US Pharm. 2013;38(8):34-37.
tract infections are relatively common in women. They may be classified
as uncomplicated or complicated depending upon the anatomy and
physiology of the urinary tract. Cystitis is an infection of the bladder
that can be managed with prescription medications as well as
nonprescription strategies. The current guidelines of the Infectious
Diseases Society of America recommend several short- and long-term
antibiotic regimens to treat uncomplicated cystitis. Preventive
strategies to manage patients with recurring cystitis are also
Urinary tract infections (UTIs) can be divided into
uncomplicated and complicated depending upon the anatomical and
pathophysiological elements of the urinary tract.1 An infection in an intact, normally functional tract is classified as an uncomplicated infection.1
If there are any urinary tract abnormalities such as an obstruction, or
the patient is predisposed to UTIs, then the infection is classed as
complicated.1 Furthermore, the infection may involve only
lower tract (bladder and urethra) or both the upper and lower tracts. In
some cases, an infection of the upper urinary tract may be classified
as a complicated infection.1
Cystitis is specifically an infection of the bladder that
can be managed with prescription medications as well as nonprescription
strategies.1 Since cystitis is so frequently encountered in
the community pharmacy setting, it is useful for pharmacist to have
in-depth knowledge of how it can be effectively managed.
In 2007, 8.6 million physician visits for UTIs were reported, of which 84% were by women.2
Women are more susceptible than men as they have a shorter urethra.
About one-fifth of all cases of UTIs end up in the emergency department.3
It has been shown that nearly one-third of all women have
had an episode of UTI by the age of 24 years, and half of all women have
had at least one uncomplicated UTI in their lifetime by the age of 32
years.2,4,5 Cystitis recurs in 25% of healthy women within 6 months of the first infection and in 20% of women within 1 year.6 The recurrence rate is directly proportional to the number of UTIs the patient has previously had.2
All these figures translate into high economic costs
(exceeding over $1 billion annually), decreased workforce productivity,
and morbidity.5,7 In older women, symptomatic and
asymptomatic bacteriuria presents a risk factor for bacteremia and
sepsis, as well as increased mortality.8
Cystitis occurs when urinary pathogens from the bowel or vagina colonize the periurethral mucosa and travel to the bladder.2 More than 80% of uncomplicated UTIs are caused by uropathogenic Escherichia coli (UPEC), 5% to 15% by Staphylococcus saprophyticus, and the remaining few cases by Enterococcus and Klebsiella species and Proteus mirabilis.5-7
Diabetes, a history of recurring UTIs, urinary stones, and
urinary catheters as well as any other obstructions are risk factors
for developing cystitis. In females, pregnancy, a history of UTIs in a
first-degree female relative, sexual intercourse, and the use of
spermicides are additional risk factors.2 Males who are
homosexual, uncircumcised, or have had sexual contact with an infected
woman are at a higher risk of contracting a UTI.7
Signs and Symptoms
An acute uncomplicated UTI is characterized by dysuria and increased frequency and urgency to urinate.6,7,9
The urine may be dark, cloudy, or pink-tinged and foul smelling, and
the onset of symptoms is abrupt. Fever, chills, and flank pain are signs
of a complicated UTI.6,7,9
Dipstick testing detects nitrites and leucocyte esterase
as a means of screening for UTIs. Nitrites are found in urine as a
result of breakdown of nitrates by bacteria and are therefore not
present in normal urine. Leucocyte esterase is released from neutrophils
that are attracted to the infected area.10 While a dipstick
has a high negative predictive value allowing UTIs to be excluded with
confidence, it has a relatively low predictive positive value.10
In patients who are at high risk of contracting a UTI, a negative urine
dipstick test does not rule out the possibility of an infection.11 Furthermore, this method is unreliable in pregnant women and in children <3 years of age.10
The culture of a urine specimen is the most accurate way of diagnosing a UTI, although it takes longer than a dipstick test.10 Microscopic analysis may also be used to reveal pathogens present in the urine.11
At-home tests such as Azo Test Strips also detect nitrites
and leukocytes. They are useful for early detection of UTIs in patients
who experience recurrent UTIs.12 Patients should be informed
that false negatives may occur in those taking tetracycline or in
strict vegetarians who do not consume sufficient nitrates. Additionally,
patients who test within 24 hours of consuming >500 mg of vitamin C
may get a false negative, as the ascorbic acid interferes with the test.
Using the test strips during the menstrual cycle will result in a
Cystitis very rarely develops into a more severe form even
when untreated. The main goal of treatment is to ameliorate the
symptoms that the patient is experiencing.2
Phenazopyridine hydrochloride is a urinary analgesic that is widely available in many OTC preparations (TABLE 1).13
It is an azo dye that exerts a local anesthetic effect on the mucosa of
the urinary tract, providing relief from dysuria and bladder spasms.
The recommended dosage is 100 to 200 mg twice daily for 2 days. Patients
should be informed that the medication turns urine and tears dark
orange, stains contact lenses, and interferes with urinalysis.13
A number of antibiotic regimens, both conventional (7-14
days) and short term (1-3 days) are presently available to treat the
bacterial infection.14 Updated guidelines released by the
Infectious Diseases Society of America (IDSA) in 2010 can assist health
care professionals in the management of women with uncomplicated UTIs.15 The recommended dosages are listed in TABLE 2.2,15
Nitrofurantoin: Nitrofurantoin is
listed as an appropriate choice of therapy since it has similar efficacy
to trimethoprim-sulfamethoxazole (TMP-SMX), minimal resistance, and
minimal collateral damage.15 It has been used for over 50 years and is still one of the most active drugs against E coli.16
The most common adverse effects of nitrofurantoin involve the gastrointestinal (GI) tract and are normally dose related.17
These effects, including nausea, vomiting, anorexia, abdominal pain,
flatulence, and diarrhea, tend to be less common when the nitrofurantoin
is administered in its macrocrystalline form. Other side effects
include headache, drowsiness, vertigo, dizziness, nystagmus, and
intracranial hypertension. In rare cases, severe peripheral
polyneuropathy may develop, and patients may experience hypersensitivity
reactions extending up to an asthma attack. Patients should be advised
that nitrofurantoin may cause a false-positive reaction in urine tests
for glucose using copper reduction methods, and may discolor urine
Nitrofurantoin should be avoided in patients with renal
failure or pyelonephritis; in patients who are sensitive to nitrofurans;
and in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency.2,17
While nitrofurantoin is safe in pregnancy, it can cause hemolytic
anemia due to glutathione instability in the immature erythrocytes of
the fetus or newborn. For this is reason, it is best avoided near term
or during labor.18
Concomitantly administered quinolones antagonize the
action of nitrofurantoin, while probenecid and sulfinpyrazone reduce its
TMP-SMX: TMP-SMX is considered
first-line therapy, as it is effective despite increasing resistance and
has fewer ecologic adverse effects than seen with fluoroquinolones.2,15
This means that TMP-SMX has a lower likelihood of inducing resistance
to antimicrobials than fluoroquinolones. A randomized, comparative trial
showed that a 3-day course of TMP-SMX was more effective and less
expensive than a course of nitrofurantoin, cefadroxil, or amoxicillin of
the same duration at treating uncomplicated cystitis in women.19
TMP-SMX is inexpensive and relatively well tolerated, with
the most common adverse effects being those of the GI tract such as
nausea, vomiting, and anorexia, as well as skin reactions including
rash, urticaria, and photosensitivity. Rarely, hematologic complications
have led to death, particularly in elderly patients.2,17 If a
rash appears, treatment should be discontinued immediately due to the
risk of severe allergic reactions such as Stevens-Johnson syndrome with
Patients should be advised to drink adequate fluids to prevent the risk of crystalluria with SMX.17 For the same reasons, the concomitant administration of any compound that renders the urine acidic should be avoided.17
Caution should be used in patients with renal or hepatic
failure, and in severe cases TMP-SMX should be avoided altogether due to
the SMX content. Likewise, TMP should be avoided in patients with
hematologic disorders and in those with a folate deficiency. While
TMP-SMX is widely used in pregnancy, recent studies suggest it might not
be safe, particularly in the first trimester.20 Fluoroquinolones or beta-lactams may be indicated as suitable alternatives in patients who cannot tolerate TMP-SMX.2
fluoroquinolones ofloxacin, ciprofloxacin, and levofloxacin should only
be used as first-line therapy in communities with high rates of TMP-SMX
resistance (≥10%) to E coli since these agents have other important indications.2 Fluoroquinolones have been shown to have similar effects to TMP-SMX when given for 3 days to treat uncomplicated UTIs in women.14
This group of drugs has a propensity for adverse effects
including nausea, vomiting, diarrhea, headache, drowsiness, insomnia,
rash, and pruritus. In rare cases, patients may experience
pseudomembranous colitis.17 Other side effects reported
include hematologic disorders, renal effects, crystalluria, and
cardiovascular effects such as tachycardia. Patients should be advised
to maintain an adequate fluid intake to reduce the risk of crystalluria
and to avoid strong sunlight or sunlamps.17
Fluoroquinolones should be used with caution in patients
with epilepsy or other central nervous system (CNS) disorders, renal or
hepatic impairment, or G6PD deficiency.17 They should not be given to children, teenagers, and pregnant or lactating mothers because of the risk of tendon damage.17,21
The absorption of fluoroquinolones is reduced with the concomitant
administration of aluminum, magnesium, or iron-containing products.17
Beta-Lactams: Beta-lactams are generally not recommended because of limited efficacy in treating UTIs, as many strains of E coli have become resistant to ampicillin.2,3
However, these agents generally have fewer ecologic adverse effects
than are seen with parenteral broad-spectrum cephalosporins.2
The most common adverse effects associated with beta-lactams are
hypersensitivity reactions, particularly rashes and urticaria, as well
as GI disturbances.
Beta-lactams should not be prescribed to patients with a
known allergy to penicillins or cephalosporins. Unlike some other
antimicrobials available to treat UTIs, beta-lactams are considered safe
to use in pregnancy.8,22,23
Fosfomycin: While fosfomycin has
lower resistance and a lower propensity for ecologic damage, it also has
inferior efficacy when compared to TMP-SMX or fluoroquinolones.15
Its range of possible adverse effects includes nausea, headache,
diarrhea, vaginitis, skin rashes, and visual disturbances. It should be
avoided if pyelonephritis is suspected due to the risk of hepatic side
effects. Fosfomycin is considered safe in pregnancy, but its use in
pregnant women is limited.22 The fosfomycin powder contained
in the sachet must not be taken dry. It must be mixed with water before
ingesting, and may be taken with or without food.
Other Treatment Considerations: In addition
to the efficacy of the regimen, it is important to take into
consideration patient allergies, compliance history, local practice
patterns, local resistance trends, availability, and cost to the
patient.2 As many uropathogenic strains develop resistance to
antimicrobials, including TMP-SMX, the effective management of UTIs
including cystitis is becoming complicated.3
Short-course therapies have been shown to offer improved
compliance, a lower risk of adverse reactions, and lower cost compared
to conventional therapies.14 A randomized trial found that
short-course ciprofloxacin therapy of 3 to 5 days had an outcome similar
to that of conventional ciprofloxacin or norfloxacin therapy of 7 days.14
Within the short-course therapies, the single-dose regimens have shown
lower cure rates and a higher rate of recurrence than the 3-day
regimens.14 In older women, however, there is some evidence
for a 7-day antibiotic regimen, although a Cochrane review showed no
additional benefit of increased duration of therapy.24 Men
generally require a longer duration of therapy than women because of
poor tissue penetration as well as the presence of a larger number of
In cases of recurrent cystitis, the long-term goal is to minimize antimicrobial use and improve the patient’s quality of life.2 The following points should be noted when selecting the appropriate antimicrobial therapy for patients with recurrent cystitis.
• If a patient presents with a recurring case of cystitis
within a week or two of treatment for uncomplicated cystitis, she should
be advised to get a culture at a laboratory to rule out the possibility
of a resistant strain.2
• If the condition recurs at least 1 month after the first episode, a longer course of first-line therapy can be prescribed.16
The first-line drug used should be different from the one used for the
first episode, particularly if the infection has recurred within 6
months or the drug was TMP-SMX.16
A number of preventive strategies are available to
patients, although the use of some is not well established. Various
behavioral strategies may also be useful in some cases of recurring
cystitis (TABLE 3).2,13
Cranberry juice has been used for many years in the
prevention of cystitis, although a Cochrane review found no evidence to
support its use for this purpose.26 The recommended dosage is 16 oz of unsweetened juice daily or 500 mg of cranberry extract twice daily.13
Topical estrogen can be used to normalize the vaginal
flora, particularly in postmenopausal women; oral estrogens are not
effective in this regard.27 Application of 0.5 mg estriol vaginally every night for 2 weeks, followed by twice weekly administration, is recommended.13
Adhesion blockers such as D-mannose may prove useful in
preventing the adhesion of bacteria to mannosylated receptors in the
urothelium. While there are no clinical trials to evaluate these data,
dosages of ¾ to 1 teaspoon 3 times daily are thought to be ideal.2,13
Methenamine hippurate 1 g taken twice daily has been shown
to be effective for preventing cystitis, particularly when used for
In patients who are able to recognize the initial onset of
symptoms of cystitis, first-line antimicrobial regimens may be
prescribed for the patient to keep at hand.2 In other cases, a
single dose of antimicrobial therapy may be prescribed to use as soon
as possible after intercourse. The choice of the agent should be based
upon the patient’s susceptibility to and history of any drug allergies.2 Recommended dosages in such cases are listed in TABLE 4.2
Vaccine Development: A vaccine against UPEC is currently under development that may reduce the rates of incidence and recurrence of UTIs.5 Uromone, available in Spain, is a sublingual bacterial vaccine for the prevention of recurrent UTIs.29 No information regarding trials on its use in the United States was found.
Despite the range of antimicrobials available to manage
UTIs, their incidence and recurrence rates still remain high. Effective
management is further complicated by the fact that the causative
uropathogenic organisms continue to develop resistance to
antimicrobials. Pharmacists play an important role in counseling
patients on the correct use of their prescribed medications and
discussing various strategies to prevent recurrence of cystitis.
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3. Brusch JL. Cystitis in females. Medscape Reference. http://emedicine.medscape.com/article/233101-overview. Accessed March 28, 2013.
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14. McCarty JM, Richard G, Huck W, et al. A randomized
trial of short-course ciprofloxacin, ofloxacin, or
trimethoprim/sulfamethoxazole for the treatment of acute urinary tract
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practice guidelines for the treatment of acute uncomplicated cystitis
and pyelonephritis in women: a 2010 update by the Infectious Diseases
Society of America and the European Society for Microbiology and
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19. Hooton TM, Winter C, Tiu F, et al. Randomized
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21. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy
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