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Recurrent urinary tract infection in gynaecological practice

^1. Department of Urogynaecology, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK
^2. Department of Urogynaecology, Leicester General Hospital.
^3. Department of Urogynaecology, Leicester General Hospital.
^4. Reproductive Science Section, Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, Leicester LE2 7LX, UK Email: dgt4{at}le.ac.uk (corresponding author)

	Abstract

TOP Abstract Introduction Classification Pathogenesis of recurrent UTI Pathogens in UTI Diagnosis of UTI Additional investigations and... Treatment of UTI Summary References

 
Key content:

• Urinary tract infection (UTI) is the result of interaction between host defences and bacterial pathogenic mechanisms.
  
• Recurrent UTI can be associated with urinary tract abnormalities.
  
• Urinary tract imaging is useful in a minority of women to identify pathological, structural or functional abnormalities.
  
• Adequate fluid intake, topical estrogens and prophylactic antibiotics can be useful in the management of recurrent infections.
  
• Symptoms often reappear despite adequate treatment.
  

Learning objectives:

• To understand the pathogenesis of recurrent UTI in women.
  
• To appreciate the value and limitations of urinary tract imaging.
  
• To develop an appropriate management strategy.
  

Ethical issues:

• Women with dipstick haematuria, but without bacteriological confirmation of a UTI, should be referred for urological evaluation.
  
• There is no evidence that the risk of altering antibiotic resistance patterns through the use of prophylactic antibiotics outweighs the advantage of reducing UTI in susceptible individuals.
  

Please cite this article as: Harris N, Teo R, Mayne C, Tincello D. Recurrent urinary tract infection in gynaecological practice. The Obstetrician & Gynaecologist 2008;10:17–21.

Keywords midstream specimen of urine (MSSU) / prophylactic antibiotics / recurrent urinary tract infection / topical estrogens

	Introduction

TOP Abstract Introduction Classification Pathogenesis of recurrent UTI Pathogens in UTI Diagnosis of UTI Additional investigations and... Treatment of UTI Summary References

 
Urinary tract infection (UTI) is a general term that can be applied to a spectrum of clinical conditions, ranging from fulminant pyelonephritis with urosepsis to the asymptomatic presence of bacteria in the urine. Recurrent UTI can be defined as three or more episodes of UTI during a 12-month period.

Almost 50% of women experience at least one UTI during their lifetime and epidemiological studies have shown that up to 27% of women experience at least one culture-confirmed recurrence within the 6 months following initial infection.¹ The presence of haematuria and urgency during the initial infection appear to be the strongest predictors of recurrent infection. Recurrent UTI is a source of considerable morbidity and in the evaluation of these women it is important to differentiate between recurrent and incompletely treated infection, as the management of the two is likely to differ. Recurrent infection implies re-infection, which can be caused by a different organism. These infections are often associated with increased host susceptibility (see below). Incompletely treated infection implies bacterial persistence and is more likely to be associated with an underlying pathological, anatomical or functional abnormality; for example, urethral diverticulum, incompletely emptying bladder, urolithiasis.

	Classification

TOP Abstract Introduction Classification Pathogenesis of recurrent UTI Pathogens in UTI Diagnosis of UTI Additional investigations and... Treatment of UTI Summary References

 
One of the most clinically useful ways of classifying UTI is based upon whether the infection is complicated or uncomplicated. Complicated UTI occurs when an underlying anatomical or functional abnormality that predisposes to urinary infection is present. Examples of such abnormalities are urinary tract stones, duplex collecting systems and neuropathic bladders.

Urinary tract infection can also be classified according to the part of the urinary tract affected. Involvement of the bladder alone, with little or no systemic upset, is known as cystitis, whereas pyelonephritis is infection in the renal parenchyma, often with features of systemic sepsis. These classifications are important, not only for epidemiological and data collection purposes, but also to guide clinicians towards appropriate treatment.

	Pathogenesis of recurrent UTI

TOP Abstract Introduction Classification Pathogenesis of recurrent UTI Pathogens in UTI Diagnosis of UTI Additional investigations and... Treatment of UTI Summary References

 
The endpoint of any UTI is bacterial colonisation of the uroepithelium, resulting in inflammation and, occasionally, bacterial dissemination. This process involves a complex interaction between host and micro-organism. A number of factors are known to be important in the pathogenesis of UTI and it is convenient to divide these into host and microbial factors.

Host factors
The lower urinary tract has several intrinsic mechanisms designed to inhibit bacterial colonisation. Some of the general host factors that help prevent colonisation by uropathogens include:

• Unobstructed urine flow, facilitating mechanical washout of bacteria, along with the rapid urothelial cell turnover. This helps to prevent colonisation. Women with congenital or acquired functional voiding disorders, for example, spina bifida, urethral stenosis and following major pelvic surgery, may be more prone to infection, partly as a result of incomplete bladder emptying.
  
• Uromucoid (also known as Tamm–Horsfall protein), mucopolysaccharides, and immunoglobulin, which augment this barrier function and inhibit bacterial adherence.
  
• Vaginal colonisation by lactobacilli, promoted by estrogens, in premenopausal women. This colonisation results in the production of lactic acid, maintaining a low pH that inhibits growth of many pathogenic bacteria. However, in postmenopausal women, lactobacilli are not present and the vagina becomes primarily colonised with enterobacteria, in particular Escherichia coli (E. coli). This is a major factor leading to increased susceptibility to clinically significant UTI.
  

Certain host behavioural factors are known to predispose to recurrent UTI. These include voiding dysfunction, sexual intercourse frequency, use of spermicidal lubricant and the use of oral contraceptives.² Interestingly, although associated with UTI in general, such behavioural factors have not been shown specifically to influence the development of recurrent UTI.¹ Pedigree analysis suggests a genetic predisposition for UTI among certain young women and a number of putative candidate genes have been identified. For example, women who are non-secretors of blood group antigens have a three- to four-fold increased risk of developing recurrent UTI.³ Interleukin-8 receptor (CXCR1) expression, certain human leukocyte antigen (HLA) loci, Toll-like receptors, and Tamm–Horsfall protein expression are also known to influence susceptibility to UTI.^4–6 Another explanation for the pathogenesis of recurrent UTI is the observation that some bacteria can survive within the uroepithelium in quiescent intracellular reservoirs (QIRs),⁷ despite establishment of sterile urine with antibiotics.

Microbial factors
Bacterial virulence mechanisms facilitate colonisation and growth of micro-organisms within uroepithelium. There are three main categories of virulence mechanism and these often reflect an intrinsic characteristic of a particular bacterial species.

Adherence mechanisms
The most important adherence factors are thought to be fimbriae (pili), which mediate binding of bacteria to receptors on urothelial cells. Pathogenic E. coli possess two main types of fimbriae, known as type I and type P. Type I pili are present on the majority of E. coli causing lower urinary tract infection, whereas type P pili have been found in up to 80% of E. coli isolates causing pyelonephritis. In contrast, the afimbrial adherence mechanisms mainly consist of the glycocalix forming the bacterial cell wall (e.g. lipopolysaccharide). In addition, uropathogenic E. coli have a greater capacity for adherence to uroepithelial cells in women who are non-secretors of blood group antigens, than to cells from antigen secretors.

Direct virulence against the host
Bacterial production of endotoxin, exotoxin and haemolysin assist in the process of microbial invasion and may also be responsible for the generalised toxaemia that can occur with systemic urosepsis. In particular, the lipid A component of the lipopolysaccharide cell wall of Gram-negative bacteria is thought to be at least partly responsible for triggering the systemic effects of endotoxaemia.

Antibiotic resistance
Bacteria can develop resistance to antibacterial agents by various methods. These include reduced drug accumulation as a result of active efflux, antibiotic inactivation (e.g. enzymatic deactivation of penicillin by beta-lactamases) and alteration of target sites (e.g. alteration of penicillin binding protein [PBP] in MRSA).

Bacterial adherence to the uroepithelium can be followed by colonisation, tissue damage and, in some instances, invasion and dissemination. Expression of capsular K antigen, production of haemolysin and anti-IgA proteases all affect the invasive capacity and the virulence of uropathogenic bacteria.

	Pathogens in UTI

TOP Abstract Introduction Classification Pathogenesis of recurrent UTI Pathogens in UTI Diagnosis of UTI Additional investigations and... Treatment of UTI Summary References

 
The majority of community and hospital acquired urinary tract pathogens are Gram-negative bacteria. The recent ECO·SENS study⁸ was designed to investigate the prevalence and antimicrobial susceptibility of pathogens causing community-acquired UTI in 16 European countries. Within the community setting, 70–80% of UTIs are caused by E. coli. However, the Gram-positive organisms (especially Staphylococcus saprophyticus) may be responsible for up to 8% of infections and exhibit seasonal variability.⁸ Other organisms occasionally encountered include Klebsiella, Pseudomonas spp, Proteus spp. and Enterococcus faecalis. Genitourinary candidiasis and tuberculosis can cause infection, particularly in immunocompromised women.

	Diagnosis of UTI

TOP Abstract Introduction Classification Pathogenesis of recurrent UTI Pathogens in UTI Diagnosis of UTI Additional investigations and... Treatment of UTI Summary References

 
The diagnosis of clinically significant UTI requires both clinical assessment of symptoms and bacteriological evaluation. Most UTIs result in urothelial inflammation and women experience a variety of symptoms, including dysuria, urinary frequency, urgency and haematuria. A recent meta-analysis⁹ of evidence relating to the use of rapid urinalysis showed that dipstick assessment offers a useful screening test if both urinary nitrite and leucocyte esterase are assessed. Nitrites are produced from the reduction of urea by urea-splitting bacteria. Leucocyte esterase is produced as a result of leucocyte degradation in urine and can be regarded as a surrogate marker of pyuria. However, these tests have limited sensitivity and/or specificity when used in isolation and we would advocate use of the urine dipstick as a screening tool for UTI. If a positive result for leucocyte esterase or nitrite is demonstrated, a midstream specimen of urine (MSSU) should be sent for formal bacteriological evaluation (see below). If there is a clinical suspicion of UTI, empirical treatment with antibiotics and appropriate advice on fluid intake should be given before the MSSU results are available. In asymptomatic women, it may be more appropriate to wait for the results before commencing antimicrobial treatment.

Pyuria is conventionally defined as the presence of >10 white blood cells (WBCs) per high power field (HPF) in microscopy of a centrifuged urine specimen. However, levels of pyuria as low as 2–5 WBCs/HPF can be important in women with appropriate symptoms. The presence of sterile pyuria (i.e. no bacteria are identified) should lead the clinician to consider a diagnosis of urinary tract tuberculosis, although there are other causes of sterile pyuria.

The gold standard bacteriological evaluation of an uncomplicated UTI comprises microscopy, quantitative culture and sensitivity testing of a freshly voided MSSU. In women with indwelling urinary catheters, a catheter specimen of urine (CSU) is required and in children, a suprapubic aspiration may be necessary. Further systemic assessment is indicated if severe infection is suspected or if the woman is systemically unwell.

The MSSU should be processed as soon as possible; each bacterium will form a single colony on the culture plate. The microbiological criteria for diagnosing UTI are not arbitrary but based on a series of elegant experiments by Kass that correlate UTI syndromes with the quantity of organisms in urine. The number of colony-forming units (CFUs) conventionally taken to indicate infection is 100 000 per ml.¹⁰ However, clinically significant UTI can still be present with lower counts under certain clinical circumstances, for example following suprapubic aspirations and when pure growths of a single organism are identified.

	Additional investigations and imaging

TOP Abstract Introduction Classification Pathogenesis of recurrent UTI Pathogens in UTI Diagnosis of UTI Additional investigations and... Treatment of UTI Summary References

 
Women with a single, uncomplicated UTI do not generally need any further investigation. However, development of a second or subsequent infection is an indication for further evaluation. At the very least this should involve ultrasonography of the renal tract. Additional investigations are determined by the clinical scenario. For example, if renal stones are suspected, we would recommend initial assessment with an X-ray of the kidneys, ureter and bladder (KUB) and more detailed evaluation with intravenous urography (IVU) or computerised tomography (CT), where indicated. If voiding dysfunction is likely, uroflowometry is usually the initial investigation.

Where formal urological evaluation is deemed necessary, it is usually focused initially on the lower urinary tract to reveal abnormalities of clinical importance. Following even a single UTI, if there is pathology requiring surgical intervention, it will almost always be associated with a history of voiding difficulty, acute retention or haematuria.¹¹

There is no consensus on the need for endoscopic evaluation in women with UTI. Most urologists would not recommend cystoscopy in younger women (<50 years of age), following a single bacteriologically proven infection. However, recent data¹² has shown that up to 8% of women >50 years of age with recurrent infection will have significant abnormalities detected during cystoscopy. It is, therefore, reasonable to consider undertaking flexible cystoscopy in women with recurrent UTI, to exclude underlying intravesical pathology.

	Treatment of UTI

TOP Abstract Introduction Classification Pathogenesis of recurrent UTI Pathogens in UTI Diagnosis of UTI Additional investigations and... Treatment of UTI Summary References

 
For simple uncomplicated urinary infection the traditional treatment is oral nitrofurantoin, trimethoprim or a suitable cephalosporin. Short course therapy (3 days) is recommended, as studies have failed to demonstrate any advantage to longer treatments.¹³ Single dose therapy is occasionally used but treatment failure rates are higher.

Women with complicated UTI require 10–14 days of antimicrobial therapy and may need parenteral medication with additional supportive treatment.

Increasing quinolone resistance (2–3%) in community-acquired E. coli infection is a cause for concern and use of this class of antibiotic in uncomplicated UTI should generally be discouraged. In addition, E. coli resistance to trimethoprim is now 15–20% in most European countries and this should inform empirical antibiotic-prescribing guidelines.⁸ However, guidance on microbial sensitivities should be obtained from the local microbiology service on a regular basis.

Recurrent UTI
Around 20–30% of women with simple cystitis develop recurrent UTIs.¹ In most cases these are uncomplicated, but a small proportion will have an underlying pathological, functional or anatomical abnormality and may require further urological investigation. In general, treatment should aim to eradicate the infection and this should be confirmed with a post-treatment MSSU.

Women who suffer recurrent infections should be encouraged to undertake additional prophylactic measures (Box 1). Most of these have a sound basis for recommendation but randomised evidence, proving efficacy, is lacking.

View larger version (44K): [in this window] [in a new window]   Box 1 Prophylactic measures for recurrent urinary tract infection

• cefalexin 125–250 mg at night
  
• trimethoprim 100 mg at night
  
• nitrofurantoin 50–100 mg at night
  

Development of candidiasis and gastrointestinal upset are occasionally seen. There is also a theoretical risk of increasing antibiotic resistance, although the regimens suggested have minimal effects on faecal and vaginal flora. Whilst not based upon any good evidence, one possible strategy is to rotate these antibiotics on a regular basis to reduce the theoretical risk of antibiotic resistance.

Unfortunately, prophylactic antibiotics may not alter the natural history of recurrences and up to 60% of women will re-establish their pattern of recurrence when prophylactic treatment is stopped.¹⁴ Nevertheless, we would suggest that, where indicated, prophylactic antibiotics should be used for 6 months in the first instance. If recurrence remains a problem, longer periods and, occasionally, indefinite use of prophylactic antibiotics will be necessary.

Alternative strategies

• Antibiotic self-commencement. Women who are prone to UTI can keep a supply of antibiotics at home and start treatment as soon as they develop symptoms. However, they should be encouraged to produce an MSSU before starting the antibiotics to allow accurate microbiological evaluation of any infection.
  
• Postcoital antibiotics. A single dose of trimethoprim, nitrofurantoin or cephalexin after intercourse can reduce UTI in some women who are prone to intercourse-related UTI.
  

Box 2 shows a simple algorithm for use in the management of women with recurrent UTI. Not all steps are appropriate in every case but it provides a useful strategy for formulating treatment.

View larger version (22K): [in this window] [in a new window]   Box 2 Algorithm for use in management of recurrent UTI

	Summary

TOP Abstract Introduction Classification Pathogenesis of recurrent UTI Pathogens in UTI Diagnosis of UTI Additional investigations and... Treatment of UTI Summary References

In the management of women with any type of UTI, it is important to have an appreciation of the pathogenesis, host and bacterial interaction, methods of diagnosis, treatment algorithms and local antibiotic sensitivities.

It should be remembered that 20–30% of women with UTI develop at least one recurrent infection. In addition, a few women have underlying anatomical or functional abnormalities (complicated UTI) and require further evaluation and treatment. The majority of women, however, do have any significant underlying abnormalities. An algorithm for managing women with recurrent UTI is presented above.

	References

TOP Abstract Introduction Classification Pathogenesis of recurrent UTI Pathogens in UTI Diagnosis of UTI Additional investigations and... Treatment of UTI Summary References

 

1. Foxman B. Recurring urinary tract infection: incidence and risk factors. Am J Public Health 1990;80:331–3.[Abstract/Free Full Text]
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3. Stapleton AE, Stroud MR, Hakomori SI, Stamm WE. The globoseries glycosphingolipid sialosyl galactosyl globoside is found in urinary tract tissues and is a preferred binding receptor in vitro for uropathogenic Escherichia coli expressing pap-encoded adhesins. Infect Immun 1998;66:3856–61.[Abstract/Free Full Text]
4. Finer G, Landau D. Pathogenesis of urinary tract infections with normal female anatomy. Lancet Infect Dis 2004;4:631–5. doi:10.1016/S1473-3099(04)01147-8[Medline]
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8. Kahlmeter G. Prevalence and antimicrobial susceptibility of pathogens in uncomplicated cystitis in Europe. The ECO.SENS study. Int J Antimicrob Agents 2003;22 Suppl 2:49–52. doi:10.1016/S0924-8579(03)00229-2
9. St John A, Boyd JC, Lowes AJ, Price CP. The use of urinary dipstick tests to exclude urinary tract infection: a systematic review of the literature. Am J Clin Pathol 2006;126:428–36.[Medline]
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12. Lawrentschuk N, Ooi J, Pang A, Naidu KS, Botlon DM. Cystoscopy in women with recurrent urinarytract infection. Int J Urol 2006;13:350–3. doi:10.1111/j.1442-2042.2006.01316.x[Medline]
13. Michael M, Hodson EM, Craig JC, Martin S, Moyer VA. Short versus standard duration oral antibiotic therapy for acute urinary tract infection in children. In: Cochrane Database Syst Rev 2003. p. CD003966.
14. Albert X, Huertas I, Pereiró II, Sanfélix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women. In: Cochrane Database Syst Rev 2004. p. CD001209.
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