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Urinary tract infection (recurrent):
antimicrobial prescribing
NICE guideline
Draft for consultation, May 2018
This guideline sets out an antimicrobial prescribing strategy for recurrent
urinary tract infections. It aims to optimise antibiotic use and reduce
antibiotic resistance.
See a 2-page visual summary of the recommendations, including tables to
support prescribing decisions.
Who is it for?
Health professionals
People with recurrent urinary tract infections, their families and carers
The guideline contains:
the draft recommendations
summary of the evidence.
Information about how the guideline was developed is on the guideline’s
page on the NICE website. This includes the full evidence review, details of
the committee and any declarations of interest.
Recommendations
The recommendations in this guideline are for preventing urinary tract
infections (UTI) in adults, young people and children with recurrent UTI who
do not have a catheter.
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1.1 Preventing recurrent urinary tract infections
1.1.1 Manage an acute UTI as outlined in the NICE guidelines on lower
UTI (cystitis), acute pyelonephritis or catheter-associated UTI.
1.1.2 Be aware that recurrent UTI:
includes lower UTI (cystitis) and upper UTI (acute pyelonephritis)
may be due to relapse (with the same strain of organism) or
reinfection (with a different strain or species of organism)
is particularly common in women.
Referring for specialist assessment and investigations
1.1.3 Refer the following people with recurrent UTI for specialist
assessment and investigations because there may be underlying
anatomical or functional abnormalities:
men (taking an individualised approach that takes account of
factors such as multimorbidity)
people aged 16 years and over with recurrent upper UTI (acute
pyelonephritis).
1.1.4 Refer pregnant women (aged 16 years and over) to an obstetrician
for specialist assessment and investigations if recurrent UTI is
diagnosed during pregnancy.
1.1.5 Refer children and young people under 16 years to a paediatric
specialist for assessment and investigations, in line with the NICE
guideline on urinary tract infection in under 16s: diagnosis and
management.
See the evidence and committee discussion on antibiotic prophylaxis.
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Treatment for women with recurrent UTI who are not pregnant
D-mannose and vaginal oestrogen
1.1.6 Consider D-mannose
1
as a self-care treatment for women with
recurrent UTI who are not pregnant and have had no improvement
after behavioural and personal hygiene measures. Take account of:
the severity and frequency of previous symptoms
the risk of developing complications
the woman’s preferences for self-care treatments.
1.1.7 Consider the lowest effective dose of vaginal oestrogen
2
(for
example, estriol cream) for postmenopausal women with recurrent
UTI and no improvement after behavioural and personal hygiene
measures. Discuss the following with the woman to ensure shared
decision-making:
the severity and frequency of previous symptoms
the possible benefits of treatment, including for other related
symptoms, such as vaginal dryness
the risk of developing complications from recurrent UTIs
possible adverse effects such as breast tenderness and vaginal
bleeding (which should be reported because it may require
investigation)
the uncertainty of endometrial safety with long-term or repeated
use.
preferences of the woman for treatment with vaginal oestrogen.
1
D-mannose used in the study was a 1% solution. D-mannose is a sugar that is
available to buy as powder or tablets; it is not a medicine.
2
Vaginal oestrogen formulations used in the studies were topical cream, vaginal ring
and pessary. These 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. Informed consent should be
obtained and documented. See the General Medical Council's Good practice in
prescribing and managing medicines and devices for further information.
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Review treatment at least every 6 months, or earlier if agreed with
the woman.
1.1.8 Do not offer oral oestrogens (hormone replacement therapy)
specifically to prevent recurrent UTI in postmenopausal women.
See the evidence and committee discussion on self-care and oestrogens.
Antibiotic prophylaxis
1.1.9 For women with recurrent UTI who are not pregnant and have had
no improvement after the management options in
recommendations 1.1.6 and 1.1.7, consider single-dose antibiotic
prophylaxis when exposed to triggers (see the recommendations
on choice of antibiotic prophylaxis). Take account of:
the severity and frequency of previous symptoms
the risk of developing complications
previous urine culture and susceptibility results
previous antibiotic use which may have led to resistant bacteria
the woman’s preferences for antibiotic use.
1.1.10 When single-dose antibiotic prophylaxis is given, give advice about:
how to use the antibiotic (not exceeding the maximum
prophylactic dose per day)
possible adverse effects of antibiotics, particularly diarrhoea and
nausea
returning for review after 3 months, or other agreed time
seeking medical help if there are symptoms of an acute UTI.
See the evidence and committee discussion on antibiotic prophylaxis and
antibiotic dosing and course length.
1.1.11 For women with recurrent UTI who are not pregnant and have had
no improvement after single-dose antibiotic prophylaxis or have no
identifiable triggers, consider continuous antibiotic prophylaxis (see
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the recommendations on choice of antibiotic prophylaxis). Take
account of:
any further investigations (for example, ultrasound) that may be
needed to identify an underlying cause
the severity and frequency of previous symptoms
the risks of long-term antibiotic use
the risk of developing complications
previous urine culture and susceptibility results
previous antibiotic use which may have led to resistant bacteria
the woman’s preferences for antibiotic use.
1.1.12 When continuous antibiotic prophylaxis is given, give advice about:
the risk of resistance with long-term antibiotics, which means
they may be less effective in the future
possible adverse effects of long-term antibiotics
returning for review after 3 months, or other agreed time
seeking medical help if there are symptoms of an acute UTI.
See the evidence and committee discussion on antibiotic prophylaxis.
Treatment for men and pregnant women with recurrent UTI
1.1.13 For men and pregnant women with recurrent lower UTI who have
had no improvement after behavioural and personal hygiene
measures, consider continuous antibiotic prophylaxis (see the
recommendations on choice of antibiotic prophylaxis) with
specialist advice. Take account of:
any further investigations (for example, ultrasound) that may be
needed to identify an underlying cause
the severity and frequency of previous symptoms
the risks of long-term antibiotic use
the risk of developing complications
previous urine culture and susceptibility results
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previous antibiotic use which may have led to resistant bacteria
the person’s preferences for antibiotic use.
Give advice in line with recommendation 1.1.12.
See the evidence and committee discussion on antibiotic prophylaxis.
Treatment for children and young people under 16 years with recurrent
UTI
1.1.14 For children and young people under 16 years with recurrent lower
UTI and no improvement after behavioural and personal hygiene
measures, consider continuous antibiotic prophylaxis (see the
recommendations on choice of antibiotic prophylaxis) with
specialist advice. Take account of:
underlying causes following specialist assessment and
investigations
the uncertain benefit of antibiotic prophylaxis for reducing the
risk of recurrent UTI and the rate of deterioration of renal scars
the severity and frequency of previous symptoms
the risks of long-term antibiotic use
the risk of developing complications
previous urine culture and susceptibility results
previous antibiotic use which may have led to resistant bacteria
preferences for antibiotic use.
Give advice in line with recommendation 1.1.12.
See the evidence and committee discussion on antibiotic prophylaxis.
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1.2 Self-care
1.2.1 Give verbal and written advice about behavioural and personal
hygiene measures to people with recurrent UTI that may help to
reduce the risk of UTI.
1.2.2 Consider D-mannose in non-pregnant women with recurrent UTI as
in recommendation 1.1.7.
1.2.3 Explain that evidence is inconclusive about whether cranberry
products or probiotics (lactobacillus) reduce the risk of UTI in
people with recurrent UTI.
See the evidence and committee discussion on self-care.
1.3 Choice of antibiotic prophylaxis
1.3.1 When prescribing antibiotic prophylaxis for recurrent UTI:
follow the recommendations in table 1 for people aged 16 years
and over
follow the recommendations in table 2 for children and young
people under 16 years.
1.3.2 Review treatment success with the person every 3 months (or other
agreed time) and discuss a trial of stopping antibiotic prophylaxis
as appropriate.
Table 1. Adults and young people aged 16 years and over
Antibiotic prophylaxis
1,2
Dosage and course length
3
First choice
Trimethoprim
4
100 mg single dose or
100 mg at night continuously
Nitrofurantoin – if eGFR
≥45 ml/minute
5
50 to 100 mg single dose or
50 to 100 mg at night continuously
Second choice
Amoxicillin
250 mg single dose or
250 mg at night continuously
Cefalexin
125 mg single dose or
125 mg at night continuously
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Pivmecillinam
6
200 mg single dose or
200 mg at night continuously
1
See BNF for appropriate use and dosing in specific populations, for example,
hepatic impairment, renal impairment, pregnancy and breast feeding.
2
Choose antibiotics according to recent culture and susceptibility results where
possible, with rotational use based on local policies. Select a different antibiotic for
prophylaxis if treating an acute UTI.
3
Doses given are by mouth using immediate release medicines, unless otherwise
stated.
4
Teratogenic risk in first trimester of pregnancy (folate antagonist; BNF, April
2018). Manufacturers advise contraindicated in pregnancy (trimethoprim summary
of product characteristics).
5
Avoid at term in pregnancy; may produce neonatal haemolysis (BNF, April 2018).
6
Not known to be harmful in pregnancy, but manufacturer advises avoid (BNF,
April 2018).
Abbreviations: eGFR, estimated glomerular filtration rate; SPC, summary of
product characteristics
Table 2. Children and young people under 16 years
Dosage and course length
3
Children under 3 months
Refer to paediatric specialist
Children aged 3 months and over (specialist advice only)
First choice
3 to 5 months, 2 mg/kg at night (maximum
100 mg per dose) or 12.5 mg at night
6 months to 5 years, 2 mg/kg at night
(maximum 100 mg per dose) or 25 mg at night
6 to 11 years, 2 mg/kg at night (maximum
100 mg per dose) or 50 mg at night
12 to 17 years, 100 mg at night
3 months to 11 years, 1 mg/kg at night
12 to 17 years, 50 mg to 100 mg at night
Second choice
12.5 mg/kg at night (maximum 125 mg per
dose)
1 to 11 months, 62.5 mg at night
1 to 4 years, 125 mg at night
5 to 17 years, 250 mg at night
1
See BNF for children for appropriate use and dosing in specific populations, for
example hepatic and renal impairment.
2
Choose antibiotics according to recent culture and susceptibility results where
possible. If 2 or more antibiotics are appropriate, choose the antibiotic with the
lowest acquisition cost.
3
The age bands apply to children of average size and, in practice, the prescriber
will use the age bands in conjunction with other factors such as the severity of the
condition and the child’s size in relation to the average size of children of the same
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age. Doses given are by mouth using immediate release medicines, unless
otherwise stated.
Abbreviations: eGFR, estimated glomerular filtration rate.
See the evidence and committee discussion on choice of antibiotic
prophylaxis and antibiotic dosing and course length.
Terms used in the guideline
Recurrent urinary tract infection
Recurrent UTI in adults is defined as repeated UTI with a frequency of 2 or
more UTIs in the last 6 months or 3 or more UTIs in the last 12 months. The
diagnosis of recurrent UTI should be confirmed by urine culture (European
Association of Urology (EAU) guidelines on urological infections [2017]).
Recurrent UTI is diagnosed in children and young people under 16 years if
they have:
2 or more episodes of UTI with acute pyelonephritis/upper UTI, or
1 episode of UTI with acute pyelonephritis plus 1 or more episode of UTI
with cystitis/lower UTI, or
3 or more episodes of UTI with cystitis/lower UTI.
See the NICE guideline on urinary tract infection in under 16s.
Triggers
Some people (mainly women) may be able to identify 1 or more triggers (for
example, sexual intercourse) that often brings on a UTI. These triggers may
vary for different people.
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Summary of the evidence
Self-care
Probiotics (lactobacillus)
Lactobacillus did not significantly reduce the risk of recurrent infection in
premenopusal women with a history of previous urinary tract infection (UTI;
1 or more episode in the last 12 months) compared with placebo (low
quality evidence). This was based on a systematic review and
meta-analysis of randomised controlled trials (RCTs; Grin et al. 2013).
When the analysis was restricted to 2 RCTs with ‘effective strains’ of
lactobacillus, there was a statistically significant difference (16.1% versus
32.3%: number needed to treat [NNT] 7 [range 4 to 64]; moderate quality
evidence).
In most studies lactobacillus was used following a UTI treated with
antibiotics until the infection resolved. Lactobacillus pessaries were used in
4 RCTs and a drink preparation was used in 1 RCT.
Evidence for lactobacillus compared with antibiotic prophylaxis
(co-trimoxazole) in postmenopausal women with 1 or more previous UTI
found, overall, no significant differences between treatment options (low
quality evidence). This was based on 1 RCT included in a systematic
review (Schwenger et al. 2015).
No safety data were reported for lactobacillus compared with placebo. Data
for lactobacillus compared with antibiotic were reported narratively, and the
reason for not pooling data was unclear. One systematic review reported
no significant difference in the number of people experiencing at least 1
adverse event with lactobacillus compared with antibiotics (Schwenger et
al. 2015; low quality evidence).
No systematic reviews or RCTs were identified that included data on
lactobacillus in men or children.
Cranberry products
A range of cranberry products are available; a liquid preparation (juice or
syrup), tablets or capsules were used in the included studies.
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In adults with recurrent UTI or a previous history of UTI, cranberry products
used for up to 12 months did not significantly reduce the risk of recurrent
infection in non-pregnant women (19.9% versus 22.8%) or elderly adults
(men and women; 9.7% versus 12.6%), compared with placebo or no
treatment (very low to moderate quality evidence). This was based on a
systematic review and meta-analysis of RCTs (Jepson et al. 2012).
There was no significant difference between cranberry products and
antibiotics (trimethoprim or co-trimoxazole) in reducing the risk of recurrent
infection in women (51.1% versus 40.4%; moderate quality evidence;
Jepson et al. 2012).
In children with a previous history of 1 or more UTIs or ‘repeated
symptomatic UTI’, cranberry products used for up to 12 months did not
significantly reduce the risk of recurrent infection compared with placebo or
no treatment (16.3% versus 29.5%), and when compared with antibiotics
(trimethoprim; 10.7% versus 15.4%; Jepson et al. 2012; low quality
evidence).
Evidence for cranberry products reducing the risk of antimicrobial
resistance compared with antibiotics was conflicting. Cranberry products
reduced the risk in premenopausal women compared with antibiotic
prophylaxis (co-trimoxazole) during a 12-month treatment period
(Beerepoot et al. 2011; moderate quality evidence). However, the risk was
not reduced in children during a 12-month treatment period (including
children with vesicoureteral reflux [VUR]; Uberos et al. 2012; moderate
quality evidence).
There were no significant differences in gastrointestinal adverse events in
adults treated with cranberry products compared with no treatment or
antibiotics (Jepson et al. 2012; low quality evidence).
No data were identified for adverse effects of cranberry products in
children.
D-mannose
D-mannose (200 ml of 1% solution once daily in the evening) used for up to
6 months significantly reduced the risk of recurrent infection in
non-pregnant women compared with no treatment (14.6% versus 60.8%,
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NNT 3 [range 2 to 3]; high quality evidence). This was based on 1 RCT in
non-pregnant women presenting with a current UTI and a history of
recurrent UTI (Kranjcec et al. 2014). All women were treated with
ciprofloxacin 500 mg twice a day for 7 days for their current infection.
There was no significant reduction in recurrent infection when D-mannose
was compared with antibiotic prophylaxis (nitrofurantoin 50 mg a day) over
the 6-month study period (Kranjcec et al. 2014; low quality evidence).
There were significantly fewer adverse events (such as diarrhoea, nausea
and vaginal burning) with D-mannose compared with antibiotics in
non-pregnant women (7.8% versus 28.2%, number needed to harm
[NNH] 5 [range 4 to 10]; Kranjcec et al. 2014; high quality evidence).
No systematic reviews or RCTs were identified that included data on
D-mannose in pregnant women, men or children.
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Committee discussion on self-care
Based on their experience, and the need to minimise inappropriate use of
antibiotics, the committee agreed that people should be given advice about
behavioural and personal hygiene measures to reduce the risk of UTI, such
as:
the adequate intake of fluids
not delaying habitual and post-coital urination
wiping from front to back after defaecation
not douching or wearing occlusive underwear.
Probiotics (lactobacillus)
The committee discussed the evidence for the probiotic lactobacillus. While
there was some evidence to support the use of ‘effective strains’, there was
no information on which lactobacillus products were included in this analysis.
They also noted the high drop out rate in the study.
Based on evidence, the committee agreed that people should be told that
there is inconclusive evidence to recommend the use of lactobacillus to
prevent recurrent UTIs.
Cranberry products
The committee recognised that cranberry products are used widely.
However, the evidence showed that these products were not effective in
reducing the risk of recurrent UTI in different populations (non-pregnant
women, pregnant women, elderly men and women, and children). However,
some studies may not have been able to show any benefit for cranberry
products due to their design, for example, the duration of the study was too
short or a population of women at lower risk of recurrence had been
selected.
The committee also noted the conflicting evidence for cranberry products in
reducing the risk of antimicrobial resistance.
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Based on evidence, their experience and resistance data, the committee
agreed that people should be advised that there is inconclusive evidence to
recommend the use of cranberry products to prevent recurrent UTIs.
D-mannose
The committee was aware of the mechanism of action of D-mannose, which
is also in cranberry products. Based on their experience, the committee
agreed that D-mannose may be easier to use than cranberry products (once
a day).
Based on evidence, the committee agreed that D-mannose was effective in
reducing the risk of recurrent UTI in non-pregnant women, and noted the low
NNT of 3 (range 2 to 3) over 6 months, compared with no treatment.
However, this was based on 1 small RCT. The committee agreed to make a
recommendation to consider its use as a self-care intervention in
non-pregnant women with recurrent UTI.
Oestrogens
Oral oestrogens (with or without progestogens) taken for up to 4 years did
not significantly reduce the risk of recurrent infection in postmenopausal
women with recurrent UTI compared with placebo (moderate quality
evidence). This was based on a systematic review and meta-analysis of
RCTs (Perrotta et al. 2008). Recurrent UTI was defined as 3 or more
episodes in the last 12 months or 2 or more episodes in the last 6 months.
Vaginal oestrogen cream (estriol cream 0.5 mg applied topically at night for
2 weeks then twice weekly) for 8 months significantly reduced the risk of
recurrent infection in postmenopausal women compared with placebo
(16.0% versus 62.8%, NNT 3 [range 2 to 4]; high quality evidence). This
was based on 1 RCT in the Perrotta et al. (2008) systematic review.
Vaginal oestrogen cream was also significantly more effective than oral
antibiotics (ofloxacin 600 mg a day) in reducing the risk of recurrent
infection over a 3-month study period (7.4% versus 80.0%, NNT 2 [range 2
to 2]; low quality evidence). However, no difference was seen 2 months
after treatment was stopped (very low quality evidence). This was based on
1 RCT included in the Perrotta et al. (2008) systematic review.
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Vaginal oestrogen administered via a vaginal ring in 12 week cycles, for a
total of 36 weeks significantly reduced the risk of recurrent infection in
postmenopausal women compared with placebo (50.9% versus 80.0%,
NNT 4 [range 3 to 9]; Perrotta et al. 2008, moderate quality evidence).
However, vaginal oestrogen administered via a pessary (used daily for 2
weeks then once every 2 weeks) significantly increased the risk of
recurrent infection in postmenopausal women compared with an oral
antibiotic (nitrofurantoin 100 mg a day) over a 9-month study period (67.4%
versus 51.8%; Perrotta et al. 2008; low quality evidence).
Oral and vaginal oestrogens increased adverse events (such as breast
tenderness and vaginal bleeding) in postmenopausal women compared
with placebo, no treatment or oral antibiotics. The NNH was 5 [range 3 to
14] for oral oestrogens (high quality evidence) and 5 [range 3 to 11] for
vaginal oestrogens (Perrotta et al. 2008; low to high quality evidence).
Oestrogens (hormone replacement therapy [HRT]) increase the risk of
venous thromboembolism, stroke, endometrial cancer (reduced by a
progestogen), breast cancer, and ovarian cancer; there is an increased risk
of coronary heart disease in women who start combined HRT more than 10
years after menopause (MHRA Drug Safety Update, September 2007;
British National Formulary [BNF], April 2018). Before prescribing HRT,
health professionals should consider carefully the potential benefits and
risks for every woman. See the NICE guideline on menopause: diagnosis
and management for more information on using vagainal oestrogen for
urogenital atrophy.
Vaginal oestrogens should be used in the smallest effective amount, for the
shortest duration to minimise systemic effects. The endometrial safety of
long-term or repeated use of topical vaginal oestrogens is uncertain;
treatment should be reviewed at least annually, with special consideration
given to any symptoms of endometrial hyperplasia or carcinoma (MHRA
Drug Safety Update, September 2007; BNF, April 2018). The NICE
guideline on menopause: diagnosis and management recommends that
women using vaginal oestrogen should report unscheduled vaginal
bleeding to their GP.
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Committee discussion on oestrogens
Based on evidence of a lack of effectiveness and taking account of
MHRA safety advice, the committee agreed to not recommend oral
oestrogens (hormone replacement therapy) specifically to prevent
recurrent UTI in postmenopausal women.
Based on evidence, the committee agreed that vaginal oestrogens
were effective in reducing the risk of recurrent UTI in
postmenopausal women, although this was based on small
numbers of women and appears to diminish when the treatment is
stopped. They noted the low NNTs for recurrent infection compared
with placebo (NNT 3 [range 2 to 4] for topical cream; NNT 4 [range
3 to 9] for vaginal ring), and also when a topical cream was
compared with antibiotics (NNT 2 [range 2 to 2]). However,
oestrogen administered via a pessary was less effective than
antibiotics.
Based on evidence and their experience, the committee recognised
the adverse effects of vaginal oestrogens (such as breast
tenderness and vaginal bleeding), which may require additional
investigations. They noted the rate of adverse events appeared high
in the studies (NNH 5 [range 3 to 11]) for vaginal oestrogens.
The committee was aware of MHRA safety advice on the use of
vaginal oestrogens; they agreed this was important for women and
prescribers to discuss, but that it should not prevent the safe use of
an effective treatment for recurrent UTI.
Vaginal oestrogens are not licensed for preventing recurrent UTI,
although oestrogen deficiency is a known risk factor. The committee
noted that there do not appear to be any effective, licensed,
non-antimicrobial alternatives for preventing recurrent UTI in
postmenopausal women.
Based on evidence, their experience and data on antimicrobial
resistance, the committee agreed that vaginal oestrogens could be
considered for postmenopausal women with recurrent UTI, with
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review at least every 6 months, or other agreed time. The
committee recognised that this was a preference-sensitive decision
and the benefits and harms of vaginal oestrogens need to be
discussed with the woman, taking account of other symptoms the
woman may want to address, such as vaginal dryness. The
committee agreed that, before vaginal oestrogen is given, women
should be asked about their preferences and give advice about the
possible risks and benefits, returning for review and reporting
unscheduled vaginal bleeding.
The committee could not make any firm conclusions from the
evidence or their experience about different vaginal oestrogen
products. They agreed that this will need to be considered with the
woman on an individual basis.
Antibiotic prophylaxis
The main complication of lower UTIs, including recurrent infections, is
ascending infection leading to pyelonephritis. Most episodes of
pyelonephritis are uncomplicated and result in no residual kidney damage.
However, complications can include impaired renal function or renal failure,
septicaemia and preterm labour in pregnancy (NICE clinical knowledge
summary on pyelonephritis).
In pregnancy, asymptomatic bacteriuria can lead to pyelonephritis; and
symptomatic UTI has been associated with developmental delay or
cerebral palsy in the infant, and foetal death (NICE clinical knowledge
summary on UTI (lower) - women).
In men with UTIs, prostate involvement is common, which may lead to
complications such as prostatic abscess or chronic bacterial prostatitis, and
urinary stones are a possibility (NICE clinical knowledge summary on UTI
(lower) - men).
In children, UTIs can lead to renal scarring, but more often this is preceded
by acute pyelonephritis rather than cystitis. Renal scarring is more common
in children with vesicoureteral reflux, where recurrent UTIs are more likely
(NICE clinical knowledge summary on UTI - children).
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Efficacy of antibiotic prophylaxis
Antibiotic prophylaxis for 6 to 12 months significantly reduced the risk of
recurrent infection (using microbiological criteria) in non-pregnant women
with recurrent UTI (2 or more ‘uncomplicated’ episodes in the last 12
months) compared with placebo (12.3% versus 65.5%, NNT 2 [range 2 to
3]; high quality evidence). This was based on a systematic review and
meta-analysis (Albert et al. 2004). However, there was no significant
difference when recurrent infections were reported after the period of
prophylaxis (very low quality evidence).
Antibiotic prophylaxis with nitrofurantoin for at least 3 months significantly
reduced the risk of recurrent infection in a mixed population of adults
(including non-pregnant women and men) and children (mainly females)
with recurrent UTI when compared with placebo or no treatment (22.5%
versus 59.0%, NNT 3 [range 3 to 4]; low quality evidence). This was based
on a systematic review and meta-analysis of RCTs (Muller et al. 2017).
Antibiotic prophylaxis with nitrofurantoin 50 mg three times a day for the
duration of pregnancy significantly reduced the risk of recurrent
asymptomatic bacteriuria in pregnant women who were admitted to hospital
with acute pyelonephritis (32.6% versus 59.3%, NNT 4 [range 3 to 13])
compared with no treatment (monitoring alone; moderate quality evidence).
This was based on 1 RCT (n=102) included in a systematic review
(Schneeberger et al. 2015). However, antibiotic prophylaxis did not
significantly reduce the risk of recurrent UTI (including pyelonephritis) in
pregnant women, or birth outcomes such as pre-term birth, low birthweight
and miscarriage (Schneeberger et al. 2015; very low to low quality
evidence).
Antibiotic prophylaxis with nitrofurantoin or co-trimoxazole for at least
6 months (duration not reported in all studies) did not significantly reduce
the risk of recurrent infection in children under 18 with recurrent UTI
compared with placebo or no treatment (very low quality evidence). This
was based on a systematic review and meta-analysis of RCTs (Williams
and Craig 2011). Not all studies had clearly defined inclusion and exclusion
criteria, and some had a small proportion of children with vesicoureteral
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reflux (VUR). However, the result did not change when the analysis was
restricted to studies that included children without VUR (very low quality
evidence).
Antibiotic prophylaxis for at least 2 months (co-trimoxazole in most studies)
did not significantly reduce the rate of deteriorated renal scars in children
under 18 years (with or without VUR) compared with placebo or no
treatment (very low quality evidence). This was based on a systematic
review and meta-analysis of RCTs (Dai et al. 2010).
There was no significant difference in the rate of antimicrobial resistance
antibiotic prophylaxis compared with placebo in children under 18 years
(Williams and Craig 2011, very low quality evidence).
Safety of antibiotic prophylaxis
Antibiotic-associated diarrhoea occurs in 2 to 25% of people taking
antibiotics, depending on the antibiotic used (NICE Clinical Knowledge
Summary [CKS]: diarrhoea – antibiotic associated).
Allergic reactions to penicillins occur in 1 to 10% of people and
anaphylactic reactions occur in less than 0.05%. People with a history of
atopic allergy (for example, asthma, eczema, and hay fever) have a higher
risk of anaphylactic reactions to penicillins. People with a history of
immediate hypersensitivity to penicillins may also react to cephalosporins
and other beta-lactam antibiotics (BNF, April 2018). See the NICE guideline
on drug allergy: diagnosis and management for more information.
Nitrofurantoin should be used with caution in those with renal impairment. It
should be avoided at term in pregnancy because it may produce neonatal
haemolysis. Adults (especially the elderly) and children on long-term
therapy should be monitored for liver function and pulmonary symptoms
(BNF, April 2018).
Trimethoprim has a teratogenic risk in the first trimester of pregnancy
(folate antagonist; BNF, April 2018). Manufacturers advise contraindicated
in pregnancy (trimethoprim summary of product characteristics).
In non-pregnant women, there was no significant difference in serious
adverse effects with antibiotic prophylaxis compared with placebo, but
there was a significant increase in the number of ‘other adverse effects’
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(low quality evidence). This was based on a systematic review and
meta-analysis of RCTs (NNH 13 [range 7 to 70]; Albert et al. 2004).
In children, there was no significant difference in the incidence of adverse
effects reported or the number of withdrawals due to adverse events with
antibiotic prophylaxis compared with placebo or no treatment (Williams and
Craig 2010; very low quality evidence).
No systematic reviews or RCTs were identified that assessed the adverse
effects of antibiotic prophylaxis in pregnant women.
See the summaries of product characteristics for information on
contraindications, cautions and adverse effects of individual medicines.
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Committee discussion on antibiotic prophylaxis
People aged 16 years and over with recurrent UTI
Based on evidence and their experience, the committee agreed that
antibiotic prophylaxis was effective in reducing the risk of recurrent UTI in
non-pregnant women, although this benefit was not seen after the
treatment is stopped. They noted the low NNTs for recurrent infection
compared with placebo (NNT 2 [range 2 to 3]). However, they also
recognised the increased risk of harms with antibiotic prophylaxis
compared with placebo.
Based on evidence, the committee agreed that antibiotic prophylaxis was
also effective in a mixed population of people with recurrent UTI,
including pre- and postmenopausal women, men and children (NNT 3 [3
to 4]). However, interpretation of the evidence was more difficult due to
variations in the populations studied and antibiotic choice, dosage and
duration.
The committee discussed the evidence specifically in pregnant women,
which found that antibiotic prophylaxis was effective in reducing the risk
of recurrent asymptomatic bacteriuria in pregnant women (NNT 4 [range
3 to 13]). However, they recognised that the study had a number of
limitations. The study was small and not powered to show any benefit in
pre-term births. The population was pregnant women who were admitted
to hospital with acute pyelonephritis. The committee noted that
nitrofurantoin is not an appropriate choice of antibiotic to show benefit in
this population. They were also aware that UTI has been associated with
developmental delay or cerebral palsy in the infant, and foetal death.
Taking account of the benefits and harms of antibiotic prophylaxis and
the need to minimise antimicrobial resistance, the committee agreed that
antibiotic prophylaxis could be considered in people aged 16 years and
over with recurrent UTI, but only after other management options had
been unsuccessful (behavioural and personal hygiene measures,
managing any triggers and using non-antimicrobial treatments, if
appropriate. The committee recognised the importance of reviewing
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antibiotic prophylaxis, and considered that every 3 months (or other
agreed time) was reasonable based on possible adverse effects of
antibiotics, the risk of resistance with long-term antibiotics, and the
possible need for any further investigations if recurrence of UTIs
continues. People should also know to seek medical help if they
experience symptoms of an acute infection despite taking prophylaxis.
The committee recognised the limitations of the evidence on antibiotic
prophylaxis in pregnant women and men, and the lack of evidence to
support the use of non-antimicrobial treatments. Therefore, the
committee agreed that it was appropriate to refer all pregnant women to
an obstetrician if recurrent UTI is diagnosed during pregnancy. They also
agreed that most men with recurrent UTI should be referred for further
specialist investigation and management, taking an individualised
approach that takes account of multimorbidity. The committee agreed
that any decision to prescribe antibiotic prophylaxis in pregnant women
or men should be under specialist advice.
The committee also recognised the higher risks associated with recurrent
upper UTIs (pyelonephritis), and agreed that it was appropriate to refer
these people for further specialist investigation and management.
The committee also recognised the equality considerations for managing
recurrent UTI in transgender people, due to anatomical differences
between women and men.
Children and young people under 16 years with recurrent UTI
The committee was aware that the NICE guideline on urinary tract
infection in under 16s: diagnosis and management makes
recommendations on referring children and young people with recurrent
UTI to a paediatric specialist for assessment and investigations.
The committee was also aware of the recommendation in this guideline
that antibiotic prophylaxis could be considered for children and young
people with recurrent UTI.
Based on evidence, the committee noted that antibiotic prophylaxis does
not appear to be effective in reducing the risk of recurrent UTI in children.
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However, there was considerable uncertainty in the evidence (all very
low quality).
Based on their experience, the committee agreed that most cases of
recurrent UTI in children and young people are due to a functional or
structural abnormaility of the urinary tract.
Taking account of the uncertainly in the evidence and the need to
minimise antimicrobial resistance from long-term antibiotic use, the
committee agreed that antibiotic prophylaxis could be considered in
children and young people under 16 years, but only under specialist
advice when other management options had been unsuccessful. This
would be an individualised decision following an assessment of
underlying causes, taking into account the severity and frequency of
previous symptoms and the risk of developing complications.
The committee recognised the importance of reviewing antibiotic
prophylaxis, and considered that every 3 months (or other agreed time)
was reasonable based on possible adverse effects of antibiotics, the risk
of resistance with long-term antibiotics, and the possible need for any
further investigations if recurrence of UTIs continues. People should also
know to seek medical help if they experience symptoms of an acute
infection despite taking prophylaxis.
Choice of antibiotic prophylaxis
Antibiotic prophylaxis with nitrofurantoin (various doses: 100 mg a day,
75 mg a day, 50 mg a day or 50 mg twice a day) for at least 3 months
significantly reduced the risk of recurrent infection in a mixed population of
adults (including non-pregnant women and men) and children (mainly
females) compared with methenamine hippurate (NNT 7 [range 4 to 102];
low quality evidence). However, there was no significant difference
between nitrofurantoin and either trimethoprim, beta lactams or quinolones
(very low to low quality evidence). This was based on a systematic review
and meta-analyses of RCTs (Muller et al. 2017).
Antibiotic prophylaxis with nitrofurantoin (1–1.5 mg/kg daily) for 6 months
significantly reduced the risk of having a positive urine culture at the end of
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the study period in children with recurrent UTI compared with trimethoprim
(2–3 mg/kg daily; NNT 3 [range 2 to 8]) and reduced the risk of having a
recurrent symptomatic UTI compared with co-trimoxazole (2 mg/kg daily;
NNT 6 [range 3 to 27]; very low to moderate quality evidence). However,
there was no difference with nitrofurantoin compared with cefixime
(2 mg/kg daily; 6 to 12 months; moderate quality evidence). This was
based on a systematic review of single RCTs (Williams and Craig 2010).
Overall, antibiotic prophylaxis with nitrofurantoin (for at least 3 months)
increased the risk of mild (not defined) adverse effects compared with other
antibiotics in a mixed population of adults and children (30.6% versus
11.7%; NNH 5 [range 4 to 6]; Muller et al. 2017; low quality evidence).
When specific antibiotics were compared, there were significantly more
mild adverse effects with nitrofurantoin compared with beta-lactams
(NNH-7 [range 4 to 28]), trimethoprim (NNH 3 [range 2 to 4]) and
methenamine (NNH 3 [range 2 to 6]), but no difference between
nitrofurantoin and quinolones or co-trimoxazole (Muller et al. 2017; very low
to moderate quality evidence).
In children, there were significantly fewer adverse events with nitrofurantoin
compared with trimethoprim (NNH 2 [range 1 to 8]), but significantly more
adverse events with nitrofurantoin compared with cefixime (NNH 3 [range 2
to 6]; moderate quality evidence). This was based on a systematic review
of single RCTs (Williams and Craig 2010).
No systematic reviews or RCTs were identified that included data on the
choice of antibiotic in pregnant women.
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Committee discussion on choice of antibiotic prophylaxis
Based on evidence of no major differences in clinical effectiveness
between classes of antibiotics, the committee agreed that the choice of
antibiotic prophylaxis should largely be driven by minimising the risk of
resistance. Resistant bacteria are a particular concern in UTIs and,
where possible, any previous urine culture and susceptibility results, and
antibiotic prescribing for UTI, should be checked and antibiotics chosen
accordingly.
Based on their experience and resistance data, the committee agreed
that a different antibiotic should be selected for antibiotic prophylaxis if an
acute UTI is being treated. They also recognised that rotational use of
antibiotics may be needed, based on local policies.
The committee discussed that, if antibiotic prophylaxis is needed to
prevent an infection that is not life threatening, a narrow-spectrum
antibiotic should generally be first choice. Indiscriminate use of broad-
spectrum antibiotics creates a selective advantage for bacteria resistant
even to these ‘last-line’ broad-spectrum agents, and also kills normal
commensal flora leaving people susceptible to antibiotic-resistant harmful
bacteria such as Clostridium difficile. For infections that are not life
threatening, broad-spectrum antibiotics need to be reserved for second-
choice treatment when narrow-spectrum antibiotics are ineffective.
Based on evidence, their experience and resistance data, the committee
agreed to recommend trimethoprim or nitrofurantoin (based on culture
and susceptibility results) as first choice antibiotics for prophylaxis. These
antibiotics have less effect on the normal intestinal microflora in
gastrointestinal tract, which is particularly imprortant when continuous
antibiotic prophylaxis is used.
Trimethoprim should only be prescribed if a lower risk of resistance is
likely, for example if trimethoprim has not been used in the last 3
months, if previous urine culture results suggest trimethoprim
susceptibility (but this was not used as treatment) and in younger
women in areas where local epidemiology data suggest resistance is
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low. There is a higher risk of trimethoprim resistance with recent use
and in older people in residential facilities. Trimethoprim is
contraindicated in pregnant women.
Nitrofurantoin is not recommended for people with an eGFR
<45 ml/minute. With long term use there is a lower risk of resistance of
nitrofurantoin compared with trimethoprim, but this needs to be
balanced against the increased harms, such as pulmonary fibrosis.
The committee was aware that nitrofurantoin suspension is currently
substantially more expensive than trimethoprim suspension and, if
both antibiotics are appropriate, the one with the lowest acquisition
cost should be chosen.
Based on evidence, their experience and resistance data, the committee
agreed to recommend cefalexin or amoxicillin (based on culture and
susceptibility results) as second-choice antibiotics for prophylaxis.
Pivmecillinam is an alternative in people aged 16 years and over (but
manufacturer advises avoid in pregnant women).
Amoxicillin and cefalexin are broad spectrum antibiotics that have a
similar spectrum of activity and can be used if bacteria are susceptible.
Pivmecillinam has less effect on the normal intestinal microflora in
gastrointestinal tract.
Antibiotic dosing and course length
Single-dose antibiotic prophylaxis (used when exposed to conditions that
may trigger a UTI) was not significantly different to continuous antibiotic
prophylaxis in the number of women with at least 1 recurrent infection over
a 12-month study period in postmenopausal women with recurrent UTI (3
or more episodes in the last 12 months; 80.6% versus 70.3%; moderate
quality evidence). This was based on 1 RCT (Zhong et al. 2011).
The conditions for using the single-dose antibiotic were determined by the
woman’s experience, such as walking for a long time or sexual intercourse.
The choice of antibiotic (nitrofurantoin, amoxicillin, co-trimoxazole,
quinolones or cephalosporins) varied and was determined on a case by
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case basis, depending on the woman’s previous antibiotic use and
following an antibiotic susceptibility test.
In 1 RCT (reported in a systematic review by Albert et al. 2004) single dose
ciprofloxacin (250 mg) taken immediately after sexual intercourse was as
effective as a continuous daily dose in non-pregnant women in reducing the
risk of recurrent UTI during the period of prophylaxis (Albert et al. 2004; low
quality evidence).
There were significantly fewer adverse events with single-dose antibiotic
prophylaxis compared with continuous antibiotic prophylaxis (NNH 3 [range
2 to 9]; Zhong et al. 2011; moderate quality evidence).
There was no significant difference in the number of non-serious adverse
effects between those who took a single dose of ciprofloxacin (250 mg)
immediately after sexual intercourse, or daily at night (Albert et al. 2004;
low quality evidence).
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Committee discussions on antibiotic dosing and course length
Based on evidence, the committee was aware that a range of doses and
course lengths were used for continuous antibiotic prophylaxis. The
committee agreed that usual daily doses for continuous prophylaxis
should be used. The duration of treatment needs to be determined on an
individual basis with a review of treatment success every 3 months (or
other agreed time), to include discussion of a trial of stopping antibiotic
prophylaxis as appropriate.
The committee discussed the evidence for using single-dose antibiotic
prophylaxis (including post-coital single-dose antibiotics) in non-pregnant
women. Based on evidence, their experience and antimicrobial
resistance data, the committee agreed that single-dose prophylaxis was
as effective as continuous prophylaxis, with fewer adverse effects in
non-pregnant women with an identifiable trigger, and should be
considered as the first option for antibiotic prophylaxis in this group of
women. Prophylaxis needs to be tailored to individual woman’s personal
triggers, and advice given about how to use the antibiotic (not exceeding
the maximum prophylactic dose per day). Antibiotics for single-dose
prophylaxis would be kept at home to avoid uneccessary GP and
pharmacy visits.
No evidence from systematic reviews and RCTs was identified for using
a course of antibiotics to keep at home for treating an acute UTI in
people with recurrent UTIs (also known as stand-by antibiotics). The
committee recognised that they may have a role in some specialist
cases, but was not able to make a recommendation on their use.
Other considerations
Medicines adherence
Medicines adherence may be a problem for some people with medicines
that require regular dosing or longer treatment duration (for example,
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continuous antibiotic prophylaxis). See the NICE guideline on medicines
adherence.
Resource implications
Recommended antibiotics (nitrofurantoin, trimethoprim, amoxicillin and
cefalexin) are available as generic formulations, but there is currently no
generic formulation of pivmecillinam, although the cost is comparable to
other generic antibiotics, see Drug Tariff for costs.
Nitrofurantoin 25mg/5ml oral suspension is more expensive than other oral
suspensions, such as trimethoprim 50mg/5ml. The cost of a 300 ml bottle
of nitrofurantoin is £446.95 compared with £2.30 for a 100 ml bottle of
trimethoprim (Drug Tariff, April 2018).