A urinary tract infection is an infection anywhere in the urinary tract. These often cause inflammation of the urethra (urethritis), bladder (cystitis), or kidneys (pyelonephritis).The symptoms depend on the area affected.
Causes and incidence
Urethritis is often due to a sexually transmitted infection, such as gonorrhoea, but may have other causes. Cystitis and pyelonephritis are almost always the result of a bacterial infection that has travelled up the urinary tract from the urethra; the causative organisms are often bacteria from the rectum that have entered the urethra. Backflow of urine into the ureters from the bladder (vesico-ureteric reflux) causes recurrent urinary infection in children that often results in acute pyelonephritis. Infectious organisms may also be carried to the urinary tract in the bloodstream. Infections of the urethra are more common in men. Infections further up the urinary tract are more common in women, and are more likely to occur during pregnancy. However, an enlarged prostate gland is often a predisposing factor to bladder or kidney infection in men. In both sexes, causes of urinary tract infections include stones, bladder tumours, congenital abnormalities of the urinary tract, or defective bladder emptying as a result of spina bifida or a spinal injury. The risk of a urinary tract infection can be reduced by care over personal hygiene, regularly emptying of the bladder, and drinking plenty of fluids.
Types and symptoms
Urethritis causes a burning sensation when urine is passed. Cystitis causes a frequent urge to pass urine, lower abdominal pain, haematuria (blood in the urine), and, often, general malaise with a mild fever. Pyelonephritis causes fever, pain in the back under the ribs, and sometimes also violent shivering, nausea, and vomiting.
Urethritis can lead to the formation of a urethral stricture (narrowing of a section of the urethra). Cystitis does not usually cause complications unless the infection spreads to the kidneys. Pyelonephritis, if left untreated, can lead to permanent kidney damage, septicaemia (blood poisoning), and septic shock.
Diagnosis and treatment
Urinary tract infection is diagnosed by examination of a urine culture. Further investigations using intravenous urography or ultrasound scanning may be necessary. Most urinary tract infections are treated with antibiotic drugs. Increasing fluid intake and taking preparations such as potassium citrate that make the urine less acidic can relieve the symptoms.
Urinary tract infection in detail - technical
Urinary tract infection (UTI) is a common condition, accounting for 1 to 3% of all primary care consultations in the United Kingdom. It affects patients of both sexes and all ages. The commonest organism causing uncomplicated community-acquired bacterial UTI is Escherichia coli.
Aetiology and pathogenesis
The occurrence and course of a UTI is influenced by the integrity of the host defence and by bacterial virulence factors. Disruption of the highly specialized transitional cell epithelium which lines the urinary tract, incomplete bladder emptying, anatomical abnormalities, and the presence of a foreign body, such as a urinary catheter, can all contribute to disruption of the host defence and increase the likelihood of infection. Sexual intercourse, use of condoms, and use of spermicides all increase the risk, and genetic factors influence the susceptibility of some people, e.g. girls with the P1 blood group are at increased risk of acute pyelonephritis. Bacterial characteristics that determine their ability to cause infection include specific mechanisms to adhere to the uroepithelium (‘pili’ or ‘fimbrias’ in the case of certain E. coli), or adaptations allowing them to colonize foreign surfaces, such as a urinary catheter (proteus), and subsequently cause infection.
Clinical features and diagnosis
Presentation—UTI can present in a number of ways, but most commonly with some combination of dysuria, urgency, frequency, polyuria, suprapubic tenderness, and haematuria. Asymptomatic infection is common, especially in older people, but it is not justified to send a urine sample from an asymptomatic patient for culture, with the notable exceptions of pregnant women and prior to invasive urological surgery when treatment is mandatory.
Diagnosis—acute uncomplicated UTI can often be diagnosed on symptoms alone and submission of a sample for microbiological testing is unnecessary (exceptions to this rule include pregnancy and those patients with abnormal host defences). Current United Kingdom and European guidelines on the level of bacterial counts required to diagnose ‘significant’ infection are variable and should not be used as the sole determinant of whether antibiotic treatment should be initiated.
Differential diagnoses (‘culture negative syndromes’)—these include (1) chlamydial infection, which must be identified and treated to avoid long-term complications such as infertility; also (2) urethral syndrome and (3) painful bladder syndrome (interstitial cystitis), which significantly affect a patient’s quality of life and for which treatment is often unsuccessful.
Investigation—beyond microbiological testing, further investigation of women with uncomplicated UTI is seldom justified. In men, and those women with features indicating complicated infection, investigation for an underlying cause should be considered: diabetes must be excluded, and anatomical or functional abnormality of the urinary tract sought, as appropriate, by imaging, cystoscopy, and urinary flow studies.
Antibiotics—trimethoprim remains the first choice for community-acquired UTI in most areas. Complicated UTI (see below) is caused by a wider spectrum of organisms, and recommendations for treatment differ. Guidelines on specific antibiotic treatment and duration of treatment are available, but with increasing antibiotic resistance (including of E. coli to Trimethoprim), local microbiological advice should be taken into account when choosing antibiotic treatment.
Prevention of recurrent uncomplicated UTI—many clinicians advise patients with such recurrence to take measures to improve perineal hygiene, to empty the bladder after sexual intercourse, to maintain a high fluid intake, and (if vesicoureteric reflux is suspected) to practise double voiding, but the evidence that these measures are effective is weak. Long-term antibiotic prophylaxis reduces the rate of recurrent UTI, but at the risk of adverse effects. Nightly, thrice weekly, and postcoital prophylaxis have all been shown to be of benefit, but there is no evidence to support the use of rotating antibiotic prophylaxis regimen. Cranberry products and methenamine hippurate are effective in some patients. Oestrogens are not recommended for the routine prevention of recurrent infection in postmenopausal women, but may be of benefit in those with marked atrophic vaginitis. Vaccines against uropathogenic bacteria can prevent recurrent UTI, but these are not widely used in routine clinical practice in the United Kingdom.
Complicated urinary tract infections
Complicated UTIs are those occurring in a patient with abnormal host defence. It is uncommon for any man with an anatomically normal urinary tract to suffer a UTI. An important differential diagnosis in men is prostatitis—an umbrella term used to describe a disparate group of conditions, the treatment of which is often unsatisfactory.
Urethral catheterization—UTI occurs after 2% of in/out urethral catheterizations and after 10 to 30% of 5-day indwelling catheterization, and is nearly inevitable in patients with long-term indwelling catheters. This is an important cause of hospital-acquired infection, significantly increasing the risk of Gram-negative septicaemia and mortality. However, management of patients unable to empty their bladder fully for reasons such as prostatic outflow obstruction or neurogenic bladder dysfunction because of spinal cord injury is often difficult without medium- or long-term urinary catheterization. Use of prophylactic antibiotics to cover short-term catheter insertion may be justified, but this is not the case in patients with long-term catheters, although regular bladder washouts and methenamine may be of some benefit. Treatment of asymptomatic bacteriuria in patients with anatomically abnormal urinary tracts or with indwelling urinary catheters is unjustified and likely only to lead to the emergence of antibiotic-resistant urinary infection. Clean, intermittent self-catheterization should be considered as an alternative where possible.
Urinary tract stones—these are an important cause of recurrent and relapsing UTIs that are difficult or impossible to treat with antibiotic therapy alone, repeated courses of which often encourage the development of resistant organisms. Removal of stones is often difficult and requires repeated interventions. Identification of the stone type and prevention of formation of further stones is an important part of any treatment plan.
Anatomically abnormal kidneys—inherited renal abnormalities such as polycystic kidneys are often complicated by UTI, which can be difficult to treat if the infection involves a cyst that may be difficult to identify and can be sheltered from antibiotic penetration. Renal transplant recipients are at an increased risk of UTI due to a variety of factors, including the anatomy of the transplant kidney, postoperative catheterization, and immunosuppressive medication. Unusual viral organisms such as polyoma (BK) virus may cause infection in this group of patients.
Vesicoureteric reflux—the normal bladder prevents reflux of urine into the ureters during micturition. Congenital abnormalities of the vesicoureteric junction can allow this to occur, as can acquired abnormalities such as bladder outflow obstruction, which disrupts normal host defence against ascending infection and thus makes children (particularly girls) more prone to ascending UTI. Cortical defects (‘scars’) in the upper and lower poles of the kidneys are frequently found in such children. These may be caused by ascending infection causing acute pyelonephritis, but similar appearances can occur in the absence of UTI and are likely due to renal dysplasia, inherited along with abnormal insertion of the ureters into the bladder. Progressive kidney failure may occur in such patients, but it is more likely that this is due to the late effects of renal dysplasia and congenital reduction in renal mass, rather than to the effects of scarring caused by ascending infection. Clinical trials comparing long-term prophylactic antibiotics for the first 5 years of life vs surgical ureteric reimplantation have shown similar incidence of symptomatic UTI in both treatment groups; whether either treatment reduces the risk of progressive kidney failure remains uncertain.
Pregnancy—there is a significantly increased risk of acute pyelonephritis in pregnant women with untreated bacteriuria, many of whom will be asymptomatic. Late pyelonephritis is associated with an increased incidence of preterm delivery and low birth weight, hence the need in pregnancy to screen for and treat UTI promptly with antibiotics.
Ascending UTI is rarely complicated by unusual conditions such as acute papillary necrosis or perinephric abscess. These can lead to destruction of renal parenchymal tissue and long-standing renal impairment, usually in the context of abnormal host defence such as diabetes or urinary tract obstruction. Malakoplakia is an extremely rare complication of bacterial UTI, characterized by destructive tumour-like granulomatous infiltrates in the urinary bladder, kidneys, and (occasionally) other organs. Other causes of UTI may need to be considered depending on the patient’s ethnic background and medical and travel history, e.g. fungal infections, tuberculosis, and schistosomiasis.
Infection of the urinary tract is important for different reasons in different age groups. In infants and children, ascending infection is thought to be a preventable cause of renal parenchymal scarring and eventual renal failure, although it is controversial how frequently this occurs. In adult women, recurrent lower urinary tract infection (‘cystitis’) is a common cause of time off work. In all age groups, persistent or relapsing infection is an important indicator of abnormal host defences, usually due to abnormal anatomy or function of the urinary tract, and may result in irreversible renal damage unless the underlying cause is dealt with. Urinary tract infections (UTI) are the cause of over 50% of Gram-negative septicaemic episodes. In older people, nonspecific symptoms including toxic confusional states are often due to occult UTI.
‘Urinary tract infection’ refers to bacterial or fungal infection of the kidneys, renal pelvis, ureters, or bladder (viral infections may involve the urinary tract, as in Hantaan virus infection or BK virus nephropathy, but viruria more commonly reflects systemic viral infection). Infections primarily involving the urethra are nearly always sexually acquired and are dealt with elsewhere.
‘Pyelonephritis’ refers to infection primarily involving the kidneys and collecting systems. ‘Cystitis’ refers to infections localized to the urinary bladder. ‘Recurrent’ UTI are due to repeated reinfection, whether by similar organisms on each occasion or by different species; ‘relapsing’ and ‘persistent’ infections are due to the continued presence of the same organism, suppressed or not suppressed during antibiotic therapy. ‘Uncomplicated’ UTI occurs in an anatomically and functionally normal urinary tract; ‘complicated’ infection refers to all infections occurring in patients either with impaired host defence (e.g. diabetes), or with abnormal urinary tract function (e.g. pregnancy), or abnormal urinary tract anatomy (e.g. urinary tract obstruction).
Symptomatic bacterial UTI is one of the commonest bacterial infections. Around 1% of boys and 3% of girls will develop a UTI during childhood, and 50% of women will be treated for at least one UTI during their lifetime, with recurrent infections in a significant minority. UTI is rare in men until after the age of 60, when the rising prevalence of impaired bladder emptying leads to an increased incidence of infection. Asymptomatic bacteriuria is found in about 10% of elderly men and in 20% of elderly women. UTI is one of the commonest bacterial infections managed in primary care, and is the cause of 1 to 3% of all primary care consultations in the United Kingdom. UTI is responsible for over 25% of all community-acquired bacteraemias, more than any other source of infection. The Nosocomial Infection National Surveillance System reported that in England (1997–2002), 8.5% of hospital-acquired bacteraemias were due to catheter-associated UTI and 5.2% due to non-catheter-associated UTI.
The commonest causative organisms in uncomplicated bacterial UTI are Gram-negative gut organisms, particularly Escherichia coli (Bullet list 1). This reflects the fact that most infections reach the urinary tract via the urethra from the perineum. However, as discussed below, only some subtypes of E. coli and only some of the other species of gut organisms have the necessary virulence characteristics to enable infection of the normal urinary tract. E. coli is the third most common organism causing hospital-acquired bacteraemia. Complicated UTIs are caused by a broader spectrum of bacteria, including Gram-positive in addition to Gram-negative organisms and those with multiple resistance to antibiotics.
- ◆ Escherichia coli
- ◆ Klebsiella pneumoniae
- ◆ Proteus
- ◆ Pseudomonas
- ◆ Enterococcus
- ◆ Staphylococcus saprophyticus (in sexually active females)
The occurrence and course of UTI are influenced by the integrity of the host defence and bacterial virulence factors.
Most UTIs are acquired by ascent of the infecting organism up the urethra; only a very small minority result from haematogenous spread or—even less commonly—from vesicoenteric fistulas. The renal pelvis, ureters, bladder, and urethra possess a highly specialized transitional cell epithelium, which normally maintains complete impermeability to all components of urine, including toxins and water. This is maintained by tight junctions between the surface layers of epithelial cells, with a very high transepithelial electrical resistance. In the bladder, this impermeability has to be maintained despite repeated large changes in surface area as the bladder fills and empties. This is maintained by unfolding and refolding of the large, highly folded ‘umbrella’ cells that form the uppermost layer of the epithelium, together with insertion and endocytosis of vesicles, ready-lined with uroplakin, a hexagonal transmembrane protein found only on the surface of umbrella cells. In experimental models, infection is associated with a marked reduction in transepithelial resistance and loss of tight junctions, allowing components of urine to stimulate pain fibres and inflammatory cytokine release.
Ascending infection takes place in a series of steps, at each of which defective host defence increases the chance of successful establishment of infection.
Frequency and completeness of bladder emptying
For an ascending infection to become established in the bladder, the number of organisms needs to reach a critical mass. The chance of this happening is reduced by increased urine flow rate, causing dilution of organisms within the bladder, and by frequent voiding, which also flushes the urethra and helps to prevent ascent of organisms into the bladder. This is termed ‘hydrokinetic’ defence. Habitual infrequent voiding is thought to be a risk factor for recurrent UTI for this reason. Patients with recurrent UTIs are routinely advised to increase fluid intake and frequency of voiding, and some women report that a high fluid intake alone is enough to clear symptomatic infection. Incomplete voiding, which may be present in both sexes and is not necessarily due to outflow obstruction (Bullet list), is an important cause of increased susceptibility to urine infection.
Bullet list 2 Some causes of incomplete bladder emptying
- ◆ Bladder outflow obstruction
- • Benign prostatic hypertrophy
- • Prostate cancer
- • Strictures—bladder neck, urethral
- • Uterine prolapse
- ◆ Detrusor underactivity
- ◆ Abnormal bladder innervation
- • Spinal cord injury
- • Autonomic neuropathy, e.g. diabetes
During normal micturition urine is expelled into the urethra, while retrograde flow (‘reflux’) of urine into the ureters is prevented because muscular contraction of the bladder wall results in closure of the vesicoureteric junctions. Reflux of urine into the ureters can occur if this mechanism is defective, sometimes as far as the renal pelvis, followed by return to the bladder once bladder contraction has finished. The most common cause of reflux is abnormal insertion of the ureters into the bladder, which occurs as a relatively frequent developmental anomaly. The other major cause is abnormally high intravesical pressure, e.g. in high-pressure chronic retention of urine due to bladder outflow obstruction, or in neurogenic bladder in patients with partial spinal cord lesions. Whatever the cause, reflux of urine results in failure to expel all bladder urine during micturition and therefore significantly impairs host defence against infection, as well as being associated with a greatly increased risk of infection ascending to the kidneys and causing acute pyelonephritis. Vesicoureteric reflux is frequently found in children with UTI. The question of whether ascending infection is a cause of renal damage in children with reflux is discussed later in this chapter.
Foreign bodies, stones, and privileged sites
The presence of a foreign body, such as a urinary catheter or ureteric stent, or a stone within the urinary tract, creates a protected site where uropathogenic organisms can adhere and multiply, relatively protected from both hydrokinetic and mucosal defence mechanisms. In this situation it is often impossible to eradicate urine infection unless the foreign body or stone is removed, and prolonged use of antibiotics often results in the acquisition of resistance by the infecting organism. Urinary infection is nearly inevitable after a few weeks of bladder catheterization. Other ‘privileged’ sites include renal cysts (as in polycystic kidney disease, discussed below) and bladder diverticulae.
Many women first experience acute cystitis shortly after becoming sexually active. Most women have transient bacteriuria after sexual intercourse, which develops into symptomatic cystitis only in a minority. In case–control studies of young women, the risk of UTI was associated with vaginal intercourse, and increased further by condom use. These findings are explained by the mechanical effect of intercourse encouraging ascent of organisms up the urethra, an effect that may be exacerbated by condom use, particularly without lubricants. The risk of UTI is also increased by a change in sexual partner, which may reflect male to female transmission of uropathogens. Use of spermicides as an adjunct to barrier contraceptive methods is also associated with an increased rate of periurethral colonization with E. coli and other uropathogens and with an increased risk of symptomatic UTI, probably because the active component in spermicides (nonoxynol-9) is bactericidal against lactobacilli. The protective effect of micturition soon after intercourse, based on the supposition that washout of recently introduced bacteria will prevent establishment of infection, remains unproven.
Vaginal and periurethral flora
Vaginal secretions are normally colonized by lactobacilli that appear to protect against colonization by uropathogenic bacteria such as E. coli. The mechanism of this protection is uncertain, but may in part be related to the maintenance of an acidic pH, which suppresses growth of some uropathogenic bacteria. Suppression of this normal vaginal colonization by antibiotic treatment or by spermicide use increases the risk of colonization of the periurethral mucosa by uropathogenic bacteria and subsequent ascending UTI. In addition, atrophic vaginitis caused by oestrogen deficiency is associated with the absence of lactobacillus colonization, which may be part of the reason for the increased risk of UTI in postmenopausal women.
In laboratory studies, adherence of E. coli to both vaginal and buccal cells is greater in cells taken from women with recurrent UTI than in cells from healthy controls, and women with recurrent UTI more frequently have gut colonization by uropathogenic strains of E. coli, suggesting that they experience more frequent UTIs because they are more susceptible to colonization of the periurethral area by uropathogenic bacteria. It appears that this difference in susceptibility to colonization and infection, especially in patients in whom there is no other defect of host defence (such as vesicoureteric reflux), is due to genetically determined differences in the extracellular antigens to which bacteria adhere, in particular in the expression of blood group antigens.
The density of glycosphingolipids is higher in patients with the P1 blood group than those with the P2 blood group, and the P1 blood group is a risk factor for acute pyelonephritis among girls without vesicoureteric reflux. Expression of the large oligosaccharide A, B, H blood-group antigens on the cell surface partially or completely obscures the smaller glycosphingolipids, preventing them from being bound by type P pili, which is why women with the secretor phenotype, in which these antigens are both expressed on the cell surface and secreted, are less prone to most E. coli infections than nonsecretors. Nonsecretors also have an increased inflammatory response (fever and acute phase response) to urinary infection compared with secretors, and nonsecretors are over-represented among patients with urographic evidence of reflux nephropathy. However, some E. coli strains only bind to cells from subjects who are secretor-positive blood group A.
Another aspect of host defence is the local production of antimicrobial peptides, secreted by uroepithelial cells into the urine, and the secretion of immunoglobulin A into the urine. However, there is little convincing evidence that impaired local IgA secretion is responsible for increased susceptibility to UTI. Patients with defects in systemic immunity, whether cellular or humoral, do not appear to be at greatly increased risk of UTI; the risk of UTI with AIDS is only increased in homosexual men practising anal intercourse.
Bacterial virulence factors
The ability of a bacterium to colonize the gut and periurethral mucosa, and subsequently to adhere to the uroepithelium, is a major determinant of its ability to cause clinical infection, particularly if other host defences are intact. This ability to adhere is governed by specific interaction between bacterial adhesins, located on the tips of thin filaments (‘pili’ or ‘fimbrias’), with genetically determined glycoproteins on the cell surface of the host cell. Type 1 fimbrias bind to mannose-containing glycoproteins that are present on the surface of uroepithelial cells, but also to Tamm–Horsfall protein, which is present in urine and can competitively inhibit binding of bacteria to cell surface glycoproteins. Type P pili bind the α-galactosyl-1,4-β-galactose disaccharide sequence present in some glycoproteins and glycosphin-golipids, including the human P blood-group antigen system, and also on the cell surface of uroepithelial cells as well as red cells.
Some uropathogens are particularly adapted to colonizing foreign surfaces, particularly those coated by biofilm or mucin; for example, proteus are able to transform into a swarming phenotype with massive flagellas, organize into rafts, and move very rapidly against the flow of urine—they are therefore important causes of infection in patients with indwelling urinary catheters and those with ileal conduits. Staphylococcus saprophyticus, an important cause of UTI in sexually active young women, is probably better able to cause UTI than S. aureus or S. epidermidis because of its possession of a lactosamine adhesion, permitting adherence to uroepithelial cells.
Following adherence, fimbrias appear to retract, drawing the organism closer to the surface of the uroepithelial cell. Adherence is followed by apoptosis, exfoliation, and excretion of infected superficial cells and replacement by less differentiated cells, a process that may also contribute to host defence.
Bacterial adherence results in the local production of interleukin 8 (IL-8), which results in neutrophil migration through the uroepithelium into the bladder. Inflammatory cytokine release may also be promoted by soluble bacterial stimuli, such as lipopolysaccharide.
A few species of bacteria, collectively known as ‘uropathogenic’ bacteria, together account for most UTIs (Table 1); the presence of nonuropathogenic species suggests an abnormality of host defence. Within uropathogenic species there are strains that are capable of causing infection and other strains that are far less likely to do so: uropathogenicity is determined by expression of cell surface molecules determining adhesion to receptors on uroepithelial cells, toxin production, factors conferring resistance to the membrane attack complex, and virulence factors.
|Table 1 Usefulness of inspection and dipstick testing in the diagnosis of UTI|
|Test||Utility||False positive||False negative|
|Cloudy appearance||Suggestive||Phosphate crystals||Common|
|Haematuria||Unreliable||Renal disease, stones, tumours||Common|
|Leucocyte esterase||Highly suggestive||Some antibiotics||Boric acid|
|Nitrite||Highly suggestive||Few||Gram +ve infection|
Clinical features of UTI
The commonest presentation of UTI is with ‘cystitis’, a symptom complex associated with lower UTI in which many of the symptoms are directly attributable to increased bladder irritability caused by local infection. Typical symptoms—not all of which are specific for lower UTI—are listed in Bullet list 3. Dysuria may be due to urethritis or vaginitis, but these are usually not associated with urinary frequency, and may be associated with vaginal discharge or itching and with specific findings on vaginal examination. There is considerable overlap between the symptoms of UTI (urgency, frequency, and urge incontinence) and idiopathic overactive bladder, but dysuria and haematuria are uncommon in this condition.
Bullet list 3 Common symptoms of lower UTI
- ◆ Severe dysuria, often described as ‘scorching’ or ‘like peeing barbed wire’, worse towards the end of or immediately after micturition
- ◆ Increased urinary frequency
- ◆ Urgency—the sensation of a strong desire to pass urine
- ◆ Strangury—the feeling of needing to pass urine despite just having done so
- ◆ Offensive-smelling urine, often described as ‘strong’ or ‘fishy’
- ◆ Macroscopic haematuria
- ◆ Urge incontinence—leakage of urine associated with the desire to pass urine
- ◆ Constant lower abdominal aching, not just in the genital area but also in the back, flanks, and lower abdomen
- ◆ Nonspecific malaise, aching all over, nausea, tiredness, irritability, and cold sweats
Genuine inflammation of the bladder wall may or may not be present, and it is important to remember that there may be noninfective causes of increased bladder irritability, such as chemical- or drug-induced cystitis and radiation cystitis, and pinworm/threadworm infection. Most patients with cystitis (bacterial infection confined to the bladder) do not have fever, nor is there evidence of an acute phase response.
By definition, this is an incidental finding in patients whose urine is cultured despite the absence of urinary tract symptoms. It is seldom justified to send a urine sample from an asymptomatic patient for culture, so this diagnosis should only rarely be made in clinical practice. Two important exceptions are during pregnancy and prior to invasive urological surgery (see below). Elderly patients with asymptomatic bacteriuria are also at increased risk of death, but this is probably because bacteriuria is a marker of poorer general health, and antibacterial treatment has not been shown to improve survival in this situation.
The term ‘acute pyelonephritis’ denotes infection within the renal pelvis, with or without active infection within the renal parenchyma. The diagnosis is usually made on the basis of the presence of flank pain (usually unilateral), fever, rigors, raised C-reactive protein (or erythrocyte sedimentation rate (ESR) or plasma viscosity), neutrophilia, and evidence of urine infection on culture of a midstream urine sample. However, rigorous tests to localize the site of infection (discussed below) show that the correlation between the presence or absence of bacteriuria in the upper urinary tract and the presence or absence of flank pain, systemic symptoms, and an acute phase response is dismally poor; many patients with infection confined to the bladder have flank pain and fever, whereas over 60% of elderly women with asymptomatic bacteriuria have upper tract infection. The symptoms and signs of so-called ‘acute pyelonephritis’ are therefore in reality those of a marked host response to UTI, irrespective of whether organisms are multiplying in the renal pelvis or in the bladder.
Inspection and dipstick testing
In a ‘classic’ case of established UTI the urine is cloudy, has an offensive smell, and is positive for blood, protein, leucocyte esterase, and nitrite on dipstick urinalysis. In this situation it is reasonable to make a diagnosis of UTI without further delay, and to institute empirical treatment. Whether a midstream urine sample should also be sent to the laboratory for confirmation and identification of the causative organism depends on the clinical situation, as discussed below. However, in many situations the diagnosis is not so obvious, and the diagnostic accuracy of inspection and dipstick testing less good.
Cloudy urine may be caused by bacteria and pyuria, but may also be caused by amorphous phosphate crystals that form in normal urine as it cools. Low concentrations of bacteria and white cells will not cause sufficient turbidity to be detected on visual inspection. An offensive, fishy smell is highly suggestive of UTI, but relatively infrequent.
Macroscopic haematuria can certainly occur as a result of severe cystitis, but is frequently absent in genuine UTI and is more often due to glomerular bleeding or urothelial bleeding as a result of tumours or stones. Dipstick detection of haematuria is neither sensitive nor specific for the detection of UTI. Proteinuria can occur in UTI as a result of the release of proteins from white cells, but is neither specific nor sensitive.
Leucocyte esterase is an enzyme released by white cells and a reliable test for pyuria, which is in most situations a major diagnostic criterion for UTI, as discussed in the next section. A positive test indicates 10 white cells/ml. Note, however, that transport of urine samples in containers containing boric acid can result in false-negative leucocyte esterase tests, as the boric acid inhibits the enzyme.
Nitrite is produced by most uropathogens, which reduce urinary nitrate to nitrite, but not by Gram-positive organisms. A positive test for nitrite is highly suggestive of UTI. False-negative tests can be seen in patients with low dietary nitrate and in those taking high-dose ascorbic acid. The diagnosis of acute uncomplicated UTI is highly likely with a history of two urinary symptoms, and the likelihood is increased further with specific combinations of symptoms (e.g. dysuria and frequency without vaginal discharge), or a positive nitrite test.
A combination of visual inspection and dipstick testing is a reasonable screening test for patients in whom uncomplicated UTI is suspected on clinical grounds: in this situation, crystal-clear urine and negative dipsticks for nitrite and leucocyte esterase make the diagnosis of UTI very unlikely (Table 1). The worst that is likely to happen if the diagnosis is missed is that the patient will re-present with more obvious abnormalities due to progression of the UTI to a more severe stage. However, in situations in which it would be important not to miss the opportunity to start treatment early, e.g. in patients with known abnormalities of host defence, pregnancy, or previous acute pyelonephritis, or in suspected atypical infections, formal microscopy and culture of the urine is required. An algorithm for diagnosis of suspected uncomplicated UTI in adult women is shown in.
Microscopy and culture of urine
The diagnosis of bacterial infection in the urinary tract might appear straightforward, relying on culture of freshly voided urine. However, urine samples are very easily contaminated during voiding by bacteria from the perineal skin (or, to a lesser extent, the foreskin in males), resulting in false-positive results. The only certain way to circumvent this problem is to take urine directly from the bladder, either by suprapubic needle aspiration of urine from the bladder, which is invasive and seldom performed in clinical practice, or by urethral catheterization, which carries a 1 to 2% risk of introducing infection into the bladder. In men, contamination of the voided urine sample can largely be avoided by retraction of the foreskin prior to voiding. In women, the reliability of urine culture can be improved by instructing women to part the labia with one hand and ensuring collection of a midstream sample, without either the initial portion or the ‘afterdrip’, but is not improved further by perineal washing or antiseptic use. These precautions only reduce the risk of contamination, rather than abolishing it altogether.
Microscopy of urine samples allows quantification of pyuria—the presence of white blood cells in the urine. However, the methodologies used to report pyuria vary enormously: microscopy of urine that has been centrifuged and resuspended, with reporting of the number of cells per high-power field, gives results which bear little relation to leucocyte excretion rate or to counting cells from unspun urine in a counting chamber, when significant pyuria is usually defined as a urinary white cell count of 10 leucocytes/µl or more.
Bacterial UTI is by far the commonest cause of pyuria, and symptomatic patients with pyuria whose urine cultures are reported as showing no significant pathogens should be suspected either of having ‘low-count’ bacteriuria due to early infection, or infection with a slow-growing organism, chlamydial infection, or one of the causes of sterile pyuria (Bullet list 4). However, vaginal leucorrhoea can also result in ‘false-positive’ pyuria.
Bullet list 4 Causes of ‘sterile pyuria’
- ◆ Partially treated bacterial UTI
- ◆ Bacterial UTI with a ‘fastidious’ organism
- ◆ Chlamydial urethritis
- ◆ ‘False-negative’ urine cultures due to contamination of midstream urine sample with antiseptic
- ◆ Contamination by vaginal leucocytes
- ◆ Chronic interstitial nephritis:
- • Analgesic nephropathy
- • Sarcoidosis (urinary white cells may be lymphocytes, not neutrophils)
- ◆ Urinary tract stones
- ◆ Acute interstitial nephritis, e.g. allergic interstitial nephritis (urinary white cells may be eosinophils)
- ◆ Papillary necrosis:
- • Diabetes
- • Sickle-cell disease
- ◆ Renal tract tuberculosis
- ◆ Fever
Microscopy also gives information on whether the urine sample is contaminated by cells from the periurethral area. Squamous cells are five to seven times larger than red cells and are easily recognized on microscopy: their presence in a midstream urine sample has conventionally been taken to indicate contamination, but they may originate from the urethra or from the epithelium of the vulva and vagina, as well as from areas of squamous metaplasia in the bladder, which is a common finding; and squamous cells are frequently seen in urine obtained by bladder catheterization, showing that their presence is not an absolute indicator of contamination.
Once a urine sample is obtained, the conditions under which it is cultured determine whether any organisms present grow. Standard laboratory culture conditions are designed to encourage the growth of recognized urinary pathogens (if present), but may not be optimal for the growth of atypical organisms or of those not usually recognized as urinary pathogens. Because small numbers of organisms are frequently cultured from urine as a result of contamination, growth of an organism is conventionally reported as a ‘significant growth’ if it meets several criteria. These are summarized in Bullet list 5
Bullet list 5 Criteria for the diagnosis of UTI
- ◆ There is a pure growth, i.e. of a single organism
- ◆ The organism grown is a ‘recognized’ urinary pathogen
- ◆ Quantitative urine culture results in >105 cfu/ml
- ◆ There is significant pyuria on urine microscopy, and few if any squamous cells
Genuine mixed growth of two or more bacteria may occur in complicated UTI (Bullet list 6), as may the growth of an organism not usually associated with the urinary tract. The spectrum of organisms recognized as capable of causing genuine UTI is widening. S. saprophyticus was only fairly recently recognized as a cause of UTI in sexually active women, and it is possible that other true urinary pathogens are yet to be identified, perhaps accounting for some cases of the so-called urethral syndrome (see below). ‘Low-count’ bacteriuria may reflect genuine bladder infection, particularly in early UTIs, and may occur in patients who have increased their fluid intake and are ‘diluting’ their bacterial counts by generating a high urinary output; also in patients infected with slow-growing organisms such as S. saprophyticus.
Bullet list 6 Conditions in which genuine mixed-growth UTI may occur
- ◆ Ileal conduits
- ◆ Neurogenic bladder
- ◆ Vesicocolic fistula
- ◆ Urinary tract stones
- ◆ Renal abscesses
- ◆ Long-term indwelling urinary catheters or stents
The criterion of 105 cfu/ml was originally validated in asymptomatic women, but subsequent studies showed that nearly 50% of women presenting with frequency and dysuria had genuine bladder infection but with counts between 102 and 105 cfu/ml on culture of a midstream urine sample. If symptomatic women with counts of between 102 and 104 cfu/ml are left untreated, most will have persistent symptoms and counts of more than 105 cfu/ml 2 days later. Current European guidelines advise that the number of colony counts that should be considered to indicate UTI should vary according to the clinical context, e.g. with lower counts being accepted as indicative of infection in the presence of symptoms. However, implementation of these criteria by laboratories would require high-quality clinical details to be provided at the time of submission of the urine sample, and most laboratories adhere to the 105 criterion. In men, bacterial counts of 103 cfu/ml or more are very likely to reflect significant infection, as the potential for significant contamination is lower.
The presence of pyuria further increases the likelihood that low counts are significant, although pyuria is not always present in proven bladder infection, particularly if the sample is taken early after the onset. The traditional method of expressing urinary white cell counts as cells per high-power field is very poorly reproducible as the volume in a high-power field is extremely variable. If a counting chamber or equivalent is used, then a criterion of 10 white cells/mm3 separates patients with genuine bacteriuria from those without.
Localization to upper or lower urinary tract
Tests to discover whether infection is confined to the bladder or whether it has spread to involve one or both kidneys are very seldom necessary, but may be required if, for example, surgical removal of a kidney because of recurrent infection is contemplated. The ‘gold standard’ for diagnosis of upper UTI is culture of urine obtained from each ureter by direct catheterization during cystoscopy, but such an invasive procedure can only be justified in exceptional circumstances, and even then may be difficult to interpret due to contamination of ureteric samples by bladder urine during passage of the catheters.
An alternative to ureteric catheterization is the Fairley test, which involves a bladder washout using neomycin and fibrinolytic enzymes. Urine is cultured following completion, to confirm eradication of bladder bacteria, and then at 10, 20, and 30 min after completion of the washout. Bacteriuria returns slowly, if at all, in patients with infection confined to the bladder, but because the washout procedure has no effect on bacteria in the upper urinary tracts, rapid reappearance of bacteriuria indicates upper UTI. Using this test it has been shown that both upper and lower UTI are frequently asymptomatic and that flank pain and fever are extremely unreliable indicators of the presence of upper UTI.
Detection (by immunofluorescence staining) of immunoglobulin-coated bacteria is suggestive of tissue invasion, but is not reliable compared with ureteric catheterization or Fairley tests. This may be partly because tissue invasion can also occur in severe lower UTI, such as that complicating urethral catheterization. Raised concentrations of urinary β2-microglobulin occur in the presence of tubular damage due to ascending infection, but may also be found patients with chronic kidney disease. Renal excretory function usually remains unchanged during acute pyelonephritis unless obstruction is present, but acute renal failure is occasionally seen, often associated with coincident use of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics. Abnormal appearances on contrast CT scanning and/or dimercaptosuccinyl acid (DMSA) scanning have been reported, including generalized renal swelling, focal areas of decreased parenchymal enhancement, and perirenal abscess formation, with the development of cortical scars and calyceal diverticulae if imaging is repeated on follow-up. In general, the more severe the infection is clinically (assessed by acute phase response, duration of fever, etc.), the more marked the radiological abnormality. However, significant loss of renal excretory function following acute pyelonephritis in patients without diabetes, obstruction or pre-existing reflux nephropathy/dysplasia, is remarkably uncommon even on long-term follow-up, and the significance of such scars is therefore uncertain.
Differential diagnosis of UTI
Occasionally patients may present with symptoms and signs highly suggestive of UTI, with or without pyuria, but with negative urine cultures. These patients may have ‘false-negative’ urine cultures, e.g. a low growth of a genuine pathogen; infection with a ‘fastidious’ organism, the presence of which is not detected by routine laboratory cultures; or they may have a noninfectious cause. It is dangerous to label symptoms in such patients as psychogenic; prolonged symptoms combined with numerous unsuccessful trials of antibacterials, or with different explanations from different doctors, may result in psychological stress, which in turn may amplify symptoms, and there is little evidence that psychological disease is the primary problem, even in a subgroup.
Urethral syndrome and chlamydial urethritis
The term ‘urethral syndrome’ was used in the past as a synonym for the typical symptoms of cystitis, namely frequency, urgency, and dysuria. More recently it has been applied to the subgroup of women with typical symptoms but in whom a recognized urinary pathogen cannot be cultured from the urine. A significant proportion of these patients, particularly those with pyuria, have chlamydial urethritis.
Chlamydial infection can be confirmed by culture of a urethral swab or by detection of chlamydia antigens on an endocervical or urethral swab or first-pass urine specimen by nucleic acid amplification techniques. It can be treated with tetracyclines, but as the infection may be sexually transmitted it is also important to treat the patient’s sexual partner(s), who may be asymptomatic. Patients with confirmed chlamydial infection should also be tested for gonorrhoea.
Other patients with urethral syndrome have ‘low-count’ infection with a true bacterial urinary pathogen. Vaginal infection or atrophy should be excluded, as these can cause similar symptoms.
The pathogenesis and optimal management of the remaining patients with frequency and dysuria, but with no identifiable bacterial infection, remains controversial. There is controversy over the role of ‘fastidious bacteria’ that are difficult to grow in the laboratory, particularly lactobacilli. Empirical antibiotic treatment is equally successful in eradicating symptoms in women presenting to primary care whether or not urinary pathogens are found on urine culture, suggesting that the syndrome is frequently due to bacterial infection that is not detected by routine laboratory urine culture. However, a few women with persistent symptoms do not respond to antibiotics, and in these women repeated courses of antibiotics are likely to lead to the emergence of antiobiotic-resistant organisms, which may later cause true infection that is difficult to treat. Psychological distress is common in patients with persistent lower urinary tract symptoms, but the prevalence of emotional or psychiatric disorders is no higher in women presenting to general practitioners with dysuria and frequency whose urine cultures are negative than in those with proven cystitis. Urologists often offer such women urethral dilatation on the assumption that the symptoms are due to urethral spasm or stricture, but there is minimal evidence beyond clinical anecdote that this procedure is of any benefit; one randomized controlled trial showed no difference in outcome between urethral dilatation and cystoscopy alone.
Women with recurrent episodes of frequency and dysuria, with or without pyuria, whose urine cultures remain sterile should be carefully evaluated for the presence of vaginitis (either infective or atrophic). It is justified in this situation to obtain urine direct from the bladder during an episode, preferably by suprapubic aspiration or alternatively by urethral catheterization, and ensure that this is cultured in conditions permitting the identification of fastidious or low-growing organisms. In urine obtained direct from the bladder, any growth of organisms is clinically significant. Any infection so detected should be treated, preferably with a prolonged course of an appropriate antibiotic to ensure complete eradication. If no infection can be detected, cystoscopy is required to exclude noninfective causes of cystitis.
Painful bladder syndrome/interstitial cystitis
Painful bladder syndrome/interstitial cystitis is a chronic bladder syndrome of unknown aetiology. It is characterized by bladder pain (which classically worsens on bladder filling and diminishes with bladder emptying), urgency, frequency, and nocturia, despite—by definition—sterile urine. The syndrome often coexists with other conditions, particularly irritable bowel syndrome. Urine microscopy shows pyuria. Cystoscopy shows variable inflammation, sometimes with ulceration (Hunner’s ulcers, first described in 1914). Bladder biopsies show a chronic inflammatory infiltrate; mast cell infiltration is common, but is also seen in infective cystitis. The condition may progress to cause contracture of the bladder.
Many of these features would be explained by an acquired defect in the barrier function of the uroepithelium, but the cause of such a defect remains unclear. It remains possible that infection by a fastidious organism is responsible for initiating the disease in some patients. Numerous therapies have been tried, including dietary restriction (citrus fruits, caffeine, alcohol and carbonate drinks may worsen symptoms); various oral drugs (pentosan polysulphate sodium, hydroxyzine, amitriptyline, antibiotics, ciclosporin, gabapentin); instillation of intravesical agents including heparin, glycosoaminoglycans and bacille Calmette–Guérin (BCG); and most commonly hydrodistension. In severe cases, where all other therapeutic options have failed, bladder augmentation or cystectomy with urinary diversion may be necessary.
This presents similarly, although often more acutely and with macroscopic haematuria. It may be caused by acrolein (a metabolite of cyclophosphamide), ifosfamide, NSAIDs (particularly tiaprofenic acid), and danazol.
Ketamine abuse can result in severe inflammation of the urothelium, associated with decreased bladder compliance and high-pressure vesicoureteric reflux, sometimes resulting in obstructive kidney damage. The syndrome typically presents with severe lower urinary tract symptoms, with urinary frequency, urgency, dysuria, urge incontinence, with or without painful haematuria. On cystsoscopy the macroscopic appearances can be mistaken for interstitial cystitis. The histological appearances mimic carcinoma in situ. The natural history remains uncertain, and no treatment has yet been shown to be effective.
Radiation-induced cystitis is seen in patients who have been treated for bladder or gynaecological malignancy.
Clinical investigation - distinction between uncomplicated and complicated UTI
The clinical approach to investigation and treatment of patients with UTI—including whether to send a urine sample for culture, how long to treat for, and whether to send a repeat sample to confirm eradication of infection—depends on making a distinction between ‘uncomplicated’ and ‘complicated’ UTI. Although this is sometimes straightforward—for instance, UTIs in pregnant women and in catheterized patients are, by definition, ‘complicated’—sometimes the decision on whether to investigate for an underlying cause of ‘complicated’ UTI depends solely on the presenting features.
Most women with uncomplicated cystitis do not require investigation other than urine culture, and may even be treated empirically, the choice of antibiotic being based on locally prevalent sensitivity patterns of the most common uropathogens, rather than waiting for the results of culture and sensitivity. The yield in such women of investigation with cystoscopy and/or intravenous urography is low. Because minor abnormalities such as duplex collecting systems are common in the general population, these will often be found in women presenting with cystitis, but detection of such abnormalities does not lead to any change in treatment. Investigation of women should therefore be reserved for those with atypical features (Bullet list 7).
Box 7 Indications for further investigation in females with UTI
- ◆ Genuine mixed growth
- ◆ Failure of standard antibiotic treatment to eradicate infection
- ◆ Relapsing infection (repeated detection of the same organism, as identified by antibiotic sensitivity pattern, or more detailed typing)
- ◆ Confirmed infection with organisms not usually recognized as uropathogens
- ◆ Infection with proteus
- ◆ Marked acute phase response (or symptoms of ‘acute pyelonephritis’), suggesting tissue invasion
- ◆ Persistent haematuria after treatment of infection
- ◆ Asymptomatic bacteriuria, for no known cause
In men, UTI is nearly always associated with an underlying abnormality of host defence, and all men with proven UTI should therefore be offered investigation.
Table 2 shows the important abnormalities that need to be excluded if investigation is thought to be necessary. Whether adults should be investigated for vesicoureteric reflux is open to doubt, as there is no good evidence that antireflux surgery (e.g. ureteric reimplantation, injection of Teflon around the ureteric orifice) is of benefit in preventing either ascending infection or renal damage.
|Table 2 Clinical investigation of UTI|
|Abnormality to be excluded||Investigation|
|Urinary tract stones||Ultrasonography, plain radiography (KUB), intravenous urography, CT urographya|
|Anatomical abnormalities of the upper tract (e.g. papillary necrosis, reflux nephropathy)|
|Urinary tract obstruction|
|Impaired bladder emptying||Urinary flow studies|
a Choice of imaging dependent on local facilities.
Uncomplicated asymptomatic bacteriuria
The only situations in which treatment of asymptomatic bacteriuria is mandatory are during pregnancy and prior to invasive urological surgery; these situations are discussed below.
The two main aims of antibiotic treatment in UTI are to achieve rapid resolution of symptoms, and to prevent recurrent episodes of infection in the individual patient to minimize the emergence of antibiotic resistance of organisms. Rational treatment of UTI requires the physician to balance the costs and dangers of treatment (including cost of the drug, risk of unwanted side-effects, and the induction of resistance) with benefit.
Is treatment necessary at all? Many women with recurrent uncomplicated cystitis report that they can clear their own infections by increased fluid intake and frequent voiding. Many buy alkalinizing agents (e.g. potassium citrate) to ameliorate the symptoms, which work by reducing bladder irritability. Placebo-controlled studies have confirmed that infection may clear spontaneously, although this may take several weeks or even months, and a small percentage of women remain infected until given antibiotics. There is therefore no justification in insisting on antibiotic treatment in those who wish to try to do without.
Choice of antibiotic
It is usually impracticable to await the results of culture and sensitivity testing, if these tests are justified at all. The choice of antibiotic is therefore usually empirical, based on the likelihood that the drug will clear the infection (efficacy), cost, side-effect profile, and the risk of selection of resistant organisms, both in the patient being treated and in the community.
The efficacy of antibiotics is not fully predictable from in vitro sensitivity testing, which is probably part of the reason why trimethoprim (with or without sulphamethoxazole) remains the first-line choice in many areas, despite an upward trend in resistance rates. This is at least in part because many antibiotics are concentrated in the urine to levels far greater than those found in tissues, and at these concentrations may remain active against organisms that are reported to be resistant to the concentrations found in tissues, which are usually used to define resistance in vitro. However, increasing resistance in vitro to trimethoprim is sure to lead sooner or later to increased clinical failure rates, as has already been observed for β-lactam antibiotics. Some of the clinical properties of the most commonly used antibiotics are reviewed in Table 3. The most recent recommendations of the United Kingdom Health Protection Agency for treatment of UTI in primary care are summarized in Table 4.
|Table 3 Clinical properties of antibiotics commonly used for UTIs|
||Increasing rates of in vitro resistance|
|β-lactams (e.g. amoxicillin, cephalosporins)||
|β-lactams with β-lactamase inhibitor (e.g. co-amoxiclav)||
|Quinolones, e.g. ciprofloxacin||
|Table 4 Health Protection Agency recommendations for the treatment of UTI in the community|
|Uncomplicated UTI, i.e. no fever or flank pain||
|Second line—depends on susceptibility of organism isolated, e.g. nitrofurantoin, amoxicillin, cefalexin, co-amoxiclav, quinolone, pivmecillinam|
|UTI in pregnancy and men||Send MSU for culture. Short-term use of trimethoprim or nitrofurantoin in pregnancy is unlikely to cause problems to the fetus||
||See BNF for dosage||7 days|
|Recurrent UTI women ≥3/yr||Post coital prophylaxis is as effective as prophylaxis taken nightly. Prophylactic doses||
||Stat postcoital OR OD at night|
BD, twice daily; MSU, midstream urine; OD, once daily; QSD, four times daily; TDS, three times daily.
Note: Amoxicillin resistance is common, therefore only use if culture confirms susceptibility. In elderly people (>65 years), do not treat asymptomatic bacteriuria; it occurs in 25% of women and 10% of men and is not associated with increased morbidity.
In the presence of a catheter, antibiotics will not eradicate bacteriuria; only treat if systemically unwell or pyelonephritis is likely.
Duration of treatment
Although a single high dose of an antibiotic will cure many women, cure rates are higher with 3-day courses, and higher still with 7-day courses. However, the risk of adverse effects is also related to the duration of treatment. In general, longer courses (e.g. up to 7 days) should be given to elderly women, and for UTIs caused by S. saprophyticus.
Alternatives to antibiotic therapy
Cranberry juice and tablets, methenamine hippurate, and treatment of atrophic vaginitis with topical oestrogens have all been used in the prevention of UTI (see below), but there is no proven role for any of these interventions in the treatment of an established UTI.
Uncomplicated ‘acute pyelonephritis’
Choice of antibiotic
The antibiotic chosen in this situation needs good tissue penetration as well as high urinary excretion, and must be fully active against the infecting organism at typical serum concentrations. It is therefore much more important to identify the infecting organism and its antibiotic sensitivity pattern by sending urine (or blood from patients in hospital) for culture. However, empirical treatment must be started while awaiting culture and sensitivity results, as acute pyelonephritis can evolve rapidly into a life-threatening illness.
Oral therapy with a quinolone antibiotic (ciprofloxacin, ofloxacin, norfloxacin) is probably the best choice, although trimethoprim or trimethoprim–sulphamethoxazole are alternatives if local rates of resistance among uropathogens remain low. Treatment with β-lactam antibiotics, even if the infecting organism is fully sensitive in vitro, is associated with a high rate of recurrence compared with treatment by other agents. Patients with septicaemia should receive a quinolone (for which oral administration is as effective as intravenous) or a combination of an aminoglycoside with ampicillin plus β-lactamase inhibitor, or an extended-spectrum cephalosporin with or without an aminoglycoside. Once-daily administration of aminoglycosides is as effective as thrice-daily and reduces the risk of toxicity.
Duration of therapy
It is widely recommended that acute pyelonephritis is treated with a significantly longer course of antibiotics than acute cystitis (Table 4). Since, as discussed above, the clinical distinction between acute pyelonephritis and cystitis relies on the presence of fever, flank pain, and an acute phase response, and since all of these may be present in acute cystitis with no involvement of the upper urinary tract and entirely absent in acute pyelonephritis, what these recommendations really mean is that those patients demonstrating a more marked host response should be treated more aggressively and for longer. It is therefore reasonable to suggest that in a patient with systemic symptoms (including flank pain) and fever; or leucocytosis, or a raised C-reactive protein, plasma viscosity, or ESR; antibiotic treatment should be continued until these abnormalities have disappeared. A 14-day course is as effective as a 6-week course in uncomplicated acute pyelonephritis, and a 7-day course may be sufficient for patients with mild illness.
Prevention of recurrent uncomplicated UTI
Lifestyle and personal hygiene
It is common practice to advise women with UTI to change their lifestyle, e.g. by voiding after intercourse, double micturition, wiping themselves from front to back after micturition, and increasing fluid intake. A systematic review concluded that the evidence for lifestyle advice was not based on good evidence, and stated “routine advice about adopting or discontinuing any particular lifestyle factors should not be offered to patients with bacterial UTI”. However, absence of evidence of benefit is not the same as evidence of absence of benefit, and for individuals with recurrent and/or complicated UTI, individualized advice along these lines is reasonable.
Long-term prophylactic antibiotics
Some women with recurrent cystitis choose to have antibiotic treatment for each infection as it arises, particularly if they are allowed to self-administer treatment as soon as symptoms start. Others may opt for prophylactic treatment. Long-term low-dose antibiotic treatment is effective in reducing the rate of infection in such women, although not to zero, and with a significant risk of adverse effects (e.g. gastrointestinal symptoms, rash, vaginal irritation). Prophylactic treatment should be considered in women with at least two symptomatic infections per year and probably works by preventing colonization of periurethral tissues by uropathogens.
Trimethoprim (100 mg at night) is widely used for prophylaxis because it achieves very high concentrations in vaginal fluid and may therefore remain active against organisms that are resistant to the concentrations used in in vitro sensitivity testing. Nitrofurantoin (100 mg at night) has also been widely used, and may be more effective, but can cause rare but serious adverse effects (pulmonary and hepatic toxicity) with long-term therapy, making regular monitoring of liver enzymes and lung function tests necessary. Because both are well absorbed they do not reach high concentrations in the colon, hence emergence of resistant strains in colonic flora is uncommon, whereas this problem does arise with long-term use of β-lactam antibiotics. Long-term use of quinolones is expensive and associated with a significant risk of selection of resistant strains. A number of dosage regimens have been used, including nightly treatment, thrice-weekly treatment, and postcoital treatment, with no convincing evidence of the superiority of one regimen over another. There is no evidence to support the use of ‘rotating’ antibiotic prophylaxis.
Cranberry juice or tablets
Cranberry juice contains proanthocyanidin, which inhibits adherence of P-fimbriated E. coli. Cranberry products are not regulated and the concentration of the active ingredient varies considerably. On meta-analysis, cranberry juice or tablets significantly reduce the number of symptomatic UTIs in women over a 12-month period, but with a significant drop-out rate. No direct comparison of cranberry products and antibiotic prophylaxis in preventing UTI has been reported, but the number needed to treat to prevent one infection is higher for cranberry products than for nightly antibiotic prophylaxis, or postcoital antibiotic prophylaxis. Patients on coumarin anticoagulation should avoid cranberry products.
While cranberry juice and tablets may be effective in the prevention of UTI, there have been no trials assessing their use in treatment of UTI.
Methenamine is hydrolysed in acid urine to produce formaldehyde, a powerful antiseptic. Use of this drug is not associated with the emergence of antibiotic resistance. There is limited evidence that long-term methenamine treatment can reduce the rate of recurrent UTIs in women without upper tract abnormalities.
Treatment of atrophic vaginitis
There is significant heterogeneity in the results of trials examining the effects of topical oestrogens on prevention of recurrent UTI. This may be due to differences in inclusion criteria. Oestrogens are not recommended for the routine prevention of recurrent UTI in postmenopausal women, but they may be of benefit in individuals with marked atrophic vaginitis. Vaginal oestrogens can cause side effects including breast tenderness and vaginal bleeding, discharge, and irritation.
Attempts to prevent recurrent urinary infection by re-establishing colonization by lactobacilli have so far not yielded convincing results.
There are currently two vaccines available and recommended for patients with recurrent UTI. Uro-vaxom is an orally administered bacterial extract consisting of immunostimulating components derived from 18 uropathogenic E. coli strains. Studies have shown it to be effective in the prevention of UTI as compared to placebo, but no comparison to antibiotic prophylaxis has been made.
Strovac is a whole-cell bacterial extract which is administered intramuscularly. It is derived from a number of uropathogenic strains, including E. coli, E. faecalis, and Proteus mirabilis. There is some evidence to suggest it reduces the risk of reinfection compared to placebo, although further studies are needed.
As discussed previously, ‘complicated’ UTIs are those occurring in a patient with abnormal host defence, and as a result are often more severe.
UTI in men
In the first year of life, UTI is commoner amongst boys than girls; circumcision reduces the risk. UTI in men is uncommon, as the length of the urethra and the fact that the penile mucosa is seldom colonized with faecal organisms including uropathogens confer major protection against ascending infection. The occurrence of UTI in a man therefore suggests an abnormality of host defence, which may predispose to more severe infection and should be investigated unless the cause is immediately obvious (e.g. the presence of a urinary catheter). Risk factors that may be identified by investigation are listed in Bullet list 8
Bullet list 8 Possible causes of UTI in men
- ◆ Bacterial prostatitis and prostatic calcification
- ◆ Lack of circumcision
- ◆ Impaired bladder emptying (particularly if this has resulted in bladder catheterization or instrumentation)
- ◆ Anal intercourse
- ◆ Urinary tract stones
- ◆ Reflux nephropathy
Prostatitis is a common cause of visits in primary care and of urological referrals. It can cause considerable morbidity, and patients may remain symptomatic for years. The National Institutes of Health (NIH) consensus classification of prostatitis syndromes is summarized in Bullet list 9
Bullet list 9 National Institutes of Health classification of prostatitis syndromes
- ◆ Acute bacterial prostatitis
- ◆ Chronic bacterial prostatitis
- ◆ Chronic prostatitis/chronic pelvic pain syndrome
- A Inflammatory
- B Noninflammatory
- ◆ Asymptomatic inflammatory prostatitis
Adapted from National Institutes of Health classification of prostatitis syndromes.
Acute bacterial prostatitis
Acute bacterial prostatitis causes fever, rigors, backache, and dysuria, and may result in acute urinary retention. Symptoms and signs of epididymitis may also be present. Rectal examination reveals an enlarged, tender prostate. Bacteriuria and pyuria are related to the prostate and bladder. Untreated, acute prostatitis may culminate in prostatic abscess formation. The causative organism (commonly E. coli) can be identified on urine culture. An antibiotic which has good tissue penetration (e.g. trimethoprim, a tetracycline, or a quinolone) should be used and continued for 4 weeks, as it is thought that this reduces the risk of chronic prostatitis.
Chronic bacterial prostatitis
This is an uncommon syndrome caused by the persistence of a uropathogen (usually Gram-negative organisms or enterococcus) within the prostate, with repeated episodes of acute infection caused by the same organism on each occasion, and few if any symptoms between episodes. Obtaining bacteriological proof that the infecting organism is ‘hiding’ in the prostate gland between acute episodes is difficult. The ‘textbook’ method described by Stamey and Mears involves culture of four specimens obtained during voiding of the bladder: the first 10 ml voided and a midstream sample are collected; the patient then interrupts the flow of urine, bends forward, and digital prostatic massage is performed, resulting (sometimes) in the collection of a few drops of ‘expressed prostatic secretions’; finally, voiding is completed and a fourth sample collected. Prostatitis is diagnosed when bacterial counts are highest in the expressed prostatic secretions and the final voided urine sample; urethritis, by contrast, results in high counts in the first sample. Because of its complexity and the unpleasantness of performing digital prostatic massage per rectum during interrupted micturition, this test is very rarely performed in practice, and many patients are simply treated with a prolonged course of a quinolone antibiotic. α-Blockers have been shown to reduce recurrence rate, possibly by reducing reflux of urine into prostatic ducts during micturition.
Acute and chronic bacterial prostatitis are the best understood but least common of the prostatitis syndromes. More than 90% of symptomatic patients have chronic prostatitis/chronic pelvic pain syndrome.
Chronic prostatitis/chronic pelvic pain syndrome
Chronic urological pain is the primary component of this disorder. Patients may also complain of dysuria, strangury, urinary frequency, and pain during sexual intercourse, but have no evidence of bacterial infection on cultures of prostatic secretions, semen, or postmassage urine specimens. Certain conditions must be excluded, including active urethritis, urological cancer, significant urethral stricture, or neurological disease affecting the bladder.
Patients with this symptom complex may be further subclassified as having inflammatory or noninflammatory pelvic pain syndrome according to the presence or absence of leucocytes in semen. Occasionally, patients are found to have evidence of prostatic inflammation on biopsy, or to have leucocytes in prostatic fluid in the absence of symptoms, in which case they are regarded as having asymptomatic inflammatory prostatitis.
There is no gold standard for diagnosis, nor a clear understanding of the pathophysiology, no correlation between symptoms and prostatic histology, and no satisfactory treatment for this ill-understood group of conditions. As in the urethral syndrome in women, some cases may be caused by persistent infection by fastidious bacteria, such as chlamydia or mycoplasma; a prolonged trial of a tetracycline is therefore often used. Other treatments include regular prostatic massage, NSAIDs, α-blockers, and 5-α reductase inhibitors. α-Blockers have been shown to be of some benefit in all types of symptomatic chronic prostatitis in one randomized study.
UTI occurs after 2% of in/out urethral catheterizations, after 10 to 30% of 5-day indwelling catheterization, and is nearly inevitable in patients with long-term indwelling catheters. It is an important cause of hospital-acquired infection, increasing the risk of Gram-negative septicaemia fivefold and carrying a threefold increase in mortality after adjustment for age, severity and type of underlying illness, duration of catheterization, and renal function. Organisms enter the bladder either by migration between the catheter and the urethral mucosa or by ascent up the column of urine in the lumen after entry into the drainage system following contamination at disconnection or drainage points. Although most infections are probably caused by ascent of the patient’s own faecal flora, investigation of clusters of infections by highly antibiotic-resistant organisms showed that inadequate hand-washing by hospital staff may also cause some infections.
A sample obtained directly from the catheter (not from the drainage bag) represents bladder urine, when any bacterial growth should be considered as evidence of UTI; low-count infection (e.g. <102 cfu/ml) usually progresses within days to higher counts. Mixed growths are common in patients with long-term catheterization and may be associated with mixed-growth bacteraemia.
Risk factors for the acquisition of infection include increasing duration of catheterization, increasing age, female sex, renal impairment, diabetes mellitus, and the nature of the underlying illness. Use of prophylactic antibiotics is associated with a delay in the onset of infection and may be justified in high-risk patients requiring catheterization for at least 24 h and up to 14 days, whereas in those with long-term catheters, use of prophylactic antibiotic simply increases the risk of emergence of antibiotic-resistant pathogens without any benefit. Use of silver alloy-coated catheters, or use of antibiotic-impregnated catheters, also reduces the risk of infection in the short term, but not in long-term catheterization, and may be justified in high-risk patients; no direct comparisons of these two interventions have been performed; both are more expensive than standard catheters, and the balance of cost and benefit remains uncertain. Progress is being made in the development of new catheter materials that may provide further resistance against colonization by microorganisms.
Urethral catheters should not be inserted unless absolutely necessary (is knowledge of hourly urinary output really going to change your management?). Early removal of urethral catheters reduces the risk of symptomatic UTI. Suprapubic catheters are associated with lower risks of UTI and a lower rate of recatheterisation in postsurgical patients, but their use may be associated with a higher risk of complications. If a urethral catheter is used, catheter care should follow appropriate guidelines (e.g. as provided by the National Institute for Health and Clinical Excellence in the United Kingdom).
Clean intermittent self-catheterization should be considered as an alternative to long-term urethral catheterization. Whether prophylactic antibiotics further reduce the risk of UTI amongst patients undertaking intermittent self-catheterization remains uncertain.
Condom drainage should be used as an alternative to urethral catheterization in men unless there is obstructive nephropathy; this form of bladder drainage reduces the risk of UTI fivefold and is better tolerated.
Treatment of asymptomatic bacteriuria in patients with anatomically abnormal urinary tracts or with indwelling urinary catheters is unjustified and is likely only to lead to the emergence of antibiotic-resistance urinary infection.
Abnormal bladder emptying
Incomplete bladder emptying, removing the ‘washout’ part of host defence, greatly increases the risk of UTI, as in patients with prostatic bladder outflow obstruction and those with neurogenic bladder due to spinal cord injury. Long-term catheterization only increases these risks. Where possible, the cause of incomplete bladder emptying should be treated. However, patients shown on urodynamic study to have underactive detrusor activity will not benefit from prostatectomy or α-blockade and may require long-term intermittent self-catheterization.
Bladder dysfunction in patients with neurogenic bladder, e.g. due to spina bifida or spinal cord injury, depends on the level of injury. Patients with lesions above T11 have hyperreflexic bladder activity, often with sphincter dyssynergia (failure of the sphincter to relax during detrusor contraction), resulting in a high-pressure system, often with high-pressure reflux, combined with impaired emptying. In combination with UTI, this frequently results in progressive renal damage. Those with lesions below L1 have decreased detrusor activity with large amounts of residual urine, which also increases the risk of UTI. Diabetic neuropathy may also cause decreased detrusor activity. The aim of treatment in both situations is to achieve a low-pressure bladder with low residual volumes. This may involve teaching patients to utilize reflexes to induce bladder contraction and sphincter relaxation, condom drainage for incontinence, anticholinergics to reduce detrusor overactivity, sphincterotomy, augmentation cystoplasty, and intermittent self-catheterization. Urethral catheterization should be avoided wherever possible.
There is no evidence that regular use of antiseptics to wash the perineum and urethral meatus are of benefit. Bladder washouts with saline or boiled (and then cooled to body temperature) water may be of benefit in eliminating mucus in patients with augmentation cystoplasties. Antiseptic bladder washouts are of minimal value in prevention, probably because uropathogens become embedded in a biofilm adherent to the bladder wall. Methenamine, a drug that releases formaldehyde into acidic urine, may be of some benefit in preventing infection.
Treatment of UTI in patients with abnormal bladder emptying should be reserved for those with evidence of invasive infection. The diagnosis is obvious in those with cloudy urine combined with fever, rigors, and flank pain, but it is important to remember that symptoms and signs—particularly flank pain, dysuria, urgency, and frequency—may be absent in those with neurological dysfunction.
Patients with asymptomatic bacteriuria who undergo invasive urological procedures that are associated with mucosal bleeding are at high risk of postprocedure bacteraemia and clinical sepsis syndromes, and there is evidence that preoperative antibiotic treatment of asymptomatic bacteriuria (ideally, the night before the procedure, continued until completion or removal of an indwelling catheter, whichever is the later) reduces these risks.
Ileal or colonic conduits have been used for many years in patients requiring cystectomy for malignancy, and occasionally (although increasingly less frequently) for nonmalignant conditions such as neurogenic bladder. Such conduits are frequently complicated by urine infection as the bowel mucosa and the mucus it produces readily permits adherence of uropathogens. Upper urinary tract dilatation is common, irrespective of whether the ureteric anastomoses are designed to be nonrefluxing or not, and there is a high incidence of recurrent ‘acute pyelonephritis’ with flank pain, fever, and rigors. Diagnosis of UTI in patients with a conduit requires insertion of a catheter to the far end of the conduit and collection of urine via the catheter, rather than culture of urine collected from the conduit bag. Preventive measures include ensuring that the ileal segment is as short as possible at the time of surgery and ensuring a high fluid intake. The belief that cranberry juice reduces the incidence of UTI by reducing bacterial adherence is as yet unproven, although it seems likely that treatments designed to interfere with bacterial adherence or with mucin production are more likely than antibiotic treatment to help prevent symptomatic infection in these patients.
Renal tract stones
Renal tract stones are an important cause of persistent or relapsing UTI, as they provide a ‘hiding place’ in which organisms are protected from antibiotics. Management of such patients is complicated, as it may be impossible to eradicate infection without aggressive stone management (which may involve extracorporeal shock-wave lithotripsy, percutaneous and ureteroscopic stone removal). Attempts at stone removal may be complicated by septicaemia unless combined with antibiotic treatment, yet prolonged antibiotic therapy may encourage the emergence of resistance in the infecting organism.
Infection stones are caused by chronic infection with urease-producing organisms, usually P. mirabilis, and account for around 5% of urinary tract stones. These stones are made of struvite (MgNH4PO4.6H2O), which forms as a result of the action of the alkaline pH caused by the production of ammonium and hydroxyl ions from the breakdown of urea by urease. Pure struvite stones may result from de novo UTI by a urease-producing organism, and are commoner in women and (probably) in patients with pre-existing anatomical abnormalities of the upper urinary tract such as reflux nephropathy, pelviureteric junction obstruction, or urinary diversion. They may also form as a secondary complication of metabolic stones. Struvite stones often expand to fill the entire renal pelvis, forming ‘staghorn’ calculi, but such calculi should not be assumed to be due to infection (rather than a metabolic cause) without demonstration of chronic infection by a urease-producing organism and/or biochemical analysis showing that the stone is made of struvite. The usual presentation is with symptomatic ‘acute pyelonephritis’ and alkaline urine; renal colic is unusual due to the large size of the stones. Treatment is with a combination of antibiotics and stone removal, which is imperative to prevent stone recurrence. Urease inhibitors (acetohydroxamic acid, propionhydroxamic acid) may reduce stone recurrence but are too toxic for clinical use.
Autosomal dominant polycystic kidney disease
Cystitis is common in women with polycystic kidney disease, and in 20% it is the presenting clinical finding, but there is no evidence that host defence in the lower urinary tract is abnormal. However, the risk of upper UTI is increased, and its diagnosis and treatment complicated. Acute parenchymal infection presents as acute pyelonephritis with flank pain, fever, and infected bladder urine, and usually responds to conventional therapy. Infection of cysts is more difficult to diagnose: the urine may be sterile and there may be no pyuria if the infected cyst does not communicate with the urinary space. Presentation is with fever and a discrete area of tenderness in the affected kidney. Blood cultures are the most reliable way of making a bacteriological diagnosis. Imaging studies, looking for cysts with increased fluid density, septations, and thick walls, are seldom conclusive, as similar appearances may occur normally or after previous cyst haemorrhage. The spectrum of causative organisms suggests that ascending infection rather than haematogenous spread is the usual route of infection. Hydrophilic antibiotics, including aminoglycosides and β-lactam antibiotics, penetrate poorly into those cysts which maintain large ionic gradients, whereas quinolones, trimethoprim–sulphamethoxazole, doxycycline, and clindamycin achieve better penetration. Prolonged courses of antibiotics are usually needed to eradicate infection, with surgical resection a last resort.
UTI is the commonest bacterial infection after renal transplantation. Risk factors include urethral catheterization in the early postoperative period, the use of ureteric stents, pre-existing abnormalities of bladder emptying (such as diabetic autonomic neuropathy, previous bladder outflow obstruction, small contracted bladders in anuric patients on dialysis), anatomical abnormalities in the upper urinary tract (such as reflux nephropathy), contamination of the transplanted organ during retrieval and storage, abnormal drainage of urine from the transplanted kidney, vesicoureteric reflux into the transplant, areas of renal infarction, and immunosuppression. The commonest causative bacteria are those found in the general population with UTI, but many organisms not usually considered as urinary tract pathogens may also cause significant infection in these patients. Many infections are asymptomatic. Prophylactic antibiotics may reduce the early postoperative risk and many centres use co-trimoxazole as it also reduces the risk of pneumocystis pneumonia. Antibiotic treatment must be chosen with care because of the risk of interactions with immunosuppressive treatment and of nephrotoxicity.
Infection with Corynebacterium urealyticum can cause ‘encrusted pyelitis’ in transplant kidneys, in which the pelvis of the transplant kidney becomes encrusted with calcified material, which can cause obstruction and thus transplant dysfunction. The CT appearances are characteristic. The calcification comprises struvite (magnesium ammonium phosphate), as in infection stones. Management is difficult, and comprises prolonged antibiotic therapy and surgical excision of the calcified material, if possible.
Infection with BK virus (a polyoma virus) may cause cystitis, ureteric stenosis, and interstitial nephritis (easily mistaken for acute rejection) in renal transplant recipients. The diagnosis may be suggested by recognition of infected transitional uroepithelial cells on urine cytology (‘decoy’ cells), quantitative PCR of blood and urine for BK virus, and confirmed by histological recognition of inclusion bodies on renal biopsy. Treatment is by reduction of immunosuppression, but this is often complicated by further rejection.
Asymptomatic bacteriuria early in pregnancy is associated with the development of acute pyelonephritis in up to 30% of patients (20–30 times the risk in women without bacteriuria) if left untreated. It is commoner in women of lower socioeconomic status and is associated with an increased incidence of preterm delivery and low birth weight, particularly if the pregnancy is complicated by acute pyelonephritis towards term. The increased risk of pyelonephritis is attributed to ureteric dilatation caused primarily by progesterone-induced smooth muscle relaxation.
Antibiotic treatment of asymptomatic infection reduces the risk of acute pyelonephritis and of preterm delivery and low birth weight. Similar benefit is seen from a short course of treatment and from continued antibiotic prophylaxis. The optimum duration of antibiotic treatment for UTI in pregnancy is uncertain; the recent Health Protection Agency guidelines (Table 4) recommend a 7-day course. Whatever duration of treatment is used, follow-up urine cultures at each antenatal visit should be performed to ensure that bacteriological cure has been achieved.
Vesicoureteric reflux (retrograde flow of urine up into the ureters and, in severe cases, as far as the renal pelvis) is often found in children with recurrent UTI. At the time of first diagnosis of UTI or subsequently, a few such children are found to have a characteristic pattern of renal parenchymal scarring at the upper and lower poles, with underlying clubbing and distortion of calyces. This pattern of scarring has become known by a variety of terms, including ‘reflux nephropathy’ and ‘chronic pyelonephritis’. Patients with reflux nephropathy have an increased risk of recurrent UTI, may develop infection or stones, and some develop hypertension, proteinuria, and progressive renal impairment with an inexorable progression to endstage renal failure. Under the age of 1 year, when only relatively severe cases come to clinical attention, slightly more boys than girls are affected; in older children the disease is diagnosed up to five times more frequently in girls, possibly because the disease is often discovered during investigation of UTI, which is commoner in females. Reflux nephropathy is commonly familial, best modelled by an autosomal dominant pattern of inheritance with variable penetrance. Linkage has been demonstrated to an area of chromosome 1 in some large pedigrees.
The diagnosis of reflux nephropathy is conventionally made in adults by intravenous urography, which permits the detection both of focal parenchymal scarring and the underlying calyceal abnormality. Ultrasound scanning can show focal scarring but does not allow visualization of the calyces. DMSA isotope scanning is the most sensitive test for the detection of parenchymal scars, and is widely used in children, as there are few alternative causes of focal scarring in this age group. Lateral displacement of the ureteric orifices can be demonstrated by Doppler ultrasound in most patients with reflux nephropathy. Demonstration of vesicoureteric reflux by direct or isotopic micturating cystography is commonly used to confirm the diagnosis in children, but is rarely justified in adults, as the absence of reflux could be due to spontaneous resolution of reflux with age (it often resolves in childhood), and its presence seldom justifies a change in clinical management. The histological appearances of ‘chronic pyelonephritis’ are well described and may occasionally be seen in patients with no scarring on urography or even DMSA scanning, probably because the scars are too small in these patients to be detected radiologically.
The conventional view is that reflux nephropathy is ‘postinfectious focal renal scarring’ and caused by the ascent of infected urine into the renal pelvis and then into the collecting ducts and renal parenchyma via compound papillas (papillas in which more than one collecting duct opens into the pelvis) that are found at the upper and lower poles, but not in the middle calyces—explaining the polar distribution of scars. Sequential radiological imaging studies in children with UTIs appear to support this theory, with the emergence of new scars up until the age of around 5 years, after which it is thought that maturation of the papillas prevents entry of infected urine into the renal parenchyma. Experimental infection in pigs causes a pattern of scarring very similar to that seen in human reflux nephropathy.
An alternative hypothesis is that at least some children with the radiological diagnosis of reflux nephropathy have congenital renal dysplasia, caused by abnormal nephrogenesis in utero, and associated with abnormal embryogenesis of the ureterovesical junction leading to vesicoureteric reflux. Vesicoureteric reflux is often found in the rare genetic syndromes that include renal dysplasia, and in nonsyndromic renal dysplasia or aplasia, vesicoureteric reflux in the contralateral ureter is commonly seen. This theory would explain the presence of classic reflux nephropathy in neonates and in children with no documented history of UTI. Even the emergence of new scars during the first 5 years of life could be due to differential growth around areas of renal dysplasia. The rarity with which acute pyelonephritis in adults results in renal impairment, even in the presence of radiological evidence of scar formation, is perhaps further evidence that progressive loss of renal function is more likely to be due to ‘remnant nephropathy’ in dysplastic kidneys rather than the result of postinfectious scarring alone.
These two hypotheses have different implications for the prevention of reflux nephropathy. Proponents of the ‘postinfectious focal renal scarring’ theory believe that diagnosis in infancy and treatment to prevent the ascent of infected urine into the renal pelvis until at least the age of 5 years should prevent the emergence of renal scarring and the later sequelae of hypertension, proteinuria, and progressive renal failure; by contrast, such treatment will not prevent these sequelae if reflux nephropathy is a disease of embryogenesis. Of course, the two theories are not mutually exclusive: in an individual patient reflux nephropathy may be due to the interaction of dysplasia and ascending infection during infancy. Antireflux surgery (ureteric reimplantation) and long-term prophylactic antibiotic treatment have been compared in several large randomized trials. Surgery is more effective at preventing episodes of acute pyelonephritis than medical treatment, but no other major differences in outcome were observed, and potential complications of antireflux surgery include ureteric obstruction, itself a potent cause of renal parenchymal damage. In modern practice, open surgical ureteric reimplantation is now seldom performed, having been replaced by endoscopic techniques involving subureteric or intraureteric injection of dextranomer/hyaluronic acid copolymer. However, this form of antireflux surgery has not been tested in large randomized controlled trials.
Long-term antibiotic prophylaxis has been shown to be superior to placebo in prevention of infection in children with a history of symptomatic urinary infection, with or without vesicoureteric reflux, but the differences were small. Whether or not antibiotic prophylaxis prevents upper tract scarring has not been tested in adequately powered placebo-controlled trials.
Eradication of asymptomatic infection in children with or without proven vesicoureteric reflux used to be widely practised in the hope that it would prevent ascending infection and renal damage. However, prophylactic treatment for 2 years of covert bacteriuria in schoolgirls without renal scarring has no effect on glomerular filtration rate at age 18, but is associated with lower fractional reabsorption of glucose and with a smaller increment in glomerular filtration rate and greater degrees of glycosuria during subsequent pregnancy. Screening for asymptomatic bacteriuria with the aim of preventing these minor abnormalities is not currently thought justified. Pooled analysis of recent trials that have included a placebo arm show no clear evidence of benefit from long-term prophylaxis, either in terms of reduction of symptomatic UTIs or in reduction of the acquisition of new cortical scars.
Whatever the cause of reflux nephropathy, there is little doubt that women with it are more prone to recurrent acute pyelonephritis than those with anatomically normal upper urinary tracts, particularly during pregnancy.
Invasive/destructive renal parenchymal infection
As discussed above, ascending infection may cause the clinical syndrome of ‘acute pyelonephritis’ but seldom causes significant renal parenchymal damage. However, this is not the case if there is further impairment of host defence against infection, particularly by diabetes or urinary tract obstruction.
Acute papillary necrosis
This is an unusual complication of acute pyelonephritis, but more likely to occur in older people and especially those with diabetes. It should be suspected, as should urinary stones, in the patient with symptoms and signs of acute pyelonephritis who also has pain suggesting renal colic. This situation requires immediate imaging, usually with ultrasonography, to exclude urinary obstruction, and if obstruction is present then it must be relieved urgently, most often by antegrade nephrostomy.
The use of NSAIDs is associated with an increased incidence of chronic renal papillary necrosis, perhaps because they compromise the renal medullary circulation. It therefore seems reasonable to say that these agents should be discontinued, at least temporarily, in the presence of acute pyelonephritis.
Renal carbuncle is the formation of renal cortical abscesses, often only in one kidney, caused by blood-borne infection, usually associated with untreated S. aureus septicaemia. It is most commonly seen in intravenous drug abusers and patients with diabetes. There is usually a significant time delay between the initial infection and presentation with renal carbuncle, typically 6 to 8 weeks. Presenting symptoms include fever, malaise, and abdominal or flank pain, and are often nonspecific. Because the infection is limited to the renal cortex and does not communicate with the collecting system, the urine is sterile and acellular. Blood cultures are usually negative. Radiological studies show a semisolid, thick-walled mass, percutaneous aspiration of which yields pus.
Pyonephrosis is bacterial infection within a completely obstructed collecting system, for instance due to an obstructing ureteric stone. Patients usually present with fever, rigors, and flank pain, and have a marked neutrophilia and acute phase response. Radiological differentiation from hydronephrosis relies on the presence of echogenic material and/or septae in the pelvicalyceal system, and confirmation is by percutaneous aspiration; as with other localized UTIs, the voided bladder urine may be sterile. Untreated pyonephrosis rapidly results in complete destruction of the renal parenchyma, followed by death from complications of sepsis if nephrectomy is not performed; correction of obstruction and aggressive intravenous antibiotic therapy may prevent this if instituted soon enough.
Perinephric abscess may complicate renal carbuncle or, more commonly, acute pyelonephritis—particularly if complicated by an anatomical or functional abnormality of the urinary tract. Typical presenting symptoms are those of acute pyelonephritis, with flank pain, fever, and rigors. If the abscess does not communicate with the collecting system, e.g. in abscesses caused by haematogenous spread or complicating obstruction or renal cysts, there may be no lower urinary tract symptoms, no pyuria, and the urine may be sterile. Response to antibiotic treatment is much less rapid than in patients with uncomplicated acute pyelonephritis. Diagnosis is by ultrasonography, urography, or CT, followed by percutaneous (or occasionally surgical) aspiration, drainage, and culture of the aspirate. Prolonged antibiotic treatment of the organism identified is needed, stopping only when there is evidence that the infection has resolved, based on resolution of fever and of the acute phase response, and repeated radiological studies. This may take as long as 8 weeks.
Xanthogranulomatous pyelonephritis is an atypical form of chronic infection of the renal parenchyma in which bacterial infection, usually in the presence of obstruction or staghorn calculi, results in formation of granulomas with the accumulation of lipid-rich foamy macrophages. The process may be multifocal and can be complicated by extension into the perinephric fat, causing perinephric abscess. Patients are typically febrile and ill, with a history of progressive weight loss, anaemia, and malaise, without lower urinary tract symptoms, and have a mass in the flank on examination. Radiologically, the multifocal mass crossing tissue planes may be indistinguishable from a renal cell carcinoma, which may also cause systemic symptoms such as fever, anaemia, and weight loss. Although both require surgical excision, radical surgery can be avoided if the diagnosis is made preoperatively.
Emphysematous pyelonephritis is a rare and life-threatening form of acute pyelonephritis in which there is tissue necrosis together with formation of hydrogen and CO2, which accumulate in pockets in the renal parenchyma, perinephric space, and collecting systems—’gangrene of the kidney’. The typical patient is an obese, elderly woman with type 2 diabetes; urinary tract obstruction is another important risk factor. Presentation is with fever, vomiting, and abdominal pain. The patient is often extremely ill with hypotension, neutrophilia, and renal impairment. The commonest causative organism is E. coli; clostridial infection has not been reported. Even with aggressive medical treatment the mortality is high, and although occasional successes with antibiotics combined with percutaneous drainage have been reported, the standard treatment is nephrectomy.
Malakoplakia (Greek: ‘soft plaque’) is a rare disease characterized by destructive tumour-like granulomatous infiltrates in the urinary bladder, kidneys, and occasionally other organs. Bladder involvement usually presents with haematuria, frequency, and dysuria; renal involvement presents with fever, flank pain, and renal enlargement, and may frequently be bilateral. The diagnosis may be suspected at cystoscopy or on renal imaging, but is confirmed histologically by detection of large eosinophilic granular macrophages containing characteristic intracellular lamellated 5- to 10-µm inclusion bodies. It is caused by bacterial UTI, commonly E. coli, together with an ill-understood acquired defect of microtubule assembly within phagocytic cells, resulting in the accumulation within the cytoplasm of bacterial remnants that subsequently calcify. Treatment with bethanechol (to stimulate intracellular cGMP and thus microtubule assembly) and ascorbic acid (to stimulate the intracellular hexose monophosphate shunt, which is involved in phagocytosis) have been recommended on theoretical grounds, but seldom arrest the disease. The best chance of avoiding nephrectomy comes from the use of long-term quinolone antibiotics such as ciprofloxacin, which penetrate macrophages well.
Genitourinary tuberculosis is an uncommon late manifestation of tuberculosis, and is often clinically silent, with few if any systemic symptoms. Most cases of renal tuberculosis probably result from haematogenous spread, although unilateral disease is common. Seeding of infection from above leads to ulceration and distortion of the collecting system, pelvis, and ureter, followed by stricture formation and calcification. Obstruction and parenchymal infection may eventually lead to ‘autonephrectomy’. The disease is usually detected either during investigation of asymptomatic sterile pyuria or during investigation of irritative lower urinary tract symptoms or haematuria due to bladder involvement. Reactivation of disease may result from acquired deficiency of 1,25-dihydroxyvitamin D. Occasionally, renal tuberculosis may present with a cold abscess in the flank. Chronic renal failure due to bilateral diffuse interstitial renal tuberculosis may occur, and may account for some of the excess of chronic renal failure in Asian immigrants in the United Kingdom.
Diagnosis of renal tuberculosis is by culture of early morning urine samples. Treatment is with rifampicin, isoniazid, pyrazinamide, and ethambutol for 2 months, followed by rifampicin and isoniazid for a further 4 months. It should be supervised by a physician experienced in the chemotherapy of tuberculosis, and with adjustment of the dose of ethambutol in the presence of renal impairment. Corticosteroids may help to prevent or reverse ureteric obstruction, which may otherwise require stent insertion or surgery to prevent renal destruction. Nephrectomy is seldom necessary.
Schistosoma haematobium infection in the venules of the urinary bladder may cause irritative symptoms and terminal haematuria, starting 2 to 3 months after the initial infection. Eosinophilia may be present. The diagnosis is made by detection of ova in a midday terminal urine specimen or by cystoscopy and biopsy. Treatment is with systemic anthelmintic drugs, currently praziquantel.
Fungal UTIs typically occur in patients whose host defence is compromised by indwelling urethral catheters or ureteric stents, previous wide-spectrum antibiotic therapy, immunosuppressive drugs, or diabetes. Most infections are caused by candida. Many patients with funguria have asymptomatic colonization, but some develop life-threatening ascending disease. Severity of infection does not correlate with pyuria. It is important to differentiate funguria from contamination of voided urine by candida in patients with vaginal candidiasis. Many infections clear spontaneously on removal of the urethral catheter, although this can take many months.
Treatment options for patients thought to be at high risk of invasive infection (e.g. patients with diabetes with indwelling catheters, renal transplant recipients) include removal of the catheter or nephrostomy tube wherever possible; continuous bladder irrigation or antegrade perfusion via a nephrostomy tube with amphotericin B at 50 mg/litre if the tube cannot safely be removed; and oral fluconazole. For patients whose tube cannot safely be removed, a combination of amphotericin B irrigation and fluconazole is reasonable, but evidence comparing the options is very limited. Patients with clinical features of acute pyelonephritis require parenteral antifungal treatment, adjusted to in vitro sensitivities.
Fungaemia is often complicated by renal parenchymal infection, possibly because the hypertonic and hypoxic conditions in the renal medulla favour transformation of candida from the yeast to the mycelial phase. Infection starts with multiple cortical abscesses and progresses to invasion of the renal pelvis and ureter, with eventual obstruction by fungus balls.
Likely future developments
Current methods for prevention and treatment of uncomplicated and complicated UTI are unsatisfactory, with persisting high morbidity and mortality from complicated infection and increasing rates of antibiotic-resistant organisms. Development of new antibiotics is likely only to remain half a step ahead. We hope to see major advances in the prevention of UTI, perhaps with the development of substances designed to inhibit bacterial adherence to the uroepithelium, new compounds for vaccination, and the development of new catheter materials and of alternatives to urethral catheterization.
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