OBSTRUCTION AND INFECTION

Urinary tract infection

Neil S Sheerin

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Abstract
Urinary tract infection is one of the commonest infections to affect humans. Uncomplicated infections occur most commonly in otherwise healthy women when uropathogenic bacteria, usually Escherichia coli, ascend from the perineum into the bladder and overcome host innate immunity. Complicated infections occur in patients with an anatomical or functional abnormality of the urinary tract. The diagnosis is made on the basis of symptoms and diagnostic precision is improved by urinalysis. Urine culture is important with severe, recurrent or complicated infection and when the diagnosis is unclear, for example, in children and the elderly. Most women with symptoms that resolve quickly do not require further investigation but in children, men and patients with recurrent or severe infection, imaging of the renal tract, functional testing and cystoscopy should be considered to exclude an underlying abnormality. Empirical antibiotic treatment started on the basis of symptoms and directed by urinalysis is suitable for uncomplicated cystitis but should be altered based on culture results for more severe infections. Three days antibiotic treatment is usually sufcient for uncomplicated cystitis in women. Longterm or post-coital antibiotics are effective treatments for patients with recurrent infection in whom non-antibiotic strategies have failed.

Three days of antibiotics is sufcient to treat uncomplicated cystitis in women. Men should be treated for 7 days with an antibiotic that penetrates into the prostate UTI is a common hospital-acquired infection. Reducing the duration of catheterization is critical in reducing infection rates Uropathogenic bacteria can internalize into epithelial cells of the urinary tract and form intra-epithelial colonies, which are a potential reservoir for recurrent infection

symptomatic and asymptomatic bacteriuria is a common nding in women and the elderly. UTI can be classied as complicated or uncomplicated. Uncomplicated UTI occurs in the absence of any anatomical or functional abnormality within the urinary tract and is the commonest type of infection. Complicated UTI occurs in the presence of an abnormal urinary tract or other factor that increases susceptibility to infection. The common causes of complicated UTI are listed in Table 1.

Epidemiology
Asymptomatic bacteriuria is found in 1e2% of school-age girls and 5% of women, but is rare in males. The prevalence increases with age; bacteriuria is found in 21% of women and 12% of men over the age of 65 years, and in over 40% of people living in institutions.1 Acute uncomplicated cystitis is the commonest form of symptomatic UTI, affecting 15% of women each year and, cumulatively, 40% of women at some point in their life (30% of these have recurrent infections). Symptomatic infection

Keywords antibiotics; cystitis; host defence; pyelonephritis; urinary tract

infection

Introduction
The term urinary tract infection (UTI) is applied to any infection in the urinary tract and is one of the most common bacterial infections, affecting about 40% of women at some point in their life. UTI can cause life-threatening sepsis, but most infections are less severe. Nevertheless, UTI causes signicant distress to the individual and is associated with high healthcare and social costs. In the USA UTIs are responsible for 7 million clinic visits annually, with a cost exceeding $1.6 billion. UTI is most commonly bacterial, but fungal, viral and parasitic infections can occur. Infection of the bladder causing cystitis is the most common UTI but infection can occur in other parts of the urinary tract, causing pyelonephritis, urethritis and prostatitis. Bacterial colonization of the urinary tract is not always

Common causes of complicated urinary tract infection

Bladder outow obstruction Prostatic disease Urethral stricture Bladder neck obstruction Neuropathic bladder Multiple sclerosis Diabetes mellitus Spina bida Spinal cord trauma Catheterization or stent Renal tract stone disease Instrumentation of the renal tract Renal or urinary tract malignancy Reux Duplex system Ileal conduit Pregnancy Glycosuria Kidney transplant Immunosuppression Table 1

Neil S Sheerin BSc PhD MBBS MRCP is Professor of Nephrology at Newcastle University and Honorary Consultant Nephrologist at Freeman Hospital, Newcastle upon Tyne, UK. After qualifying from Guys Hospital he trained in hospitals in London and Leicester, before returning to Guys Hospital to complete his Nephrology training. His research interests include innate immune mechanisms of renal injury, urinary tract infection and progressive renal brosis. Conicts of interest: none declared.

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is less common in men in the absence of an anatomical or functional abnormality. Nosocomial (hospital-acquired) UTI is most commonly catheter associated; UTI develops in 25% of patients who require a catheter for over 7 days with a 5% daily risk. UTI adds to the duration and cost of hospital admission and nosocomial uropathogens form a reservoir of antibiotic-resistant bacteria.

Bacteria causing urinary tract infection

Community- Hospital- Pyelonephritis acquired acquired Escherichia coli Proteus mirabilis Klebsiella pneumoniae Enterococcus faecalis Pseudomonas aeruginosa Staphylococcus saprophyticus Staphylococcus aureus Others Table 3 77% 4% 4% 4% 2% 4% e 5% 56% 6% 7% 9% 4% e 3% 15% 69% 3% 9% 6% e e e 13%

Aetiology
In the majority of patients UTI develops in the absence of any obvious structural or functional abnormality within the urinary tract. Under normal circumstances the urinary tract is sterile and infection develops only when bacterial virulence overcomes normal host defence mechanisms (Table 2). Escherichia coli is the most common uropathogen in both the community and hospitals, whereas Proteus mirabilis, Staphylococcus saprophyticus, Enterococcus faecalis, Klebsiella pneumoniae and Pseudomonas aeruginosa each cause less than 10% of cases (Table 3). Host factors Sterility is maintained by physical factors (Table 2), including the uni-directional ow of urine, frequent and complete emptying of the bladder, and separation of the bladder from a source of pathogens. The urine represents a hostile environment and bacterial growth is inhibited by high osmolality and low pH. The urinary tract epithelium expresses Toll-like receptors, which respond to pathogenassociated molecules, and synthesize antibacterial peptides (defensins and cathelicidins). The synthesis and release of proinammatory cytokines and chemokines by epithelial cells initiates an innate immune response promoting leucocyte inltration and activation. Neutrophils, which directly kill complementopsonized bacteria, are the predominant cell type and are critical in defence against UTI. The secretion of the P blood group antigen and TammeHorsfall protein (uromodulin) interferes with bacterial adhesion to epithelial cells, and colonized epithelial cells undergo apoptosis and are shed into the urine. Although there is evidence of an adaptive immune response in UTI e for example pathogenspecic immunoglobulin A (IgA) is found in the urine following infection e it is unclear whether this is important in the defence against further infection.

Bacterial virulence factors To overcome the ow of urine, uropathogenic bacteria express mbrial adhesions with which they bind to glycoproteins and glycolipids on the epithelial surface. Fimbriae are lamentous structures that project from the surface of the bacteria with an adhesin protein at their tip, which is responsible for binding to the host epithelium. Type 1 mbriae bind mannose residues on uroplakin proteins that line the bladder, and are found on pathogens that cause cystitis. P mbriae bind a Gala1-4Galbcontaining glycosphingolipid on renal epithelium and are associated with pyelonephritis. Uropathogens also produce toxins, haemolysin and colony-necrotizing factor, which disrupt epithelial integrity and permit bacterial invasion. Generally, uropathogens are resistant to the lytic effects of serum (complement resistant). Pathogenesis of infection In most cases the uropathogens originate in the rectal ora and colonization of the perineum and periurethral area precedes the development of infection. Colonization is inhibited by the normal bacterial ora, including Staphylococcus epidermidis, lactobacilli and corynebacteria, which are disrupted by antibiotics and postmenopausal oestrogen deciency. Uropathogens then use their mbrial adhesions to ascend through the urethra to the bladder and kidney. The shorter length of the urethra and the proximity of the urethral meatus to the perineum explain the higher rate of infection in women. Uropathogenic bacteria also have the capacity to internalize into and divide inside host epithelial cells, potentially providing a reservoir for recurrent infection. Several factors are associated with risk of acute infection, including sexual activity, the use of a diaphragm and spermicidebased contraception, a history of previous or recurrent UTI,2 and genetic factors that increase susceptibility to uncomplicated UTI (Table 4). Fifty percent of women presenting with UTI will have a maternal history of UTI.3 Although associations between UTI and some genes (blood group secretor status and interleukin 8 receptor) have been reported, genetic factors are not fully understood.

Host defence and bacterial virulence factors

Host defence Directional ow of urine Complete bladder emptying Normal commensal bacteria Neutrophils Complement Antimicrobial peptides Defensins Cathelicidins Low urine pH TammeHorsfall protein (uromodulin) Blood group secretor status Table 2 Bacterial virulence Fimbrial adhesions Type 1 mbriae P mbriae Serum resistance Toxin production Haemolysin Colony-necrotizing factor Iron sequestration

Complicated UTI
Complicated UTI occurs if there is an anatomical or functional abnormality of the renal tract (Table 1). Because the normal

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Risk factors for urinary tract infection (UTI)

Female>male Complicated urinary tract anatomy Incomplete bladder emptying Recent or recurrent UTI Sexual intercourse Diaphragm and spermicidal contraception Disruption of normal bacterial ora Recent antibiotic use Post-menopausal alteration in vaginal ora Pregnancy Family history of UTI Non-secretor status Table 4

host defence is disturbed the requirement for virulence factors is lost and the spectrum of pathogens increases. The most frequent associations are disruption of the normal ow of urine or a foreign body within the urinary tract. Infection in the presence of obstruction can lead to pyonephrosis, which is an indication for urgent intervention. Otherwise, management should include treatment of the acute infection, followed when possible by reversal of the underlying pathology. If the pathology is not reversible, the risk of recurrence will be increased.

Pyelonephritis is an infection involving the renal parenchyma. Although the pathogenic bacteria normally reach the kidney via the ascending route, symptoms of cystitis are not always present (only 50% of cases). In addition to local symptoms (loin pain, haematuria and possibly symptoms of cystitis), systemic symptoms such as fever, rigors, vomiting and septic shock are common and frequently severe. C-reactive protein and erythrocyte sedimentation rate will frequently be raised and blood cultures are positive in 20% of cases. Although infection is normally focal, diffuse infection causing renal failure can occur. Particularly in patients with diabetes, severe infection can cause papillary necrosis, and emphysematous pyelonephritis can occur if infection is with a gas-forming organism (often E. coli, a facultative anaerobe). Emphysematous pyelonephritis is a life-threatening infection that frequently requires nephrectomy. An abscess, either within the kidney or extending beyond the renal capsule (perinephric abscess) can form, and this should be considered if symptoms and signs of infection do not resolve with appropriate antibiotic treatment. Urethritis usually presents with dysuria and urethral discharge, although it is commonly asymptomatic. It is predominantly a sexually transmitted disease caused by Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium or Trichomonas vaginalis. Prostatitis can either be acute or chronic, depending on the duration of symptoms, and represents the most common recurrent UTI in males.6 It commonly presents with perineal or scrotal pain, frequency, urgency and dysuria. This symptom complex usually indicates infection but more chronic presentations can occur in the absence of infection.

Clinical features of UTI

Colonization of the urinary tract, usually dened as more than 105 bacteria/ml in freshly voided urine, causes a spectrum of clinical presentations. UTI, particularly in children and the elderly, may not present with typical symptoms and the diagnosis can easily be missed. Vigilance and timely initiation of treatment may prevent irreversible kidney damage and unnecessary admission to hospital. Asymptomatic bacteriuria is the presence of more than 105 bacteria/ml of urine on two occasions in the absence of other features of infection. Asymptomatic bacteriuria increases the risk of developing symptomatic UTI; 8% of women with asymptomatic bacteriuria develop a symptomatic UTI within 1 week.4 In most circumstances asymptomatic bacteriuria does not require treatment, as this would involve unnecessary antibiotics and the recurrence rate is high. One group in which screening and treatment are indicated is pregnant women,5 in whom asymptomatic bacteriuria is associated with pyelonephritis and low birth weight. Screening is also performed before urological intervention. Cystitis describes infection in the bladder and is the most common form of UTI. It typically presents with dysuria, frequency, urgency, suprapubic pain, haematuria and offensive or cloudy urine. When these typical symptoms are present the clinical diagnosis of UTI presents few problems. Systemic symptoms such as fever, nausea and vomiting, although rare, can also be present.

UTI with a negative urine culture

It is not uncommon for patients to present with symptoms of UTI but with a negative urine culture. Table 5 lists possible causes of this presentation. Urethral syndrome is an ill-dened syndrome, usually occurring in women who present with symptoms of UTI but have negative urine culture and fail to respond to antibiotics. It is important to exclude sexually transmitted infection, but in many no cause can be found. Infection with a fastidious organism may be responsible. Sterile pyuria is the presence of white cells in the urine (with or without symptoms) in the absence of an identiable uropathogen. Infections such as urethritis or with a fastidious organism should be considered. Discussion with a microbiologist is essential to identify pathogens when there is strong clinical suspicion of UTI. Early morning urine samples should be sent to exclude mycobacterial infection. If pyuria persists patients should be referred for urological assessment to exclude underlying causes, such as urinary tract malignancy or stones. Idiopathic interstitial cystitis occurs in the absence of an identiable cause. It presents with lower urinary tract symptoms that can be severe and debilitating.

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Causes of culture-negative urinary tract symptoms

Antibiotics in urine Urinary tract malignancy Idiopathic interstitial cystitis Fastidious organisms Mycobacterial infection Schistosomiasis Fungal infection Viral infection Chlamydia trachomatis Mycoplasma hominis Ureaplasma urealyticum Gardnerella vaginalis Inammation Cyclophosphamide Post-irradiation Bladder stone NSAIDs Table 5

patients with severe pyelonephritis require further assessment. Ultrasonography, with post-micturition bladder residual, abdominal X-ray, urodynamics and cystoscopy are used. Investigation of children is complex, depends on age at presentation, and includes micturating cystography and dimercaptosuccinic acid (DMSA) renography.9

Treatment
The natural history of cystitis is resolution of symptoms in 4e7 days. The benet of non-antibiotic treatments, such as increased uid intake and cranberry juice, is unproven. Antibiotic treatment is effective and reduces the duration of symptoms. For women with uncomplicated cystitis empirical treatment with a 3-day course of antibiotics will achieve a cure in 85e90%;10 this is more effective than a single dose and equivalent to longer regimens. In the UK trimethoprim or nitrofurantoin are recommended.11 Delaying antibiotics for up to 48 hours to allow resolution of symptoms can reduce antibiotic use without signicantly prolonging symptoms.7 For men, due to the increased likelihood of complicated infection and/or prostatitis, at least a 7-day course is recommended. A quinolone is preferable to trimethoprim because of better tissue penetration into the prostate.12 Milder forms of pyelonephritis can be treated with oral antibiotics, initially started empirically but subsequently based on culture results. NHS clinical knowledge summaries recommend 7 days of ciprooxacin or 14 days of co-amoxiclav for men and non-pregnant women, and 10e14 days of cephalexin for pregnant women. Treatment of more severe infections requires hospital admission, intravenous antibiotics (often combination therapy including an aminoglycoside) and uids, converting to oral antibiotics for up to 14 days after clinical improvement. The choice of antibiotic will depend on the clinical scenario and may differ in patients with renal impairment or cystic kidney disease. Treatment of asymptomatic bacteriuria is required only in pregnancy and before instrumentation of the urinary tract.

Diagnosis of UTI
A presumptive diagnosis of UTI can be made on the basis of the history and clinical examination, particularly when classical features are present. However, only 65% of women presenting with symptoms of cystitis will have a conrmed infection.7 The presence of leucocyte esterase, nitrite (formed by the conversion of nitrate to nitrite by most Gram-negative bacteria) and microscopic haematuria are associated with UTI (positive in 90%, 76% and 75% of patients respectively with a positive culture). Proteinuria may also be present. Dipstick urinalysis is frequently used to test for infection and improves diagnostic precision,7 although it may not be needed if there is a strong clinical suspicion. Individual tests have a poor negative predictive value and are not good at excluding UTI, but if all are negative UTI is unlikely. Microbiological analysis remains the gold standard for diagnosing UTI. The bacterial count (colony-forming units (cfu)), the type of bacterium isolated, its antibiotic sensitivities, and urinary white and red cell count per unit volume are all reported. A bacterial count of more than 105 cfu/ml is classically regarded as signicant but counts of more than 103 in patients with typical symptoms are signicant, as are any bacteria in a suprapubic aspirate. Treatment of uncomplicated lower tract disease will usually be started empirically and, provided attention is paid to local resistance patterns, treatment is likely to be successful, so urine culture and sensitivity testing is not required.8 However, urine culture is important in severe, complicated or recurrent infection when the risk of treatment failure is higher. In the absence of clinical features, urine culture is indicated only in pregnant women and before urological intervention.

Prevention of recurrent infection

Several interventions to reduce recurrent infections, such as increased uid intake and complete bladder emptying, are logical but unproven. The Cochrane review on the use of cranberries to prevent UTI concluded that cranberry preparations were effective in reducing re-infection in young women over a 12-month period. Trials of probiotic and oestrogen cream to re-establish normal vaginal/perineal ora have produced inconsistent results. Longterm, low-dose, nocturnal antibiotics or post-coital antibiotics are both very effective for women with frequent infections.13

Antibiotic resistance
As with all bacterial infections the rate of antibiotic resistance among uropathogenic bacteria is increasing. As many uropathogenic bacteria are resident in the gut, they will be exposed to oral antibiotics used for any indication. The rates of antibiotic resistance of the common uropathogens in eight UK centres are given in Table 6. E. coli will frequently be resistant to oral penicillins and cephalosporins, but retains sensitivity to nitrofurantoin and quinolones. Patients with resistant isolates have a longer time to symptom resolution, higher re-consultation rates and more frequent need for multiple courses of antibiotics.

Investigation
After the initial diagnosis young women with symptoms that respond rapidly to treatment do not require investigation. Children, men (more than one infection), women with recurrent infection and

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Susceptibility to oral antibiotics among common uropathogenic bacteria15

Amoxicillin Escherichia coli Enterococcus faecalis Klebsiella pneumoniae Proteus mirabilis Table 6 51% 100% 1% 73% Cefradine 79% 72% 5% Trimethoprim 73% 85% 58% Nitrofurantoin 96% 100% 16% 0% Ciprooxacin 98% 95% 87%

Resistance rates will vary from region to region and depend on whether the infection develops in the community or in hospital. The National Institute for Health and Clinical Excellence (NICE) advises that each region should monitor resistance patterns on a regular basis. Since treatment for UTI is usually initiated empirically it is important to be familiar with local resistance patterns.

Rare infections of the urinary tract

Mycobacterial infection is rare in developed countries. It is difcult to diagnose and can cause progressive kidney damage if untreated. Antituberculous chemotherapy is the usual treatment although surgery is sometimes required. Fungal infections are most commonly seen in patients with diabetes or a structurally abnormal renal tract, or both. Candida albicans is the most common pathogen. BK virus infection: BK virus is a small polyomavirus that can affect the renal tract of severely immunocompromised patients, causing cystitis and nephropathy (particularly in the kidney transplant population). Schistosoma haematobium infection (bilharzia) is common in endemic areas. Early disease presents with symptoms of UTI, late-stage disease typically with urinary tract obstruction due to brotic strictures, and there is an increased risk of malignancy (squamous cell carcinoma). A

UTI in specic populations

UTI in children is common; 2% of children experience at least one UTI before the age of 10 years.14 Infection presents as a febrile illness with no localizing features and can prove difcult to diagnose. In addition, there is the added difculty of obtaining a urine sample for culture. Prompt diagnosis, investigation and treatment of UTI are required to minimize the risk of scarring and progressive renal damage. Children with a combination of infection and reux of urine from the bladder into the ureter and kidney are at particularly high risk of renal damage (reux nephropathy). A group of diseases, including reux nephropathy (also called chronic pyelonephritis) and dysplastic kidneys, accounts for 20% of renal failure in children and contributes to hypertension and renal impairment in adults. Although important in some cases, kidney damage can occur in the absence of infection. The treatment and screening of children, especially young and male children, for reux and other renal tract abnormalities depends on age, and detailed recommendations have recently been provided by NICE.9 UTI in pregnancy can occur in up to 20% of pregnancies and is associated with an adverse outcome. Between 2% and 9% of pregnant women will have asymptomatic bacteriuria in the rst trimester and 30% will develop symptomatic infection. Urine should be cultured at presentation and bacteriuria treated with 3e7 days of oral antibiotics. Repeat screening should be performed and those women with recurrent bacteriuria should receive prophylactic antibiotics. UTI in urology patients is common. Bacteriuria develops in 5% of patients with a urinary catheter per day and even short-term catheterization is associated with a 10% risk of UTI. Any structural abnormality predisposes to UTI, which can be recurrent and require long-term prophylactic antibiotics. UTI in kidney transplant recipients is the commonest infection in the early post-transplant period due in most cases to abnormal anatomy, catheterization and ureteric stenting than to immunosuppression. Acute pyelonephritis in a transplanted kidney should be treated promptly as it can lead to scarring in the transplant kidney and is associated with a poorer long-term transplant outcome.

REFERENCES 1 Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J Med 1993; 329: 1328e34. 2 Hooton TM, Scholes D, Hughes JP, et al. A prospective study of risk factors for symptomatic urinary tract infection in young women. N Engl J Med 1996; 335: 468e74. 3 Scholes D, Hooton TM, Roberts PL, Stapleton AE, Gupta K, Stamm WE. Risk factors for recurrent urinary tract infection in young women. J Infect Dis 2000; 182: 1177e82. 4 Hooton TM, Scholes D, Stapleton AE, et al. A prospective study of asymptomatic bacteriuria in sexually active young women. N Engl J Med 2000; 343: 992e7. 5 Lin K, Fajardo K. Screening for asymptomatic bacteriuria in adults: evidence for the U.S. Preventive Services Task Force reafrmation recommendation statement. Ann Intern Med 2008; 149: W20e4. 6 Grabe M, Bishop MC, Bjerklund-Johansen TE, et al. Guidelines on urological infections. European Association of Urology, 2009. 7 Little P, Turner S, Rumsby K, et al. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study. Health Technol Assess 2009; 13:iiieiv, ixexi: 1e73. 8 Car J. Urinary tract infections in women: diagnosis and management in primary care. Br Med J 2006; 332: 94e7.

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9 Urinary tract infection in children. National Institute for Health and Clinical Excellence, 2010. 10 Katchman EA, Milo G, Paul M, Christiaens T, Baerheim A, Leibovici L. Three-day vs longer duration of antibiotic treatment for cystitis in women: systematic review and meta-analysis. Am J Med 2005; 118: 1196e207. 11 NHS clinical knowledge summaries: pyelonephritis e acute 2009. 12 Scottish Intercollegiate Guidelines Network. Management of suspected bacterial urinary tract infection in adults: a national clinical guideline 2006. 13 Melekos MD, Asbach HW, Gerharz E, Zarakovitis IE, Weingaertner K, Naber KG. Post-intercourse versus daily ciprooxacin prophylaxis for recurrent urinary tract infections in premenopausal women. J Urol 1997; 157: 935e9. 14 Yared A, Edwards KM. Reevaluating antibiotic therapy for urinary tract infections in children. Arch Pediatr Adolesc Med 2005; 159: 992e3. 15 Farrell DJ, Morrissey I, De Rubeis D, Robbins M, Felmingham D. A UK multicentre study of the antimicrobial susceptibility of bacterial pathogens causing urinary tract infection. J Infect 2003; 46: 94e100.

Practice points
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Uncomplicated cystitis in women can be treated with immediate empirical antibiotics directed by urinalysis results Treatment can be delayed by up to 48 hours without a signicant effect on duration of symptoms, to reduce antibiotic use Urine culture is not always required. It is necessary in severe, complicated or recurrent infection, in children and when the diagnosis is uncertain A total of 3 days of antibiotic treatment is sufcient for women with uncomplicated cystitis Men require a longer duration (7 days) of treatment due to possibility of prostatitis or complicated infection Asymptomatic bacteriuria requires treatment only in pregnancy and before urological procedures. Screening should be restricted to these groups

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