counts are clinically relevant:

• ≥ 103 colony-forming units (cfu) of uropathogen/mL of a mid-stream sample of urine in acute uncomplicated cystitis in a woman

• ≥ 104 cfu uropathogen/mL of mid-stream sample of urine in acute uncomplicated pyelonephritis in a woman

• ≥ 105 cfu uropathogen/mL of mid-stream sample of urine in a woman, or ≥ 104 cfu uropathogen/mL of mid-stream sample of urine in a man or in straight catheter urine in women in a complicated UTI.

               In a suprapubic bladder puncture specimen, any count of bacteria is relevant. Asymptomatic bacteriuria is diagnosed if two cultures of the same bacterial strain (in most cases the species only is available) taken ≥ 24 hours apart show bacteriuria of ≥ 105 cfu uropathogen/mL.

               In clinical routine assessment, a number of basic criteria must be looked at before a diagnosis can be established, including:

• clinical symptoms

• results of selected laboratory tests (blood, urine)

• evidence of the presence of microbes by culturing or other specific tests.

Table. Criteria for The Diagnosis of A UTI, as Modified According to IDSA/ESCMID Guidelines.

Category

Description

Clinical features

Laboratory Investigations

1

Acute uncomplicated UTI Dysuria, in women; acute uncomplicated cystitis in women

urgency, frequency, suprapubic pain, no urinary symptoms in 4 weeks before this episode

≥ 10 WBC/mm3

≥ 103 cfu/mL*

2

Acute uncomplicated Fever, pyelonephritis

chills, flank pain; other diagnoses excluded; no history or clinical evidence of urological abnormalities (ultrasonography, radiography)

≥ 10 WBC/mm3

≥ 104 cfu/mL*

3

Complicated UTI

Any combination of symptoms from categories 1 and 2 above; one or more factors associated with a complicated UTI (see text)

≥ 10 WBC/mm3

≥ 105 cfu/mL* in women

≥ 104 cfu/mL* in men,

or in straight catheter urine in women

4

Asymptomatic bacteriuria

No urinary symptoms

≥ 10 WBC/mm3

≥ 105 cfu/mL* in two consecutive MSU cultures

≥ 24 hours apart

5

Recurrent UTI (antimicrobial prophylaxis)

At least three episodes of  uncomplicated infection documented by culture in last 12 months: women only; no structural/functional abnormalities

< 103 cfu/mL*

MSU = mid-stream sample of urine; UTI = urinary tract infection; WBC = white blood cells. All pyuria counts refer to unspun urine. *Uropathogen in MSU culture.

Acute Uncomplicated Cystitis in Pre-menopausal, Non-pregnant Women

               At this stage in life, the incidence of acute uncomplicated cystitis is high and this infection is associated with considerable morbidity. Therefore, even small improvements in diagnostics, therapy or prophylaxis have a high impact on public health.

     Incidence, Risk Factors, Morbidity

               A prospective study at a university health centre or a health maintenance organization (HMO) revealed an incidence of 0.7 per person-year in the university cohort and 0.5 per person-year in the HMO cohort. Cohort and case control studies in young women showed that the risk is strongly and independently associated with recent sexual intercourse, recent use of diaphragm with spermicide, preceding asymptomatic bacteriuria, a history of recurrent UTI, the age of first UTI and history of UTI in the mother. On average, each episode of this type of UTI in pre-menopausal women was shown to be associated with 6.1 days of symptoms, 2.4 days of restricted activity, 1.2 days in which they were not able to attend classes or work and 0.4 days in bed.

     Diagnosis

               A non-pregnant pre-menopausal woman presenting with acute dysuria usually has one of three types of infection:

• acute cystitis

• acute urethritis, caused by Chlamydia trachomatis, Neisseria gonorrhoeae, or herpes simplex virus

• vaginitis caused by Candida spp. or Trichomonas vaginalis.

             Acute cystitis is more likely if the woman complains of urgency and suprapubic pain; has suprapubic tenderness; is a diaphragm-spermicide user; has symptoms that mimic those of previously confirmed cystitis; or has recently undergone urethral instrumentation. Although approximately 40% of women with cystitis have haematuria, this is not a predictor of a complicated infection. Urethritis caused by N. gonorrhoeae or C. trachomatis is relatively more likely if a women has had a new sexual partner in the past few weeks or if her sexual partner has urethral symptoms; there is a past history of a sexually transmitted disease (STD); symptoms were of gradual onset over several weeks and there are accompanying vaginal symptoms such as vaginal discharge or odour. Vaginitis is suggested by the presence of vaginal discharge or odour, pruritus, dyspareunia, external dysuria and no increased frequency or urgency.

             Urinalysis (e.g. using a dipstick method) to look for pyuria, haematuria and nitrites is indicated if a UTI is suspected. Pyuria is present in almost all women with an acutely symptomatic UTI and in most women with urethritis caused by N. gonorrhoeae or C. trachomatis; its absence strongly suggests an alternative diagnosis. The definitive diagnosis of a UTI is made in the presence of significant bacteriuria, the definition of which remains somewhat controversial. The traditional standard for significant bacteriuria is ≥ 105 cfu uropathogen/mL in voided mid-stream sample of urine, based on studies of women with acute pyelonephritis and asymptomatic bacteriuria that were carried out four decades ago. Several more recent studies have shown that this is an insensitive standard when applied to acutely symptomatic women and that approximately one-third to one-half of cases of acute cystitis have bacteriuria < 105 cfu/mL. For practical purposes, colony counts ≥ 103 cfu/mL should be used for the diagnosis of acute uncomplicated cystitis (see the Table above). Sterile pyuria is defined as the presence of leukocytes without bacteria.The determination of a urine culture is generally not necessary in women with uncomplicated cystitis because the causative organisms and their antimicrobial susceptibility profiles are predictable. Also, culture results become available only after the patient’s symptoms have resolved or are considerably improved. Voided mid-stream sample of urine or straight catheter (by trained urological personnel) urine cultures should probably be performed if the patient’s symptoms are not characteristic of a UTI. The laboratory must be instructed to look for ‘low count’ bacteriuria if such UTIs are to be detected. A pelvic examination is indicated if any of the factors suggesting urethritis or vaginitis listed above are present or if there is doubt as to the diagnosis. A pelvic examination should include a careful evaluation for evidence of vaginitis, urethral discharge, or herpetic ulcerations; a cervical examination for evidence of cervicitis and cervical and urethral cultures for N. gonorrhoeae and C. trachomatis (or other sensitive and specific tests in first-voided urine in the morning, such as polymerase chain reaction tests).

Acute Uncomplicated Pyelonephritis in Non-pregnant, Pre-menopausal Women

     Diagnosis

             Urinalysis is indicated to look for pyuria and haematuria. In contrast to cystitis, 80-95% of episodes of pyelonephritis are associated with > 105 cfu uropathogen/mL. For routine diagnosis, a breakpoint of 104 cfu/mL can be recommended. An evaluation of the upper urinary tract with ultrasound should be performed to rule out urinary obstruction. Additional investigations, such as an unenhanced helical computed tomography (to rule out urolithiasis), an excretory urogram or DMSA scan, according to the clinical situation should be considered if the patient remains febrile after 72 hours of treatment to rule out further complicating factors, e.g. urolithiasis, renal or perinephric abscesses. Routine performance of an excretory urogram in patients with acute uncomplicated pyelonephritis has little value because most adults with uncomplicated acute pyelonephritis have a normal upper urinary tract.

Recurrent (uncomplicated) UTIs in Women

    Background

               Recurrent urinary tract infection is defined in the literature by three episodes of UTI in the last 12 months or two episodes in the last 6 months. Risk factors for recurrent urinary tract infection are genetic and behavioural. Some studies estimate that 20-30% of women who have a UTI will have a recurrent urinary tract infection. Women who are non-secretors of blood group substances have an increased occurrence of recurrent urinary tract infection. A secretor is defined as a person who secretes their blood type antigens into body fluids and secretions, such as saliva, etc. A non-secretor on the other hand puts little to none of their blood type antigens into these fluids. In the USA about 20% of the population are non-secretors. Women with recurrent urinary tract infection have an increased frequency of urinary infection in first-degree female relatives. In addition, E. coli, the most common uropathogen, adheres more readily to epithelial cells in women who experience recurrent urinary tract infection. Behavioural factors associated with recurrent urinary tract infection include sexual activity, with a particularly high risk in those who use spermicides as a birth control method. According to cohort and case control studies, risk factors associated with recurrent urinary tract infection in sexually active premenopausal women are frequency of sexual intercourse, spermicide use, age of first UTI (less than 15 years of age indicates a greater risk of recurrent urinary tract infection) and history of UTI in the mother, suggesting that genetic factors and/or long-term environmental exposures might predispose to this condition. Following the menopause, risk factors strongly associated with recurrent urinary tract infection are vesical prolapse, incontinence and post-voiding residual urine. Other risk factors such as blood group substance non-secretor status and a history of UTI before the menopause need to be confirmed by further research.

               Recurrent UTIs result in significant discomfort for women and have a high impact on ambulatory health care costs as a result of outpatient visits, diagnostic tests and prescriptions. Different approaches have been proposed for the prevention of recurrent urinary tract infection, including non-pharmacological therapies, such as voiding after sexual intercourse or the ingestion of cranberry juice, and the use of antibiotics as preventive therapy given regularly or postcoital prophylaxis in sexually active women.

               With respect to antibiotic prophylaxis, it is not known which antibiotic schedule is best or the optimal duration of prophylaxis, the incidence of adverse events, or the recurrence of infections after stopped prophylaxis or treatment compliance.

UTIs in Post-menopausal Women

               The normal vagina contains only low numbers of Gram-negative enteric bacteria because of competition from the resident microbial flora. Lactobacilli account for the low vaginal pH. They tend to be less abundant in postmenopausal women and after antimicrobial therapy. Oestrogens are presumed to exert a protective force against recurrent UTIs in post-menopausal women because they enhance the growth of lactobacilli and decrease vaginal pH. Gram-negative enteric bacteria do not ordinarily colonize the vagina in postmenopausal women unless these women are prone to recurrent UTIs. In post-menopausal women with recurrent UTIs, therapy with oral or intravaginal oestriol reduced significantly the rate of recurrence. For other patients, an antimicrobial prophylactic regimen should be recommended in addition to hormonal treatment. In the case of an acute UTI, the antimicrobial treatment policy is similar to that in pre-menopausal women. Short-term therapy in post-menopausal women is not, however, as well documented as in younger women.