Introduction

Urinary tract infections (UTIs) are a common cause of morbidity in women, affecting 50% of adult women at least once in their lives. In women aged 20–65 years, at least 20% will suffer an infection each year. Each year, approximately 5% of women will present to their general practitioners with dysuria and frequency (Hamilton-Miller 1994), and approximately half of these will have a UTI. It has been estimated that, on average, a case of uncomplicated acute cystitis results in 6.1 days of symptoms, 2.4 days of restriction of activities and 0.4 days in bed (Foxman and Frerichs 1985a). In women, the incidence of UTI increases with age and with the onset of sexual activity, and is highest amongst the elderly. In children under 1 year of age, the prevalence is higher in boys than girls, with a male:female ratio of 3 : 1–5 : 1. UTI in the neonate should be considered to be secondary to an underlying anatomical abnormality until proven otherwise (Kunin 1987).

The prevalence of UTI increases significantly with increasing age, and is higher in women than in men. In the elderly, the prevalence may be as high as 50%, especially if the woman is institutionalized (Boscia and Kaye 1987). This high prevalence in the elderly is thought to be secondary to cerebrovascular accidents, reduced mental and functional capacity, the use of bladder catheters and diabetes.

Approximately 25–30% of affected women will develop recurrent UTI that is not related to an underlying anatomical or functional abnormality of the urinary tract (Hooton 2001, Finer and Landau 2004).

This chapter will concentrate on UTI in the adult female and discuss strategies for treatment and prevention.

Terminology and Definitions

UTI is defined as inflammation of the urinary tract due to microbial invasion. There is considerable overlap in the clinical presentations of the various syndromes, including cystitis, pyelonephritis and urethritis. Complicated UTI is UTI associated with functional or anatomical abnormalities that increase the risk of serious complications or treatment failure, such as conditions which cause obstruction or relative stasis of urinary flow (Box 58.1).

Urine samples collected directly from the bladder, ureter or renal pelvis should 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 (CFUs). The absolute number needed to define significant bacteriuria depends on the sample type. The threshold of more than 10⁵ CFU/ml has been a standard for the definition of significant bacteriuria using carefully collected midstream urine (MSU) since the 1950s (Kass 1956). A significant proportion of patients with UTI will have less than 10⁵ CFU/ml (Johnson and Stamm 1987, 1989). Therefore, current recommendations (Warren et al 1999) suggest more than 10³ CFU/ml for a diagnosis of cystitis, and more than10⁴ CFU/ml for a diagnosis of pyelonephritis. An important consideration with these diagnostic criteria is that they rely on careful collection of the MSU. This requires that care is taken in the instruction and support that patients are given to collect these samples. Bacteriuria is common in association with any long-term catheter and is not in itself an indication for treatment of UTI.

Asymptomatic bacteriuria is defined as the presence of more than 10⁵ CFU/ml in two MSU samples in the absence of symptoms (Zhanel et al 1990). Cystitis is an inflammation of the bladder which may be due to infection or a variety of other causes. Urethritis is inflammation of the urethra and may be a consequence of a wide range of causes including UTI, sexually transmitted diseases such as chlamydia, vaginitis, trauma and allergy. Bacterial pyelonephritis is infection of the renal pelvices which may be acute or chronic.

Microbiology of Urinary Tract Infection

The majority of UTIs are caused by facultative bacteria and, occasionally, by fungi and viruses. Escherichia coli accounts for up to 70% of community-acquired infections (Grüneberg 1994), with the remainder predominantly caused by Staphylococcus saprophyticus and a variety of Gram-negative rods within the Enterobacteriaceae. In hospital-acquired infections, approximately 50% are caused by E. coli, 15% by Enterococcus spp. and the remainder by members of the Enterobacteriaceae, Pseudomonas spp., Staphylococcus spp. and yeasts (Bryan and Reynolds 1984). Hospital-acquired UTIs are frequently associated with iatrogenic risk factors such as instrumentation, and also with patient comorbidities. Antibiotic resistance is also much more likely to complicate hospital-acquired UTI.

Pathogenesis

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

Bacterial virulence factors

The ability of bacteria to adhere to uroepithelial cells is a prerequisite for infection to occur, and reduces the chance of the bacteria being cleared from the urinary tract during voiding. There are various adherence factors, 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 (Zafriri et al 1987). There are many different types of adhesins, such as type 4 pili, outer membrane proteins, curli, filamentous haemagglutinins and adhesive pili. Other virulence factors that may facilitate infection are specific to each pathogen. These include the surface antigens on E. coli and haemolysins that are produced to help degrade cells, and aerobactins that enhance iron uptake which 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 (Gunther et al 2002). The virulence of UPEC has been attributed mainly to the presence of type 1 fimbriae, a mannose-binding adhesion protein called ‘FimH’ (Abraham et al 1988). Another pathogenic mechanism is the development of intracellular UPEC pods which act as a reservoir for infection (Anderson et al 2003). These pods contain bacteria that are encased in a polysaccharide matrix and protected by a uroplakin coating which help to evade host defence mechanisms and antimicrobials. This initiates the invasion into cells to develop intracellular bacterial communities. It is this reservoir that can serve as a source of bacteria that may reinitiate infection (Figure 58.1)

Figure 58.1 Intracellular bacterial communities extend like pods into the bladder lumen. Infected bladders were bisected, fixed and visualized by either scanning electron microscopy (SEM) or light microscopy [haematoxylin and eosin (H&E) staining]. (A–C) SEM images of a pod on the surface of a C3H/HeJ mouse bladder infected with UTI89 for 24 h show large intracellular communities of bacteria inside pods. Scale bars: 50 µm (A), 5 µm (B), 0.5 µm (C). (D) SEM revealed no pods in C3H/HeJ bladders infected with MG1655. Scale bar: 50 µm. (E) H&E-stained sections of UTI89-infected C3H/HeJ mouse bladders show a bacterial factory 6 h after inoculation (top panel) and a pod 24 h after inoculation (bottom panel). Bacteria in the pod were densely packed, shorter and completely filled the host cell. Video microscopy has shown that bacterial factories mature into pods. Scale bars: 20 µm. (F) Pods were evident in wild-type C3H/HeN bladders infected with UTI89. Scale bar: 50 µm. (G) Confocal Z-section series from whole-mounted bladder infected with UTI89 expressing green fluorescent protein from the plasmid pcomGFP and stained with antibody to uroplakin (primary antibody) and tetramethyl rhodamine isothiocyanate-labelled secondary antibody, showing uroplakin coating the surface of pods. The series depicts the lumenal surface on the left and progresses through the epithelium toward the right. Optical section thickness: 1 µm. All images are representative of the entire sample surface and are from bladders harvested 24 h after inoculation, unless otherwise indicated.

Source: Anderson GG, Palermo JJ, Schilling JD, Roth R, Heuser J, Hultgren SJ 2003 Intracellular bacterial biofilm-like pods in urinary tract infections. Science 301: 105–107.

Host factors

Regular voiding flushes the urinary tract of pathogens and the acidity of urine inhibits bacterial growth. A healthy vaginal flora is thought to be essential in reducing infection. This flora is predominantly lactobacilli and this maintains an acidic pH in the vagina. Lactobacilli and uromucoid in the urine are thought to interfere with bacterial adherence and colonization. It is also thought that the composition of the 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, the flora has reduced lactobacillus composition (Kirjavainen et al 2009). The glycosaminoglycan layer of the bladder also serves as a protective layer preventing bacterial adherence.

Factors that increase the risk of infection include:

• impaired bladder emptying which can occur with neurogenic disorders such as diabetes, multiple sclerosis, cerebrovascular events and anatomical abnormalities. Anticholinergic drugs may also impair bladder emptying;

• instrumentation of the urinary tract which may traumatize the urethra;

• foreign bodies such as catheters and stones increase the risk of infection as they are a focus for infection;

• pelvic tumours and inflammatory bowel disorders may invade the bladder directly and also 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 non-secretors of histo-blood group antigens, and E. coli is found to adhere better to uroepithelial cells of non-secretors than secretors (Lomberg et al 1986, Sheinfeld et al 1989). Further evidence for a genetic susceptibility is that female relatives of women with recurrent UTI are more likely to suffer from UTI as an adult (Hopkins et al 1999);

• in menopausal women, the lack of oestrogen reduces lactobacillus growth and, with the rise in vaginal pH, leads to a predisposition to growth of enterobacteria (Cardozo 1996); and

• sexual intercourse and contraception are strongly associated with the onset of UTI (Hooton et al 1996, Foxman et al 1997). Sexual intercourse not only results in trauma and disruption to the uroepithelial cells, but may also introduce rectal and vaginal bacteria into the urethra. In a woman who has had sex in the previous 48 h, the odds ratio for a UTI is increased 60 times over a woman who has not (Nicolle et al 1982). The use of spermicides with diaphragms alters vaginal flora, increases vaginal pH and decreases lactobacilli concentration, promoting colonization with E. coli.

In addition to all these factors, there is 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 is the Toll-like receptor (TLR) family (Samuelsson et al 2004, Zhang et al 2004, Anderson-Nissen et al 2007). These receptors function to initiate appropriate host immune defences when triggered by a pathogen. There are 11 TLRs; TLR4 is the best characterized and is present on the epithelial cells of the bladder and kidney, and promotes cytokine and chemokine responses to Gram-negative pathogens. This TLR4 response can still occur even once intracellular bacterial invasion has occurred. The importance of host-mediated immunity can be seen in women with recurrent UTI. A study comparing vaginal, urine and blood samples from 22 women wirh recurrent UTI and 17 controls showed an aberrant immune response. Women with recurrent UTI had defective T-cell activation and a lower concentration of tissue-repair-associated vascular endothelial growth factor (Kirjavainen et al 2009).