Cystitis and Urethritis

Annelie Brauner

Milan Chromek

Bacteriuria, which is bacteria in the urine, is often (but not necessarily) a sign of infection. Therefore, it is important to put the results from bacterial urine culture into the context of the patient, including clinical symptoms, results of other laboratory tests, as well as methodology used.

Urine samples can be obtained in different ways. In adults, the most common sampling is clean-catch voided urine. In infants up to 1 year of age, however, suprapubic bladder aspiration is recommended, whereas for toddlers it is more common to collect with a urine collecting bag. From patients with an indwelling urinary catheter the urine sample has to be obtained through the catheter. These differences in modes of collection of urine samples inevitably result in differences in the type and number of bacteria isolated.

DEFINITIONS

Urinary tract infections (UTIs) in general can be symptomatic or asymptomatic. Symptomatic UTI can be divided into infections restricted to the lower urinary tract (bladder and urethra) to the upper urinary tract (kidney) or infections with systemic involvement, which is urosepticemia. The focus of this chapter is on infections of the lower urinary tract.

Symptomatic Urinary Tract Infection

Acute Cystitis and Urethritis

Cystitis is defined as an inflammation of the urinary bladder. Urethritis is an inflammation of the urethra. Both are most commonly caused by a bacterial infection; in which case, they are also referred to as lower UTIs.

Classic symptoms of lower UTIs are dysuria, urinary frequency, and suprapubic pain sometimes in combination with hematuria, but normally without fever. The extent of symptoms varies between different patients and can be very mild to severe. Other diseases can mimic lower urinary tract bacterial infections like vaginitis, interstitial cystitis, and pelvic inflammatory disease.

Asymptomatic Bacteriuria

Asymptomatic bacteriuria (ABU) refers to bacteriuria in patients with no clinical UTI symptoms. For women ≥10 ⁵ colony forming units (CFU) per mL in two consecutive clean-catch urine samples is required for the diagnosis of asymptomatic bacteriuria, whereas for men only one clean-catch urine sample with ≥10 ⁵ CFU per mL is required—or a single catheterized urine specimen with one single bacterial strain of ≥10 ² CFU per mL in women or men. ¹

CLASSIFICATION

Acute cystitis and urethritis can be classified as uncomplicated verus complicated UTI, nosocomial versus community-acquired UTI, and sporadic versus recurrent UTI.

Uncomplicated UTI occurs in persons with normal urinary tract, whereas complicated UTI occurs in individuals with functional or structural changes, implying deteriorated voiding predisposing for bacteriuria.

Nosocomial UTI are infections that occur 48 hours or more after admission to the hospital or as a result of health care, whereas community-acquired UTI are UTIs not included in the previous group.

Sporadic UTI include a single UTI treated with antibiotics during 6 months or maximum two UTIs needing antibiotics during 1 year, whereas recurrent UTI comprise at least two antibiotic treated UTIs during 6 months or three or more antibiotic treated UTI during 1 year.

Recurrent UTI can be further divided into relapse or reinfection. Relapse infection includes a recurrent infection with the same bacteria as the previous UTI, whereas a reinfection is caused by different bacteria than in the previous infection. Superinfection is a new infection during antibiotic treatment and where the new bacterial strain is resistant to the used antibiotic.

ETIOLOGY

By far the most common bacterial uropathogen is Escherichia coli , causing more than 80% of UTIs among female ambulatory patients. In men and hospitalized patients, E. coli is
still the most commonly isolated bacteria, but with a lower frequency. Other common uropathogenic bacteria include Klebsiella pneumoniae , Proteus mirabilis , enterococci, Streptococcus agalactiae, and Staphylococcus saprophyticus . ²,³ S. saprophyticus is the only urinary pathogen with a seasonal variation, being most common during the late summer and early autumn months. ⁴

In patients with long-term indwelling catheters, bacteriuria is almost inevitably found after about 14 days. Initially, a single species of bacteria is found but later a polymicrobial flora is common, with a wide variety of infecting microorganisms found. In patients with long-term catheters Proteus mirabilis, Providencia stuartii, Morganella morganii, Klebsiella pneumoniae, E. coli, and Pseudomonas aeruginosa are most commonly isolated. In patients with short-term catheters, staphylococci are also common. Although staphylococci seldom cause symptomatic UTIs, they contribute to bacterial biofilm formation.⁵,⁶

Unusual causes of urethritis and cystitis include urethritis caused by Neisseria gonorrhoeae and Chlamydia trachomatis. They have a distinct pathogenesis and symptoms that can be similar to acute cystitis. They are usually described among sexually transmitted diseases. Adenoviruses (mainly type 11) cause epidemic hemorrhagic cystitis in children, especially in boys, but may cause endemic cystitis as well. ⁷ Other infectious causes, which are much less common, include Herpes simplex virus; atypical bacteria, like Mycoplasma genitalium and Ureaplasma urealyticum; Mycobacteria; fungi and parasites; Trichomonas spp.; and Schistosoma haematobium . There are also noninfectious forms of cystitis and urethritis—for example, traumatic cystitis, interstitial cystitis, eosinophilic cystitis, and hemorrhagic cystitis—which are described elsewhere.

EPIDEMIOLOGY

UTIs are among the most common bacterial infections. ³,⁸ Prevalence is different depending on the age and gender of the patient. The overall risk in childhood before puberty is 3% to 5% in girls and 1% to 2% in boys. ⁹,¹⁰ In the neonatal period, the incidence of bacteriuria is about 1%, and this is also the only period when UTI is more prevalent in males than females.¹¹ After 1 year of age the incidence of UTIs reaches 2% in boys and 8% in girls. ¹² During the reproductive period, the gender difference becomes even more pronounced and UTIs are some 50-fold more common in women as compared to men. Approximately 20% of women between 24 and 64 years old have at least one episode of dysuria each year, most of these being caused by bacterial infections. ¹³ Almost half of all women will experience at least one episode of UTI during their lifetime ⁸ and about 25% of these have recurrent infections. In the United States alone, UTIs account for approximately 11 million office visits and 1.7 million emergency room visits each year, resulting in almost half a million hospitalizations at a cost of $3.5 billion. ⁸,¹⁴,¹⁵ This figure probably underestimates the true incidence because many lower tract UTIs resolve without medical attention.

ROUTE OF INFECTION

UTIs are most commonly ascending infections caused by bacteria mainly from the intestinal tract or vagina. Hematogenous spread of infections to the urinary tract is rare and restricted to a few pathogens, such as S. aureus and Mycobacterium tuberculosis, which cause primary infections elsewhere in the body. Lymphatic spread from sites of infection elsewhere, bacterial spread through a fistula from the bowel, and retrograde infection from the prostate or kidney are very unusual but may also occur.

The perineum is a couple of square centimeters area of skin between the anal and urogenital regions. This is also a place that is highly colonized by bacteria from the gastrointestinal tract and vagina, and from where the bacteria may reach the urinary tract. ¹⁶ In the majority of cases, the bacteria are cleared off from the bladder. Sometimes, they persist and colonize the urinary tract causing asymptomatic bacteriuria or even symptomatic UTI. ¹⁶ The short female urethra is an insufficient anatomic barrier to the entry of bacteria, which may be massaged easily into the bladder. This may explain the association of UTIs and bacteriuria with sexual activity. ¹⁷ Bacteria may also be introduced into the bladder during catheterization of the urethra. Single catheterization of the bladder in ambulatory patients results in a 1% incidence of subsequent UTI. ¹⁸ Finally, voiding dysfunction in children is also clearly associated with recurrent UTI ¹⁹ and complex treatment of the dysfunction resulted in a substantial decrease of the frequency of UTI attacks. ²⁰ All these observations suggest that ascendance of bacteria from perineum to the urethra and urinary bladder is the most common route of UTI.

PATHOGENESIS

Bacterial Factors in the Pathogenesis of Urinary Tract Infection

How do harmless commensal bacteria from the perineum become urinary pathogens? It is believed that some bacterial clones from the gut can acquire specific virulence characteristics, which increase their ability to adapt to new niches. These virulence and fitness properties are frequently encoded in specific genetic elements called pathogenicity islands. Virulence factors are here defined as proteins or macromolecular structures that contribute to causing disease, whereas fitness factors offer a competitive advantage during infection, but are not required for virulence. A combination of virulence and fitness factors form a specific type that could be called uropathogenic bacterium. However, despite many common features, there is no single profile that would cause UTI. ²¹,²² Uropathogenic bacteria use a multistep scheme of pathogenesis that consists of adhesion, colonization, invasion, survival, and host damage. ²³ Bacterial factors can accordingly be described as adhesion and colonization factors, survival and immune escape factors, and toxins (for details, see Chapter 21).

Host Factors in the Pathogenesis of Urinary Tract Infection

The urinary tract is located in a fragile region in close proximity to the outside environment. Around 2 L of urine a day, produced by the kidneys, are emptied close to the rectum, the area highly colonized by bacteria. Still, the urinary tract is very resistant against infection. It was observed by urologists more than 100 years ago that, despite extensive instrumentation (e.g., frequent catheterization), and even without aseptic precautions, some individuals never or very seldom developed UTI. ²⁴,²⁵ This observation has later been confirmed experimentally, showing that bacteria introduced to the urinary bladders of healthy volunteers were rapidly eliminated. ²⁶ In accordance, only very high concentrations of bacteria, or a combination of bacteria and an irritant substance such as paraffin or turpentine, were needed to establish UTI in experimental animals. ²⁷,²⁸

In order to successfully colonize the urinary tract and cause infection, bacteria must overpower the specific anatomic organization of the urinary tract as well as chemical defense components of urine and the urinary tract mucosa. Moreover, recognition of uropathogens by human urinary epithelium leads to a strong inflammatory response.

Anatomic Properties of the Urinary Tract

The draining system of the urinary tract is covered with urothelium, a firm carpet of epithelial cells. Urothelium is transitional epithelium consisting of three to seven layers of cells: the basal layer of stem cells, one or more intermediate layer(s), and the superficial layer, usually referred to as umbrella or facet cells. Normal human bladder urothelium is arranged in an increasing complexity from base to surface. Urothelial cells of all layers are connected by interdigitations of cytoplasmic processes and by desmosomes. Adjacent surface cells, in addition, are linked by tight junctions. This organization enables the urothelium to withstand frequent changes in bladder volume with changes in pressure on the bladder wall. ²⁹

The urothelium is exposed to large changes in hydrostatic pressure with the surface superficial cells and is in contact with urine varying in pH, osmolality, and containing a number of cytotoxic substances. Therefore, cell membranes of umbrella cells need a unique lipid and protein composition that contributes to the low permeability of the membrane and that controls the passage of water, ions, solutes, and large macromolecules across the mucosal surface of the cell into the underlying tissue. The apical surface of umbrella cells is folded and contains specialized uroplakin membrane domains, which undergo active reorganization. ³⁰,³¹ During the initial phase of bladder filling, the apical membrane unfolds. In the latter phase of filling, the cytoplasmic vesicles are inserted to the apical membrane to accommodate the increasing bladder volume. Emptying of the bladder is then accompanied by endocytosis of the cytoplasmic vesicles and folding of the apical membrane. ³²,³³ In addition to the highly specialized urothelium, a mucous layer on the surface of the urinary bladder has been described. ³⁴,³⁵ This layer seems to be very thin, and substantially differs from the mucus in the gastrointestinal tract. It consists mainly of glycosaminoglycans and is most likely membrane-bound rather than secreted. ³⁶

Urine flow, regular bladder emptying, and the valve mechanisms of the urinary tract have traditionally been considered the most important protective mechanisms maintaining this area free of microbes. Accordingly, studies in patients with anomalies of the urinary tract indicate their importance in the protection against bacteria. ³⁷ Functional abnormalities of the lower urinary tract directly influence the entry of uropathogens into the urinary tract and may lead to recurrent UTIs, mainly in children. ¹⁹,²⁰ For premenopausal women a new sexual partner, increased frequency of intercourse, and use of spermicides are recognized as risk factors. ³⁸ In postmenopausal women the loss of estrogen results in change of the vaginal flora, with decreased growth of lactobacilli, as well as thinning of the vaginal epithelium and decreased amounts of glycogen which contribute to the risk of recurrent UTIs.

Mucosal Antimicrobial Mechanisms

Although regular urine flow and valve mechanisms of the urinary tract protect the urinary tract against the excessive growth of bacteria, they are not enough to completely eliminate pathogens. This has been demonstrated using an in vitro model of the urinary bladder ²⁶ as well as mathematical simulation. ³⁹ In accordance, the mucosa of the urinary bladder has been shown to possess antimicrobial properties in vitro. ⁴⁰ Only a combination of mechanical and chemical antimicrobial factors may explain the high efficiency of the urinary tract in eliminating bacteria. Although chemical antimicrobial mechanisms of the urinary tract mucosa have so far not been systematically analyzed, a number of molecules inhibiting the growth of bacteria in the urinary tract or killing bacteria have been identified: Tamm-Horsfall protein, secretory IgA, antimicrobial proteins, and peptides, namely lactoferrin, β-defensin 1 and 2, and cathelicidin.

Recognition of the Presence of Bacteria

The first cell layer in contact with invading bacteria is the urothelium. The presence of uropathogenic bacterium induces a robust immune response already after a short contact with urothelial cells. After sensing the presence of uropathogenic bacteria, epithelial cells react in different ways. They produce substances toxic to bacteria, like nitric oxide, cathelicidin, and β-defensin-2. ⁴¹,⁴²,⁴³ Exfoliation of superficial umbrella cells is also an important protective mechanism, which helps clearing bacteria from the bladder.⁴⁴ Despite the effective first line of epithelial defence, uropathogens may sometimes persist or even multiply and invade the host. Therefore, the epithelium possesses efficient tools in order to engage the help of professional
immune system cells. Epithelial cells in the urinary tract and kidney, in response to pathogens, produce a number of chemokines and proinflammatory cytokines. ⁴⁵ Chemokines attract professional immune system cells, and cytokines activate them. Out of a number of chemokines, interleukin 8 seems to be of crucial importance because of its chemoattraction of neutrophils. ⁴⁶,⁴⁷ Cytokine-mediated upregulation of adhesion molecules and cytokine receptors facilitates the process of migration of immune cells. Amongst them, the CXCR1 receptor on renal epithelial cells has been shown to facilitate transepithelial migration of neutrophil granulocytes and bacterial clearance during UTI. ⁴⁸ Neutrophils accumulate in the inflamed tissue and kill bacteria by different mechanisms: either phagocytosis or the release of the toxic content of their granules. ⁴⁹ The influx of neutrophils is followed by an influx of other professional immune cells, namely monocytes/macrophages and lymphocytes, which are predominantly important in later stages of infection.

SYMPTOMS

The symptoms of a UTI substantially differ depending on age and type of infection. The symptoms in infants and young children are very nonspecific and UTIs are usually diagnosed first in the stage of upper urinary tract involvement, or septicemia. The signs may involve tachypnea, dyspnea, as well as icterus in neonates and poor feeding, fever, and vomiting in infancy. Therefore, UTIs must always be excluded in unwell children or children with unexplained fever. After infancy, the classic symptoms of lower UTIs—dysuria, urgency, and frequency—are more usual. Adults with urethritis and cystitis typically have frequent and urgent voiding of small volumes of urine and dysuria and nocturia is common. Sensation of lower abdominal discomfort also is a frequent symptom. The urine may be turbid or even bloody in one third of cases. ⁵⁰ Some infections may progress after 1 or 2 days to develop a clinical picture of upper UTI, including flank or abdominal pain, fever, and vomiting, but acute cystitis very seldom progresses to cause septicemia. On the contrary, the infection may resolve spontaneously even without antimicrobial therapy. Still it cannot be justified to withhold antimicrobial therapy. ⁵¹,⁵²

Studies localizing bacteria by laboratory or imaging techniques have demonstrated a poor correlation between clinical manifestations and localization results. Moreover, UTIs often are asymptomatic in the elderly ⁵³ ; and other diseases may also manifest by frequency, urgency, nocturia, and incontinence in this age group. Likewise, patients with neurogenic bladders, a long-term indwelling catheter, or intermittent catheterization usually have unspecific or no symptoms referable to the bladder when a UTI develops. ⁵ Therefore, there should be a low threshold for microbiologic examination of the urine in these patient groups.