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UROLOGY BOARD REVIEW MANUAL
PUBLISHING STAFF
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Bruce M. White
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EXECUTIVE DIRECTOR
OF OPERATIONS
Acute and Complicated
Urinary Tract Infection in
Women
Series Editor and Contributor:
Bernard Fallon, MD
Professor of Urology
Department of Urology
University of Iowa
Iowa City, IA
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Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 2
Acute Uncomplicated Cystitis . . . . . . . . . . . . 2
Recurrent Uncomplicated Cystitis and
Asymptomatic Bacteriuria. . . . . . . . . . . . . . . 5
Acute Uncomplicated Pyelonephritis . . . . . . 8
Complicated UTI . . . . . . . . . . . . . . . . . . . . . 9
Future Directions in Treatment and
Prevention of UTI . . . . . . . . . . . . . . . . . . . 12
References . . . . . . . . . . . . . . . . . . . . . . . . . 14
Cover Illustration by Christine Armstrong
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Urology Volume 11, Part 3 1
UROLOGY BOARD REVIEW MANUAL
Acute and Complicated Urinary Tract
Infection in Women
Bernard Fallon, MD
INTRODUCTION
Urinary tract infection (UTI) is an inflammation of
the urothelium of the bladder (cystitis) or kidneys (pyelonephritis) secondary to invasion by bacteria or other organisms, which is usually characterized by bacteriuria
and pyuria. UTI may occur as an isolated acute episode
or as a series of recurrent infections with different bacterial isolates (a reinfection) or with an organism cultured
from a previous infection (bacterial persistence). Persistent
infection often is associated with anatomic or pathologic anomalies of the urinary tract or with the presence of
a foreign body, such as a bladder drainage catheter. UTI
may be classified as uncomplicated or complicated. Uncomplicated infections are those occurring in the absence of
comorbid conditions, such as a structural abnormality
of the urinary tract, urinary calculi, advanced age, or
chronic disease (eg, diabetes mellitus).
UTI is a common and costly illness that can be associated with severe morbidity and death. An estimated 150
million UTIs occur each year worldwide and cost $6 million in direct health care expenditures.1 In the United
States, UTI is not a reportable disease, so it is difficult to
accurately assess its incidence. Nevertheless, in 1997 UTI
accounted for 7 million office visits and 1 million emergency department visits, resulting in 100,000 hospitalizations.2 The estimated annual cost of treating communityacquired UTIs in the United States is $1.6 billion.2
Catheter-associated UTI—the most common nosocomial infection in the United States—occurs at a rate of 1 to
1.5 million cases per year, affects 10% of short-term
catheterized patients, and costs an estimated $400 per
episode.3 Approximately 250,000 cases of acute uncomplicated pyelonephritis occur in the United States annually.4 UTIs are much more likely to occur in women than
in men, affecting about 25% of women before age 40 and
50% during their lifetime. Sexually active young women
are common victims of this illness, and incidence and
prevalence increase with age.
This manual examines the pathogenesis of bacterial
UTIs in women and outlines a recommended clinical
2 Hospital Physician Board Review Manual
approach to these infections. A discussion of nonbacterial UTIs as well as UTIs in men, children, and pregnant
women is beyond the scope of this review.
The majority of community-acquired UTIs in women
are caused by Escherichia coli. In a recent analysis of 4342
urine isolates from women with an outpatient diagnosis
of acute cystitis, E. coli was the identified uropathogen in
86% of cases; Staphylococcus saprophyticus accounted for
another 4% of cases and other Enterobacteriaceae for
the remainder.5
In most cases, uncomplicated UTI can be easily and
effectively treated with appropriate antibiotic therapy.
Given the expanding array of antibiotic choices, it is
important that physicians choose carefully, as improper
use of these medications can contribute to the growing
problem of bacterial resistance. In part to help physicians
make appropriate therapeutic choices, the Infectious
Diseases Society of America (IDSA) recently published
evidence-based guidelines for treatment of uncomplicated UTIs in women, which have been endorsed by the
American Urologic Association.6
ACUTE UNCOMPLICATED CYSTITIS
CASE PRESENTATION
A 19-year-old woman presents to her family physician with a 24-hour history of urinary frequency and
urgency, dysuria, and lower abdominal pain. The physician suspects acute bacterial cystitis, which leads her to
probe for further historical details.
The patient denies any other symptoms, including
vaginal drainage or irritation or upper or lower gastrointestinal problems. She has never had a serious illness or
surgery, and she has no history of past infections or recent
exposure to antibiotic therapy. The patient recently became sexually active for the first time, with a partner who
also was never previously sexually active. She uses a diaphragm for birth control. She has had no foreign travel.
On physical examination the patient is afebrile, with
normal vital signs. The remainder of the examination is
A c u t e a n d C o m p l i c a t e d U r i n a r y Tr a c t I n f e c t i o n i n Wo m e n
normal except for mild suprapubic tenderness and
tenderness of the urethra and bladder on pelvic examination.
The physician prescribes a 10-day course of oral levofloxacin (250 mg/day) for presumed acute uncomplicated UTI. She instructs the patient to return in 2 weeks
for follow-up urinalysis.
• Should this patient have undergone further evaluation?
EVALUATION OF UNCOMPLICATED UTI
It is reasonable to assume that this patient has an
uncomplicated UTI. Her history essentially excludes any
potential venereal, fungal, or gastrointestinal disease
from the differential diagnosis. History and physical
examination also reveal no evidence suggesting pyelonephritis, such as flank or back pain or fever. There is
no history of previous stone disease, no rebound tenderness that might lead to a suspicion of appendicitis or
other acute gastrointestinal conditions, and little possibility of pregnancy.
Two simple noninvasive tests are available for diagnosing uncomplicated UTI in the office: microscopic
analysis of the urinary sediment and urine culture and
sensitivity testing. Current evidence suggests that it is
acceptable to treat patients with uncomplicated UTI
empirically, without obtaining urinalysis or urine culture
and sensitivity testing. However, the rapidity and accuracy of urine dipstick testing plus microscopic examination
of the urine would argue for performing these tests in
patients seen in ambulatory settings. Although not as reliable for confirming UTI, the urine dipstick test is sufficient for guiding therapy when it confirms the presence
of inflammatory cells (leukocyte esterase) and/or gramnegative bacteria (nitrite). Microscopic evaluation confirms the diagnosis in most cases and may occasionally
support the diagnosis when the dipstick test is negative.
Urinalysis
Urinalysis is easily performed and relatively reliable
for diagnosing UTI. In most cases a midstream voided
urine specimen should be collected, although catheterization may be necessary in some very obese patients.
Suprapubic aspiration is rarely necessary in adults. In
one study, simple urinalysis was 95.8% sensitive in detecting culture-proven UTI, but the positive predictive value
(PPV) was only 45%; the PPV increased to 100% if testing for both leukocyte esterase and nitrite were positive.7
The sensitivity of microscopic detection of infection was
100%; the specificity was only 40% but increased to 94%
if more than 10 bacteria/µL or more than 50 leuko-
cytes/µL were seen (Figure 1; see page 8).7 The negative
predictive value of no detectable leukocytes was 95%.7
The need for urinalysis in uncomplicated UTI can
be questioned on the basis of some recent studies. In
one study, patients with a history of recurrent uncomplicated UTIs were reported to accurately self-diagnose
and self-treat infection.8 Patient self-diagnosis of UTI
was proven by culture results in 84% of cases, with
another 11% having pyuria, and clinical and bacteriologic cures were achieved in 92% and 96% of patients,
respectively.8 In another study comparing telephonebased to office-based management of suspected UTI,
telephone diagnosis and treatment was supported by
positive single-organism culture results in 64% of patients.9 In addition, patients in both study groups reported equal symptom scores and treatment satisfaction rates at 0, 3, and 10 days post-treatment.9
Urine Culture and Sensitivity Testing
Performed properly, a urine culture can definitively
diagnose UTI. The test typically is regarded as positive
when 105 or more colony-forming units of microbe per
milliliter of cultured urine are found. However, in as
many as 40% of UTIs, urine cultures may grow less
colony-forming units, because of less incubation time in
the frequently emptied bladder and slow doubling time
in urine.10 Urine cultures require time for processing and
growth plus additional time to identify the microbe and
determine antibiotic sensitivity. Delaying treatment until
culture and sensitivity results are available is unwarranted
in cases of uncomplicated UTI, as clinical response to
empiric therapy typically occurs before results return,
allowing patients to feel better quicker and avoid the
added costs of diagnosis. However, if a patient continues
to be symptomatic after empiric therapy, urine culture
and sensitivity testing followed by appropriate antibiotic
treatment would be indicated.
• Was the treatment prescribed for this patient appropriate?
TREATMENT OF ACUTE UNCOMPLICATED CYSTITIS
The IDSA guidelines recommend that standard initial empiric therapy for acute uncomplicated cystitis in a
healthy, nonpregnant woman should be a 3-day course
of trimethoprim-sulfamethoxazole (TMP-SMZ).6 The
guidelines also note that trimethoprim alone and ofloxacin are equivalent to TMP-SMZ in efficacy and that
other fluoroquinolones are probably similar in effectiveness. However, unless bacterial resistance to TMP-SMZ is
known to be a problem in the area, the fluoroquinolones are not recommended as first-line therapy due to
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Table 1. Modes of Action and Resistance of Various Antibiotic Classes
Antibiotic Class
Mode of Action
Mode of Bacterial Resistance
β-Lactams (penicillin,
cephalosporins)
Inhibit cell wall mucopeptide synthesis; bactericidal
β-Lactamase production; change in cell wall
pore size and penicillin binding site
Nitrofurantoin
Inhibits protein and cell wall synthesis; interferes
with metabolism; bactericidal
Unknown
TMP-SMX
Inhibits dihydrofolate reductase; bactericidal
Increased folate acquisition from tissues
Quinolones
Inhibit DNA gyrase and topoisomerase IV; bactericidal
Mutation in DNA gyrase binding site; change
in cell wall pore size
Aminoglycosides
Block 30-S ribosomal subunit, inhibiting protein
synthesis; bactericidal
Production of aminoglycoside-modifying
enzymes and decreased drug uptake
TMP-SMX = trimethoprim-sulfamethoxazole. (Adapted with permission from Schaeffer AJ. Urinary tract infections. In: Walsh PC, Retik AB,
Vaughan ED Jr, Wein AJ, editors. Campbell’s urology. 8th ed. Philadelphia: WB Saunders; 2002:539.)
their higher cost and the unnecessary risk of promoting
fluoroquinolone resistance.6
Although the treatment chosen by the case physician
is likely to be successful, a less expensive antibiotic than
levofloxacin (a fluoroquinolone), such as nitrofurantoin
or TMP-SMX, would be more appropriate. E. coli sensitivity to these older antibiotics is still adequate to expect
successful elimination of the infection. Physicians have
come to expect that new, effective antibiotics will continue to be developed and made available. It is certain
that these medications will be increasingly costly, but it is
also possible that the misuse of effective agents may ultimately result in bacterial metabolism adapting to the
point of panresistance. Until 1995, ciprofloxacin was the
dominant fluoroquinolone used for UTI treatment.11
The more expensive levofloxacin was introduced in
1997 and is now used far more often than the once popular ciprofloxacin.12 Yet, the in vitro activity of ciprofloxacin against E. coli, Proteus mirabilis, and Pseudomonas
aeruginosa remains equal to or greater than that of levofloxacin.13 As use of fluoroquinolones increases among
those treating UTIs, greater resistance can be anticipated in uncomplicated infections.
A second criticism of the treatment prescribed for
the case patient is the duration of therapy (10 days). In
reviewing the available evidence, the IDSA concluded
that a 3-day course of therapy is equally effective as a
7- or 10-day course in acute uncomplicated cystitis, with
less risk of side effects.6 A 3-day course is superior, however, to 1 day of therapy.6
Continuing symptoms after 3 days of therapy warrant a follow-up evaluation, including a urine culture.
In patients who respond quickly to therapy, follow-up is
not strictly necessary, but a urinalysis is often done
about 2 weeks following treatment.
4 Hospital Physician Board Review Manual
Antimicrobial Resistance
The common bacterial causes of UTI, most notably
E. coli, are generally highly sensitive to the commonly
used antibiotics. However, treatment of UTI is complicated by the increasing prevalence of antibiotic-resistant
strains of E. coli. Table 1 lists the mechanism of action of
various antibiotics used to treat UTI as well as identified
modes of resistance. As various antibiotics have become
more popular, resistance of common bacteria has increased (Table 2). For example, E. coli resistance to fluoroquinolones increased from less than 1% in 1991 to
about 6% in 2000.12 Fluoroquinolone resistance of nonE. coli isolates is significantly higher in women older than
age 50 than in those younger than 50.14
Evidence suggests that community laboratories may
overestimate resistance rates. For example, in a study
from New Zealand, the rate of trimethoprim resistance
of E. coli in urine isolates sent to the central study laboratory was 11.5%, compared with cumulative resistance
rates of 19% reported by local community laboratories.15 In the United States, antibiotic resistance rates
have been found to vary significantly from one region
to another. For instance, in a national study based on
more than 100,000 isolates, resistance of E. coli to TMPSMX varied from 10% in the Northeast to 22% in the
West (P < 0.001).14 In another study analyzing the
clonal composition of E. coli, 28 of 55 (51%) TMPSMX–resistant E. coli isolates from California were clonal group A, and 18 of 47 (38%) isolates from Michigan
and Minnesota were clonal group A.16 Most of these
clonal group A isolates were serotype O11:H(nt) or
O77:H(nt); only 4% of the TMP-SMX–sensitive E. coli
were clonal group A.16 The fact that urine culture and
sensitivity testing is obtained more frequently in cases of
initial antibiotic failure to eradicate infection may
A c u t e a n d C o m p l i c a t e d U r i n a r y Tr a c t I n f e c t i o n i n Wo m e n
produce bias toward overestimation of resistance rates
in many studies. Also, because many antibiotics achieve
extremely high levels in urine, in vitro resistance does
not necessarily translate into clinical failure.
CASE CONCLUSION
The patient’s symptoms improve within 24 hours.
After 5 days, the patient stops taking the levofloxacin
and stores the remaining 5 pills in her medicine cabinet
in case she develops another infection in the future. A
urinalysis obtained 2 weeks later is normal. At the followup visit, her physician suggests that she may want to
switch to using birth control pills rather than a diaphragm. A diaphragm, she explains, may cause pressure
on the urethra, increasing the likelihood of bacterial
ingress, and the spermicide on the diaphragm may be
bactericidal to vaginal lactobacilli, promoting coliform
colonization.17
RECURRENT UNCOMPLICATED CYSTITIS AND
ASYMPTOMATIC BACTERIURIA
CASE PRESENTATION
A 44-year-old married woman presents to her primary care physician with symptoms of urinary frequency, small voided volumes, and dysuria. The patient has a
history of recurrent UTI beginning at age 18. She has
experienced an average of 2 to 3 infections per year,
which always respond within a few days to antibiotic therapy. On occasion she has not sought treatment, and the
infections have subsided spontaneously. Her physician
occasionally obtains urine culture and sensitivity testing.
Most cultures reveal E. coli as the cause, although in one
case several years ago P. aeruginosa was identified.
On physical examination the patient is afebrile, with
normal vital signs. The examination is significant only
for suprapubic tenderness. Microscopic urinalysis in the
office reveals many bacteria and white blood cells. A
urine specimen is sent for culture and sensitivity testing.
• What bacterial and host factors reduce or increase
the likelihood of uncomplicated UTI?
Generally speaking, an uncomplicated UTI may become established when uropathogenic organisms colonize the vaginal introitus and periurethral area and subsequently ascend into the lower urinary tract (bladder)
or upper tract (one or both kidneys) and elicit a host
response. Several bacterial and host factors interact to
make UTI more or less likely to occur.
Table 2. Uncomplicated Urinary Tract Infection:
Resistance Trends
Drug
1992
1996
Ampicillin
29%
38%
Cephalothin
20%
28%
TMP-SMX
8%
16%
Ciprofloxacin
0.3%
0.3%
Nitrofurantoin
7%
6%
TMP-SMX = trimethoprim-sulfamethoxazole. (Data from Gupta K,
Scholes D, Stamm WE. Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in
women. JAMA 1999;281:736–8.)
BACTERIAL VIRULENCE FACTORS IN UTI
Certain strains of uropathogenic E. coli possess bacterial characteristics that appear to influence the occurrence and severity of UTI.
Adherence to Host Epithelial Cells
Bacterial adherence to host epithelial cells was first
described in 1977.18 It is now known that uropathogenic
E. coli may have several types of fimbriae (also called pili)
involved in adhesion to bladder or kidney epithelial cells.
Type 1 fimbriae. Type 1 fimbriae are found in almost
all cases of E. coli cystitis.19 Type 1 fimbriae bind to mannose in mucoprotein and are said to be mannose-sensitive,
as they produce hemagglutination in the presence of
mannose. The typical type 1 fimbriated bacterium has
200 to 500 pili on its surface, each about 7 nm long and
1 µm wide. They are mainly composed of about 1000
copies of the protein FimA, which recognizes the host
receptor.20 Type 1 fimbriae recognize and bind to glycoproteins on urothelium, which is the first step in UTI
development.21 They also facilitate invasion into the
superficial cells and perhaps into deeper epithelial cells,
thus providing a more stable environment for the invading bacteria than superficial urothelial cells, which may
slough off as a result of inflammatory reaction to the
infection.22 Type 1 fimbriae activate bladder mast cells,
possibly resulting in the release of inflammatory mediators (eg, histamine, tumor necrosis factor-α [TNF-α],
leukotriene B4). These molecules may account for the
urinary symptoms of frequency, urgency, and pain on
voiding.23 Of some interest is the finding that cranberry
juice inhibits the binding of type 1 fimbriated E. coli to
urinary mucosal cells.24
P fimbriae. P fimbriae are mannose-insensitive, producing hemagglutination in vitro in the absence of
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mannose. P fimbriae bind to glycolipids found on
P blood group antigens and renal uroepithelial cells. In
one study, P fimbriae were found on 91% of E. coli isolates producing pyelonephritis and only 19% of those
causing cystitis.25 As with type 1 fimbriae, P fimbriae are
phase-variable (ie, the fimbriae are not always present
on the bacteria). Pathogenicity is greater in the fimbriated phase. In addition to enhancing bacterial colonization of upper tract urothelium, P fimbriae increase
the host response to UTI, as indicated by increased neutrophil numbers in the urine and higher levels of the
cytokines interleukin (IL)-6 and IL-8. P fimbriae also
reduce the number of bacteria needed to establish colonization of the urine, as demonstrated by successive
cultures and colony counts.26
Other E. coli adhesins. Two other E. coli adhesins (ie,
X fimbriae and S fimbriae) have been identified, and
new families of adhesins are being described. An example is the O75X adhesin, originally named for the E. coli
serotype with which it is associated. It is now included in
the Dr family of nonfimbriated adhesins, which have a
common receptor—the Dr(a+) blood group antigen—
localized on the decay-accelerating factor (DAF) molecule, which protects tissues from autologous complement attack.27 The Dr adhesins are the third most
common colonization factors. Children and pregnant
women are the groups most likely to be infected with
Dr-expressive E. coli. Dr adhesins also are associated
with a higher risk of recurrent UTI.28
Genetic Characteristics of Uropathogenic Strains
Uropathogenic E. coli strains have genomes that are
20% longer than other, nonpathogenic fecal strains.29
They also have pathogenicity islands, which are pieces of
DNA not found in the genomes of nonpathogenic
strains. Pathogenicity islands are more often associated
with E. coli strains that cause pyelonephritis than strains
that produce cystitis. These DNA segments have genes
for the production of type 1 and P fimbriae, toxins (eg,
α-hemolysin, cytotoxic necrotizing factor, capsular and
O antigens), and iron-uptake systems such as aerobactin.30 The pap operon is responsible for the production of P fimbriae; hemolysin production is controlled
by hlyA.31 Other genes may allow uropathogenic E. coli
to accumulate iron from the tissues. Pathogenicity islands are unstable and variable and may allow bacteria
to adapt to their environment as a UTI progresses. Deletions of these DNA segments could conceivably allow
for future development of nonpathogenic strains to be
used in vaccination of patients who are victims of frequent UTIs.
6 Hospital Physician Board Review Manual
HOST FACTORS IN UTI
Mechanical and Physiologic Factors
An important host defense mechanism is normal
voiding, which flushes the offending organisms. Likewise, ureteral peristalsis helps to block the ascent of
pathogens to the kidneys. A large fluid intake may help
by diluting the concentration of bacteria and causing
more frequent voiding. The relatively low pH of urine,
along with urea and organic acid concentration, also
inhibit bacterial growth.32
In premenopausal women, the vagina has a thick,
vascular, estrogen-rich epithelial layer that facilitates
colonization by lactobacilli. These lactobacilli metabolize glucose to lactic acid and maintain a pH of 3.5 to
4.5, producing a hostile environment for uropathogenic bacteria. Overuse of antibiotics, spermicides, or antifungal agents may decrease Lactobacillus colonization,
increasing vaginal pH and leading to colonization with
uropathogenic E. coli.
Immunologic Factors
Increased epithelial cell receptivity to uropathogens
and local humoral immune response are believed to
play a role in UTI development in certain women. In
one study, 30 women with a history of recurrent UTI
were compared with 30 controls, and the concentrations of serum and urine antibodies against mixed coliform antigen and clinical isolates were determined via
enzyme-linked immunosorbent assay (ELISA); the surface hydrophobicity of the organisms also was determined. Women with a history of recurrent UTI had increased vaginal binding of bacteria as well as low urine
levels of secretory IgA, indicating lower local immunity.33
Lewis blood group antigens also appear to play a role
in development of UTI. Women who are Le(a+b+) or
Le(a–b+) phenotypes are said to be secretors, and those
who are Le (a+b–) or Le (a–b–) are nonsecretors. Secretors
have fewer UTIs. In a population of women with acute,
uncomplicated pyelonephritis, 41% were nonsecretors,
compared with a noninfected control group in which
22% were nonsecretors (P < 0.001).34 The protective
effect of the secretor phenotype may be due to fucosylated structures at the cell surface in the urothelium,
which decrease receptor availability for the bacteria.35
Nonsecretors may have specific E. coli–binding glycolipids on the urothelial cell membrane.36
Tamm-Horsfall mucoprotein is produced in the loop
of Henle and distal convoluted tubule and is found in
the surface mucin lining the urothelium. Type 1 fimbriae of uropathogenic E. coli adhere to Tamm-Horsfall
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mucoprotein and are then unable to bind to the mucosal cells, thus reducing the likelihood of UTI.37
The urinary and vaginal epithelia are covered by thin
layers of fluid containing antimicrobial proteins and peptides, such as lysosomes, lactoferrin, peroxidases, and
defensins. Defensins are cationic peptides involved in
regulating the immune response and inflammation,
which are antimicrobial to many gram-positive and gramnegative organisms. Defensins also may be found in neutrophil granules and permeate the membrane pores of
bacteria.38 HBD-1 is a β-defensin expressed in the kidney
and female genital tract and found in urine, which is
thought to form an antimicrobial barrier on uroepithelial
cells. Its concentration rises 3-fold in pyelonephritis.
Urinary pathogens are phagocytosed by leukocytes
released in response to infection.39 Chemokines such as
IL-6, IL-8, platelet-derived growth factor, and TNF-α are
produced by epithelial cells in response to infection. IL-8
is attached to receptors CXCR1 and CXCR2 on neutrophils, aiding their recruitment across the infected
epithelium. CXCR1 receptors have been found deficient
in human pyelonephritis.40 Serum levels of IgM and IgA
are elevated in pyelonephritis and probably aid in bacterial phagocytosis.41 These antibodies are not thought to be
important in the prevention of further infection.
• How do antibiotics gain access to bacteria?
Antibiotic sites of action are in the periplasm, the
inner (or cytoplasmic) membrane, and the cytoplasm
of the bacterial cell. Antibiotics must cross the outer
membrane of gram-negative bacteria and the cytoplasmic membrane of all bacteria to gain access to their target molecules. Most antibiotics diffuse through pores in
the lipid layers of the membranes.42 Change in pore size
is one of the mechanisms by which bacteria may develop resistance to various antibiotics (eg, β-lactams, fluoroquinolones). Some antibiotics, such as rifamycin, are
actively transported across the membranes and therefore are present in far higher concentrations within the
cytoplasm of the bacteria, thus requiring much smaller
doses to produce bactericidal activity. Study of the active
transport mechanism of rifamycin may allow for the
rational design of antibiotic molecules with similar abilities to cross bacterial membranes.43
• Returning to the case, what factors should guide management of this patient?
MANAGEMENT OF RECURRENT UNCOMPLICATED
CYSTITIS
Recurrent infection is an annoying problem for
many women who develop an initial UTI, but there is
no evidence that recurrent UTI produces renal damage, hypertension, or other pathologic change. In one
longitudinal study of 235 women with histories of UTI
who were followed for a mean of 7.4 years, clusters of
infections were noted to occur in 46% of the women,
with 2 to 12 infections per cluster. Eighty-five percent of
the isolates were E. coli; 50 different O groups were identified, but 3 of these (O4, O6, and O75) accounted for
49% of the infections.44 The mean number of infections in all patients was 0.6 per year; women who received prophylaxis had 0.8 infections per year, as
opposed to 3.1 infections per year in those not receiving prophylaxis.44 Recurrent symptoms following an
apparent cure can represent a relapse of the previous
infection (ie, persistence of the same bacterial pathogen from within the urinary system) but more often
are the result of a reinfection by another pathogen.
Treatment and Prevention
Essentially, the treatment of uncomplicated cystitis
is the same regardless of whether it is a first or a recurrent episode. It is interesting to note, however, that up
to 80% of acute uncomplicated UTIs in women will
resolve without antibiotic therapy.45 In one randomized trial, 27 of 35 infections resolved within 3 days on
nitrofurantoin, compared with 19 of 35 infections that
cleared after 3 days on placebo (P = 0.008).46 It has
been found that the rate of UTI recurrence in patients
treated with antibiotics and in those who receive no
treatment is similar (about 40%).45
Voiding within 15 minutes of intercourse reduces the
relative risk of recurrent infection to 0.40.47 Prophylactic antibiotic therapy may prevent UTI while prophylaxis is ongoing, but the rate of infection returns to the
previous level once the antibiotic is stopped.48
CASE CONCLUSION
The patient’s physician is familiar with the IDSA
guidelines for treatment of uncomplicated UTI and, on
the basis of these recommendations, prescribes an initial dose of ciprofloxacin 250 mg twice daily for 3 days.
The patient’s symptoms rapidly resolve. Her urine culture results return a significant growth of E. coli, and a
follow-up urine culture 2 weeks later is negative for bacterial growth. The physician then prescribes TMP-SMX
once daily for 6 months as prophylaxis against future
infections, and the patient has no further UTIs during
that time.
Shortly afterward, the patient comes to the physician’s office for an unrelated complaint. Recalling an
article he recently read, the physician relates information from a study indicating that heterosexual partners
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Figure 1. Microscopic urine specimen containing large numbers
of bacteria and 5 to 10 leukocytes per high-power field. Culture
revealed pansensitive Escherichia coli.
Figure 2. Histologic specimen from a patient with acute pyelonephritis. The interstitium of the kidney is severely invaded by
bacteria and polymorphonuclear leukocytes.
were more likely to share uropathogenic E. coli than
commensal E. coli.49 If this is true, the physician reasons,
the patient may benefit from having her husband tested for the uropathogen and, if the test returns positive,
treated.
asymptomatic infection in lower-risk groups will usually
be followed shortly by development of new infection by
different strains that may be more difficult to eliminate or
may produce acute symptomatology.
• If this patient initially had been seen for a routine
physical examination and was found to have asymptomatic bacteriuria, would it be appropriate to treat
the infection?
ACUTE UNCOMPLICATED PYELONEPHRITIS
ASYMPTOMATIC BACTERIURIA
Asymptomatic bacteriuria refers to the presence of
significant numbers of bacteria in the urine in the absence of UTI symptoms. In general, it is recommended
that asymptomatic bacteriuria not be treated, except in
certain patients at higher risk (eg, diabetic or pregnant
women). Even in diabetic patients with asymptomatic
bacteriuria, treatment is controversial. Antibiotic therapy and placebo have been found to be associated with
similar late acute infection rates, hospitalization rates,
development of first symptomatology, and risk of acute
pyelonephritis.50 Interestingly, in vitro studies have
shown a much higher rate of adherence of type
1-fimbriated E. coli to the uroepithelium of diabetic
patients than to uroepithelial cells of nondiabetic controls (P = 0.001).51 No difference in the rate of adherence of P fimbriated or nonfimbriated bacteria to
either cell type was noted.
Growth of Proteus species should be treated in an
attempt to avoid struvite stone formation. More virulent
organisms may produce a higher level of pyuria and local
inflammation.52 E. coli is isolated less frequently in asymptomatic than in symptomatic infections. Treatment of
8 Hospital Physician Board Review Manual
CASE PRESENTATION
A 34-year-old woman who has had occasional UTIs
in the past presents to her local emergency department
with a 24-hour history of worsening nausea, vomiting,
fever, and back pain. The patient reports that a day before the onset of these symptoms she began to experience urinary frequency, nocturia, and dysuria. Physical
examination reveals suprapubic and right flank tenderness and a temperature of 40° C. There is no rebound
tenderness. Urinalysis reveals multiple bacteria and
leukocytes as well as 1 to 3 red blood cells per highpower field; the urine is positive for leukocyte esterase
and nitrite on dipstick examination. The patient’s white
blood cell count is 13,000/mm3. A urine specimen is
sent for culture and sensitivity testing, and the patient is
admitted to the hospital for treatment of presumed
acute pyelonephritis.
• How certain is the diagnosis? Should further blood
tests or imaging studies be obtained?
DIAGNOSIS OF ACUTE UNCOMPLICATED PYELONEPHRITIS
This patient’s clinical presentation suggests acute
pyelonephritis (Figure 2). Interestingly, there is no definitive test that confirms a diagnosis of pyelonephritis
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rather than cystitis. All the characteristic signs and
symptoms of acute pyelonephritis may sometimes be
found in cases in which the infection is localized to the
bladder by careful localization studies.53 However, these
studies, including the bladder washout test54 or bilateral ureteral catheterization,55 are mainly of historical
interest and require too much manipulation of the urinary tract to be of clinical use. Likewise, detection of
antibody-coated bacteria by fluorescence assay56 or
ELISA,57 which was initially felt to be diagnostic of
pyelonephritis, has largely fallen into disuse because of
the lack of sensitivity and specificity of these tests.
Further blood tests beyond the initial complete blood
count are not necessary in most patients. C-reactive protein may be elevated. Erythrocyte sedimentation rate will
be quite high. These tests, however, are not recommended. Serum creatinine and electrolyte levels are
unlikely to be abnormal unless both kidneys are involved or the patient is acutely ill or septic. Radiologic
evaluation of the urinary tract also is unnecessary to
make a diagnosis of acute uncomplicated pyelonephritis but may be indicated later, if the patient fails to
respond to antibiotic therapy within a few days.
• How should this patient be treated? Is hospitalization necessary?
TREATMENT OF ACUTE UNCOMPLICATED
PYELONEPHRITIS
The bacteriology of acute uncomplicated pyelonephritis is the same as that of acute uncomplicated cystitis, and the sensitivity of the organisms is likely to be
similar and broad. Many patients can be treated as outpatients. However, the IDSA guidelines recommend
hospitalization for patients with high fever, chills, and
very high white blood cell counts, to ensure that sepsis
does not develop.6 In addition, those with significant
nausea and vomiting may be admitted for rehydration
and initial parenteral antibiotic therapy.
In accord with the IDSA guidelines, because of this
patient’s more severe symptoms, intravenous fluid administration is advisable along with parenteral antibiotic therapy for the first few days, until the illness begins
to resolve.6 Antibiotics of choice include ciprofloxacin
400 mg every 12 hours, levofloxacin 500 mg every
12 hours, or ampicillin 1 g every 6 hours with gentamicin 1 to 1.5 mg/kg every 8 hours. When the acute illness has resolved, the patient could be released from
the hospital on oral therapy with TMP-SMX or a quinolone. Treatment is continued for a total of 7 days,
which is adequate for cure of pyelonephritis.58 For treatment of pyelonephritis on an outpatient basis, 7 days of
ciprofloxacin 500 mg twice daily, levofloxacin 500 mg
once daily, or gatifloxacin 400 mg once daily may be
considered as equivalently effective regimens.59
Continuing fever with an elevated white blood cell
count may be an indication of a structural abnormality
of the urinary tract or the development of a complication, such as an abscess (Figure 3). In a case of acute
pyelonephritis, intravenous pyelography (IVP) will typically show increased size of the affected kidney, which
may be focal enlargement if the infection is limited to a
particular area, along with delayed excretion of the contrast medium and some mild dilation of the collecting
system and ureter on delayed films. Plain films of the
abdomen should be carefully examined for the presence of a stone. Gas shadows could alert one to the presence of emphysematous pyelonephritis. Ultrasonography is quite nonspecific in pyelonephritis but may
serve to rule out a renal stone, abscess, or tumor. Computed tomography is superior to IVP or ultrasonography in detecting anatomic abnormalities or complications of the acute infection. Any precipitating or
complicating conditions discovered on radiologic evaluation will need to be appropriately treated, usually by
ureteral or percutaneous drainage catheters, before the
acute infection will respond well to antibiotics.
CASE CONCLUSION
The patient is treated with rehydration and intravenous levofloxacin (500 mg every 12 hours). No imaging studies are performed. The patient rapidly improves,
and her white blood cell count drops to 7000/mm3. She
is discharged after 2 days and placed on oral levofloxacin (500 mg/day) for another 7 days. Two weeks later,
follow-up urine culture and sensitivity testing are negative for bacterial growth. The patient has no further
UTIs during a follow-up period of 4 years.
COMPLICATED UTI
CASE PRESENTATION
A 64-year-old woman presents to the emergency
department of her local hospital. She has become increasingly ill at home over a 10-day period. She initially
developed dysuria and urinary frequency but more recently noted bilateral flank and back discomfort and
mild fever, which have worsened over the last 3 days.
She reports that she has had several UTIs in the past
5 years, and antibiotic therapy with cephalosporins and
fluoroquinolones has produced symptomatic relief
within 1 or 2 weeks in all previous episodes. She has
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B
A
never undergone imaging studies. The patient has had
insulin-dependent diabetes for 30 years. Three years
ago she underwent a vaginal operation for stress incontinence, but she still has leakage despite needing to
strain to urinate.
Physical examination reveals a woman who is 5′2′′
tall and weighs 180 lb. Her temperature is 41° C, blood
pressure is 110/60 mm Hg, and pulse is 106 bpm. Her
skin appears dehydrated. Her head, neck, heart, and
lung examinations are within normal limits, as is her
sensorium. Her abdomen is soft, with tenderness in the
right costovertebral angle, flank, and right lower quadrant. Her genitalia are normal except for the presence
of a cystocele. Her extremities are normal.
A urethral catheter is passed and 1200 mL of foulsmelling urine drain. Urinalysis reveals numerous bacteria, white blood cells, and 10 to 15 red blood cells. A
urine specimen is sent for culture and sensitivity testing.
• What is the likely bacteriology of this patient’s infection?
10 Hospital Physician Board Review Manual
Figure 3. Intravenous pyelogram (IVP) from a 45-year-old
patient with fever and right flank pain unresponsive to an initial
course of parenteral antibiotics. The right kidney was poorly
visualized on the IVP, and a retrograde pyelogram (A) was performed, which revealed distortion of the right upper pole collecting system. An arteriogram (B) was then performed, showing no perfusion of the area. Renal abscess was diagnosed and
treated by percutaneous drainage and antibiotic therapy.
MICROBIOLOGY OF COMPLICATED UTI
This patient is suffering from a complicated UTI.
She is diabetic, postmenopausal, and does not empty
her bladder well, and her history is worrisome for structural abnormalities of the urinary tract. These host
complications are sufficient for significant infection,
bacteremia, and septicemia to develop, even with colonization by relatively nonvirulent organisms such as
enterococci.
First complicated UTIs are likely to be caused by
antibiotic-sensitive organisms, but subsequent infections are progressively more resistant. In some patients,
bacteria are harbored within struvite stones and also on
the biofilm that coats catheters and ureteral stents. If
such stones and foreign bodies are not removed completely and associated anatomic abnormalities are not
corrected, bacterial persistence will occur, often with
multiple organisms,60 resulting in frequently recurring
infection.
Among women with complicated UTI, E. coli is the
most common organism isolated (Table 3), with
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P. mirabilis and Klebsiella pneumoniae also frequently
found. Interestingly, E. coli strains isolated from complicated UTIs have less virulence genes and pathogenicity
islands than those from uncomplicated acute UTIs. Of
E. coli isolates from uncomplicated pyelonephritis cases,
84% were of known urovirulent serotypes compared
with only 30% to 50% of those isolated in complicated
infections.61 Also, P fimbrial expression is significantly
lower in complicated UTIs. Similar observations have
been made with E. coli strains isolated from patients with
bacteremia due to complicated UTI, as compared to
organisms isolated from patients with uncomplicated
UTI.62
Table 3. Bacteriology of Complicated Urinary Tract
Infection
Pseudomonas aeruginosa
2.0–19.0
• What is biofilm?
Others
6.1–20.0
Biofilm is a thin layer of organisms that may grow on
uroepithelial surfaces, catheters, or stents. It is formed
by the initial attachment of bacteria, which then secrete
a matrix of glycocalices. Host salts and proteins, including Tamm-Horsfall mucoprotein, then complex with
the matrix and may obstruct catheters and stents
through deposition of struvite and calcium phosphate
salts.63 The glycocalyx matrix protects the bacteria from
antibiotic activity, antibodies, and phagocytosis. Catheter or stent biofilm is most likely to be associated with
infection by Staphylococcus aureus and P. aeruginosa, but
Proteus, Providencia, and Morganella species may also be
involved.64 Urease-producing organisms convert urea
to ammonia, thus increasing urinary pH and encouraging the deposition of struvite salts. This is the same
process that accounts for the formation of struvite
stones in the kidneys. Oral ciprofloxacin or ofloxacin
has been found to adsorb on to stents at concentrations
higher than the minimum inhibitory concentrations of
many uropathogens65 and may be effective in preventing infection in patients who require stenting for relatively long periods, but not permanently.
Gram-positive organisms
• How should this patient be managed? What is appropriate treatment of complicated UTI?
TREATMENT OF COMPLICATED UTI
Treatment of complicated UTI varies with the severity of illness and nature of the underlying complications. Patients who are moderately ill (no fever, nausea,
or vomiting) may be treated as outpatients. This patient, however, is very ill with high fever and could be on
the verge of sepsis. Immediate laboratory investigations
should include complete blood count, serum creatinine and electrolytes, blood glucose level, and arterial
blood gases. A blood culture also is essential.
Organism
Prevalence (%)
Gram-negative organisms
Escherichia coli
21.0–54.0
Klebsiella pneumoniae
1.9–17.0
Enterobacter species
1.9–9.6
Citrobacter species
4.7–6.1
Proteus mirabilis
0.9–9.6
Providencia species
18.0
Enterococci
6.1–23.0
Group B streptococci
1.2–3.5
Coagulase-negative staphylococci
1.4–3.7
Staphylococcus aureus
0.9–2.0
Candida species
0–5.0
Adapted with permission from Nicolle LE. Urinary tract pathogens in
complicated infection and in elderly individuals. J Infect Dis 2001;183
(Suppl 1):S6.
Resuscitation with intravenous saline and an insulin
pump should be started and intravenous broad-spectrum
antibiotic therapy should be instituted immediately. Initial
therapy most commonly is with ampicillin 2 g every
6 hours, plus gentamicin 1.5 mg/kg every 8 hours. This
can be modified within a few days, depending on clinical
response and urine culture results. A relatively high dose
of an appropriate fluoroquinolone is recommended for
2 to 3 weeks thereafter. Radiologic studies should be obtained as soon as the patient is sufficiently stable to look
for urinary tract structural abnormalities.
It is exceedingly important to correct underlying
anatomic abnormalities of the urinary tract in cases of
complicated UTI, as excellent drainage of the urine is a
primary defense mechanism. Thus, any obstructive
lesions should be surgically corrected when clinically feasible (Figure 4). Catheters or stents of any type should be
removed as soon as clinically possible and should be
changed at regular, reasonably short intervals to prevent
the accumulation of biofilm and entrenched bacteria. In
one study of 250 patients with double J stents, those
indwelling for 30 days or less had a colonization rate of
4.2%, whereas stents left for more than 90 days were colonized in 34% of cases. The colonization rate was 24%
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FUTURE DIRECTIONS IN TREATMENT AND
PREVENTION OF UTI
Bacterial metabolism is increasingly understood, and
the genomes of bacteria are being fully elucidated.
Several areas of research show promise for the future
treatment and prevention of UTI.
A
B
Figure 4. Ureteropelvic junction (UPJ) obstruction in a 38-yearold patient with recurrent urinary tract infection associated with
left flank pain. Urine culture revealed Proteus mirabilis. Radiologic
investigation, including retrograde pyelogram (A), revealed UPJ
obstruction on the left side. A double J stent was placed (B) for
temporary drainage.
in women and 14% in men, while it was 3.3% in patients
with no systemic illness compared with 40% in patients
with diabetes, chronic renal failure, and diabetic nephropathy.66
Stones in the upper urinary tract or bladder must be
completely removed. Residual fragments, especially if
relatively large, may continue to harbor and protect
urease-producing organisms.
CASE CONCLUSION
The patient is admitted and treated as described
above. She improves symptomatically within 5 days. Her
temperature slowly returns to normal. Her initial blood
cultures are positive for E. coli. Her urine culture and sensitivity testing grows E. coli and P. mirabilis, with colony
counts greater than 105. An IVP is performed, which
reveals a large stone in a small, hydronephrotic right kidney and a normal left kidney (Figure 5). A renal scan
reveals that the left kidney has 80% of the total renal
function and the right kidney 20%.
As the patient improves, her antibiotic regimen is
changed to levofloxacin 500 mg daily by mouth, in accordance with sensitivity results. She is started on intermittent catheterization and discharged from the hospital
after 7 days. Her creatinine clearance is calculated to be
85 mL/min at discharge, and a right nephrectomy is performed without complication 2 weeks later. She is maintained on levofloxacin in the interval, and for another
week after the nephrectomy is done. Pathologic examination of her kidney reveals chronic pyelonephritis and
a struvite stone.
12 Hospital Physician Board Review Manual
GLYCOSPHINGOLIPID DEPLETION
Host cell surface glycosphingolipids (GSLs) act as
receptors for the P fimbriae of many uropathogenic
E. coli. NB-DNJ is a glucose analogue that inhibits the
biosynthesis of ceramide-based GSLs. In vitro studies of
NB-DNJ–treated human kidney cells exposed to a variety of P-fimbriated uropathogenic E. coli revealed progressively decreased bacterial adherence with increased
concentrations of NB-DNJ, compared with no NB-DNJ
treatment (control group).67 The same researchers fed
NB-DNJ to mice for 14 days and subjected the mice to
intravesical infection with P-fimbriated uropathogenic
E. coli. Renal GSL content was reduced, urinary bacterial counts were reduced, and there was inhibition of
neutrophil recruitment, indicating reduced mucosal inflammation.67 Further work in the area of GSL inhibition may lead to new strategies for preventing UTIs and
less reliance on antibiotic therapy as prophylaxis, thus
reducing the potential for development of resistant
strains of uropathogenic E. coli.
LOW-POTENCY ESTROGEN THERAPY
Conjugated estrogens are high-potency hormones
that are hydroxylated to the low-potency form of estriol,
the main estrogen found in urine. Estriol binds selectively to vaginal receptors as opposed to endometrial
receptors. Vaginal estriol application is an effective treatment for postmenopausal atrophic vaginitis and urinary
symptoms.68 It is also known that vaginal lactobacilli can
be restored in postmenopausal patients with vaginal estriol treatment. Women who received vaginal estriol in a
randomized double-blind study had 0.5 episodes of UTI
per year compared with 5.9 UTIs per year in those receiving placebo.69 In 60% of the estriol-treated group,
vaginal Lactobacillus colonization was restored in less than
1 month (compared with 0% in the placebo group), and
vaginal pH was reduced from the pretreatment level of
5.5 ± 0.7 to 3.6 ± 1.0 post-treatment.
The risks of chronic use of low-potency estrogens in
postmenopausal women for prevention of UTI are not
well known. Certainly they are contraindicated in patients with endometrial or breast cancer, and in those
A c u t e a n d C o m p l i c a t e d U r i n a r y Tr a c t I n f e c t i o n i n Wo m e n
A
B
Figure 5. Intravenous pyelogram for case patient (ie, diabetic, postmenopausal woman with high fever, bilateral flank and back pain,
and suspected urinary tract structural anomaly). (A) Plain abdominal film reveals a large right-sided calculus. There is no gas present
to suggest emphysematous pyelonephritis. (B) After injection of contrast medium, the right renal collecting system appears dilated,
with a filling defect produced by the stone in the middle and lower calyceal areas. The left kidney is normal.
with hepatic or thromboembolic disease. Further research in this area may lead to reduction in UTI rates in
elderly women and also reduction in antibiotic usage
and resistance.
PROBIOTICS
Probiotics are living exogenous organisms that are
administered to treat or prevent disease. Exogenous lactobacilli reduce the risk of UTI.70 Of the many strains of
Lactobacillus, two may be most useful for colonization of
the vagina—L. rhamnosus GR-1 and L. fermentum RC-14.71
These strains have been found to be adherent to uroepithelial and vaginal cells, resist spermicide, and produce
surfactant that inhibits growth of many uropathogens.
Larger clinical studies are required to demonstrate the
effectiveness of probiotics in the treatment and prevention of UTI in younger as well as postmenopausal women.
VACCINES
The high incidence of UTI makes it an attractive disease for researchers to attempt vaccine development.
Potential populations for vaccination might be the
elderly, patients with diabetes or neurogenic bladder,
and children with reflux, among others.
One currently available vaccine, SolcoUrovac (Solco
Basel Ltd., Basel, Switzerland), consists of heat-killed
bacteria from 10 human uropathogenic strains (6 E. coli,
2 Proteus, 1 each of Enterococcus and Klebsiella). This vaccine has been used as a vaginal suppository in a randomized placebo-controlled study to prevent reinfections in women with histories of recurrent UTI and has
been found to have no adverse reactions and to delay
the interval to reinfection.72
Also in development are antibodies against FimH.
The FimH adhesin is critical for the binding of type 1
fimbriated E. coli to bladder mucosa and has a role in
cytokine and chemokine stimulation as well as leukocyte recruitment. Anti-FimH adhesin antibodies block
bacterial binding to bladder cells in vitro.73 Active and
passive immunization of mice with FimH reduced in
vivo colonization of the bladder mucosa by more than
99% in the murine cystitis model.73
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16 Hospital Physician Board Review Manual