Urinary tract infections (UTIs) are one of the most common clinical problems worldwide and can result in significant morbidity. They affect 50% of adult women in their lifetime and 25% to 30% will have a recurrent infection.¹ The prevalence of UTI increases with age affecting 1% of female infants, 3% to 5% of adult women, and up to 50% of elderly men and women.² It is the single most common cause of nosocomial infection associated with the use of indwelling catheters and can result in life-threatening sepsis.^3,4 Worldwide, it is estimated that 150 million cases occur per year⁵ presenting a huge burden on health care resources.

A UTI is defined as inflammation of the urinary tract due to microbial invasion of the urinary tract that presents as a number of clinical syndromes including cystitis, pyelonephritis, and urethritis. In this chapter we cover asymptomatic bacteriuria (ASB), urethritis, cystitis, pyelonephritis, and to a limited extent sexually transmitted diseases (STDs).

Definitions: Bacteria may be present in the urinary tract without associated inflammation and this is termed ASB. Urethritis is inflammation of the urethra for which there are a wide variety of causes including microbial invasion (eg, STDs), trauma, fungal infection, and allergy. Cystitis and pyelonephritis are inflammations of the bladder and renal parenchyma, respectively, and are most frequently, but not always, caused by microbial invasion (usually by bacteria) (Table 17-1). Most infections are sporadic, occur in patients without identified comorbidities or anatomical abnormalities of the urinary tract, and involve the lower urinary tract. In the 25% to 30% of women who develop UTI recurrence most cases are unrelated to an underlying anatomical or functional abnormality.^1,6 A complicated UTI is a UTI associated with functional or anatomical abnormalities of the urinary tract that increase the risk of serious complications or treatment failure, such as conditions that cause obstruction or relative stasis of urinary flow.

Natural History

In children up to one year of age 1.1% of girls and 1.2% of boys may suffer a symptomatic UTI. In school-age children a UTI has been reported in 8% of girls and 2% of boys.⁷ UTI in the neonate should be considered to be secondary to an underlying anatomical abnormality until proven otherwise.⁸ The sequelae of UTI in neonates and young children include pyelonephritis and renal scarring especially if infection has occurred before the age of five years; therefore, a thorough assessment is required in this age group. Vesicoureteric reflux is a significant etiological factor in the occurrence of UTI in the young.

Each year approximately 5% of women will present to their general practitioners with dysuria and frequency⁵ and approximately half will have a UTI. The incidence of UTIs is more common in females than in males; it increases in females with age and with the onset of sexual activity.

In the elderly, UTI prevalence is as high as 50% especially in those who are institutionalized.⁹ In part, this high prevalence probably reflects comorbidities such as diabetes and the prevalence of risk factors such as urinary catheters.

In young women a UTI can present as ASB, cystitis, or pyelonephritis. The incidence of ASB in nonpregnant women is 4%–7%.¹⁰ In pregnancy, the risk of developing a symptomatic UTI is much higher and 10% to 30% of women with ASB develop pyelonephritis. UTI during pregnancy has been associated with an increased risk of prematurity, perinatal mortality, and perinatal complications.¹¹

Microbiology

The majority of UTIs are caused by facultative bacteria and occasionally by fungi and viruses. These tend to originate from the gastrointestinal tract and ascend into the genitourinary system. Escherichia coli is the commonest organism and accounts for up to 70% of community-acquired infections.¹² It is now recognized that the E. coli infection may not be of a single strain but of a number of subtypes of which subtypes 01, 02, 04, 06, 07, and 075 are the most common agents causing infection. The remainder of bacterial infections are predominantly caused by Staphylococcus saprophyticus, and a variety of gram-negative rods within the genus enterobacteriaceae. In hospital settings, approximately 50% of UTIs are caused by E. coli, 15% by Enterococcus, and the remainder by members of the enterobacteriaceae, Pseudomonas, Staphylococcus, and yeasts.¹³ Hospital-acquired UTIs are frequently associated with iatrogenic risk factors such as instrumentation, and also with patient comorbidities. Antibiotic resistance is a growing problem and more likely to complicate hospital-acquired UTI. A number of sexually transmitted organisms such as Chlamydia trachomatis and herpes can colonize the urinary tract causing symptoms of cystitis.

Pathogenesis

There are a number of host, iatrogenic, and bacterial factors that contribute to the pathogenesis of UTI. Foreign bodies such as urinary catheters are a major risk factor for infection through mechanisms that include urethral trauma, compromise of local immunity, and by providing protected niche(s) for microbial proliferation and a surface for biofilm production.

Bacterial Virulence Factors

The ability of bacteria to adhere to uroepithelial cells is a prerequisite for infection to occur. This adherence reduces the chance of the bacteria being cleared from the urinary tract during voiding. There are various factors that promote adhesion, called adhesins; E. coli possess surface organelles called pili that act as adhesins. These adhesins attach to complementary structures on the uroepithelial cell wall and act not only to promote infection but also to help promote growth and toxin production.¹⁴ There are many different types of adhesions such as type four pili, outer membrane proteins, curli, filamentous hemagglutinins, and adhesive pili. Other virulence factors that may facilitate infection are specific to each pathogen. These include the surface antigens on E. coli and hemolysins that are produced to help degrade cells and aerobactins that enhance iron uptake that encourages E. coli growth.

Much of our understanding of UTI comes from the study of uropathogenic E. coli (UPEC). The type of pili of the different strains of UPEC may determine the site of disease in the urinary tract as they have specific cell affinity.¹⁵ The virulence of UPEC has been attributed mainly to the presence of type one fimbriae, a mannose-binding adhesion protein called FimH.¹⁶ Another pathogenic mechanism is the development of intracellular UPEC pods that act as a reservoir for infection.¹⁷ These pods contain bacteria that are encased in a polysaccharide matrix and protected by a uroplakin coating that helps evade host defense mechanisms and antimicrobials. This then invades cells to develop intracellular bacterial communities (IBCs). This reservoir can then serve as a pool of bacteria that may reinitiate infection. The formation of IBC together with evasion of the immune system contributes to bacterial resistance to therapy: IBCs have been seen in the urine of women with acute and recurrent UTI.¹⁸

Host Factors

Regular voiding flushes the urinary tract of pathogens and the inherent acidity of urine inhibits bacterial growth. A healthy vaginal flora is also important in reducing infection. Changes in vaginal flora can affect UTI prevalence as seen after the menopause when the risk of UTI increases. The vaginal flora is predominantly lactobacilli and this maintains an acidic pH in the vagina. Periurethral lactobacilli and uromucoid in the urine are thought to interfere with bacterial adherence and colonization of the lower urinary tract. It is also thought that the composition of the vaginal flora is important as it provides a continuous microbial stimulus to the host immune system such that it is primed to respond to pathogens. In women with recurrent UTI, vaginal flora has reduced Lactobacillus composition.¹⁹ The glycosaminoglycans layer of the bladder also serves as a protective layer preventing bacterial adherence.

Examples of host factors that increase the risk of infection include impaired bladder emptying, urethral trauma, foreign bodies, pelvic tumors, glycosuria, genetic factors, hypoestrogenic states, sexual intercourse, and use of spermicides (Table 17-2). Impaired bladder emptying can occur with neurogenic disorders such as diabetes, multiple sclerosis, cerebrovascular events, and anatomical abnormalities. Anticholinergic drugs and prior anti-incontinence surgeries may also impair bladder emptying. Significant vaginal prolapse can lead to impaired emptying as the urethra is kinked. Urethral trauma can occur after catheterization or surgery to the urethra.

Foreign bodies such as catheters and stones increase the risk of infection as they are a focus for infection. Pelvic tumors and inflammatory bowel disorders may directly invade the bladder and affect bladder emptying. Glycosuria that occurs in diabetes mellitus is a potent culture medium for bacterial growth.

Genetic factors have been postulated to increase the risk of recurrent infection.

Women with recurrent infection are more likely to be nonsecretors of histo-blood group antigens and E. coli is found to adhere better to uroepithelial cells of nonsecretors than of secretors.^20,21 Further evidence for a genetic susceptibility is that female members of families with women with recurrent UTI are more likely to suffer from UTI as an adult.²² There is also some work suggesting a defect in innate immune deficiency in those prone to acute pyelonephritis.²³

In menopausal women, lack of estrogen reduces Lactobacillus growth and, with the rise in vaginal pH, leads to a predisposition to growth of enterobacteria.²⁴ Sexual intercourse and specific types of contraception are strongly associated with the onset of UTIs.^6,25 Sexual intercourse not only results in trauma and disruption to the uroepithelial cells but may also introduce rectal and vaginal bacteria into the urethra. The odds ratio for a UTI is increased by 60 times in a woman who has had sex in the previous 48 hours over a woman who has not.²⁶ The use of spermicides with diaphragms is an additional risk factor as it alters vaginal flora, increases vaginal pH, and decreases lactobacilli concentration, promoting colonization with E. coli. This association is seen across all ages including the postmenopausal woman.²⁷

In addition to all the above factors, there is also a well-developed and effective innate and adaptive host response to bacterial invasion. The mucosal lining of the urinary tract has a number of immune surveillance molecules that function to recognize invading pathogens. The best characterized of these surveillance molecules is the Toll-like receptor (TLR) family.^28-30 There are 11 TLR of which the TLR4 is the most well characterized and is present on the epithelial cells of the bladder and kidney. These receptors function to initiate appropriate host immune defenses when triggered by a pathogen and promote cytokine and chemokine responses to gram-negative pathogens. TLR4 responses can still occur even once intracellular bacterial invasion has occurred helping to fight infection. The importance of this host-mediated immunity can be seen in women with recurrent UTI who have defective T-cell activation and a lower concentration of tissue repair–associated vascular endothelial growth.¹⁹

Management

Clinical management of UTI varies widely and often treatment is initiated on clinical diagnosis alone. In general, a careful history and examination should identify complicated from uncomplicated infections. In those with uncomplicated infections, antibiotics are often used empirically on the basis of a history and urinalysis only. In 62% of women with symptoms of a UTI, UTI diagnosis is confirmed in the laboratory.³¹ Although a number of clinical algorithms have been developed, the cost-effectiveness of these is unclear.³² Please see Table 17-3 for conditions associated with complicated UTIs.

The clinical history is the first important step in UTI management and can identify any predisposing features such as recent UTI, recent urinary tract operations, recent sexual intercourse, and the use of the contraceptive diaphragm and condom. Poor bladder emptying secondary to neurological disorders or the use of anticholinergic therapy, pregnancy, the presence of pelvic tumors, and diabetes mellitus may also predispose to infection.

Clinical examination should include a general systemic examination especially if the patient is febrile. Examination of the costovertebral angles is required to elicit signs of pyelonephritis. If a neuropathy is suspected, a neurological examination of the S2–S4 nerve roots should be performed, assessing for sensation around the buttocks. A gynecological examination should be done to exclude residual urine, a pelvic mass, or pregnancy. Differential diagnoses include detrusor overactivity, cystitis, bladder stones or tumors, ovarian torsion or cysts, ectopic pregnancy, and miscarriage.

There is no recognized commensal microbial colonization of the bladder, ureters, or renal pelvis, so urine samples collected directly from these sites from asymptomatic individuals would be expected to be sterile. Urine passed through the urethra always contains some bacteria derived from the terminal urethra. Significant bacteriuria is defined by the culture of increased numbers of bacterial colony-forming units (cfu) from a sample of urine. The absolute number needed to define significant bacteriuria depends on the sample type. The threshold of >10⁵ bacterial cfu/mL has been a standard for the definition of significant bacteriuria using carefully collected midstream urine (MSU) since the 1950s.³³ A significant proportion of patients with UTI (particularly with Staphylococcus spp.) will have <10⁵/mL. Current recommendations suggest >10³ cfu/mL for a diagnosis of cystitis and >10⁴ cfu/mL for a diagnosis of pyelonephritis.³⁴ ASB is defined as the presence of >10⁵ bacterial cfu/mL in two MSU samples in the absence of symptoms.³⁵ An important consideration with these diagnostic criteria is that they rely on the careful collection of the MSU. This requires that care is taken in the instruction patients are given to ensure that samples are collected carefully. Prior to an MSU sample, the periurethral area should be cleaned and a midstream sample taken. Bacteriuria is common in association with any long-term catheter use and is not by itself an indication for treatment of UTI.

Presentation

A UTI may present as an ASB, acute cystitis, or more seriously as acute pyelonephritis, bacteremia, and renal failure. The classic symptoms of acute cystitis include dysuria, frequency, urgency, and suprapubic pain. If the upper urinary tract is involved, hematuria, flank pain, and fever may also occur. In children and the elderly the classic clinical features of a UTI may not be present. In young children clinical features of a UTI may be nonspecific such as failure to thrive or abdominal pain. In the elderly, UTIs can often be asymptomatic but can present as confusion and general malaise.

In cases of acute cystitis or urethritis there is often suprapubic tenderness and occasionally fever. The clinical presentation of acute pyelonephritis is often much more florid, the patient often looking unwell with a pyrexia and tachycardia. There is usually flank tenderness and if severe, features of septicemia may be present. In young children and the elderly clinical signs may be nonspecific and atypical in nature.

Investigations should be aimed to help select appropriate treatment and to exclude any underlying cause that may predispose to recurrence.³⁶

Urinalysis

Freshly voided urine may be cloudy if it contains large numbers of cells (eg, bacteria, red or white blood cells). Urine that has been allowed to stand may also become cloudy as a result of the formation of crystals as the urine cools.

Commercial stick tests are available for detection of various urinary components and are inexpensive. The tests that are most useful are those for the detection of white blood cell leucocyte esterase and nitrites (formed from the conversion of urinary nitrate by bacteria). A clear freshly voided urine with negative nitrite and leucocyte tests indicates that UTI is unlikely (a high negative predictive value). The stick tests are not reliable to exclude ASB, when the patient has recently received antibiotics, in the immunocompromised, if there are delays in testing the urine, or if the numbers of bacteria are <10⁵ bacterial cfu/mL.³⁷ Patients with suspected UTI should be treated empirically and promptly even with negative stick test results. In pregnancy, in the immunocompromised, in those with complicated infections, and where previous empirical therapy has failed, it is imperative that urine culture is performed and treatment commenced if symptoms are present even if the urinalysis is negative.

Urine Microscopy and Culture

Urine culture has traditionally been the gold standard for the diagnosis of UTI. The quantitative criteria for diagnosis of bacteriuria or infection require that the sample is carefully collected and ideally cultured within 24 hours. If a catheter is in place, the sample should be taken by syringe aspiration or via a drainage port. Urine samples can be stored overnight at 4°C. Borate can be used as a preservative but if used it is important that the container be filled to the correct level to ensure that the borate concentration is within the correct range to act as a preservative rather than as a disinfectant.