DOI: 10.1111/tog.

12644 2020;22:115–21
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Recurrent urinary tract infections: a critical review of the

currently available treatment options
Mike Negus BA BM MRCOG,
a,
* Christian Phillips MD, FRCOG,
b
Richard Hindley MSc FRCS(Urol)
c

a
Specialist Registrar in Obstetrics and Gynaecology, Gynaecology Department, Royal Hampshire County Hospital, Winchester, Hampshire
SO22 5DG, UK
b
Consultant Urogynaecologist, Gynaecology Department, Basingstoke and North Hampshire Hospital, Aldermaston Road, Basingstoke, Hampshire
RG24 9NA, UK
c
Consultant Urologist, Urology Department, Basingstoke and North Hampshire Hospital, Aldermaston Road, Basingstoke, Hampshire
RG24 9NA, UK
*Correspondence: Mike Negus. Email: drnegus@doctors.org.uk

Accepted on 20 May 2019. Published online 13 February 2020.

Key content  Management strategies to prevent recurrent UTI

 Urinary tract infections (UTIs) are the most common infections in are heterogeneous.
women worldwide. Prevalence increases with age to 20% over the
Learning objectives
age of 60. Recurrence is common. 
 UTI is a clinical and socio-economic burden and a cause of
To understand the rationale of why preventing recurrent UTI
(rUTI) is important.
significant psychological distress to the patient.  To develop an awareness of the non-physical effects of rUTI.
 Acute UTI needs swift assessment, diagnosis and treatment to
 To understand the critical appraisal of the current and developing
prevent ascending or systemic infection.
treatments for rUTI.
 Antibiotics remain the mainstay of treatment in acute UTI; it is
thought that up to 50% of antibiotic prescriptions are Keywords: antibiotic resistance / prophylaxis / recurrent urinary
inappropriate or unnecessary and may increase the risk of tract infection / treatments
bacterial resistance.

Please cite this paper as: Negus M, Phillips C, Hindley R. Recurrent urinary tract infections: a critical review of the currently available treatment options.
The Obstetrician & Gynaecologist 2020;22:115–21. https://doi.org/10.1111/tog.12644

The most common bacterium associated with UTI is

Introduction
Urinary tract infections (UTIs) are a significant clinical and
socio-economic burden.1 Annually, more than 150 million
people are diagnosed with a UTI worldwide.2 UTI is the most
common infection in women worldwide.3 In the UK, 1–3%
of primary care consultations and 15% of primary care
antibiotic prescriptions are directly related to UTI.4
The diagnosis of UTI is made by the presence of clinical
symptoms (dysuria, suprapubic tenderness, urinary urgency
and frequency) and the presence of bacteria in urine culture
(>105 cfu/ml), which indicates that the bacteria have infected
the urothelial layer of the urinary tract. This threshold may
be too high and limit diagnosis. It is possible for a patient to
be asymptomatic, despite the presence of bacteria in the
urine; this is described as asymptomatic bacteriuria.5 This
nomenclature may convey a less serious event, and often a
clinical decision is made not to treat infections with lower
levels of cultured bacteria. However, it is possible for lower
level uropathogens to cause chronic damage to
the urothelium.
Escherichia coli (E. coli), which is most often looked for in
culture. These bacteria can swiftly invade susceptible
urothelial cells within the lower urinary tract and multiply
rapidly in the protected environment of the host cells’
cytoplasm.6 One bacterium can produce 10 000–100 000
daughter bacteria within 24 hours.6 This is the initiation of
the UTI pathology.
The main risk factors for UTI include being female, use of
spermicides, sexual intercourse and renal tract anomalies.7
Usually, as is the case with most bacterial infections, the
treatment of a UTI is with antibiotics. Local treatment
guidelines for a single isolated UTI may vary, but
trimethoprim or nitrofurantoin would generally be
considered the first-line treatment option. Gentamicin is
often considered an appropriate second-line treatment.
As suggested by the number of UTIs treated in primary
care, most are uncomplicated and can be treated with oral
antibiotics. If the infection is severe or complicated, or if the
infection appears to be ascending into the upper urinary
tract, admission into hospital for intravenous antibiotics may

ª 2019 Royal College of Obstetricians and Gynaecologists 115

 Treatment of recurrent urinary tract infections
be required. As well as the possibility of the pathogen
ascending into the upper urinary tract (pyelonephritis), other
sequelae of UTI can be serious. These include abscess
formation, facilitation of preterm birth in pregnancy and
repeat infections. Repeat episodes of UTI can result in renal
scarring, which in turn may precede hypertension and even
chronic renal failure.8 Management of recurrent UTI (rUTI)
is of paramount importance because repeat courses of
antibiotics to treat rUTI can result in bacteria developing
resistance to the mechanism of action of previously effective
antibiotics.6 The issue of antibiotic resistance is a great
concern, especially with the rising prevalence of multi-drug-
resistant uropathogenic E. coli.
The European Commission (EC) has reported that 2–3%
of women between the ages of 15 and 24 years will have
microbiologically culturable bacteriuria. This increases to
20% of women aged 65–80 years.9 The same report predicts
that the population of countries within the EC will increase
by 50% by 2030, which would therefore increase the number
of UTIs.
It is suggested that the annual healthcare cost of
investigating and treating UTI in the USA could be as
much as $2.5 billion.10 Further socio-economic research has
found that each episode of an acute UTI results in an average
of 6.1 days of disability and 2.4 days of school/work absence
in the USA.11 It is likely that this could be extrapolated
throughout Western countries. Alongside the fiscal costs of
UTI lies the psychological cost of the disease. The
psychological impact of clinical symptoms can be assessed
using the Hospital Anxiety and Depression Scale (HADS).
HADS is an extensively investigated, reliable and simple
method of measuring the impact of clinical symptoms on
anxiety and depression within the healthcare population.
A cross-sectional, population-representative study
involving 8284 individuals suggested that patients
experiencing lower urinary tract symptoms resulted in
significantly increased (P < 0.001) scores for both anxiety
and depression, compared with those without.12 The
importance of treatment on psychological wellbeing is
demonstrated in a study of 575 women treated for 90 days
with nonmicrobial UTI treatment and followed up at
180 days. This study found that the mean HADS score
decreased by 32% following treatment.13
UTI is an acute event caused by bacteria invading the
urothelial lining of the urinary tract. If a patient experiences
at least three UTIs in a year, or two UTIs in 6 months, it can
be defined as an rUTI14. Prevention of a problem is preferred
to cure, and preventing disease is at the heart of the
UK Government’s recent guidance on health for the
nation.15 The numerous treatment modalities currently
recognised for preventing rUTI are outlined and
discussed below.
116
Low-dose antibiotic prophylaxis
Antibiotic therapy is a well-established and clinically
successful treatment for acute UTI. The National Institute
for Health and Care Excellence (NICE) suggests that patients
should undergo a full clinical assessment prior to initiation of
antibiotics for the treatment of UTI.5 In an ideal scenario, a
midstream urine sample should also be sent for culture prior
to commencing antibiotics. However, recent work has
suggested that delaying the prescription of antibiotics may
result in patients being twice as likely to require admission to
hospital because of the sequelae of UTI. A balance must
therefore be struck between unnecessary antibiotic
prescriptions and attempts to prevent complicated UTI.16
The use of urinalysis alone is often inaccurate in
diagnosing UTI. Treatment should, therefore, be initiated
on the correlation of symptoms and urine culture. Further
caution is advised in catheterised patients, as asymptomatic
colonisation is common.5
Analysis of 19 clinical studies (incorporating 1120 women)
comparing antibiotic treatment with placebo has shown that
antibiotics are more effective than placebo in eradicating
bacteriuria and relieving UTI symptoms.17 This is
substantiated in a meta-analysis by Albert et al. (2004)18 of
ten trials comparing antibiotics with a placebo. The results of
this analysis suggest that the rate of microbiological recurrence
of UTI per patient year was 0–0.9 for women on antibiotics,
compared with 0.8–3.6 with placebo. The relative risk of
microbiological recurrence was reported as 0.21 in favour of
treatment with antibiotics. The number needed to treat with
antibiotics to reduce microbiological recurrence was 1.85.
All studies reviewed suggest that antibiotics are effective in
the treatment of rUTI. However, antibiotic use does have some
adverse effects. The US National Institutes of Health has
recently initiated a project19 to map the Human Microbiome
and classify the ‘resident’ flora/bacteria. This work has shown
the existence of a female urinary microbiota,19 which is likely to
be, in most people, protective in nature. Antimicrobial use
alters the delicate balance of natural flora that lives within the
human body and creates an environment for harmful
organisms to thrive. One study included in the review by
Albert et al.18 found a significant increase in both oral and
vaginal candidiasis in 1120 women who were treated with
nitrofurantoin compared with placebo.18 The same review also
demonstrated an increase in gastrointestinal symptoms in the
women treated with nitrofurantoin. These findings were
confirmed in a study that found an association between
nitrofurantoin and adverse gastrointestinal effects.20 Most of
the effects are relatively innocuous and, in reality, are well
tolerated by the patients. However, the study did show that
liver toxicity and, in extreme cases, liver failure, can be seen
with nitrofurantoin use. There are also documented cases of
ª 2019 Royal College of Obstetricians and Gynaecologists

nitrofurantoin causing acute and chronic pulmonary toxicity,
which can result in pulmonary fibrosis if not recognised,
especially with long-term antibiotic use.21 The decision to
initiate any treatment should be taken with care, but this study
highlights the risk of nitrofurantoin when used for rUTI
prophylaxis and that the decision to start treatment should be
well considered.
One further concern with long-term antibiotic use is the
development of bacterial resistance. This has been on the
increase for nearly 30 years.22 Data released by NICE have
shown that nearly one-third of E. coli-related UTIs are
resistant to the usual first-line antibiotic prescribed.23
NICE released draft guidance aiming to reduce bacterial
resistance to antibiotics by tailoring the prescription to
symptoms. The guidance suggests that prescribers should be
aware of the risk of clinical complications of UTI and have
knowledge of the patient’s previous antibiotic use. Other
antibiotic regimens that aim to prevent rUTI include
postcoital, rescue and self-dip and treat.
There are significant concerns with the development of
antibiotic resistance.24 In the UK, it is suggested that 43% of
community-acquired UTIs in children were resistant to one
antibiotic and up to 17% of the UTIs investigated in the same
cohort were multi-drug-resistant (resistant to more than three
antibiotics).25 Resistant organisms create a big problem for
healthcare provision. They take longer to cure, usually result in
multiple visits to the general practitioner, and are likely to
increase the number of visits to the emergency department,
with a subsequent increase in hospital admissions.25 Increased
antibiotic resistance has led to a call for the development of
preventive measures for rUTI. However successful the research
into preventive treatments becomes, the first-line treatment for
acute UTI is – and is likely to remain – the initiation of
antibiotics.6 The aim of this treatment is preventing
uncomplicated lower UTI ascending into the ureters and
kidneys, but it is vital that antibiotic use is tailored to local
bacterial strains and any known resistance.6
There has been a worldwide drive to find alternative
treatments for UTI that are non-antimicrobial. In 2016, Yang
published a review of known and potential treatments.26
Here, we concentrate on and compare and contrast available
nonmicrobial treatment modalities for rUTI.
Chinese herbal medicine
Chinese herbal medicine (CHM) has been used to treat UTI
for millennia. However, the mechanism of action is unclear,
and there is a lack of robust data to support its use.
Studies have compared CHM versus placebo and versus
current conventional biomedical treatments. A review of
these trials, which appeared favourable towards CHM,
concluded that the studies were of overall poor quality and
bias prevented robust conclusions from being drawn.4
ª 2019 Royal College of Obstetricians and Gynaecologists
Negus et al.
Following this conclusion, however, data from a trial of
542 women (422 postmenopausal) using CHM for rUTI
treatment suggested that Er Xian Tang (specifically
formulated for the treatment of both acute and recurrent
UTI) was more effective than generic CHM.27 The authors
suggested that robust randomised controlled trials (RCTs)
would be beneficial to ascertain the efficacy of CHM in the
management of rUTI.
Methenamine
Methenamine is an inactive weak base that slowly hydrolyses
in urine (owing to its acidic nature) to form ammonia and
formaldehyde. Formaldehyde has antimicrobial properties
that are thought to denature the protein structure of bacteria.
It is neither bactericidal nor bacteriostatic, but its nonspecific
action makes most organisms susceptible and no organisms
are resistant. Thirteen studies of 2032 women suggested that
methenamine may be beneficial for patients at risk of rUTI.
Women taking methenamine were found to be 76% less
likely to develop UTI compared with placebo. However, the
studies were deemed to be of poor quality, and the author
encouraged caution when clinically interpreting the results.28
Cranberries and D-mannose
In the past, cranberry juice has been recommended to
manage rUTIs. The mechanism of action is thought to be
associated with aggregation of parts of the cranberry on the
pili on the surface of bacteria, which reduces the bacteria’s
ability to adhere to and subsequently penetrate the urothelial
cells. The bacteria become clumped together and are
subsequently excreted in the urine. A few small studies
have assessed the efficacy of cranberry juice and suggested
that cranberries are superior to standard management, but
inferior to antibiotic treatment29 for the prevention of UTI.
Antibiotic use was, however, associated with a markedly
(23–28%) elevated rate of antibiotic resistance compared
with cranberry juice. In a 2012 Cochrane systematic review,30
data were collated from studies involving 4473 patients and
no statistically significant benefit was found for women
treated with cranberry juice for rUTI. As such, current NICE
and Royal College of Obstetricians and Gynaecologists
(RCOG) guidelines recommend against the use of
cranberry for management of rUTI.6
D-mannose is a sugar derived from cranberry juice and, as
such, the mechanism of its action is the same. After
randomisation to either treatment with D-mannose
powder, nitrofurantoin or no treatment, the results of a
study of 308 women suggested no difference in the UTI
recurrence rates between D-mannose and nitrofurantoin.
Women receiving both treatments had fewer UTIs in the
follow-up period than the women randomised to no
117
 Treatment of recurrent urinary tract infections

Acute UTI
Diagnosis on symptoms/
`

signs/urine dip
Send MSU

Antibiotic treatment

>3 UTI in 12 months = rUTI

Refer to secondary care

Cystoscopy
Renal USS Treat abnormalities
Voiding studies

Normal investigations

Premenopausal Postmenopausal

GAG replacement Further acute UTI

Offer low-dose
4x weekly installations Continue vaginal estrogen vaginal estrogens
2x monthly installations Offer GAG

Follow-up 12 months Follow-up 12 months

Discharge to primary care

Figure 1. Suggested treatment algorithm based on currently available treatments and data on efficacy. Abbreviations: GAG = glycosaminoglycan;
MSU = midstream specimen of urine; rUTI = recurrent urinary tract infection; USS = ultrasound scan; UTI = urinary tract infection.

treatment.31 The authors of the study suggested that although
these initial results were encouraging for the use of D-
mannose powder, more data from alternative studies are
required to validate them. On the strength of this small RCT,
NICE has recommended that nonpregnant women may wish
to try D-mannose as a self-care treatment.
Lactobacilli
Lactobacillus is a genus of bacterium that is found in the
intestines and produces lactic acid. It is described as a probiotic,
which is defined by the World Health Organization as a live
microorganism that, when administered in adequate quantities,
confers health benefits to the host.
Lactobacilli have been compared with antibiotics,32 but the
results were without doubt in favour of treatment with
antibiotics. The antibiotic group had fewer UTIs in the
follow-up period and a shorter time to first recurrence. Of
concern, however, was the increased rate of antibiotic
resistance in the group treated with antibiotics.
Again, the rate of antibiotic resistance shown here is
concerning, but although Lactobacilli have been suggested to

118 ª 2019 Royal College of Obstetricians and Gynaecologists


be safe and effective,33 further robust data are needed to
confirm their efficacy with regular use.
Urethral dilatation
There is a paucity of data relating to urethral dilatation as a
treatment modality for rUTI. However, it is still widely
practised in some units. Data from 100 women randomly
assigned to either urethral dilatation or cystoscopy alone for
symptomatic UTI revealed no significant difference in the
number of UTIs at 6 months post-treatment.34 However,
subjectively, irrespective of the microbiological findings in
the follow-up period, 30% of the women assigned to urethral
dilatation reported that their symptoms had completely
resolved. Fifty percent reported that their symptoms had
improved, if not resolved.
Estrogens
Estrogen receptors are present in the vagina, urethra, trigone
of the bladder and pelvic floor musculature. A fall in estrogen
levels during menopause causes the vaginal pH to rise. The
more alkalotic environment is detrimental to the normal
vaginal flora – specifically, Lactobacilli. This in turn facilitates
a habitat more conducive to uropathogenic Gram-negative
bacteria. Administration of exogenous vaginal estrogen has
been shown to decrease vaginal atrophy and increase vaginal
levels of Lactobacillus.35
NICE guidance on the use of estrogens in treating rUTI is
predominantly based on a systematic review and meta-
analysis of RCTs by Perotta et al. (2008).36 NICE suggest that,
in postmenopausal women, vaginal estrogens are effective in
preventing rUTI but systemic estrogens are not. However,
there are some risks associated with estrogen use (e.g. breast
tenderness and increased risks of breast and endometrial
cancers). These are predominantly related to systemic
estrogen use in postmenopausal women.37.
Glycosaminoglycans
The urothelium of the bladder comprises three distinct
layers. From deep to superficial, they are the basal,
intermediate and surface (umbrella) layers. The surface
layer is covered by a glycosaminoglycan (GAG) layer of
disaccharides, which is hydrophilic and has a strong negative
charge. The GAG layer easily binds water molecules, resulting
in a well-hydrated and non-adhesive bladder surface.38 The
function of the GAG layer is proposed to be an antibacterial
coating of the bladder to prevent bacterial (specifically,
bacterial pili) adherence.39 Removal of the GAG layer has
been shown to increase bacterial adherence 100-fold.40
Subsequent research has shown that a deficiency in the
GAG layer increases the rate of UTI.41 Damage to the
ª 2019 Royal College of Obstetricians and Gynaecologists
Negus et al.
urothelial cells beneath the GAG layer is thought to be
critical to most chronic bladder pathologies.42 Pro-
inflammatory chemokines, such as interleukin-8, guide
neutrophil granulocytes to the area of urothelial damage.
Chronic urothelial damage and neurogenic inflammation
(the inflammatory response following chronic insult to the
bladder nerve supply after depletion of the GAG layer)
has been shown in bladder sections with deficient GAG
layers.43 Histology has also shown that GAG supplements
reduce neutrophil transmigration and halt the subsequent
inflammatory process.44
To date, replacement of the GAG layer with synthetic
hyaluronic acid (HA) has shown promise in its efficacy and
tolerability when used as rUTI prophylaxis. An initial study
of 57 women randomly allocated to treatment with a GAG
layer replacement of HA and chondroitin sulphate (CS)
showed that the mean number of UTIs per patient per year
and mean time to first UTI following treatment was
significantly reduced in the follow-up period.45 Patient
quality of life was significantly increased in the treatment
group and no serious adverse events were reported. Data
comparing a GAG layer replacement (HA-CS) with
antibiotics in 276 women, across seven European sites,
reported significant improvements in the mean number of
UTIs per patient per year and mean time to first UTI in the
HA-CS group.46 However, it should be noted that this was a
case–control study and did not have a randomised design.
Further studies have corroborated the beneficial effects of
GAG replacement in the management of recurrent UTIs and
its effect on bladder symptoms, sexual function and quality
of life.47
The results of these studies, although not definitive owing
to the small size and non-randomised design, highlight the
promising nature of GAG layer replacement. Therefore, in
the current climate of ever increasing antibiotic resistance,
further prospective, randomised trials are needed.
Sublingual vaccination
In 1796, Edward Jenner was the first to demonstrate
vaccination by using cowpox to prevent smallpox.
Vaccination works by inducing an immune response
against an antigen. This response occurs in response to
proteins and sugars (receptors) present on the surface of the
antigen, which are alien in phenotype to the host.
Mucosal surfaces act as the boundary between the external
environment and the respiratory, gastrointestinal and
urogenital systems. They are the main barrier against
pathogens attempting to enter the body. Sublingual
vaccination produces a vigorous immune response against
the administered antigen. It also produces a systemic
immunoglobulin G (IgG), immunoglobulin A (IgA) and
cytotoxic T-lymphocyte response, resulting in protective
119
 Treatment of recurrent urinary tract infections
immunity. A sublingual therapeutic vaccination has now
been developed against UTI. It contains a mixture of equal
amounts of selected strains of E. coli, Klebsiella pneumoniae,
Proteus vulgaris and Enterococcus faecalis.
Data on the efficacy of this sublingual vaccination are
currently sparse. However, two studies have suggested that it
is highly effective in reducing rUTI in women following its
administration. In the first, a retrospective cohort study of
669 women, 330 women received the vaccination and 339
received the standard prophylactic antibiotic treatment. Of
the women who received the standard antibiotic treatment,
100% developed a UTI in the 12-month follow-up period,
compared with only 35% of the women who were treated
with the vaccine.48 In the second, a recent UK study, 78%
(59/75) of women treated with Uromune developed no
UTI in the 12-month follow-up period after treatment,
compared with 100% of the women having at least three
UTIs in the 12 months prior to treatment.49 The main
concern with any vaccination against a bacterium is that
bacteria evolve and mutate, reducing the vaccine’s
effectiveness. Further research is required; indeed, an
international double-blind RCT comparing Uromune with
placebo is currently underway. Sublingual vaccination is
currently not licensed in the UK and it does not have
approval from the US Food and Drug Administration. It is
available on a named patient basis and is not funded on the
UK’s National Health Service.
A phase 1 human trial has been published, which
compared a bioconjugate intramuscular injected vaccine
containing the O-antigens of four E. coli serotypes against
placebo.50 The primary endpoint was incidence of adverse
effects and the secondary endpoint was antibody
production. Sixty percent of the patients receiving the
vaccine and 49% of patients receiving placebo injection
reported adverse effects, although these were almost
exclusively related to the injection site. A four- to six-
fold increase in antibody titres was seen in the vaccine
group compared with placebo. Phase 2 trials are scheduled
and awaited with interest, although any success seen with
the vaccine needs to be tempered with the knowledge that
the E. coli bacteria are still able to mutate and become
resistant to the vaccine with time.
Conclusion
UTI is a notable problem affecting thousands of women. It
provides a significant clinical and socio-economic burden
and is a cause of major psychological distress to the patient.
Acute UTI needs swift assessment, diagnosis and treatment to
prevent ascending or systemic infection. Recurrent UTIs are
increasingly problematic. There is a great deal of
heterogeneity in the management strategies used to prevent
rUTI, although the evidence is varied and generally of low
120
quality. More research is needed to prove the safety and
efficacy of newer treatments. Please see Figure 1 for a
suggested treatment algorithm.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
MN researched and wrote the article. CP and RH edited the
article. All authors approved the final version.
Acknowledgements
We thank Professor Simon Jobson, Director of Health and
Wellbeing/Professor of Sport and Exercise Physiology,
University of Winchester, for providing valuable
academic advice.
Supporting Information
Additional supporting information may be found in the
online version of this article at http://wileyonlinelibrary.com/
journal/tog
Infographic S1. Management of recurrent urinary
tract infections.
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