review article
Urinary Tract Infections in Women
Ramesh hotchandani*, kk aggarwal**
Abstract
Urinary tract infections (UTIs) are one of the most common bacterial infections seen in primary care, second only to
infections of the respiratory tract. Women are particularly at risk of developing UTIs because of their short urethra, and
certain behavioral factors which include delay in micturition, sexual activity and the use of diaphragms and spermicides.
Uncomplicated UTIs are usually treated empirically with antibiotics. However, not everyone diagnosed with a UTI and
treated with an antibiotic will necessarily have a bacterial infection. At least one-half of women who suspect that they have
UTI actually do. Studies have shown that one in 7 patients given an antibiotic for UTI symptoms will return within 28 days
for a further prescription of antibiotic. Also, many UTIs are self-limiting, improving without treatment even when culture is
positive. Symptomatic treatment of uncomplicated UTI may be an option which merits further research. Phenazopyridine is a time-tested urinary tract antiseptic and analgesic that provide symptomatic relief of the pain, burning, frequency and
urgency associated with UTI.
Keywords: Urinary tract infections, symptomatic treatment, phenazopyridine, analgesic
U
rinary tract infection (UTI) is defined as the
presence of microbial pathogens in the urinary
tract with associated symptoms. When it
affects the lower urinary tract it is known as cystitis
and when it affects the upper urinary tract it is known
as pyelonephritis. UTIs are one of the most common
bacterial infections seen in primary care, second
only to infections of the respiratory tract.1 They are
particularly common among the female population
with an incidence of about 1% of school-aged girls and
4% of women through child-bearing years. Incidence
of infection in females increases directly with sexual
activity and child-bearing. In the women, 25-30% of
women between 20-40 years of age will get UTIs.2
These infections account for about 8.3 million doctor
visits each year.1 UTIs have been well-studied in
Sweden and other parts of Europe.3 These studies
have shown that one in 5 adult women experience a
UTI at some point, confirming that it is an exceedingly
common worldwide problem.3 In 2007, approximately
3.9% of office visits in USA were related to symptoms
*Head, Dept. of Nephrology, Moolchand Medcity, New Delhi
**Senior Physician and Cardiologist
Moolchand Medcity, New Delhi
involving the genitourinary tract.4 Sixty-one percent of
all UTIs are managed in the primary care setting. It is
also common for these episodes to recur.5
Predisposing factors
Women are particularly at risk of developing UTIs
because of their short urethra, and certain behavioral
factors which include delay in micturition, sexual
activity and the use of diaphragms and spermicides
which promote colonization of the periurethral area
with coliform bacteria. Infection in women most often
results from perineal or periurethral bacteria that
enter the urethra and ascend into the bladder, often in
association with sexual activity, or due to mechanical
instrumentation such as catheterization.6 Rates of
infection are high in postmenopausal women because
of bladder or uterine prolapse causing incomplete
bladder emptying; loss of estrogen with attendant
changes in vaginal flora (notably, loss of lactobacilli),
which allows periurethral colonization with gramnegative aerobes, such as Escherichia coli; and higher
likelihood of concomitant medical illness, such as
diabetes.
Reports worldwide suggest a significant peak in
the incidence of UTI for a few months each year in the
post summer season. Anderson et al reported a rise in
the incidence of UTI in August.7 They attribute this
Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012
187
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to hot and humid conditions during these months.
In a study by Hasan et al, in a tertiary Indian hospital
in New Delhi, rise in the incidence of UTI was
reported during the monsoon months i.e. from July
to September.8
Clinical Presentation
The characteristic symptoms of UTI in the adult are
primarily dysuria with irritating voiding symptoms like
urinary urgency, frequency, nocturia, painful voiding,
bladder discomfort or stranguria which greatly distress
the patient. A sensation of bladder fullness or lower
abdominal discomfort is usually present. Pain occurring
at the beginning of or during urination suggests a
urethral site of disease, whereas pain after voiding
implies pathology within the bladder or prostate area.
Sometimes a patient will relate a history of pain in the
suprapubic area.9
Because of the referred pain pathways, even simple
lower UTI may be accompanied by flank pain and
costovertebral angle tenderness. In the emergency
department, however, it is assumed that the presence
of these symptoms represents upper UTI.
Bloody urine is reported in as many as 10% of cases
of UTI in otherwise healthy women; this condition is
called hemorrhagic cystitis. Fevers, chills and malaise
may be noted in patients with cystitis, though these
findings are associated more frequently with upper
UTI (i.e. pyelonephritis).
Causative Organisms
E. coli is by far the commonest cause of uncomplicated
community-acquired UTIs in both outpatient and
inpatient settings. Other common uropathogens are
Enterococcus faecalis, Enterobacter species, Staphylococcus
saprophyticus, Klebsiella pneumoniae, Proteus mirabilis and
Pseudomonas species.10
Diagnosis
Urinalysis is mandatory in all patients who present
with dysuria. The gold standard is evaluation of a
spun midstream clean-catch urine specimen. Bacteria
or pyuria (or both) are usually found in patients with
UTI. Leukocyte esterase is 75% sensitive for detection
of UTI (although studies done in the emergency
department have demonstrated only 48% sensitivity),
but 98% specific. Positive nitrite is highly suggestive
of a UTI (90% specific), but a negative result does not
rule it out (sensitivity is only 30%).6 Urine culture
is unnecessary for most patients with consistent
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Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012
symptoms and a positive dipstick test, unless any
predisposing factors for upper tract or complicated
infection (hydronephrosis or atonic bladder) are
present.11
Management
UTIs can be classified into acute uncomplicated cystitis,
acute uncomplicated pyelonephritis, complicated UTI
and acute complicated pyelonephritis. Uncomplicated
UTIs are usually treated empirically with antibiotics as
recommended by primary care guidelines. Antibiotics
for empiric treatment of uncomplicated UTI include.9


First-line antibiotic: Trimethoprim/sulfamethoxazole
in communities with resistance rates for E. coli
<20%. Avoid in women who have been treated
within six months, as they are more likely to have
resistant organisms.
Second-line antibiotics or first-line in resistant
communities: Fluoroquinolones, such as ciprofloxacin, levofloxacin, norfloxacin and ofloxacin.
Although, antibiotic treatment supports clinical cure in
individual patients but also leads to emerging resistance
rates in the population. Resistance has increased to
various antimicrobials and more than one-quarter of
E. coli strains causing acute cystitis are resistant to
amoxicillin, sulfa drugs and cephalexin and resistance
to co-trimoxazole is now approaching these levels.
Resistance to fluoroquinolones is also rising. Akram et al
reported ciprofloxacin resistance rates ranging from
47 to 69% among the gram-negative organisms in their
study in India.12 High levels of extended-spectrum
beta-lactamase (ESBL) producers among gram-negative
community-acquired uropathogens is seen in our
country. This, along with the alarming rate of resistance
to ciprofloxacin, sulfamethoxazole-trimethoprim and
amoxicillin, precludes the use of these commonly
used antibiotics for empiric treatment of communityacquired UTI in India.13
To prevent resistance, antibiotics should be used
judiciously; they should be prescribed for as short
a period as possible. Milo and colleagues reviewed
32 randomized controlled trials (with a total of 9,605
patients) comparing three days of oral antibiotic
therapy with longer courses for women 18-65 years of
age.14 Pregnant women and women with symptoms
that suggest upper UTI (e.g., fever, flank pain, vomiting,
positive blood cultures) were excluded. For short- and
long-term resolution of symptoms, the reviewers found
no difference between a 3-day antibiotic course and a
course lasting 5-10 days. Longer courses were more
review article
effective at clearing the bacteria on follow-up culture
but also caused more adverse effects, and it was not
clear that bacterial clearance resulted in improved
patient-oriented outcomes.14
However, not everyone diagnosed by a general
practitioner with a UTI and treated with an antibiotic
will necessarily have a bacterial infection. At least
one-half of women who suspect that they have UTI
actually do.15 Fifty percent of patients consulting
with urinary tract symptoms may not have a
clinically important infection on culture. In a study by
Eshwarappa et al in a South Indian population, only
510 of the 5,564 suspected cases (9.17%) were proved
by culture.16 Studies have shown that one in 7 patients
given an antibiotic for UTI symptoms will return within
28 days for a further prescription of antibiotic.17
In many patients without additional risk factors, UTI
seems to be a self-limiting condition. Studies have
shown that many UTIs are self-limiting, improving
without treatment even when culture is positive.18 One
trial in Belgium has shown that half of the patients
were free of symptoms after three days of placebo.19
If the volume of antibiotic prescribing is to be reduced
and the increasing problem of resistant organisms
addressed, alternative diagnostic and treatment
strategies in primary care are needed.20 Symptomatic
treatment of uncomplicated UTI may be an option
which merits further research.
3-(phenylazo)-, monohydrochloride.24 It is used as a
urinary tract antiseptic and analgesic as brief adjuvant
therapy for treatment of UTI. Additionally, the
drug is used for many urologic problems involving
dysuria.25
Mechanism of Action
The precise mechanism of action of phenazopyridine
hydrochloride is not known. It is excreted in the urine,
where it acts as a topical analgesic on the mucosal
lining of the urinary tract thus relieving pain, burning,
urgency and frequency. However, it does not possess
any antimicrobial properties.
In a study undertaken recently, it was demonstrated
that
phenazopyridine
directly
inhibits
the
mechanosensitive Aδ-fibers in the normal rat bladder.
In this study, the effect of phenazopyridine on afferent
nerve activity was evaluated by direct measurement of
both Aδ- and C-fibers, and compared the outcome with
the effects of a local anesthetic (lidocaine) and of an
analgesic (acetaminophen). Intravenous administration
of phenazopyridine significantly decreased dosedependently only the Aδ-fibers but not the C-fiber
activity. According to the researchers, phenazopyridine
exerts its clinical effect in conditions of urinary
bladder hypersensitivity by direct inhibition of the
mechanosensitive Aδ-fibers.26
Clinical Efficacy
Symptomatic Treatment of Uncomplicated UTI
Analgesic Properties
Symptomatic UTIs are among the most common of
bacterial infections.21 Though relatively benign and
self-limiting, these irritating voiding symptoms like
urinary urgency, frequency, nocturia, painful voiding,
bladder discomfort or stranguria greatly distress the
patient and have a detrimental influence on patient
quality-of-life.22 Symptomatic treatment allows time
for microbiological investigation and helps to reduce
unnecessary prescribing of antibiotics. A urinary tract
analgesic would have an immense reassuring effect on
the patient. Phenazopyridine is a urinary tract antiseptic
and analgesic that has for long been used to provide
symptomatic relief of the pain, burning, frequency
and urgency associated with UTI during the first
24-48 hours of therapy.
A study was undertaken by Kirwin et al to evaluate
the effects of phenazopyridine 500 mg (two tablets
thrice-daily) administration in urogenital infections in
118 patients. It was seen that in 65 (55.1%) cases, all the
characteristic symptoms of urogenital infections were
relieved: Pain on urination was alleviated or abolished
in 95.3%; burning on urination was relieved in 93.6%;
frequency decreased in 85%, nocturia was eliminated
or reduced in 83.7%, with reduction the organized
sediment. In the remaining 53 cases, symptomatic relief
was also observed in all but a few, although, there was
no concomitant reduction in the organized urinary
sediment. Phenazopyridine was very well-tolerated
with no toxic effects observed during the two weeks of
its administration.27
Phenazopyridine
Phenazopyridine hydrochloride is an azo dye with local
analgesic and anesthetic effects on the urinary tract.23
Chemically, phenazopyridine is 2,6-Pyridinediamine,
Adjuvant to Antimicrobial Therapy in Uncomplicated UTIs
Phenazopyridine is compatible with antibacterial
therapy and can help to relieve pain and discomfort
during the interval before antibacterial therapy
controls the infection. Treatment of UTI with
Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012
189
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phenazopyridine hydrochloride should not exceed
two days because there is a lack of evidence that
the combined administration of phenazopyridine
hydrochloride and an antibacterial provides greater
benefit than administration of the antibacterial alone
after two days.28
Efficacy of phenazopyridine when administered
along with antibiotics as a short-term analgesic in the
treatment of uncomplicated UTIs was demonstrated
in a randomized, open label study. It was seen that
phenazopyridine, when given with antibiotics such as
ciprofloxacin, doxycycline within 48 hours of diagnosis,
resulted in marked reduction in urinary symptoms of
burning micturition (91%) and pain during voiding
of urine (89%).29
Phenazopyridine is widely used as an adjunct to
sulfonamides in the treatment of bacterial infections
of the urinary tract because of its proven analgesic
effect on the mucosa of the urinary tract. It does
not alter the effectiveness of sulfonamides against
uropathogenic bacterial species in mice.23 The combined
bacteriostatic activity of sulfonamide compounds
and phenazopyridine upon Balantidium coli has been
demonstrated in vitro.30,31
Another study demonstrated that bioavailability of
ciprofloxacin is enhanced by oral co-administration
with phenazopyridine. This study compared the
pharmacokinetic behavior of ciprofloxacin administered
alone versus ciprofloxacin plus phenazopyridine. While
there were no differences between the two treatments
in terms of peak plasma concentration (Cmax) and
elimination constant (ke), area under the concentrationtime curve to last measurable concentration (AUCt)
and area under the concentration-time curve
extrapolated to infinity (AUC∞) were 35% and 29%
higher, respectively, in the combined treatment arm.
In addition, a significant delay in tmax (from 1 to 1.5 hours)
and a statistical increase of 29% in mean residence
time (MRT) were also observed in the combination
group. The study concluded that phenazopyridine,
when given together with antibiotic (ciprofloxacin)
enhances its bioavailability with regard to the amount
absorbed and MRT in the body, which is beneficial
during treatment.32
Pain due to Bladder Spasms
Indwelling urinary catheter is a foreign body and its
presence may trigger spasms, or detrusor contractions
due to irritation of the trigone area.33 This complication is
distressing for the patient. Phenazopyridine hydrochloride
helps relieve the pain caused by catheters.34
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Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012
Chronic Radiation Cystitis
Radiation therapy is an integral part of adjunctive
treatment in approximately 66% of cancer patients and
its use has increased cancer survival. However, it is
associated with chronic cystitis which impairs the cancer
survivor’s quality-of-life. Phenazopyridine provides
symptomatic relief for chronic cystitis associated with
radiation therapy.35
Autonomic Dysreflexia
Phenazopyridine may be useful in the management
of autonomic dysreflexia (AD) associated with UTI.
Paola et al have reported a case of a 36-year-old man
with tetraplegia and AD triggered by cystitis, who
improved both subjectively and objectively following
the institution of a 2-day course of phenazopyridine.36
Phenazopyridine vs Other Antispsmodics
Urinary antispasmodics such as oxybutynin and
flavoxate are muscarinic receptor antagonists and exert
beneficial direct relaxant effect on smooth muscle of
the urinary tract, with local analgesic and anesthetic
effects on the urinary tract.16 However, flavoxate and
oxybutynin have anticholinergic effects such as dry
mouth, constipation and other anticholinergic effects.
Phenazopyridine has a different mechanism of action;
it has both local analgesic and anesthetic effects on the
urinary tract. Anticholinergics like oxybutynin and
flavoxate alter the absorption of some concomitantly
administered antimicrobials due to anticholinergic
effects on gastrointestinal motility.37 On the other
hand, the bioavailability of ciprofloxacin has been
shown to be enhanced by oral co-administration with
phenazopyridine. Hence, the major limitation in the use
of non selective drugs like flavoxate and oxybutynin is
often failure to obtain desired therapeutic responses
without concomitant side effects. The anticholinergic
side effects, though usually not serious, are
sufficiently disturbing to decrease patient compliance,
particularly during long-term administration.38 Also,
the lack of demonstrated effect of flavoxate in placebocontrolled studies makes it difficult to recommend
the use of flavoxate and it is definitely not a first-line
treatment.39
Safety in Pregnancy
Phenazopyridine is currently classified in pregnancy
category B. The Collaborative Perinatal Project monitored
50,282 mother-child pairs in which 1,109 exposures
anytime during pregnancy and 219 exposures during
the first-trimester were documented. Results indicated
no increase in the rates of major malformations or any
review article
other adverse effects.40 On the other hand, there are no
well-controlled studies on use of flavoxate in pregnant
women, so it should be used during pregnancy only if
clearly needed.
10. Watring NJ, Mason JD. Deciphering dysuria. Emerg Med
2008;40(9):29-34.
Conclusions
11. Car J. Urinary tract infections in women: diagnosis and
management in primary care. BMJ 2006;332(7533):94-7.
UTIs are a significant clinical problem. The associated
symptoms of burning micturition, pain during voiding
and increased frequency of urination can be a source
of great discomfort and can greatly affect patients’
quality-of-life. Uncomplicated UTIs are usually treated
empirically with antibiotics. However, antibiotics
should not be prescribed excessively, particularly in
view of the increasing prevalence of antibiotic resistance.
Symptomatic treatment is an option which allows time
for microbiological investigation and helps to reduce
unnecessary prescribing of antibiotics. Phenazopyridine
is a urinary tract antiseptic and analgesic that provides
symptomatic relief of the pain, burning, frequency
and urgency associated with UTI during the first
24-48 hours of therapy and is safe in pregnancy. Other
urinary antispasmodics such as oxybutynin and
flavoxate are useful but the bothersome anticholinergic
side effects, limits their use.
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