1.1 Six Categories of UTIs

1.2 How Do UTIs Occur?

The first step of uncomplicated UTI development is the colonisation of the periurethral region with uropathogens. These could have migrated from the anus (gut bacteria), from the vagina, or have been introduced externally (e.g. during sexual intercourse). These microbes inhabit the distal urethra and ascend towards the bladder [4]. Once in the bladder, the uropathogen uses specialised bacterial appendages (flagella and pili) and expresses adhesins in order to attach to and invade the most superficial cells of the bladder wall, the urothelium [5–7]. At this point the body’s immune system kicks in; neutrophils infiltrate the bladder and start clearing the bacteria.

Either through invasion into host cells or resistance, some bacteria are able to evade the immune response and proliferate in the bladder wall, forming biofilms. They use the nutrients within invaded host cells to survive and multiply [8]. All the while, the proteases and toxins they produce cause damage to urothelial cells [4]. At this point the symptoms of a UTI become apparent—i.e. the burning/stinging on micturition, even haematuria (blood in urine) in some cases.

The substances released by these damaged cells may promote further ascension to the kidneys. Bacterial toxins may also play a role by inhibiting ureteric peristalsis and thereby reducing the risk of being washed away by urine flow [5–7].

When uropathogens reach the kidney, they continue to produce toxins and cause cell damage [4]. The consequent inflammatory response by the body is called pyelonephritis. Pyelonephritis mostly occurs due to ascension from the bladder, but can be caused by haematogenous spread. If the inflammatory response is on-going it can cause tubular obstruction leading to interstitial oedema. This has the potential to progress to interstitial nephritis and acute kidney injury [5–7].

If untreated or improperly managed, UTIs can spread across the tubular epithelial barrier into the bloodstream causing urosepsis [4].

1.3 Natural Defences

The vast majority of UTIs are caused by bacteria [9, 10]. Even a healthy individual will exhibit some colonisation of the periurethral region. However, not all of this colonisation will lead to a urinary tract infection. The body has developed mechanisms of defence against microbial invasion.

Healthy urine has a high osmolality and an acidic pH [9, 11] making it a less hospitable environment for pathogens. UTI-causing micro-organisms prefer a more neutral pH and, when they proliferate, will change their environment so it is more suitable for further growth of their population—a urine pH of greater than or equal to 7.5 generally indicates UTI [12].

In a similar vein, the acidic environment of the vagina protects against colonisation and consequent urogenital infections. Lactobacillus is a naturally occurring coloniser of the vagina and keeps the average pH below 5; a low enough level to prevent rapid bacteria proliferation and cause disruption to the adhesion of E. coli [12]. Lactobacillus thrives in high-oestrogen environments (i.e. younger women rather than post-menopausal). This will be discussed further in the risk factors section of this chapter.

There is also the aspect of mechanical defence against UTIs. The flow of urine produced during micturition can physically flush out any harmful microbes present in the tract [11]; this is why those with UTIs are advised to drink plenty of water. Another physical barrier is the vesicoureteric valve that acts as a blockade to ascending infection [9].

In terms of mucosal immunity, a number of defensive mechanisms exist. The urothelium itself secretes chemokines, cytokines and mucosal IgA to fight off invading pathogens. A mucus-like protective glycosaminoglycan (GAG) layer lines the inner wall of the bladder and prevents toxins from reaching epithelial cells, thereby preventing cell damage and bacterial invasion [11].

1.4 What Are the Risk Factors and Why?

Despite sophisticated defence mechanisms, infections can still occur. Certain individuals are more likely to develop UTIs than others. This can be due to a range of risk factors.

1.5 Gender-Related

Females have a shorter urethra than males. This means there is a shorter urethral distance for pathogens to travel to reach the bladder and so predisposes women to UTIs [6]. On top of this, high exposure to anal pathogens can increase risks of UTIs. This could be due to faecal incontinence or sexual practices. Twenty-five percent of women who present with cystitis will have a recurrent episode in the next 6 months [8].

Use of antibiotics in women can alter the vaginal flora and allow the overgrowth of bacteria, increasing risk of infection [9]. Frequent or recent sexual intercourse is also a risk factor (in women) through the introduction of external bacteria [8]. Spermicide-coated diaphragms and condoms can cause mucosal irritation and provide potential attachment sites for uropathogens, aiding in their invasion [5, 6].

In young women, high levels of oestrogen encourage the formation of non-pathogenic lactobacilli colonies. Lactobacillus, the commensal vaginal bacterium thrives on oestrogen stimulation to proliferate and keeps the vaginal pH microenvironment acidic via the synthesis of lactic acid. This inhibits pathogenic growth. Post-menopause, the lower levels of circulating oestrogen leads to an increase in vaginal pH due to both a lack of Lactobacilli and a general loss of vaginal architecture and moisture. Consequently, the environment becomes more hospitable for harmful UTI-causing bacteria such as E. coli. This means post-menopausal women are more susceptible to these infections [13].

1.6 Functional

Once in the bladder, microbes reside in the urine until they attach themselves to the urothelium. When the bladder voids completely, it flushes out the pathogens in the urine. An inability to fully empty the bladder puts an individual at increased risk of suffering from a UTI. Incomplete voiding can be due to developmental abnormalities in the urinary tract (e.g. VUJ reflux allows pooling of urine and can facilitate ascension to the kidney [5, 6]), age-associated anatomical changes (e.g. strictures and pelvic organ prolapse) or functional loss (e.g. nerve damage, stone obstruction). Pregnancy can also cause impaired bladder emptying [9] through progesterone-mediated relaxation of smooth muscle in the bladder and ureters, and through physical compression by the enlarged uterus [5, 6].

1.7 Disease-Related/Iatrogenic

Diabetes increases the sugar levels in the urine making it a good environment for bacterial proliferation (plenty of sugar to use as a bacterial energy source). Immunosuppressive conditions such as HIV/AIDS, or drugs that decrease the body’s immunity also increase the risks of UTI as neutrophil infiltration at the attachment stage is reduced [8].

Those who have had recent instrumentation (cystoscopy, catheter, stent placement) or surgery to the urinary tract are at increased risk of UTIs via introduction of external pathogens into the system [9, 10].

1.8 Genetic

A strong family history (particularly in first-degree relatives) of recurrent UTIs suggests genetic factors can influence an individual’s susceptibility [5, 6]. Theories include decreased physiological IgA secretion by uroepithelial cells and specific vaginal mucus properties that are less inhibitory to binding of uropathogens [5, 6].

Studies have looked into genetic polymorphisms and their impact on defence mechanisms against UTIs, in particular receptors involved in the inflammatory response to infection [14]. Toll-like receptors and their signalling pathways play a big part in detecting infection and coordinating the subsequent pro-inflammatory response. This process occurs when these receptors are activated through their binding to virulence factors from uropathogens (e.g. Type 1 and P fimbriae) [15]. This sets off a cascade of signals that results in the inflammatory immune response, release of cytokines and activation of neutrophils.

In a study looking at 1261 women (aged 18–49) with asymptomatic bacteriuria, it was found that certain polymorphisms relating to the receptors driving this inflammatory response were associated with higher levels of asymptomatic bacterial colonisation, which in itself is a risk factor for UTI development [16]. Other studies have had similar results [17]. This supports the theory that a genetic component to UTI susceptibility exists.

1.9 Asymptomatic Bacteriuria

The diagnosis of UTIs is through clinical assessment and analysis of midstream urine microscopy, culture and sensitivities (MC&S)—urine dipsticks are unreliable and are not gold standard for diagnosis. However, bacteria may be present in the urine in the absence of symptoms; it is thought that around 10% of men and 20% of women aged over 65 have asymptomatic bacteriuria [18]. NICE defines asymptomatic bacteriuria as ‘Bacteria in a urine sample taken from a person who does not have any of the typical symptoms of lower or upper urinary tract infection’ and specify that this should be confirmed by two consecutive urine samples [18].

As discussed earlier, peri-urethral colonisation is common and, provided the individual has functioning host defences, most cases of asymptomatic bacterial colonisation in the urine self-resolve without the need for treatment. However, in those with decreased defences and at high risk for UTIs (pregnant women, instrumentation, immune-suppression etc.) asymptomatic bacteriuria is a risk factor for development of a UTI.

For those with bacteriuria and clinical features of a UTI, the aim and outcome of treatment is for bacterial eradication and symptomatic relief. Asymptomatic bacteriuria can also be treated to prevent future infections, but it must be stressed that the vast majority of cases do not require antibiotic therapy. According to NICE guidelines, asymptomatic bacteriuria should not be treated in non-pregnant women or in those who have a catheter [18].

However, in the presence of risk factors (e.g. pregnancy, immunosuppression, planned surgical instrumentation) asymptomatic bacteriuria should be treated in order to minimise the risk of it developing into symptomatic infection or even urosepsis.