20.2.1.1 Pathogenesis

The urinary tract is normally a sterile environment; however, pathogens can reach the bladder urothelium by ascent up the urethra, haematogenous, and lymphatic spread, or translocation of organisms from the colon. Host defence mechanisms and bacterial virulence play a multifactorial role in the development of lower UTIs.

Bacteria can increase their virulence in several ways, such as avoidance of host defences, antimicrobial resistance, and mechanisms for adhesion to the urothelium. E. coli has an extracellular capsule which can resist phagocytosis and reduce the humoral and cell‐mediated immune responses. E. coli can also release endotoxins which can destroy host erythrocytes. Proteus species have developed the ability to produce ureases which split urea into ammonia and leads to struvite stone formation.

Antimicrobial resistance of bacterial can occur through a number of mechanisms. Bacteria can alter their cell membrane permeability, preventing antibiotics from entering the cell. Similarly, bacteria can alter antibiotic binding sites on their surface membrane via genetic alteration. β‐lactam antibiotics (i.e. penicillin, carbapenems and cephalosporins) can be inactivated by bacteria producing β‐lactamase (enzyme) such as Staphylococcus aureus, enterobacteria, and N. gonorrhoeae.

Bacteria can adhere to cells through binding of a bacterial ligand to a host cell receptor. These ligands, which surround the organism in the form of pili, are antigenically specific for epithelial receptors (Figure 20.1). Pili have the ability to mediate haemagglutination. The number of pili can range from 100 to 400 and are usually 5–10 nm in diameter and up to 2 μm in length [3]. Pili express adhesins that allow the organism to adhere to tissue [3]. Type 1 (Mannose‐sensitive, associated with cystitis mainly), P (Mannonse‐resistant, associated with pyelonephritis, and S pili (seen with both bladder and kidney infections) are the most well described pili. Organisms can express either one type of pili, multiple types, or are un‐piliated (Dr adhesin‐associated UTIs, seen in pregnancy and children).

The vagina may be colonised with piliated organisms several days before the clinical onset of infection. Vaginal cells from women who seldom contract urinary infection do not allow pathogenic strains of bacteria to adhere to them, unlike those from women who become frequently infected. Similar differences occur in the mouth and may be determined by the human leucocyte antigen (HLA)‐A3 antigen.

Unpiliated organisms may be less adherent to host cells but also are less susceptible to phagocytosis. The process of change in pili is called ‘phase variation’ and is usually in response to the milieu. Through a symbiotic relationship, organisms, such as lactobacilli, act as a secondary defensive mechanism for the urinary tract by produce a protective biofilm, preventing competing pathogenic bacteria from contact with the urothelium [4–8].

20.2.1.2 Clinical Features

Symptoms often described are dysuria, pain, frequency of micturition, and urgency. Occasionally haematuria, strangury, offensive smelling urine, and suprapubic and lower back pain may be present. In women, following sexual intercourse or menstrual period, symptoms of dysuria and frequency are often the only symptoms experienced.

Clinical signs are usually suprapubic discomfort and cloudy urine (in un‐centrifuged urine, microscopy will show abundance of white cells with bacteria in the edges), occasionally accompanied by a palpable bladder if the patient is unable to void. Other signs can include warm peripheries due to sepsis, confusion, and if pyrexia, rigours and loin pain develop and can indicate an ascending infection (pyelonephritis).

20.2.1.3 Investigations

A urine dipstick test is a quick and simple first‐line investigation that can provide useful information whether pyuria or bacteriuria is present within urine [9, 10].

Microscopic urinalysis and culture of urine identifies the underlying pathogen and provides antibiotic sensitivities. Results can take up to 48 hours. Empirical treatment can be given without the results, but urine culture should be sent in all patients to exclude resistant bacterial strains [11, 12]. In practice, many women with urinary infection and pus in their urine have what is reported as sterile urine. Table 20.2 shows organisms that cause UTI.

A mid‐stream urine (MSU) specimens can be contaminated by bacteria as urine leaves the urethra, particularly in women and following urethral catheterisation. False‐positive urinalysis can also occur if a urine specimen has been left for several hours. Specimens should be refrigerated immediately and cultured within 24 hours.

Suprapubic aspiration of urine from the bladder provides the most accurate assessment of urine because it is least likely to be contaminated; in practice, this is rarely performed because it is invasive and requires a full bladder.

Recommended bacterial count that indicates significant bacteriuria: [14]

• 10³ colony‐forming units (cfu) ml of pathogens in a MSU sample in acute uncomplicated cystitis in women or recurrent UTIs.
  
• 10⁴ cfu ml⁻¹ of pathogens in an MSU in acute uncomplicated pyelonephritis in women or complicated UTIs in men.
  
• 10⁵ cfu ml⁻¹ of pathogens in an MSU in complicated UTI in women or asymptomatic bacteriuria in two consecutive MSU cultures more than 24 hours apart.

When urine is obtained from a catheter, cystoscope, or needle aspiration of the bladder, any organism signifies an infection. The concept of the colony count only applies to voided urine specimens.

In lower UTI cases, imaging studies are not required because clinical and urinalysis findings provide for accurate diagnosis. Lower UTIs in men, febrile infections, recurrent infections, suspicion of urinary tract obstruction, and the patient who is immunocompromised warrant further investigation.

Imaging modalities to consider are ultrasound, plain X‐ray, or computed tomography (CT).

Renal tract ultrasound can identify urinary retention, poor bladder emptying, and hydronephrosis. Plain film X‐ray of the kidneys, ureter, and bladder (KUB) is of little value in these patients but can help identify renal or bladder stone disease as well as for follow‐up purposes.

CT, with or without contrast, can rule out causes for renal obstruction and stone disease. Cystoscopic visualisation of the bladder can be performed for assessment of recurrent UTIs confirmed on urinalysis.

20.2.1.4 Management

Prevention is paramount. Conservative measures such as fluid advice, voiding urine following coitus, preventing constipation, and maintaining good genital hygiene can be helpful.

In the last few decades, the number of antimicrobial‐resistant organisms in the community and hospital have increased; therefore, it is important that all UTIs are treated adequately and appropriately guided by culture sensitivities and knowledge of pathogen strains within an area. Antimicrobial therapy of uncomplicated cystitis in premenopausal women are depicted in Table 20.3.

In women, continuous or postcoital antimicrobial prophylaxis for prevention of recurrent lower UTIs should be considered if conservative measures fail [11]. Any previous UTI should be adequately treated should be confirmed by a negative urine culture one to two weeks following treatment before starting antimicrobial prophylaxis.

Follow‐up is recommended in persistent recurrent cystitis or suspected underlying abnormalities.

20.2.1.5 Recurrent UTI

Nearly 30% of women will have two UTIs in a six‐month period, and 3% will have a third in the same period [15]. Table 20.4 summarises the pathophysiology and management of recurrent UTIs in men and woman.

Bacterial persistence is usually related to an underlying pathology in both men and women such as renal stone disease or fistulas. These people have relapsing UTI symptoms within days or weeks of stopping antibiotic therapy. Definitive management is to treat the underlying cause.

Women who suffer with reinfection usually do not have an underlying cause, and it is not always possible to cure them of this condition. Men on the other hand usually display signs of bladder outflow obstruction (BOO). The common causes are benign prostatic enlargement (BPE) or urethral stricture disease. For both men and woman, symptoms reoccur weeks or months after initial treatment of the infection and usually the same organism is to blame. Management for men is treatment of their underlying BOO. For women a number of antibiotic strategies can be deployed (Table 20.4).

20.2.1.6 UTI in Children

UTI is a common ailment in children of all ages, but it is not commonly seen by the urologist. The risk in the first decade of life is 1% in males and 3% in females [16]. Younger than age three months, UTI is more common in boys than girls, but after this, the trend reverses and girls are three times more likely to suffer with infections [17].

Figure 20.2 outlines the pathophysiology and risk factors for UTIs in children.

Investigations are warranted in girls who have two or more infective episodes and boys who have just one episode.

Management is dependent on underlying pathology.

20.2.3.1 Chemical Cystitis

Chemicals introduced into the bladder by iatrogenic, self‐inflicted, or accidental means can induce varying degrees of inflammation, from mild irritation to gross bladder necrosis. Diagnosis is based on history, high index of suspicion, and negative urine culture. Historically, ether was used to rupture Foley catheter balloons that would not deflate. Leakage of ether from the ruptured balloon was reported to cause severe chemical necrosis and bladder contracture [22]. Silver nitrate used for treatment of recurrent UTIs occasionally led to severe chemical cystitis.

Cyclophosphamide is commonly used in the treatment of malignancies (e.g. leukaemia) and autoimmune diseases (e.g. rheumatoid arthritis). Its metabolite, acrolein, is excreted in the urine, and with prolonged contact, commonly causes bladder inflammatory reactions leading to mucosal oedema and vasodilation resulting in increased friable capillaries (i.e. haemorrhagic cystitis), and in severe cases, full‐thickness bladder necrosis. On cystoscopy, no single bleeding vessel can be seen, but the haemorrhage may be persistent and even exsanguinating. The development of squamous cell carcinoma, adenocarcinoma, and leiomyosarcoma have been reported as the long‐term sequelae of cyclophosphamide use [23].

Other drugs and chemicals implicated to cause haemorrhagic cystitis or bladder neoplasm are depicted in Table 20.6.

20.2.3.2 Radiation Cystitis

Nearly 15–20% of patients who received radiotherapy for pelvic malignancies develop bladder complications [30]. It usually develops after 90 days from starting radiotherapy but can develop several years later [31].

Radiotherapy induces a progressive microscopic obliterative endarteritis that causes bladder mucosa ischaemia resulting in ulceration and bleeding. In injured areas, development of new friable blood vessels occurs which readily bleed after mucosal trauma, irritation, or distension. Cystoscopic features of a vascular blush on the bladder mucosa are typical of acute radiation injury. Severity tends to become less over time.

Delayed radiation injuries are progressive and irreversible. Histological features include cellular depletion, fibrosis, and obliterative arteritis [32]. Symptoms include dysuria, frequency, and urgency (small bladder capacity secondary to fibrotic changes). Treatment is aimed at symptoms (e.g. analgesia, anti‐muscarinics, or indwelling urethral catheters for small capacity bladders). Treatment for refractory radiation cystitis can be difficult but luckily is rare. Modalities include intravesical alum, formalin (will require anaesthetic as can be very painful), hyperbaric oxygen, iliac artery embolisation, or even palliative radiotherapy or even cystectomy.