Recurrent urinary tract infections

Women often suffer from urinary tract infections, and their recurrent nature means that this is something often encountered in clinical practice. Dr Bandara and Mr Fiadjoe look at the causes and assess the usual treatments, from cranberry juice to a full course of antibiotics.

 

Introduction

A urinary tract infection (UTI) is the commonest bacterial infection in women, with many suffering recurrent episodes. It is therefore one of the commonest bacterial infectious diseases encountered in clinical practice, and it carries significant financial implications.¹

An infection can be classified as either uncomplicated or complicated. The former occurs in a structurally and functionally normal urinary tract, and the latter, in the presence of an abnormal urinary tract or in the presence of a factor that increases susceptibility to infection.

 

Definition

A recurrent urinary tract infection is defined as three positive urine cultures within the preceding 12 months.² Recurrent UTIs include both relapse and re-infection. The case is considered a relapse when there is a symptomatic recurrent UTI with the same organism as that causing the initial infection, following adequate therapy.³

Re-infection is used when recurrent UTIs are caused by a different organisms to that of the original infection, or with the same organism more than two weeks after treatment of the original infection.

Re-infection could also occur in a case where the same strain as that of the original infection has caused the UTI within two weeks, if a post-treatment urine culture had been taken and demonstrated no growth.⁴ The majority of recurrent UTIs are thought to represent re-infection, although it is often difficult to differentiate between the two when caused by the same species.

 

Pathogen

Most UTIs are caused by normal bacterial flora ascending into the urinary tract through the urethra from the bowel, vagina or perineum.⁵ The anatomy of the female urinary tract is thus predisposed to developing UTIs.

The commonest pathogen causing UTIs is Escherichia coli, with up to 80 percent of cases of uncomplicated community acquired UTIs being caused by it.⁶ Staphylococcus saprophyticus is responsible for between 10 and 15 percent of UTIs, with Klebsiela, Enterococcus faecalis and Proteus mirabilis making up the majority of the remainder.

 

Epidemiology

Approximately 40 percent of women develop a UTI during their lifetime.⁷ One-third of women will have at least one episode by the age of 24,⁸ with prevalence increasing with age. Recurrent UTIs are common, with studies showing approximately 30 percent of those that suffer with a UTI going on to develop recurrent infections.⁹

 

Risk factors

Numerous studies exist, investigating possible risk factors for recurrent UTIs in women. The anatomy of the female urinary tract is a risk factor, with the urethra measuring approximately five centimetres in females in comparison to greater than 15cm in males.

 

Young women

The risk factor that has shown the strongest correlation with the development of recurrent UTIs is sexual intercourse. The increased frequency demonstrates a positive correlation with the risk of developing recurrent UTIs.¹⁰ Having a new partner or multiple partners is associated with an increased risk of developing a primary UTI and mild association with recurrent infections.⁸

The risk of developing an isolated urinary tract infection following recent intercourse has been shown to increase the risk as much as five-fold, as reported in a study by Hooton et al.⁴ This rise in risk is thought to be related to a pattern of microflora colonisation, with an increased rate of colonisation with E. coli immediately following intercourse.⁴

Spermicide exposure, another risk factor for recurrent UTIs, has also demonstrated posing an increased rate of colonisation with E. coli. Scholes et al demonstrated a two-fold increase risk of recurrent UTI with spermicide exposure in the one year prior to initial infection.¹⁰

Other risk factors for development of recurrent urinary tract infections include development of initial UTI at an early age and a maternal history of recurrent UTIs. These were the most strongly linked risk factors following frequency of sexual intercourse, demonstrating an increase in risk between two and four-fold.⁴ These findings would suggest that inherited factors might play a role.

Secretor status of histo-blood group antigens was thought to be an indicator of the chance of developing recurrent UTIs, with non-secretors being at increased risk. Studies had demonstrated that non-secretors allowed better adhesion of bacteria to uroepithelial cells.⁹

However, subsequent papers have shown inconsistent results. In a family study of children prone to pyelonephritis, expression of the interleukin-8 receptor was shown to be lower in case patients and family members, compared to age matched controls. Polymorphisms have been identified which demonstrate a reduced neutrophil response to UTIs.

Toll-like receptors have also be linked to susceptibility to UTIs, with identified associations with TLR-1, TLR-4 and TLR-5.¹¹ Further investigations may identify stronger genetic associations.

 

Postmenopausal women

The incidence of recurrent UTIs is far higher in the elderly. Risk factors in this population are considerably different to those found in younger women. Oestrogen deficiency is thought to play a major role. Oestrogen has been shown to stimulate the proliferation of Lactobacillus in the vaginal epithelium, reduce pH, and prevent vaginal colonisation of Enterobacteriaceae.¹²

Urological factors also contribute to the increased risk in postmenopausal women. Urinary incontinence, presence of a cystocoele and a large post-void residual volume all increase the risk of developing recurrent urinary tract infections.¹³

 

Diagnosis

Assessment of a patient with a possible recurrent UTI includes confirming the presence of a bacterial UTI, assessing for risk factors for complicated infection, and identifying a potential causative organism.¹⁴

A clinical evaluation including history, examination and urine dipstick is often sufficient to confirm the diagnosis of a UTI and helps avoid unnecessary antibiotic use. Signs and symptoms that help predict a positive culture include dysuria, urgency, haematuria, back pain, costovertebral tenderness and the absence of vaginal discharge or irritation.¹⁵

McIsaac et al identified three factors from initial assessment that demonstrated the strongest association with a positive urine culture. These included dysuria, a greater presence of leukocytes than a trace and any positive nitrites.¹⁶

The gold standard for diagnosis of a UTI is by demonstrating a bacterial count of greater than 1×105 in a mid-stream urine sample taken whilst the patient is symptomatic. Urine culture not only confirms the diagnosis but aids antibiotic therapy if there is no improvement with empirical treatment.

Imaging all women with recurrent UTIs is deemed unnecessary with studies demonstrating low incidence of anatomical abnormalities on cystoscopy performed on these patients.¹⁵ Postvoid residual and uroflowmetry are optional tests that can be used in postmenopausal women.¹⁵

 

Treatment

The management of acute recurrent UTIs can often take place in the primary care setting with no need for specialist opinion. Knowledge of antimicrobial sensitivity profile of pathogens causing uncomplicated UTIs in the community should guide therapeutic decisions.⁴ Current standard treatment is with a three-day course of Trimethoprim.

Extending the course of Trimethoprim to seven days identified no benefit, but an increase in adverse effects was seen.⁴ With increasing levels of reported Trimethoprim resistance, Nitrofurantoin is an effective alternative, demonstrating low levels of E. coli resistance.

However, Nitrofurantoin is ineffective against most Proteus species and some Enterobacter and Klebsiella strains.⁴ Fluoroquinolones are also effective antibiotics for UTIs but are often reserved for complicated UTIs and communities with high rates of resistance to Trimethoprim.

 

Prevention

Lifestyle modification

Numerous conservative measures have been tried to help prevent recurrent urinary tract infections. These include altering modifiable risk factors such as frequency of sexual intercourse and spermicide exposure. Voiding before and after coitus has been tried, although no significant evidence exists to prove its benefits.¹⁵

Cranberry juice has been considered an effective method of preventing recurrent urinary tract infections for many years. It is thought that cranberry juice inhibits adherence of P-fimbriated E. coli and other gram-negative uropathogens to urothelial cells.⁴ Conflicting results exists regarding its efficacy. A recent placebo-controlled trial demonstrated that cranberry juice did not significantly reduce risk in comparison to placebo groups.

However, the concurrent reduction in urinary P-fimbriated E. coli strains supports the biological plausibility of cranberry activity.¹⁷

 

Antibiotic therapy

Antibiotic use for the prevention of UTIs has been shown to reduce recurrences. A systematic review by Albert et al demonstrated that antibiotic intake reduced the number of clinical and microbiological recurrences when compared to placebo in pre- and postmenopausal women with recurrent UTIs. The relative risk of having a clinical UTI was 0.15 in favour of the antibiotic group against placebo.

The disadvantage of antibiotics was the adverse effects. The rate of adverse effects was higher in the antibiotic group, with a relative risk of 1.58 in favour of the placebo group.¹⁸ Adverse effects were dependant on the antibiotic used and ranged from oral and vaginal candidiasis to more severe reactions such as skin rash.

Once prophylactic antibiotics are stopped, UTI recurrence is shown to return to pre-treatment frequency.¹⁵ This highlights the issue of patient compliance. Patient compliance with chronic medication is often difficult, especially in young, usually healthy individuals. This will therefore have an impact on the efficacy of the treatment. The risk of antibiotic resistance with long-term antibiotics also needs consideration.

Other options that have been used to avoid continuous antibiotic usage are through postcoital antibiotics and self start antibiotics. Postcoital antibiotics involve taking a course of antibiotics within two hours of intercourse. Studies have shown the efficacy of this form of treatment in young women to be in line with long-term continuous antibiotic prophylaxis.¹⁹

Self-start antibiotics involves the prescription of a three-day course of antibiotics to be taken when the woman develops UTI symptoms. Women have been shown to be able to accurately predict the onset of a UTI, with concordance to urine culture as high as 94 percent.²⁰

This makes this method of treatment a safe and effective way of managing recurrent UTIs, whilst also reducing the amount of contact required with healthcare providers. Patients are advised to contact a healthcare provider if symptoms do not improve within 48 hours of initiating treatment.¹⁵

Choice of antibiotics are nitrofurantoin, trimethoprim (or cotrimoxazole), and fosfomycin trometamol as first-line drugs. Oral cephalosporins and quinolones should be restricted to specific indications. Antibiotic prophylaxis reduces the number of uropathogens in the gut and vaginal flora, and reduces bacterial ‘fitness’. Given the correct indication, the recurrence rate of UTIs can be reduced by about 90 percent.²¹

Due to possible adverse events and the concern of selecting resistant pathogens, according to the guidelines of the European Association of Urology, antimicrobial prophylaxis should be considered only after counselling, behavioural modification and non-antimicrobial measures have been attempted.

The choice of antibiotic, as with acute infections, is guided by knowledge of local pathogen profiles and sensitivities.

 

Oestrogen

As discussed earlier, oestrogen deficiency in postmenopausal women is thought to be a risk factor for the development of recurrent UTIs. The use of this hormone in the prevention of this ailment has been studied, and it has demonstrated variable results.

A systemic review by Perrotta et al demonstrated that oral oestrogens had no impact on the number of recurrent episodes postmenopausal women experienced. Those taking oral oestrogens reported significantly more adverse effects, such as breast tenderness, mild vaginal bleeding and spotting.²²

Use of vaginal oestrogens have shown a decrease in the number of recurrent episodes in a study by Eriksen et al, with minimal systemic absorption and therefore adverse effects.

There was also evidence of increased Lactobacilli, reduced pH and reduced colonisation of Enterobacteriaceae with vaginal oestrogen in comparison to placebo.²³ Some studies have demonstrated an improvement in other urological symptoms with topical oestrogens such as ones related to stress incontinence and an overactive bladder.²⁴

Evidence, however, is limited and this is an area requiring further investigation. The optimal type of vaginal oestrogen to use is unclear. Initial studies show that creams may be more effective than vaginal rings, though applying cream on a daily basis may not be possible for some patients, and brings the issue of compliance into play.

 

Other prevention methods

Lactobacillus crispatus vaginal suppositories have been trialled with regards to its effectiveness in reducing recurrent urinary tract infections. Results demonstrate a significant reduction in recurrent episodes,¹⁷ although further studies are required to evaluate its efficacy properly.

Investigations into the development of a safe and effective vaccine are being undertaken. A recent study has developed a possible candidate live-attenuated vaccine for the treatment and prevention of acute and recurrent urinary tract infection caused by uropathogenic E. coli.

Deletion of the O antigen ligase gene from the uropathogenic E. coli isolate resulted in a strain that stimulates urothelial cytokine secretion. Although this study is at early stages, along with numerous others, the development of a successful vaccine would be a welcome breakthrough.

 

Conclusion

Risk factors for the development of recurrent urinary tract infection differ between young women and postmenopausal women. Numerous preventative methods exist for both groups including lifestyle changes, prophylactic antibiotics and oestrogen administration in postmenopausal women.

Despite this, RUTI remains the commonest bacterial infection affecting women. Further investigations are being undertaken to identify a more definitive preventative method, including the development of a vaccine, in order to reduce the levels of morbidity in women and ease the financial burden it places on the health service.

 

Authors

Mr Paul Fiadjoe is a consultant obstetrician and gynaecologist at the Department of Obstetrics & Gynaecology at Broomfield Hospital in Chelmsford. Mr Fiadjoe has a sub-specialty interest in urogynaecology – specifically lower urinary tract disorders as shows his chosen paper topic – and pelvic reconstructive surgery and surgical techniques.
He enjoys travelling, especially to countries and cities steeped in architectural history, and he has a passion for cooking. When he’s not loyally supporting Arsenal in their tireless pursuit of silverware, he enjoys putting his own body to the test and playing a bit of football or tennis.

Dr Shane Bandara is an FY2 at the Department of Obstetrics & Gynaecology at Broomfield Hospital in Chelmsford.

 

References

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