Urinary tract infections

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36 Urinary tract infections

N.J.B. Carbarns

Key points

• Urinary tract infection (UTI) is one of the most common complaints seen in general practice and accounts for about one-third of hospital-acquired infections.
• UTI is one of the commonest reasons for prescribing antibiotics.
• Escherichia coli is the most frequent pathogen, accounting for more than three-quarters of community-acquired urinary tract infections.
• Symptoms are variable; many UTIs are asymptomatic and some present atypically, particularly in children and the elderly.
• The concept of significant bacteriuria (at least 100,000 organisms/mL of urine) is generally used to distinguish between contamination and infection, but lower counts than this can cause symptoms and disease.
• Asymptomatic UTI should be treated in children and pregnant women.
• Catheter-related UTI should be treated only when the patient has systemic evidence of infection.
• Antimicrobial sensitivity patterns are changing. E. coli is becoming increasingly resistant to amoxicillin, cephalosporins, trimethoprim and the quinolones.
• A 3-day treatment course is usually sufficient in uncomplicated lower UTI in women. Longer, 7–14-day courses are recommended for men, children and pregnant women.
• While it is not always necessary to send urine samples for laboratory analysis unless empirical treatment fails, they provide local epidemiology and antibiotic resistance data.
• Antibiotic prophylaxis may be beneficial in women with recurrent UTIs and in children with structural or functional abnormalities.

The term urinary tract infection (UTI) usually refers to the presence of organisms in the urinary tract together with symptoms, and sometimes signs, of inflammation. However, it is more precise to use one of the following terms.

• Significant bacteriuria: defined as the presence of at least 100,000 bacteria/mL of urine. A quantitative definition such as this is needed because small numbers of bacteria are normally found in the anterior urethra and may be washed out into urine samples. Counts of fewer than 1000 bacteria/mL are normally considered to be urethral contaminants unless there are exceptional clinical circumstances, such as a sick immunosuppressed patient.
• Asymptomatic bacteriuria: significant bacteriuria in the absence of symptoms in the patient.
• Cystitis: a syndrome of frequency, dysuria and urgency, which usually suggests infection restricted to the lower urinary tract, that is, the bladder and urethra.
• Urethral syndrome: a syndrome of frequency and dysuria in the absence of significant bacteriuria with a conventional pathogen.
• Acute pyelonephritis: an acute infection of one or both kidneys. Usually, the lower urinary tract is also involved.
• Chronic pyelonephritis: a potentially confusing term used in different ways. It can refer to continuous excretion of bacteria from the kidney, to frequent recurring infection of the renal tissue or to a particular type of pathology of the kidney seen microscopically or by radiographic imaging, which may or may not be due to infection. Although chronic infections of renal tissue are relatively rare, they do occur in the presence of kidney stones and in tuberculosis.
• Relapse and reinfection: recurrence of urinary infection may be due to either relapse or reinfection. Relapse is recurrence caused by the same organism that caused the original infection. Reinfection is recurrence caused by a different organism, and is therefore a new infection.

Epidemiology

UTIs are among the most common infectious diseases occurring in either the community or health care setting. Uncomplicated UTIs typically occur in healthy adult non-pregnant women, whereas complicated UTIs are found in either sex and at any age, frequently associated with structural or functional urinary tract abnormalities.

Babies and infants

UTI is a problem in all age groups, although its prevalence varies markedly. In infants up to the age of 6 months, symptomatic UTI has a prevalence of about two cases per 1000 and is much more common in boys than in girls. In addition to these cases, asymptomatic UTI is much more common than this, occurring in around 2% of boys in their first few months of life.

Children

In preschool children, UTIs become more common and the sex ratio reverses, such that the prevalence of bacteriuria is 4.5% in girls and 0.5% in boys. In older children, the prevalence of bacteriuria falls to 1.2% among girls and 0.03% among boys. Overall, about 3–5% of girls and 1–2% of boys will experience a symptomatic UTI during childhood. However, in girls, about two-thirds of UTIs are asymptomatic. The occurrence of bacteriuria during childhood appears to correlate with a higher incidence of bacteriuria in adulthood.

Adults

When women reach adulthood, the prevalence of bacteriuria rises to between 3% and 5%. Each year, about a quarter of these bacteriuric women clear their infections spontaneously and are replaced by an equal number of newly infected women, who are often those with a history of previous infections. On average, about one in eight adult women has a symptomatic UTI each year and over half of adult women report that they have had a symptomatic UTI at some time, 20% recurrently, with the peak age incidence in their early 20s. UTI is uncommon in young healthy men, with 0.5% of adult men having bacteriuria. The rate of symptomatic UTI in men rises progressively with age, from 1% annually at age 18 to 4% at age 60.

Elderly

In the elderly of both sexes, the prevalence of bacteriuria rises dramatically, reaching 20% among women and 10% among men. In hospitals, a major predisposing cause of UTI is urinary catheterisation. With time, even with closed drainage systems and scrupulous hygiene, bacteria can be found in almost all catheters and this is a risk for the development of symptomatic infection.

Aetiology and risk factors

In acute uncomplicated UTI acquired in the community, Escherichia coli is by far the most common causative bacterium, being responsible for about 80% of infections. The remaining 20% are caused by other Gram-negative enteric bacteria such as Klebsiella and Proteus species, and by Gram-positive cocci, particularly enterococci and Staphylococcus saprophyticus. The latter organism is almost entirely restricted to infections in young, sexually active women.

UTI associated with underlying structural abnormalities, such as congenital anomalies, neurogenic bladder and obstructive uropathy, is often caused by more resistant organisms such as Pseudomonas aeruginosa, Enterobacter and Serratia species. Organisms such as these are also more commonly implicated in hospital-acquired urinary infections, including those in patients with urinary catheters.

Rare causes of urinary infection, nearly always in association with structural abnormalities or catheterisation, include anaerobic bacteria and fungi. Urinary tract tuberculosis is an infrequent but important diagnosis that may be missed through lack of clinical suspicion. A number of viruses are excreted in urine and may be detected by culture or nucleic acid amplification methods, but symptomatic infection is confined to immunocompromised patients, particularly children following bone marrow transplantation, in whom adenoviruses and polyomaviruses such as BK virus are associated with haemorrhagic cystitis.

Pathogenesis

There are three possible routes by which organisms might reach the urinary tract: the ascending, blood-borne and lymphatic routes. There is little evidence for the last route in humans. Blood-borne spread to the kidney can occur in bacteraemic illnesses, most notably Staphylococcus aureus septicaemia, but by far the most frequent route is the ascending route.

In women, UTI is preceded by colonisation of the vagina, perineum and periurethral area by the pathogen, which then ascends into the bladder via the urethra. Uropathogens colonise the urethral opening of men and women. That the urethra in women is shorter than in men and the urethral meatus is closer to the anus are probably important factors in explaining the preponderance of UTI in females. Further, sexual intercourse appears to be important in forcing bacteria into the female bladder, and this risk is increased by the use of diaphragms and spermicides, which have both been shown to increase E. coli growth in the vagina. Whether circumcision reduces the risk of infection in adult men is not known, but it markedly reduces the risk of UTI in male infants.

Organism

E. coli causes most UTIs and although there are many serotypes of this organism, only a few of these are responsible for a disproportionate number of infections. While there are as yet no molecular markers that uniquely identify uropathogenic E. coli, some strains possess certain virulence factors that enhance their ability to cause infection, particularly infections of the upper urinary tract. Recognised factors include bacterial surface structures called P-fimbriae, which mediate adherence to glycolipid receptors on renal epithelial cells, possession of the iron-scavenging aerobactin system, and increased amounts of capsular K antigen, which mediates resistance to phagocytosis.

Host

Although many bacteria can readily grow in urine, and Louis Pasteur used urine as a bacterial culture medium in his early experiments, the high urea concentration and extremes of osmolality and pH inhibit growth. Other defence mechanisms include the flushing mechanism of bladder emptying, since small numbers of bacteria finding their way into the bladder are likely to be eliminated when the bladder is emptied. Moreover, the bladder mucosa, by virtue of a surface glycosaminoglycan, is intrinsically resistant to bacterial adherence. Presumably, in sufficient numbers, bacteria with strong adhesive properties can overcome this defence. Finally, when the bladder is infected, white blood cells are mobilised to the bladder surface to ingest and destroy invading bacteria. The role of humoral antibody-mediated immunity in defence against infection of the urinary tract remains unclear. Genetic susceptibility of individual patients to UTI has been reviewed (Lichtenberger and Hooton, 2008).

Abnormalities of the urinary tract

Any structural abnormality leading to the obstruction of urinary flow increases the likelihood of infection. Such abnormalities include congenital anomalies of the ureter or urethra, renal stones and, in men, enlargement of the prostate. Renal stones can become infected with bacteria, particularly Proteus and Klebsiella species, and thereby become a source of ‘relapsing’ infection. Vesicoureteric reflux (VUR) is a condition caused by failure of physiological valves at the junction of the ureters and the bladder which allows urine to reflux towards the kidneys when the bladder contracts. It is probable that VUR plays an important role in childhood UTIs that lead to chronic renal damage (scarring) and persistence of infection. If there is a diminished ability to empty the bladder such as that due to spinal cord injury, there is an increased risk of bacteriuria.

Clinical manifestations

Most UTIs are asymptomatic. Symptoms, when they do occur, are principally the result of irritation of the bladder and urethral mucosa. However, the clinical features of UTI are extremely variable and to some extent depend on the age of the patient.

Babies and infants

Infections in newborn babies and infants are often overlooked or misdiagnosed because the signs may not be referable to the urinary tract. Common but non-specific presenting symptoms include failure to thrive, vomiting, fever, diarrhoea and apathy. Further, confirmation may be difficult because of problems in obtaining adequate specimens. UTI in infancy and childhood is a major risk factor for the development of renal scarring, which in turn is associated with future complications such as chronic pyelonephritis in adulthood, hypertension and renal failure. It is therefore vital to make the diagnosis early, and any child with a suspected UTI should receive urgent expert assessment.

Children

Above the age of 2, children with UTI are more likely to present with some of the classic symptoms such as frequency, dysuria and haematuria. However, some children present with acute abdominal pain and vomiting, and this may be so marked as to raise suspicions of appendicitis or other intra-abdominal pathology. Again, however, it is extremely important that the diagnosis of UTI is made promptly to pre-empt the potential long-term consequences. National guidance has been published in the UK on paediatric UTIs to promote a more consistent clinical practice by ensuring prompt, accurate diagnosis and appropriate management (NICE, 2007). A key feature of the guidance is that children with unexplained fever should have their urine tested within 24 h and attention is given to avoiding over- or underdiagnosis, appropriate investigation and the prompt start of antibiotic treatment.

Adults

In adults, the typical symptoms of lower UTI include frequency, dysuria, urgency and haematuria. Acute pyelonephritis (upper UTI) usually causes fever, rigors and loin pain in addition to lower tract symptoms. Systemic symptoms may vary from insignificant to extreme malaise. Importantly, untreated cystitis in adults rarely progresses to pyelonephritis, and bacteriuria does not seem to carry the adverse long-term consequences that it does in children.

In about 40% of women with dysuria, urgency and frequency, the urine sample contains fewer than 100,000 bacteria/mL. These patients are said to have the urethral syndrome. Some have a true bacterial infection but with relatively low counts (100–1000 bacteria/mL). Some have urethral infection with Chlamydia trachomatis, Neisseria gonorrhoeae, mycoplasmas or other ‘fastidious’ organisms, any of which might give rise to symptoms indistinguishable from those of cystitis. In others, no known cause can be found by conventional laboratory techniques. It is important to consider the possibility of urinary tract tuberculosis, as special methods are necessary for its detection. Sometimes, the symptoms are of non-infectious origin, such as menopausal oestrogen deficiency or allergy. However, most cases of urethral syndrome will respond to standard antibiotic regimens as used for treating confirmed UTI.

Elderly

Although UTI is frequent in the elderly, the great majority of cases are asymptomatic, and even when present, symptoms are not diagnostic because frequency, dysuria, hesitancy and incontinence are fairly common in elderly people without infection. Further, there may be non-specific systemic manifestations such as confusion and falls, or alternatively the infection may be the cause of deterioration in pre-existing conditions such as diabetes mellitus or congestive cardiac failure, whose clinical features might predominate. UTI is one of the most frequent causes of admission to hospital among the elderly.

Investigations

The key to successful laboratory diagnosis of UTI lies in obtaining an uncontaminated urine sample for microscopy and culture. Contaminating bacteria can arise from skin, vaginal flora in women and penile flora in men. Patients therefore need to be instructed in how to produce a midstream urine sample (MSU). For women, this requires careful cleansing of the perineum and external genitalia with soap and water. Uncircumcised men should retract the foreskin. This is followed by a controlled micturition in which about 20 mL of urine from only the middle portion of the stream is collected, the initial and final components being voided into the toilet or bedpan. Understandably, this is not always possible and many so-called MSUs are in fact clean-catch specimens in which the whole urine volume is collected into a sterile receptacle and an aliquot transferred into a specimen pot for submission to the laboratory. These are more likely to contain urethral contaminants. In very young children, special collection pads for use inside nappies or stick-on bags are useful ways of obtaining a urine sample. Occasionally, in-and-out diagnostic catheterisation or even suprapubic aspiration directly from the bladder is necessary.

For primary care doctors located some distance from a laboratory, transport of specimens is a problem. Specimens must reach the laboratory within 1–2 h or should be refrigerated; otherwise, any bacteria in the specimen will multiply and might give rise to a false-positive result. Methods of overcoming bacterial multiplication in urine include the addition of boric acid to the container and the use of dip-slides, in which an agar-coated paddle is dipped into the urine and submitted directly to the laboratory for incubation. Both of these alternatives have difficulties. For the boric acid technique, it is important that the correct amount of urine is added to the container to achieve the appropriate concentration of boric acid (1.8%, w/v), as the chemical has significant antibacterial activity when more concentrated. When the dip-slide is used, no specimen is available on which to do cell counts.

Concerns about the relative expense and slow turn-around time of urine microscopy and culture have stimulated interest in alternative diagnostic strategies. Some advocate a policy of empirical antimicrobial treatment in the first instance, and reserve investigation only for those cases that do not respond. Others are in favour of using cheaper, more convenient screening tests, for example, urine dipsticks. It is important to be aware that there is no rapid screening test that will reliably detect all UTIs. Urine microscopy and culture remain the standard by which other investigations are measured.

Dipsticks

Dipsticks for rapid near-patient testing for urinary blood, protein, nitrites and leucocyte esterase are usually used, although there are concerns that these are reliable only when applied to fresh urine samples tested at the point of care. Assessment of colour changes on dipsticks can be subjective and automated reading systems have been developed to assist interpretation. Generally, the negative predictive value is better than the positive predictive value, so their preferred use is as screening tests to identify those specimens which are least likely to be infected and which therefore do not require culture. A perfectly valid alternative is just to hold the specimen up to the light: specimens that are visibly clear are very likely to be sterile.

The leucocyte esterase test detects enzyme released from leucocytes in urine and is ∼︀90% sensitive at detecting white blood cell counts of >10 mm−3. It will be positive even if the cells have been destroyed due to delays in transport to a laboratory. However, vitamin C and antibiotics in the urine such as cephalosporins, gentamicin and nitrofurantoin may interfere with the reaction. Although the presence of leucocytes is common in UTIs, it may also occur in other conditions. Particularly in children, white blood cells can be present for many reasons, including fever alone.

The nitrite test (also called the Griess test) detects urinary nitrite made by bacteria that can convert excreted dietary nitrate used as a food preservative to nitrite. Although the coliform bacteria that commonly cause UTI can be detected in this way, some organisms cannot, for example, enterococci, group B streptococci, Pseudomonas

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