The Diagnosis and Management of Uncomplicated Recurrent Urinary Tract Infection

This guideline was developed by a multidisciplinary expert panel: Rees J et al with the support of a grant from Aspire Pharma Ltd. See end of summary for full disclaimer.

In this summary:

• Scope of this guideline
• Defining and diagnosing recurrent UTI
  • Box 1: Typical symptoms of UTI
  • Behavioural and lifestyle modifications
  • Antibiotic treatment
  • Non-antibiotic treatments
    • Topical oestrogens
    • Methenamine hippurate
    • Vaccines
  • Non-pharmacological options
    • Cranberry
    • d -mannose
  • Specialist options
    • Intravesical GAG layer replacement
    • Intravesical antibiotics
• Useful resources for healthcare professionals

Diagnosis and Management of Patients with Recurrent Urinary Tract Infection

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Scope of This Guideline

• This guideline does not cover patients with acute uncomplicated UTI, who should be managed with a standard, 3-day course of narrow-spectrum antibiotics where possible, provided that their infection is uncomplicated. This guideline also does not cover patients with complicated recurrent UTI, so specialist referral should be considered for the following according to local pathways: 
  • pregnant women
  • men 
  • patients with recurrent or severe pyelonephritis
  • patients infected with resistant bacteria
  • patients with recurrent UTI associated with structural or functional abnormalities of the urinary tract
  • patients with recurrent UTI associated with atypical infections, such as tuberculosis or schistosomiasis
  • catheterised patients, in whom misdiagnosis is common because of colonisation (treat only when symptomatic)
  • patients with immunity compromised as a result of drugs or diseases
  • patients with chronic renal failure with oliguria, who should be seen by the renal team because of the risk of renal deterioration

Defining and Diagnosing Recurrent UTI

• Recurrent UTI is defined as two UTIs within 6 months or three UTIs within 12 months
• Diagnosis of UTI should be based on a combination of:
  • clinical diagnosis based on typical symptoms (Box 1)
  • microbiological diagnosis by appropriate use of urine dipsticks and urine culture
  • past response to antibiotic treatment of isolated episodes of acute of UTI

• A diagnosis of UTI can be considered if the patient has a strong symptom profile, even in the absence of culture‑positive urine or dipstick confirmation
  • fever can be useful to differentiate inflammatory and infective causes 
  • previous response to antibiotics for similar symptoms also supports this diagnosis
• Use of urine dipsticks
  • urine samples should ideally be taken in the early morning, because these samples will have a higher yield
  • samples should be taken midstream to avoid urethral contamination
    • consider whether patients are physically able to take a sample, especially elderly patients 
  • overhydration can impact dipstick results by diluting urine, increasing the likelihood of false-negative results
  • please refer to manufacturer’s advice on appropriate storage for urine dipsticks; incorrect storage and use may result in inaccurate results, such as false‑positive results following prolonged exposure to air
  • the presence of leucocytes and nitrites in combination has a higher predictive value of UTI than leucocytes alone
  • provide full and accurate clinical details on request forms
• A diagnosis of UTI should not be made in asymptomatic patients with a positive urine sample (asymptomatic bacteriuria)
  • dipsticks have a poor predictive value due to a high rate of false positives and false‑negatives; they may be useful in making a diagnosis when a combination of positive results including nitrites are detected in patients with classical symptoms, but a negative dipstick result, while making UTI less likely as a diagnosis, does not rule out UTI and thus must be interpreted in the light of symptoms/previous response to antibiotics
  • do not use dipsticks for asymptomatic or catheterised patients
  • diagnosis in elderly patients should not be based on positive microbiology alone, because asymptomatic bacteriuria is increasingly common with advancing age
    • use of urine dipsticks in elderly patients is associated with a high false-positive rate
    • elderly patients are often unable to provide a history of acute urinary symptoms for reasons such as delirium or dementia
    • asymptomatic bacteriuria is present in 3.6–19% of elderly patients and 15–50% of elderly individuals in long-term care
    • elderly institutionalised patients frequently receive unnecessary antibiotic treatment for asymptomatic bacteriuria despite clear evidence of side-effects with no compensating clinical benefits
• Consider referral for urinary tract ultrasound (including post-void residual volume) in patients: 
  • with very frequent infections
  • with recurrent Proteus infections (due to their association with renal calculi)
  • who do not respond to treatment
  • with post-micturition symptoms, such as a sensation of incomplete emptying, or those with a palpable bladder
• Consider a non-urgent referral for suspected bladder cancer in people aged 60 years and over with recurrent or persistent unexplained symptoms of UTI
  • who do not respond to antibiotics 
  • with new storage symptoms where UTI is not confirmed
  • with rigors, systemic illness, and loin pain
• Consider an urgent referral (within 2 weeks) for suspected bladder cancer in patients:
  • aged 45 years and over with unexplained visible haematuria without urinary tract infection or visible haematuria that persists or recurs after successful treatment of urinary tract infection
  • aged 60 years and over with unexplained non-visible haematuria and either dysuria or a raised white blood cell count

Behavioural and Lifestyle Modifications

• Advise patients with inadequate fluid intake to increase their fluid intake to at least 1.5 litres per day
  • increasing fluid intake does not reduce the risk of UTIs in patients who already drink sufficient fluids, but it may reduce the frequency of recurrent infections in those who do not drink sufficiently
  • dehydration is a particular cause of recurrent UTI in elderly individuals and should be discussed with the patient
• Optimise diabetic control
• Treat constipation and diarrhoea, particularly in elderly patients—constipation is a common underlying cause of recurrent UTI in this population
• Encourage post-coital voiding in women with intercourse‑triggered UTI

Antibiotic Treatment

• Antibiotic stewardship requires careful, reasonable, and accountable use of antibiotics to preserve their value and efficacy
  • follow the recommendations regarding choice of antibiotic when sensitivities are provided with microbiological results
• Choice of antibiotic is based on a variety of factors, including:
  • pathogens identified from urine culture
  • local variations in resistance and susceptibility patterns 
  • comorbidities; e.g. nitrofurantoin should be used cautiously in patients with renal impairment
    • refer to summaries of product characteristics for precautions and warnings
  • interactions with concomitant drugs; e.g. folate antagonism may occur when trimethoprim is used with methotrexate
    • refer to summaries of product characteristics for drug interactions
  • multiple antibiotics should not be combined unless on expert advice 
• A 3-day course of antibiotics is usually sufficient for most adult non‑pregnant women over 16 years of age
  • if the patient remains symptomatic at the end of this course, reassess the diagnosis and consider continuing antibiotics after obtaining an MSU for culture and sensitivities
• Patients with recurrent UTI can be treated via three approaches:
  • self-start antibiotics
    • many patients with recurrent UTI can accurately self‑diagnose new episodes; these patients can access antibiotics via repeat prescription, keeping a course at home to start when they develop the first symptoms of an infection
      • limit the number of repeats so that patients are reviewed after six courses
    • consider monitoring to ensure that patients are not acquiring antibiotic‑resistant organisms
  • continuous antibiotic prophylaxis
    • patients take low-dose antibiotics daily to prevent recurrence
    • consider non-antibiotic prophylaxis for all patients before starting continuous antibiotic prophylaxis
      • non-antibiotic prophylaxis may be continued as combination therapy if continuous antibiotic prophylaxis is started later
    • ask the patient to try no treatment after 3–6 months without infection and restart if UTI recurs
      • a single UTI following the cessation of prophylactic treatment is not uncommon, and patients should be informed of this possibility 
      • the recommencement of prophylactic treatment should not be triggered by a single UTI after completion of a period of prophylactic treatment
    • if a patient develops a breakthrough infection while on antibiotic prophylaxis:
      • stop prophylaxis 
      • order urine culture to check for resistant organisms 
      • use a different agent to treat the acute episode 
      • restart the original prophylaxis after the acute episode is resolved if resistance has not developed
    • audit antibiotic prophylaxis regularly and review patients who have been taking prophylactic antibiotics for 6–12 months to justify their continued use and with a view to stopping prophylaxis 
  • single-dose antibiotic prophylaxis
    • useful in women whose UTIs are trigged by intercourse with no other triggers 
      • post-coital prophylaxis should be taken within 2 hours of intercourse
      • ask the patient to try no treatment after 3 months without infection and restart if UTIs recur 
    • patients with other triggers, such as runners and cyclists, may also benefit from this approach 
    • there is no evidence that this approach leads to increased resistance compared with continuous antibiotic prophylaxis
      • consider monitoring to ensure that patients are not developing antibiotic-resistant organisms
• Side-effects of antibiotic prophylaxis
  • antibiotic prophylaxis can have side-effects such as gastrointestinal upset
  • vaginal thrush is a common side-effect of antibiotic prophylaxis, but the risk is lower than with standard treatment doses; ideally, treat the thrush, but do not stop the antibiotic
  • pulmonary toxicity is a rare side-effect of long‑term nitrofurantoin use; any patient that develops breathlessness while taking low‑dose nitrofurantoin should stop treatment and seek advice from their GP
  • long‑term nitrofurantoin use is also associated with hepatitis; patients should be monitored for signs such as brown urine
• Antibiotic failure can be defined as no significant change in the frequency of UTIs in two comparative 6-month periods, after the suitability of the antibiotic and adherence to treatment have been taken into account
  • consider a different antibiotic in patients with antibiotic resistance 
  • emphasise the importance of adherence to treatment in patients who are non-adherent to their antibiotic regimen 
  • consider non-antibiotic options 
  • refer to specialist care for consideration of specialist options

Non-antibiotic Treatments

• Consider non-antibiotic therapies in all eligible patients
  • choose therapies with clinical evidence supporting their use in the treatment of recurrent UTI
  • take into account availability, ease of administration, cost-effectiveness, contraindications, and patient preferences
• Treatments may need to be used in combination; none of the non-antibiotic treatments discussed are contraindicated with other non-antibiotic options

Topical Oestrogens

• Use of vaginal oestrogens prior to antibiotic prophylaxis in peri/postmenopausal women with oestrogen deficiency, particularly those with other symptoms of oestrogen deficiency such as vaginal itching and dryness, may be beneficial for recurrent UTI
  • because oral HRT has no effect on recurrent UTI, consider adding vaginal oestrogen to oral HRT 
  • topical oestrogens can be administered by pessary, cream, or ring according to patient preferences, but patients may not achieve good internal coverage when applying cream
  • prescribe as directed according to choice of preparation
  • topical oestrogens can be continued after the discontinuation of antibiotic prophylaxis
• Vaginal oestrogen products are not licensed for preventing recurrent UTI, so use for this indication would be off-label; the prescriber should follow relevant professional guidance, taking full responsibility for the decision, and informed consent should be obtained and documented
• Although the risk of treatment with topical vaginal oestrogens is thought to be small, it is advisable to discuss possible risks of oestrogens, in line with NICE guidance:
  • breast tenderness and vaginal bleeding in postmenopausal women compared with placebo, no treatment, or oral antibiotics
  • increased risk of venous thromboembolism, stroke, endometrial cancer (reduced by a progestogen), breast cancer, and ovarian cancer
  • increased risk of coronary heart disease in women who start combined HRT more than 10 years after menopause

Methenamine Hippurate

• Methenamine hippurate 
  • has antibacterial properties when present in the urine
  • is well tolerated and effective
  • may be ineffective in patients with neuropathic bladder or an abnormal renal tract
  • is contraindicated in patients with gout, severe renal and liver impairment, and dehydration
  • is an option for women who prefer to avoid antibiotics, but can also be taken in addition to antibiotic treatment
    • prescribe 1 g twice a day for 6 months initially, then review
    • consider advising patients to take vitamin C to acidify the urine, although the necessity of acidic urine for the activation of methenamine is unclear
    • check liver function every 3 months 
    • continue use of methenamine hippurate as a prophylactic

Vaccines

• Vaccines are immunostimulants rather than true vaccines
  • prophylactic treatment with vaccines consisting of combinations of inactivated uropathogenic bacteria has been shown to reduce the incidence and recurrence of UTIs
  • availability is an issue in the UK
  • further studies are needed to identify optimal utility, patient groups, dosing, and isolates for efficacy

Non-pharmacological Options

Cranberry

• Cranberry-based products are widely used in the prevention and treatment of UTI, may have beneficial effects with a low risk of harm 
  • the optimum dose and duration of use are unclear
  • capsules may be better than juice and high‑strength capsules may be most effective
  • cranberry may be an option for patients who do not want to take antibiotics, although SIGN guidance recommends that patients taking warfarin should avoid taking cranberry products

D -mannose

• D -mannose is not a medicine; it is a sugar that is available as a powder or tablets
  • the use of D -mannose is recommended in NICE guidance on recurrent UTI
  • D -mannose showed similar efficacy to nitrofurantoin in preventing recurrent UTI in a single, relatively small RCT
  • the dose used in this RCT was 1000 mg twice daily, but the optimum dose is unclear
  • D -mannose is well tolerated, but it should be used cautiously in patients with diabetes

Specialist Options

Intravesical GAG Layer Replacement

• Damage to or deficiencies in the glycosaminoglycan (GAG) layer of the bladder may be aetiological in recurrent UTI 
  • GAG layer therapies reduce the recurrence of UTIs with minimal side‑effects
  • GAG layer therapies are often administered by a specialist through a catheter, but a catheter-free option is available that may facilitate administration by non-specialists 
  • patients competent in self-catheterisation may be able to self-administer GAG layer therapies following training

Intravesical Antibiotics

• Intravesical installation of antibiotics, most commonly gentamicin and amikacin, has been used in specialist centres and has been anecdotally reported to be helpful for some patients; however, this approach should only be used with expert advice

Useful Resources for Healthcare Professionals

• NICE. Urinary tract infection (recurrent): antimicrobial prescribing. NICE Guideline 112. www.nice.org.uk/ng112
• Public Health England. Diagnosis of urinary tract infections (UTIs) – quick reference guide for primary care: summary table.