The urinary tract consists of the kidneys, ureters, bladder, and urethra (Figure 73-1). The function of the urinary tract is to make and process urine. Urine is an ultrafiltrate of blood that consists mostly of water but also contains nitrogenous wastes, sodium, potassium, chloride, and other analytes. Urine is normally a sterile fluid, Often, urinary tract infections (UTIs) are characterized as being either upper (U-UTI) or lower (L-UTI) based primarily on the anatomic location of the infection: the lower urinary tract encompasses the bladder and urethra, and the upper urinary tract encompasses the ureters and kidneys. Upper urinary tract infections affect the ureters (ureteritis) or the renal parenchyma (pyelonephritis). Lower urinary tract infections may affect the urethra (urethritis), the bladder (cystitis), or the prostate in males (prostatitis).

Figure 73-1 Overview of the anatomy of the urinary tract. (From Potter PH, Perry AG: *Fundamentals of nursing,* St. Louis, 1985, Mosby.)

The anatomy of the female urethra is of particular importance to the pathogenesis of UTIs. The female urethra is relatively short compared with the male urethra and also lies in close proximity to the warm, moist, perirectal region, which is teeming with microorganisms. Because of the shorter urethra, bacteria can reach the bladder more easily in the female host, thus urinary tract infections are primarily a disorder of women. For men, the incidence of urinary tract infections increases after the age of 60, when the enlargement of the prostate interferes with the removal of urine from the bladder.

Resident Microorganisms of the Urinary Tract

The urethra has resident microflora that colonize its epithelium in the distal portion; these organisms are lactobacilli, corynebacteria, and coagulase-negative staphylococci (Box 73-1). Potential pathogens, including gram-negative aerobic bacilli (primarily Enterobacteriaceae) and occasional yeasts, are also present as transient colonizers. All areas of the urinary tract above the urethra in a healthy human are sterile. Urine is typically sterile, but noninvasive methods for collecting urine must rely on a specimen that has passed through a contaminated milieu. Therefore, quantitative cultures for the diagnosis of UTIs have been used to discriminate among contamination, colonization, and infection.

Infections of the Urinary Tract

Epidemiology

UTIs are among the most common bacterial infections that lead patients to seek medical care. It has been estimated that more than 7 million outpatient visits, 1 million visits to the emergency department, and 100,000 hospital stays every year in the United States are due to UTIs. Approximately 10% of humans will have a UTI at some time during their lives. Of note, UTIs are also the most common hospital-acquired infection, accounting for as many as 35% of nosocomial infections.

The exact prevalence of UTIs is age and sex dependent. During the first year of life, UTIs are less than 2% in males and females. The incidence of UTIs among males remains relatively low after 1 year of age and until approximately 60 years of age when enlargement of the prostate interferes with emptying of the bladder. Extensive studies have shown that the incidence of bacteriuria (presence of bacteria in urine) among girls 5 through 17 years of age is 1% to 3%. The prevalence of bacteriuria in females increases gradually with time to as high as 10% to 20% in older women. In women between 20 and 40 years of age who have had UTIs, as many as 50% may become reinfected within 1 year. The association of UTIs with sexual intercourse may also contribute to this increased incidence because sexual activity increases the chances of bacterial contamination of the female urethra. Finally, as a result of anatomic and hormonal changes that favor development of UTIs, the incidence of bacteriuria increases during pregnancy. These infections can lead to serious infections in both mother and fetus.

UTIs are important complications of diabetes, renal disease, renal transplantation, and structural and neurologic abnormalities that interfere with urine flow. In 40% to 60% of renal transplant recipients, the urinary tract is the source of bacteremia, and in these patients, the recurrence rate is about 40%. In addition, UTIs are a leading cause of gram-negative sepsis in hospitalized patients and are the origin for about half of all nosocomial infections caused by urinary catheters.

Etiologic Agents

Pathogenesis

Routes of Infection

Bacteria can invade and cause a UTI via three major routes: ascending, hematogenous, and lymphatic pathways. Although the ascending route is the most common course of infection in females, ascent in association with instrumentation (e.g., urinary catheterization, cystoscopy) is the most common cause of hospital-acquired UTIs in both sexes. For UTIs to occur by the ascending pathway, enteric gram-negative bacteria and other microorganisms that originate in the gastrointestinal tract must be able to colonize the vaginal cavity or the periurethral area. Once these organisms gain access to the bladder, they may multiply and then pass up the ureters to the kidneys. UTIs occur more often in women than men, at least partially because of the short female urethra and its proximity to the anus. As previously mentioned, sexual activity can increase chances of bacterial contamination of the female urethra.

In most hospitalized patients, UTI is preceded by urinary catheterization or other manipulation of the urinary tract. The pathogenesis of catheter-associated UTI is not fully understood. It is certain that soon after hospitalization, patients become colonized with bacteria endemic to the institution, often gram-negative aerobic and facultative bacilli carrying resistance markers. These bacteria colonize the patient’s skin, gastrointestinal tract, and mucous membranes, including the anterior urethra. With insertion of a catheter, the bacteria may be pushed along the urethra into the bladder or, with an indwelling catheter, may migrate along the track between the catheter and the urethral mucosa, gaining access to the bladder. It is estimated that approximately 10% to 30% of catheterized patients will develop bacteriuria (presence of bacteria in urine).

UTIs may also occur by the hematogenous, or blood-borne, route. Hematogenous spread usually occurs as a result of bacteremia. Any systemic infection can lead to seeding of the kidney, but certain organisms, such as Staphylococcus aureus or Salmonella spp., are particularly invasive. Although most infections involving the kidneys are acquired through the ascending route, yeast (usually Candida albicans), Mycobacterium tuberculosis, Salmonella spp., Leptospira spp., or Staphylococcus aureus in the urine often indicates pyelonephritis acquired via hematogenous spread, or the descending route. Hematogenous spread accounts for less than 5% of UTIs.

Finally, increased pressure on the bladder can cause lymphatic flow into the kidneys, resulting in UTI. However, evidence for the significance of this potential route is insufficient, indicating that the ascending route remains the major mechanism for the development of UTI.

The Host-Parasite Relationship

Many individuals, women in particular, are colonized in the vaginal or periurethral area with organisms originating from the gastrointestinal tract, yet they do not develop urinary infections. Whether an organism is able to colonize and then cause a UTI is determined in large part by a complex interplay of host and microbial factors.

In most cases, the host defense mechanisms are able to eliminate the organisms. Urine itself is inhibitory to some of the urethral flora such as anaerobes. In addition, if urine has a low pH, high or low osmolality, high urea concentration, or high organic acid content, even organisms capable of growth in the urinary tract may be inhibited. If bacteria do gain access to the bladder, the constant flushing of contaminated urine from the body either eliminates bacteria or maintains their numbers at low levels. Clearly, any interference with the act of normal voiding, such as mechanical obstruction resulting from kidney stones or strictures, will promote the development of UTI. Also, the bladder mucosal surface has antibacterial properties. If the infection is not eradicated, the site of infection remains in the superficial mucosa; deep layers of the bladder are rarely involved.

In addition to the previously described host defenses, a valvelike mechanism at the junction of the ureter and bladder prevents the reflux (backward flow) of urine from the bladder to the upper urinary tract. Therefore, if the function of these valves is inhibited or compromised in any way, such as by obstruction or congenital abnormalities, urine reflux provides a direct route for organisms to reach the kidney. Hormonal changes associated with pregnancy and their effects on the urinary tract increase the chance for urine reflux to the upper urinary tract.

Activation of the host immune response by uropathogens also plays a key role in fending off infection. For example, bacterial contact with urothelial cells initiates an immune response via a variety of signaling pathways. Bacterial lipopolysaccharide (LPS; see Chapter 2) activates host cells to ultimately release cytokines such as tumor necrosis factor and interferon-gamma. In addition, bacteria can activate the complement cascade, leading to the production of biologically active components such as opsonins, as well as augment the host’s adaptive immune response. Host factors that lead to host susceptibility or resistance to uropathogens have been identified. For example, a glycoprotein synthesized exclusively by epithelial cells in a specific anatomic location in the kidney, referred to as Tamm-Horsfall protein or uromodulin, serves as an anti-adherence factor by binding to E. coli–expressing type 1 fimbriae (discussed later). Defensins, a group of small antimicrobial peptides, are produced by a variety of host cells such as macrophages, neutrophils, and cells in the urinary tract and attach to the bacterial cell, eventually causing its death.

Although many microorganisms can cause UTIs, most cases are a result of infection by a few organisms. To illustrate, only a limited number of serogroups of E. coli cause a significant proportion of UTIs. Numerous investigations indicate that UPEC possesses virulence factors that enhance their ability to colonize and invade the urinary tract. Some of these virulence factors include increased adherence to vaginal and uroepithelial cells by bacterial surface structures (adhesins, in particular, pili), alpha-hemolysin production, and resistance to serum-killing activity (Box 73-2). Also, genome sequences of some UPEC strains have been determined, indicating that several potential virulence factor genes associated with the acquisition and development of UTIs are encoded on pathogenicity islands (e.g., hemolysins and E. coli P. fimbriae). Uropathogenic E. coli (UPEC) possess pathogenicity islands containing a variety of virulence factors. By definition, pathogenicity islands (see Chapter 3) contain genes that are associated with virulence and are absent from avirulent or less virulent strains of the same species.

Box 73-2 Examples of Probable Virulence Factors of Uropathogenic E. coli

Type 1 fimbriae that bind to uroepithelial cells

Type P fimbriae that recognize kidney glycosphingolipids

Siderophores that help gather iron from the host

Alpha and beta hemolysins that lyse host erythrocytes

Capsules

Sat protein that acts as a proteolytic toxin

The importance of adherence in the pathogenesis of UTIs has also been demonstrated with other species of bacteria. Once introduced into the urinary tract, Proteus strains appear to be uniquely suited to cause significant disease in the urinary tract. Data indicate that these strains are able to facilitate their adherence to the mucosa of kidneys. Also, Proteus is able to hydrolyze urea via urease production. Hydrolysis of urea results in an increase in urine pH that is directly toxic to kidney cells and also stimulates the formation of kidney stones. Similar findings have been made with Klebsiella spp. Staphylococcus saprophyticus also adheres better to uroepithelial cells than does S. aureus or S. epidermidis.

Other bacterial characteristics may be important in the pathogenesis of UTIs. Motility may be important for organisms to ascend to the upper urinary tract against the flow of urine and cause pyelonephritis. Some organisms demonstrate greater production of K antigen(capsule or outer cell wall); this antigen protects bacteria from being phagocytosed.

Finally, despite numerous host defenses and even antibiotic treatments that can effectively sterilize the urine, a significant proportion of patients have recurrent UTIs. Studies show that uropathogens can invade superficial epithelial cells in the bladder and replicate, forming large foci of intracellular E. coli. This invasion of bladder epithelial cells triggers the host immune response, which in turn causes the superficial cells to exfoliate within hours following infection. Although this exfoliation is considered a host defense mechanism by eliminating infected cells, intracellular organisms are able to reemerge from the bladder epithelial cells and invade the underlying, new superficial layer of epithelial cells, consequently persisting within the urinary tract. Anderson and colleagues reported that intracellular bacteria mature into numerous, large protrusions on the bladder surface they referred to as “pods.” This bacterial organization—in which the intracellular bacteria are embedded in a fibrous, polysaccharide-rich matrix resembling that of a biofilm—may help further explain the persistence of bladder infections despite strong host defenses.