Vinod Nargund revisits NICE Guideline 109 on lower urinary tract infections, and highlights primary care’s central role in recognition and management

NARGUND Vinod

Vinod Nargund

Read this article to learn more about:

  • causes, symptoms, and differential diagnoses of lower urinary tract infection (LUTI)
  • investigations for uncomplicated and complicated LUTI
  • principles of treatment and judicious use of antibiotics for LUTI.

Read this article online at: GinP.co.uk/456115.article

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Lower urinary tract infection (LUTI), commonly referred to as cystitis, is defined as an infection of the urethra and bladder (see Box 1 for a glossary of terms related to urinary tract infection [UTI]).1–3 Bacterial infection is a common cause of LUTI, but other bladder and vulval conditions that mimic bacterial cystitis—such as interstitial cystitis, bladder cancer, and bladder stones—should be kept in mind (see Box 2).4,5 LUTI is associated with urinary frequency, painful micturition, urgency, and suprapubic pain; other symptoms include haematuria, strangury, and smelly urine.6,7

  • Bacteriuria describes the presence of bacteria in the urine, indicating bacterial colonisation of the bladder or an active infection3
  • Uncomplicated UTI describes a UTI in a nonpregnant person with no known relevant anatomical or functional abnormalities of the urinary tract2,3
  • Complicated UTI denotes a UTI associated with a compromised urinary tract; causes include anatomical or functional abnormalities or impaired host defences associated with immunosuppression, neurological conditions, renal failure, pregnancy, or foreign materials such as stones, catheters, and stents2,3
  • Recurrent UTI refers to recurrences of uncomplicated and/or complicated UTIs, with a frequency of at least three UTIs per year or two UTIs in the preceding 6 months3
  • Persistent infection refers to a recurrent UTI caused by the same bacterium; causes include a source of infection such as a bladder stone,2 or inadequate treatment
  • Asymptomatic bacteriuria is a laboratory diagnosis of the significant presence of a specific bacterium without any clinical symptoms.3

UTI=urinary tract infection

Box 2: Differential diagnosis of LUTI4,5

Women:

  • pyelonephritis
  • other urological or genito-urinary conditions, such as atrophic vaginitis, lichen sclerosis, lichen planus, urolithiasis, or interstitial cystitis
  • dermatological conditions such as psoriasis, irritant or contact dermatitis
  • spondyloarthropathies such as reactive arthritis or Bechet’s syndrome
  • alternative or serious diagnoses such as ectopic pregnancy
  • malignancy:
    • gynaecological malignancy (for example, ovarian cancer)
    • urological malignancy
  • other infections, such as sexually transmitted infections (for example, chlamydia, gonorrhoea, genital herpes simplex) candida, threadworm, tuberculosis, and schistosomiasis
  • trauma due to genito-urinary procedures, sexual intercourse, sexual abuse, or physical activity (such as cycling)
  • adverse drug effects—some drugs such as cyclophosphamide, opioids, and nifedipine can cause urinary tract symptoms.

Men:

  • acute prostatitis
  • bladder or renal malignancy
  • epididymitis
  • pyelonephritis
  • sexually transmitted infections
  • urethritis
  • other urological disorders, such as benign prostatic hyperplasia.

LUTI=lower urinary tract infection

© NICE. Urinary tract infection (lower)—women: what else might it be? NICE Clinical Knowledge Summary. Available at: cks.nice.org.uk/topics/urinary-tract-infection-lower-women/diagnosis/differential-diagnosis/ (accessed 24 June 2021).

© NICE. Urinary tract infection (lower)—men: what else might it be? NICE Clinical Knowledge Summary. Available at: cks.nice.org.uk/topics/urinary-tract-infection-lower-men/diagnosis/differential-diagnosis/ (accessed 24 June 2021).

The key role of general practice in improving care for LUTI

For most patients in the UK, their first port of call is the local GP; therefore, responsibility for the initial assessment and management lies with general practice. In a study of LUTI diagnosis between 2011 and 2015 involving 390 UK primary care practices and 300,354 patients, Pujades-Rodriguez et al. observed the following:8

  • the majority of patients diagnosed with LUTI (86%) received same-day antibiotic treatment
  • four out of five patients received empirical treatment, and there was no evidence of urine sample collection for microbiological investigations in most patients (83%)
  • antibiotic treatment was generally limited to trimethoprim and nitrofurantoin, reflecting national guidelines
  • the rate of recurrent LUTI (more than one episode a year) was 9% in men aged 18–64 years and 20.8% in women aged over 65 years; 1% of these men and 2.6% of the women had three or more episodes a year
  • the rate of antibiotic re-prescription was low, but was gradually increasing
  • one in five patients who required re-prescription received the same antibiotic.

These findings suggest that the care of patients with LUTI could be improved. A number of guidelines describe best practice for the treatment of UTI (see Table 1); this review focuses on NICE Guideline (NG) 109, Urinary tract infection (lower): antimicrobial prescribing,1 also taking into account NICE guidance on UTI in children and young people, and European guidance.

Table 1: Summary of UK guidelines on UTI
SourceTitleSummaryComments

NICE

NG1091

October 2018

www.nice.org.uk/ng109

Urinary tract infection (lower): antimicrobial prescribing

Specific to uncomplicated LUTI in all ages

A quick reference that includes adequate practical information; covers all ages

SIGN

SIGN 160

September 2020

bit.ly/3hMX8V9

Management of suspected bacterial lower urinary tract infection in adult women

Specific to LUTI in women

It does not cover LUTI in children aged <16 years, pregnant women, or men

Public Health England

May 2020

bit.ly/2TKzIrm

Diagnosis of urinary tract infections: quick reference tool for primary care for consultation and local adaptation

Very theoretical, containing complex flow charts—if in-depth knowledge is required on the rationale of treatments, this is the source

Covers antimicrobial stewardship; provides flow charts and evidence-based information

Northern Ireland

Medicines Management

January 2017

bit.ly/36nrkB4

Newsletter supplement: urinary tract infections (UTIs)—how to manage UTIs in different patient groups

Flow chart adapted and modified from SIGN 88 (bit.ly/3jVDLvC)

Easy to read and understand the principles of management

Public Health Wales
bit.ly/3hLS5UT

UTI downloads

All aspects of UTIs, including prevention, are discussed

A practical and useful read

UTI=urinary tract infection; NG=NICE Guideline; LUTI=lower urinary tract infection; SIGN=Scottish Intercollegiate Guidelines Network

Pathogenesis of UTI

UTI can be caused by Gram-positive and Gram-negative bacteria and fungi.2 The source of uropathogenic bacteria is usually the gut,2 and the most common bacterium in both complicated and uncomplicated UTIs is uropathogenic Escherichia coli.2,9 The starting point of uncomplicated LUTI is microbial contamination of the periurethral region and vagina (if applicable), followed by the ascension of infection into the urethra and bladder.10 Thereafter, a complex host–pathogen interaction takes place—initial bacterial colonisation of the urethra and bladder is followed by bacterial adherence to epithelial and urothelial cells and the internalisation of bacteria into urothelial cells.10 Subsequently, intracellular bacterial communities form, after which bacteria multiply intracellularly, evading host defences.10,11

Investigations for UTI

In uncomplicated UTI, the decision to treat can be made on the strength of the clinical assessment and history. The probability of infection is approximately 50% in women who present with one or more symptoms of UTI.12 Specific combinations of symptoms (for example, dysuria and frequency without vaginal discharge or irritation) increase the probability of infection to more than 90%.12 However, a combination of history taking, examination, and dipstick urinalysis is insufficient to lower the probability of infection to a level where UTI can be ruled out in patients with one or more symptoms.12

Dipstick urinalysis

Urine dipstick testing is rapid, inexpensive, and readily available to healthcare professionals in primary and secondary care.13 Dipstick urinalysis is useful when the diagnosis is in doubt. It also gives useful information on urinary pH, and highlights the presence of nitrites, leucocyte esterase, and blood in the urine.14

Positive results for nitrites and leucocyte esterase indicate the presence of bacteria in the urine; dipstick testing can diagnose UTI based on the presence of nitrates with a specificity of more than 90% and based on the presence of leucocyte esterase with a specificity of 55%.14 A false-negative reading may be the result of a delay in the examination of urine, higher specific gravity, glycosuria, proteinuria, or ascorbic acid in the urine, and does not rule out UTI.15 False-positive results are also possible, and can be due to contamination of the specimen, exposure of dipstick to the air, or phenazopyridine.15 In addition, Enterococcus, Pseudomonas, and Acinetobacter  species do not convert nitrates to nitrites—infection with these uropathogens will not result in a positive nitrite test.14

Normal urine pH is slightly acidic, varying between 4.5 and 8; a pH of 8.5 or above indicates infection with Proteus, Klebsiella, or Ureaplasma urealyticum.14 Although haematuria is not specific to UTI, the presence of blood in the urine helps to differentiate UTI from vaginal infection and urethritis.14

Urine culture is necessary in men,1 children and young people,1,16 pregnant women,1 and people with recurrent UTI and treatment failures.17

Principles of treatment

Before considering medical treatment for LUTI, it should be determined whether the patient has complicated or uncomplicated LUTI, and consideration should be given to narrowing the antibiotic spectrum whenever possible. NICE recommends that the following factors are also taken into account:1

  • the severity of symptoms
  • the risk of developing complications, which is higher in people with a known or suspected structural or functional abnormality of the genito-urinary tract, or immunosuppression
  • the evidence for back-up antibiotic prescriptions—only available for nonpregnant women with LUTI where immediate antibiotic treatment was not considered necessary
  • previous urine culture and susceptibility results
  • previous antibiotic use, which may have led to resistant bacteria
  • preferences for antibiotic use.

From a management point of view, patients are divided into four categories in NG109:1

  • nonpregnant women with LUTI
  • pregnant women and men with LUTI
  • children and young people aged under 16 years with LUTI
  • people with asymptomatic bacteriuria (ASB).

Nonpregnant women with LUTI

Women are more prone to UTI because of anatomical factors such as a shorter urethra and hormonal factors such as decreased oestrogen production after the menopause.18 Other risk factors for UTI in nonpregnant women include previous UTI, frequent sexual intercourse, vulvovaginal atrophy, disruption of local bacterial flora, diabetes mellitus, nonsecretor blood type, and genetic susceptibility.18 Use of spermicides, particularly in combination with a diaphragm, is also known to cause UTI.18

First-choice antibiotics

NICE recommends nitrofurantoin or trimethoprim as the first-choice antibiotics for LUTI in nonpregnant women.1

Nitrofurantoin works by inhibiting bacterial enzymes involved in the synthesis of DNA, RNA, and other metabolic enzymes.19 For nonpregnant women with uncomplicated LUTI, NG109 recommends 50 mg of nitrofurantoin four times a day for 3 days or, for modified-release nitrofurantoin, 100 mg twice a day for 3 days.1 For adults with severe chronic recurrent LUTI, 100 mg of nitrofurantoin four times a day for 7 days is advised.20 For prophylaxis of recurrent LUTI, 50–100 mg of nitrofurantoin to be taken at night, or one 100 mg dose following exposure to a trigger is recommended.20 Nitrofurantoin should be used only if estimated glomerular filtration rate (eGFR) is 45 ml/min/1.73m2 or with caution if eGFR is 30–44 ml/min/1.73 m2.1

Trimethoprim is an antifolate agent that prevents bacterial DNA synthesis.21 Trimethoprim is advised if a lower risk of resistance is likely1 —if trimethoprim has not been used in the preceding 3 months, if previous urine culture results suggest trimethoprim susceptibility (but this was not used as treatment), and in younger people in areas where local epidemiology data suggest resistance is low.1 In this scenario, NICE recommends 200 mg of trimethoprim twice a day for 3 days.1

Second-choice antibiotics

If symptoms of LUTI do not improve on a first-choice antibiotic taken for at least 48 hours, or the first-choice antibiotics are not suitable, NICE recommends nitrofurantoin (if not used as the first choice), pivmecillinam, or fosfomycin.1

Pivmecillinam is a beta-lactam antibiotic belonging to the penicillin group, and is bactericidal.22 A 400-mg initial dose is recommended, followed by 200 mg three times a day for a total of 3 days. Penicillin allergy is an absolute contraindication to the use of pivmecillinam.23 One noticeable side-effect of pivmecillinam is vulvovaginal thrush.23 Trace amounts are excreted in breast milk, but pivmecillinam is appropriate to use when breastfeeding.23

Fosfomycin is a bactericidal, broad-spectrum antibiotic originally isolated from Streptomyces species that irreversibly inhibits bacterial cell wall synthesis.24 It is effective against many bacteria, including multidrug-resistant (MDR) Gram-negative bacteria.24 Fosfomycin comes in the form of granules, with each sachet containing one 3-g dose.25 The granules should be dissolved in a glass of water and taken immediately on an empty stomach (2–3 hours before or after a meal), preferably at bedtime and after emptying the bladder.25 Its side-effects include dizziness and vulvovaginal infection.25

Pregnant women and men with LUTI

Offer an immediate antibiotic prescription to pregnant women and men with LUTI.1 In pregnant women and men with LUTI, a midstream urine sample should be obtained for culture and susceptibility analysis before treatment is started.1 Additionally, previous urine culture and susceptibility results and previous antibiotic usage should be taken into account.1

Pregnant women with LUTI

Profound structural and functional changes to the urinary tract take place during pregnancy, including urinary tract dilatation, hydronephrosis, sluggish ureteral peristalsis, and some degree of sphincter relaxation.26 In addition, secondary vesico-ureteral reflux occurs as a result of pressure from the gravid uterus and the effects of circulating progesterone.26 Urinary stasis, coupled with a rise in urine pH, are favourable conditions for UTIs.26

Untreated UTIs during pregnancy are associated with adverse events such as low birth weight, preterm birth, and spontaneous miscarriage.27 However, antibiotic use can also affect the birth weight of newborns.28 It is important to ensure that there is no evidence of pyelonephritis because bacterial endotoxins can initiate host inflammatory responses, leading to complications including acute kidney injury, anaemia, pre-eclampsia, and septic shock, particularly if treatment is not given at the right time.26

NICE recommends that an immediate antibiotic prescription is provided, taking into account previous culture and susceptibility results and previous antibiotic use which may have led to resistant bacteria.1 If eGFR is 45 ml/min/1.73 m2 or more, NICE recommends nitrofurantoin as the first-choice antimicrobial. Pregnant women with LUTI should receive 100 mg modified-release nitrofurantoin twice a day, or 50 mg nitrofurantoin four times a day, for 7 days—except at term, when this treatment may cause neonatal haemolysis.1

If symptoms do not improve on nitrofurantoin or any other agent taken for at least 48 hours, NICE states that amoxicillin, cefalexin, or another antibiotic recommended by local microbiologists based on culture and susceptibility results should be used as the second-choice antibiotic.1 Because resistance rates are high, amoxicillin is recommended only if culture results are available and bacteria are susceptible.1

Trimethoprim is contraindicated in pregnancy because it is a folate antagonist and carries a risk of teratogenesis when used in the first trimester.29 However, NICE acknowledges that trimethoprim is sometimes used in pregnancy when given with 5 mg folic acid daily in the first trimester,1 for example, if trimethoprim is the only drug available.

Management of ASB in pregnancy is discussed later in this article.

Men with LUTI

Men with LUTI should be offered an immediate antibiotic prescription.1 Urinary infections are rare in men before the age of 50 years, but their prevalence steadily increases thereafter.30 UTIs are less common in men than in women because of the length of the male urethra, antibacterial properties of prostatic fluid, and less frequent contamination of the periurethral region.30 As with women, most UTIs in men are caused by Gram-negative organisms from the bowel that colonise the periurethral skin.30 UTIs in men, especially when recurrent, warrant investigations to rule out any structural or functional anomalies, such as congenital abnormalities, prostatic diseases, colovesical fistula, and inflammatory bowel disease.30

NICE recommends 200 mg trimethoprim twice a day for 7 days or 100 mg modified-release nitrofurantoin twice a day (or, if unavailable, 50 mg nitrofurantoin four times a day) for 7 days as the first-choice antibiotics (if eGFR is 45 ml/min/1.73 m2 or more).1 However, if acute prostatitis is suspected, quinolones are the first-choice antibiotic (see the NICE guideline on Prostatitis (acute): antimicrobial prescribing).1,31 Nitrofurantoin is not recommended for men with suspected prostate involvement because it is unlikely to reach therapeutic levels in the prostate.1

An alternative diagnosis (such as acute pyelonephritis or acute prostatitis) should be considered in men whose symptoms have not responded to a first-choice antibiotic, and second-choice antibiotics should be selected based on recent culture and susceptibility results.1

Children and young people aged under 16 years with LUTI

NICE has produced a separate guideline, Clinical Guideline (CG) 54, that covers the diagnosis and management of first and recurrent upper UTI or LUTI in infants, children, and young people aged under 16 years.16 Urinary infections are common in children.32 Again, E. coli is the main uropathogen, accounting for approximately 80% of UTIs in children and young people; other pathogens that commonly cause UTI in children and young people include Klebsiella, Proteus, Enterobacter, and Enterococcus.33

Urine collection, preservation, testing, and interpretation of results are outlined in CG54.16 Offer an immediate antibiotic prescription for children and young people under 16 years with LUTI.1 A urine sample must be obtained from children and young people before starting antibiotic therapy.16 Urine dipstick testing is a good screening tool for establishing the diagnosis in children, and urine culture is used to confirm the diagnosis and determine susceptibility.16,33 Absence of pyuria and bacteriuria on urine microscopy effectively excludes infection in children.34

NG109 recommends trimethoprim or nitrofurantoin for the treatment of LUTI in children and young people aged 3 months and over and under 16 years as follows:

  • trimethoprim (if there is a low risk of resistance):
    • 3 months to 5 months—4 mg/kg (maximum 200 mg per dose) or 25 mg twice a day for 3 days
    • 6 months to 5 years—4 mg/kg (maximum 200 mg per dose) or 50 mg twice a day for 3 days
    • 6 years to 11 years—4 mg/kg (maximum 200 mg per dose) or 100 mg twice a day for 3 days
    • 12 years to 15 years—200 mg twice a day for 3 days
  • nitrofurantoin (if eGFR is 45 ml/min/1.73 m2 or more):
    • 3 months to 11 years—750 mcg/kg four times a day for 3 days
    • 12 years to 15 years—50 mg four times a day or 100 mg modified-release twice a day for 3 days
  • nitrofurantoin (if eGFR is 45 ml/min/1.73 m2 or more and it was not used as the first choice):
    • 3 months to 11 years—750 mcg/kg four times a day for 3 days
    • 12 years to 15 years—50 mg four times a day or 100 mg modified-release twice a day for 3 days.

NICE also recognises that nitrofurantoin suspension is currently substantially more expensive than trimethoprim suspension. If both antibiotics are appropriate, the one with the lowest acquisition cost should be chosen.1

If symptoms of LUTI get worse on a first-choice antibiotic taken for at least 48 hours, or first-choice antibiotics are not suitable, nitrofurantoin (if not used as the first-choice antibiotic), amoxicillin, or cefalexin should be used as the second-choice antibiotic as follows:

  • amoxicillin:
    • 1 month to 11 months—125 mg three times a day for 3 days
    • 1 year to 4 years—250 mg three times a day for 3 days
    • 5 years to 15 years—500 mg three times a day for 3 days
  • cefalexin:
    • 3 months to 11 months—12.5 mg/kg or 125 mg twice a day for 3 days
    • 1 year to 4 years—12.5 mg/kg twice a day or 125 mg three times a day for 3 days
    • 5 years to 11 years—12.5 mg/kg twice a day or 250 mg three times a day for 3 days
    • 12 years to 15 years—500 mg twice a day for 3 days.

Because of high resistance rates, amoxicillin is recommended only if culture results are available and the organism is susceptible to amoxicillin.1

Reassessment is required if symptoms get worse rapidly or significantly, or do not improve within 48 hours of starting treatment.1 It is prudent to reassess the child if symptoms of upper UTI (acute pyelonephritis) appear, or if there is evidence of a resistant strain on investigations.1

People with ASB

In ASB, bacteria are present in significant levels (>100,000 colony forming units per ml of urine) in two consecutive urine samples in women and one sample in men with no symptoms suggestive of UTI.3,35 An absence of urinary tract inflammation is the hallmark of ASB.36 There is no evidence of any benefit in treating ASB in otherwise healthy children, men, and nonpregnant women. ASB is not seen in healthy younger men; however, if detected, chronic bacterial prostatitis must be ruled out.3

Treating ASB in otherwise healthy individuals may lead to an increase in recurrent UTIs and even MDR bacteria.37

ASB in pregnant women

Pregnancy facilitates the progression of asymptomatic bacteriuria to symptomatic bacteriuria, which is associated with pyelonephritis and adverse obstetric outcomes.38 NICE recommends immediate antibiotic therapy, taking into account culture and susceptibility results and previous antibiotic use which may have led to resistant bacteria.1

Self-care

In NG109, NICE recommends the following for self-care:1

  • adequate fluid intake to avoid dehydration
  • paracetamol or ibuprofen for pain relief.

NICE states that there is insufficient evidence to support the use of cranberry products or urine alkalinising agents to treat LUTI.

Summary

LUTIs are one of the most common bacterial infections that present in general practice. Treating LUTIs with antibiotics is only a part of the management plan for patients. The aims of treatment could be summarised as follows: swift management of symptoms by prescribing antibiotics after an initial assessment; identification of a cause or risk factor whenever possible; prevention of further LUTIs. When treating LUTIs in men and women aged 50 and over, it is important to keep in mind other bladder conditions, particularly when urine dipstick testing shows no infection.

Vinod Nargund

Consultant Urological Surgeon, The Wellington and The Princess Grace Hospitals, London; previously St Bartholomew’s and Homerton Hospitals, London. 

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References 

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