Hospital-Acquired

The hospital environment plays an important role in determining the organisms involved in UTIs. Hospitalized patients are most likely to be infected by E. coli, Klebsiella spp., Proteus spp., staphylococci, other Enterobacteriaceae, Pseudomonas aeruginosa, enterococci, and Candida spp. The introduction of a foreign body into the urinary tract, especially one that remains in place for an extended period (e.g., Foley catheter), carries a substantial risk of infection, particularly if obstruction is present. Thirty five percent of all hospital-acquired infections are urinary tract infections. Eighty percent of those infections are associated with the use of an indwelling catheter. Consequently, UTI is the most common nosocomial infection in the United States, and the infected urinary tract is the most frequent source of bacteremia.

Miscellaneous

Other less frequently isolated agents are other gram-negative bacilli, such as Acinetobacter and Alcaligenes spp., other Pseudomonas spp., Citrobacter spp., Gardnerella vaginalis, Aerococcus urinae, and beta-hemolytic streptococci. Bacteria such as mycobacteria, Chlamydia trachomatis, Ureaplasma urealyticum, Campylobacter spp., Haemophilus influenzae, Leptospira, and certain Corynebacterium spp. (e.g., C. renale) are rarely recovered from urine. Because renal transplant recipients are immunosuppressed, these patients not only suffer from common uropathogens but are also susceptible to opportunistic infections with unusual pathogens. A study involving renal transplant recipients showed that for culture-negative urine, amplification of regions in bacterial 16S rRNA and subsequent analysis by high-performance liquid chromatography detected the presence of a number of known uropathogens as well as unusual agents. Salmonella spp. may be recovered during the early stages of typhoid fever; their presence should be immediately reported to the physician. If anaerobes are suspected, the physician should perform a percutaneous bladder tap unless urine can be obtained from the upper urinary tract by another means (e.g., from a nephrostomy tube). Communication by the clinician to the laboratory that such an agent is suspected is important for detecting such agents. In patients with “sterile pyuria,” Gram stain may reveal unusual organisms with distinctive morphology (e.g., H. influenzae, anaerobes). The presence of any organisms on smear that do not grow in culture is an important clue to the cause of the infection. The laboratory can then take the action necessary to optimize chances for recovery.

In general, viruses and parasites are not usually considered urinary tract pathogens. Trichomonas vaginalis may occasionally be observed in urinary sediment, and Schistosoma haematobium can lodge in the urinary tract and release eggs into the urine. Adenoviruses types 11 and 21 have been implicated as causative agents in hemorrhagic cystitis in children.

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.

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.

Urethritis

Symptoms associated with urethritis (infection of the urethra), dysuria (painful or difficult urination), and frequency are similar to those associated with lower UTIs. Urethritis is a common infection. Because Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis are common causes of urethritis and considered to be sexually transmitted, urethritis is discussed as a sexually transmitted disease in Chapter 74.