++
Identification and treatment of
urinary tract infections (UTIs) is important not only for explaining
and managing signs and symptoms such as fever and dysuria but also
for preventing pyelonephritis and sepsis and long-term complications
including hypertension, chronic renal disease, and renal failure.
Recurrent UTI is often a herald for anatomic and functional abnormalities
that are associated with chronic renal disease.1,2
++
Urinary tract infections may involve the urethra and/or
bladder (lower urinary tract) and the ureters, renal pelvis, calyces,
and/or renal parenchyma (upper urinary tract). Lower urinary
tract infection is usually characterized by dysuria, frequency,
urgency, and possibly suprapubic tenderness. The clinical manifestations
of acute pyelonephritis may include fever, lumbar pain and tenderness,
dysuria, urgency, and frequency in association with significant
bacteriuria.
++
Recurrence of a urinary tract infection may be caused by a relapse
or a reinfection. A relapse is a recurrence of the infection with
the same infecting microorganism, sometimes as a result of inadequate
therapy. A reinfection is a new infection caused by an organism
that is different from the one responsible for the previous episode.
Specific identification may require serotyping, pyocin typing, phage
typing, antibiotic resistance, or genetic typing of the bacterium
(eg, Escherichia coli), procedures that are not
uniformly available to the clinician. These identification techniques
may also be useful for associating individual incidents with hospital
outbreaks of infection. The term chronic infection is
sometimes used to describe (1) persistence of the urinary tract
infection associated with the same organism for many months or years
or (2) frequent recurrences over many months or years.
++
Urinary tract infections involve all age groups from neonates
to geriatric patients. Studies involving routine suprapubic puncture
in more than 1000 infants revealed the presence of bacteriuria in
0.1% to more than 1%3,4. Urinary
tract infection is more common in males, with the majority of these
infections occurring in uncircumcised infants. However, circumcision
to prevent urinary tract infection is not warranted by the low frequency
and usually mild nature of the disease. Premature infants have 2
to 3 times this rate of urinary tract infection. During preschool
years, urinary tract infection is more common in girls (4.5%)
than in boys (0.5%). Long-term surveillance studies of
school children revealed persistent bacteriuria in 1.2% of
girls and in 0.4% of boys. Each year an additional 0.4% of
girls developed bacteriuria.5 Thus the overall
prevalence in school-age girls approached 5%.5-7 These studies
indicated that the peak incidence of urinary tract infection in
children occurred between ages 2 and 6. White girls tended to have more
frequent reinfections than black girls. The incidence of urinary
tract infection in females of high school and college age is approximately
2%.
+++
Pathophysiology
and Genetics
++
Adenovirus types 11 and 21 and the human papovavirus BK have
been reported as causes of acute hemorrhagic cystitis.11-14 Symptomatic
and asymptomatic BK viruria is associated with bone marrow transplantation.
Fungi such as Candida albicans may be responsible for
UTIs (1) in patients with indwelling catheters during the course
of their treatment with antibiotics; (2) in patients immunocompromised
as a result of disease, steroids, or cytotoxic chemotherapy; and
(3) as a result of renal seeding during fungemia.
++
The ascending route is the most common pathway of UTI. Bacteria
that colonize the perineum and distal urethra may eventually spread
to the bladder. Massage of the urethra, such as occurs during masturbation
and sexual intercourse, forces bacteria into the bladder.15,16 Hematogenous
spread may occur during the course of neonatal sepsis; however, even
in infants, ascending infection leading to bacteremia is more common. Lymphatic spread
has been suggested, but it has not been proved.17 The
pathogenesis of urinary tract infection is dependent in great part
on factors associated with both the microorganism and the host.
+++
Microbial Virulence
Factors
++
A number of virulence factors of microorganisms are associated
with urinary tract infections, including size of inoculum, the presence
of pili or fimbriae effecting mucosal cell adherence (mannose-sensitive
type 1, common, P pili, X pili), surface antigens, motility, and
urease production. Experimental studies in mice have revealed that
the greater the number of organisms delivered to the kidney, the
greater the chance of inducing pyelonephritis.18 A number
of virulence factors of microorganisms are associated with UTIs,
including size of inoculum, the presence of pili or fimbriae effecting
mucosal cell adherence (mannose-sensitive type 1, common, P pili,
X pili), surface antigens, motility, and urease production. Certain
organisms are particularly virulent or adapted for the urinary tract.19,20
++
E coli O antigens are cell-wall lipopolysaccharides
that are immunogenic and induce local and systemic antibody responses
in patients with pyelonephritis. Of the 150 or more E coli O
serogroups, only a few (01, 02, 04, 06, 07, 075) are responsible
for most UTIs. These O serogroups possess large quantities of K
antigen, of which types 11, 24, 36, and 37 account for the majority
of isolates from children with pyelonephritis.21,22 The
O antigens associated with pyelonephritis appear to confer the ability
to resist agglutination and bactericidal effects of serum, unlike
the O serotypes of organisms causing cystitis.22-24
++
Another microbe pathogenic factor is the presence of carbohydrate-binding
proteins (adhesions, lectins, or hemagglutinins) often localized
to pili. Pili are important for the attachment of E coli and P
mirabilis to the urinary tract epithelium.25 Almost
all E coli contain type 1 common pili that bind
to mannose-containing receptors on epithelial cells of the urethra
and vagina and are thought to be of primary importance in colonizing
the lower urinary tract.26-28E coli isolates
from patients with cystitis have a greater avidity and adhere in
higher numbers to uroepithelial cells than do E coli fecal
isolates.29,30 Furthermore, uropathogenic E
coli and P mirabilis adapt to their environment
altering their surface composition (phase variation) such that they
lose their type 1 pili on arrival in the kidney.25,31 This
promotes renal cell attachment and the variation of mannose receptors
of type 1 pili allows escape from phagocytosis by polymorphonuclear
leukocytes.32E coli with P pili have
their favored site of attachment on the uroepithelium of the kidneys,
where receptors are distributed with greatest density.28,29 P
pili bear an adhesin called PapG that causes mannose-resistant hemagglutination
and binds to specific Gal-alpha-1,4-Gal glycolipid receptor sites
on human epithelial cells.28,30,33-35 P-fimbriae-expressing
organisms elicit higher IL-8, IL-6, and neutrophil responses than
P-fimbriae-negative organisms, confirming their virulence characteristics.36 Urinary
tract infections are more likely to occur in individuals who express
the P blood group antigen.37 A third type of pili,
X pili, are also capable of binding to uroepithelium. Their receptor
sites have not been identified; however, they also have an affinity
for the upper urinary tract.
++
Bacterial motility is also likely an important pathogenic factor.
Motile bacteria can ascend in the ureter against the flow of the
urine.38 Bacterial ascent appears to be facilitated
by the decreased ureteral peristalsis attributed to the endotoxin
of Gram-negative bacilli.
++
The production of urease by the infecting bacteria may affect
their capacity to cause pyelonephritis. When urinary tract infection was
induced in experimental animals by the retrograde administration
of P mirabilis, a urease-producing organism, there
was a high degree of correlation between the number of bacteria
in the kidney and the extent of renal damage. However, treatment
with a urease inhibitor reduced the extent of renal damage and the
number of bacteria in the kidney without a significant decrease
in the number of bacteria in the urine.39
++
UTIs are more likely to occur in individuals who express the
P blood group antigen.37 Other factors that impact
upon bacterial virulence include variations in the bacteria’s
motility38 and urease production.39
++
The known host defense mechanisms of the urinary tract include flushing
mechanisms of the bladder, antibacterial activity of urine (decoy
effect of oligosaccharides), prostatic secretions of postpubescent
males, low vaginal pH and estrogen in females, antiadherence effects
of uromucoid and mucopolysaccharide, humoral immunity, local secretory
immunity, IgA, lack of P blood group antigen, and the protective effect
of host normal flora.
+++
Urine Flow and
Chemisty
++
The flushing mechanism of the bladder enhances the spontaneous
clearance of bacteria. Voiding and dilution probably play an important
role. Overhydration can have the negative effect of diluting and
washing out the active antimicrobial substances from the medullary
and papillary areas. However, on balance, maintaining urine flow
seems prudent.
++
Extremes of osmolality, high urea concentration, low pH, and
high concentration of organic acids may each inhibit the growth
of some bacteria that cause urinary tract infections. However, with
the usual range of pH (5.5–7.0) and osmolality (300–1200),
the rate of growth of E coli has been reported
as unaffected.40,41
++
There are also sex-specific contributions to host defense.42-47 The
shorter female urethra, as compared to the male urethra, may explain the
disproportionately higher female predilection for UTI.
++
Other
factors contributing to this sex difference include an inhibitory
effect of prostatic fluid on bacterial growth,42 and
possible enhancement of the growth of some E coli strains by estrogen.43 Low
vaginal pH apparently is an important factor responsible for lack
of colonization.44 Serogroups of E coli that
usually cause urinary tract infections are more resistant to low
pH than serogroups that are less common causes of infection.45 Similarly,
low pH has an inhibitory effect on P mirabilis and P
aeruginosa.46 This phenomenon may contribute
to the higher incidence of E coli infection.
++
Glucose improves urine as a culture medium and inhibits the migrating,
adhering, aggregating, and killing functions of polymorphonuclear
leukocytes. Thus, poorly controlled diabetics are at increased risk
of UTIs.
+++
Urine Antibacterial
Activity
++
Tamm-Horsfall protein is a uromucoid rich in mannose residues
secreted by renal tubular cells.48 It may serve
as a decoy that inhibits epithelial attachment of the bacteria and
thereby prevents colonization or infection.49 Tamm-Horsfall protein
specifically competes with uroepithelial uroplakin Ia and Ib receptors
to bind type 1 fimbriated E coli.50 Antiadherence
mechanisms of the bladder (in rabbits) have been demonstrated by
pretreatment of the bladder with dilute hydrochloric acid; acid-treated bladders
had twentyfold to fiftyfold increases of bacterial adherence over
controls.51 Adherence was enhanced by ablation
of mucopolysaccharide and glycosaminoglycan from the surface of
bladder epithelium.51,52 This could result from
exposure of additional binding sites.
++
The role of humoral immunity as a mechanism of the host’s
defense against urinary tract infection remains uncertain. Acute E
coli pyelonephritis induces serum antibodies to O antigens
but rarely to K antigens.59 Increased levels of
O antibodies are not detected in sera from patients with cystitis
or asymptomatic bacteriuria. A sensitive enzyme-linked immunosorbent
assay (ELISA) detects high concentrations of E coli O
antibody in the urine of most patients with acute pyelonephritis,
with lower concentrations in patients with asymptomatic bacteriuria
and cystitis, and minimal or no specific antibody is detectable
in the urine of healthy children. Serum antibodies to O antigen,
K antigen, and type 1 pili have been found in patients with pyelonephritis.59-61 Pathogen-specific
antibody-secreting cells can be detected in 90% of children
with urinary tract infection, with a greater number detected with increasing
age. Despite the fact that IgM is not present in urine, a systemic
IgM response predominates, supporting the concept that the systemic
immune response may be more important than the local one in children.62 IgG antibody
to the lipid A component of Gram-negative rods is also detectable
and may be a measure of the severity of renal disease and tissue
destruction.63 A secretory IgA response can also
be detected in the urine in both upper and lower tract disease.64
++
The role of the host’s normal perineal flora of lactobacilli, Staphylococcus epidermidis,
corynebacteria, streptococci, and anaerobes in preventing colonization
with uropathogens is not completely understood; however, disturbing
the local ecology with (systemic) antibiotics is associated with
infection.
++
A number of factors predispose to urinary tract infection. These
include obstruction, stasis, reflux, pregnancy, sexual intercourse
(in females), hyperosmolality of renal medulla, host cell receptor
sites for attachment, immunologic cross-reactivity of bacterial
antigen and human protein, chronic prostatitis, B or AB blood type,
other genetic predispositions, and immunodeficiency. Sexual intercourse
in females produces transient bacteriuria and is associated with
an increased risk of urinary tract infection. Eighty percent of
urinary tract infections begin within 24 hours of intercourse in
sexually active women.70,71 Adult males with chronic
prostatitis are at risk for recurrent urinary tract infections because
of intermittent seeding of their urinary bladders. Other factors
such as chronic perineal irritation from soap, bubble bath, or pinworms
and trauma such as occurs by bike and horseback riding and, in older boys,
self-instrumentation, all contribute to the risk of urinary tract
infection.
++
Probably the single most important host factor affecting the
occurrence of urinary tract infections is urinary stasis resulting
from obstruction of urinary flow or bladder dysfunction. This predisposing
host condition is more frequently observed in the younger
patient and should prompt timely imaging of the urinary system. The
most common causes of stasis include congenital anomalies of the
ureter or urethra (valves, stenosis, bands), calculi, dysfunctional
or incomplete voiding, extrinsic ureteral or bladder compression,
and neurogenic bladder (functional obstruction).
+++
Vesicoureteral
Reflux and UTI
++
Reflux, the retrograde flow of urine into the ureter and kidney,
is caused by the incompetence of the normal valvular action of the
ureterovesicular junction. It may occur when this area is affected
by congenital anatomic defects, disease, or distal obstruction.
Reflux tends to perpetuate infection by maintaining a residual pool
of infected urine in the bladder after voiding. Children with vesicoureteral
reflux often develop upper UTIs and renal scarring. Reflux can be detected
in 30% to 50% of children with symptomatic or
asymptomatic bacteriuria.68 Additionally, kidneys
scarred in association with reflux are more susceptible to reinfection.
++
Interleukin-8 is produced by epithelial cells in response to
inflammation and increases in urinary tract infection. Vesicoureteral
reflux (VUR) is associated with increased interleukin-8 in urine.
This inflammatory response appears to persist after urinary tract
infection has resolved. This finding of persistent inflammation
suggests that high-grade sterile vesicoureteral reflux may be a
cause for concern in children with a history of vesicoureteral reflux.69
++
Physiologic alterations of the urinary tract that increase the
likelihood of urinary tract infection occur as a result of pregnancy.
These changes include decreased bladder and ureteral tone, decreased
ureteral peristalsis, hydroureter, and increased residual bladder urine,
all of which cause or aggravate obstruction, stasis, and reflux.
++
A genetic predisposition to
UTI may result from variations in host factors. For example, UTI
is more frequent among individuals with blood group P antigen.37,38 Women
with recurrent urinary tract infections who are ABO nonsecretors
have vaginal epithelial cells that have substantially more receptors
allowing attachment of uropathogenic E coli.77 CXCR1
is an IL-8 receptor, having three mutants with two polymorphisms.
Children that are prone to UTI, excluding those with anatomic defects
or reflux, express less CXCR1 protein than controls.78 There
are also a number of Arg753Gln allele polymorphisms of Toll-like
receptor-2 that are associated with an increased frequency of Gram-positive
uropathogens, a history of recurrent urinary tract infection, and asymptomatic
bacteriuria.79 Vesicoureteral reflux itself is
also often familial.
++
The clinical manifestations of urinary tract infections (UTIs)
depend on the age of the patient as well as the anatomic location
and severity of the infection. Symptoms in newborn infants are nonspecific
and include lethargy, irritability, poor feeding, vomiting, diarrhea,
apnea, fever or hypothermia, or prolonged jaundice and suggest systemic
infection. Symptoms in those less than 2 years of age are also characteristically
nonspecific, such as fever, and some appear to be related to the
gastrointestinal tract rather than the urinary tract: failure to
thrive, feeding problems, vomiting, diarrhea, abdominal distention,
and late-onset jaundice. Infants and children may have signs of
balanitis, prostatitis, and orchitis or overt manifestations of
sepsis. UTIs in children more than 2 to 3 years of age are often characterized
by fever, frequency, and dysuria. The signs of cystitis may also
result from other causes of urethral irritation in children, such
as bubble bath, vaginitis, pinworms, masturbation, or sexual abuse.
Abdominal pain, flank pain, and hematuria may be present. The occurrence
of enuresis in a child who has been toilet trained could also be
a manifestation of a UTI. Young infants and boys may have an obstructive
uropathy characterized by dribbling of urine, straining with urination,
or a decrease in the force and size of the urinary stream. These
findings of obstruction can be aggravated by infection. Other historic elements that should be sought include
infrequent voiding, incomplete voiding, and a weak urinary stream.
++
The manifestations of UTIs in adolescents are similar to those
in adults, including frequency, urgency, dysuria, and painful urination
of a small amount of turbid urine that occasionally may be grossly
bloody. Fever is usually absent. The differential diagnosis of cystitis
includes vaginitis, urethritis, and chemically induced irritation
from female hygiene products. In contrast, upper urinary tract infection
may be characterized by fever, chills, and flank pain or abdominal
pain. Upper and lower tract infections may coexist. Occasionally
the lower-tract symptoms may appear 1 to 2 days before the upper-tract symptoms. The
presence of costovertebral angle tenderness on examination directs
attention to the upper tract; however, its absence does not exclude
pyelonephritis. The clinical manifestations in some patients may
be so atypical that they resemble gallbladder disease or acute appendicitis.
+++
Diagnostic Evaluation
++
Physical examination should include measurement of blood pressure
because hypertension may be caused by chronic renal failure. Abdominal
examination may reveal a mass, tenderness, or organomegaly. Genital
examination should be conducted to investigate vaginitis and labial
adhesions in girls; phimosis in boys; and evidence of irritation,
sexual activity, or sexual abuse. Rectal examination allows assessment
for lax sphincter tone, which may be associated with neurogenic bladder.
Similarly, examination of the back may reveal a dimple or other
defect associated with neurogenic bladder as a result of spinal cord
involvement.
++
Laboratory examination begins with evaluation of urine. Normal
urine is a sterile, acellular, glomerular filtrate influenced by
tubular secretion and absorption. Sustained absence of inflammatory
responses on repeat urine analysis constitutes strong evidence of
absence of infection.87 Given the appropriate clinical
setting, the diagnosis is suggested
by the detection of white blood cells (WBCs) and bacteria in the
urine. Confirmation requires quantitative culture of uncontaminated
and properly processed urine. Asymptomatic bacteriuria is defined
as significant bacteriuria in a patient who has no clinical evidence
of infection. Overdiagnosis of UTIs carries the risks of unnecessary
treatment, diagnostic workup, and their attendant visits and costs.
Underdiagnosis carries the risks of continued symptoms, sepsis,
and chronic progressive renal disease.
++
Laboratory testing for UTI is best performed using a standardized
approach. Five mL of urine is centrifuged at 3000 rpm for 3 minutes,
followed by resuspension of the sediment. The occurrence of more
than 20 white blood cells per high-power field usually correlates
with significant bacteriuria of 100,000 colonies in a clean-catch sample.
However, pyuria does not necessarily indicate the presence of a
UTI. Patients of all ages with or without pyuria may or may not have
an infection. Unfortunately, false-positive results as high as 30% occur
and may be caused by vaginal washout, chemical irritation, fever,
viral infection, immunization, or glomerulonephritis. It is likely
that most patients with symptomatic UTIs will have pyuria. The performance
characteristics of a number of useful tests are indicated in eTable 238.1.
++
++
Microscopic examination of urine for bacteria is also useful.
The presence of 1 bacterium per oil-immersion field on a Gram-stained preparation
form a midstream clean-catch urine specimen, is equivalent to approximately
100,000 bacteria per milliliter urine. Ten to 100 bacteria per high-power
field on a centrifuged sediment correlates with significant bacteriuria.
The sensitivity of urine analysis is 82%, with a specificity
of 92% for detection of UTI. Urine analysis does not perform
as well in younger infants.88,89
++
Dipstick chemical tests most commonly employed include tests
for nitrite and leukocyte esterease. Nitrite detection in urine
is based on the observation that many urinary pathogens convert
nitrate to nitrite in the bladder. The nitrite strip for detection
of UTI uncommonly yields false-positive results. False-negative
results are more common (25–30%) as a result of
inadequate dietary nitrates, diuresis, an inadequate time for bacterial
proliferation, or infections caused by nitrite negative organisms,
including Staphylococcus saprophyticus, Acinetobacter species,
enterococci, and pseudomonads. The test is best used on concentrated
or first-morning samples and may have an important role for outpatient and
home monitoring following diagnosis and treatment of a UTI.90 Leukocyte
esterase testing detects enzymes generated by inflammatory cells.
This test is neither more sensitive nor more specific than the detection
of the cells themselves, but it may be easier to perform in some
clinical settings. As with pyuria, a positive test does not establish
the diagnosis of UTI.
++
Molecular detection of nucleic acids of prokaryotic cells in
urine is being developed as a screening test for urinary tract infection. Although
this strategy probably will be highly sensitive, it is also relatively
expensive and labor-intensive; thus its role in clinical-laboratory
diagnosis of urinary tract infection remains to be determined.
++
Culture of carefully collected fresh urine (less than 30 minutes
old, refrigerated or held on ice), minimizing the likelihood of contamination,
is the cornerstone of diagnosis of UTI. Quantitative culture of
urine is the standard for diagnosis. Because UTIs, particularly those
in infants and young children, have nonspecific presentations, invasive
methods for valid urine collection for culture are often required. Urine
for culture may be obtained (1) as a midstream clean-catch specimen
in adults, adolescents, and older children; (2) by catheterization; or
(3) by suprapubic aspiration in young children and infants. The
performance characteristics of the previously discussed diagnostic
tests are summarized in eTable 238.1. Suprapubic
aspiration is accomplished
by introduction of a needle in the midline 2 to 4 cm above the symphysis
pubis, after appropriate disinfection of the skin, with gentle traction
applied to the syringe plunger. The needle is advanced through the
bladder wall until urine flows into the syringe. Success with this
procedure is maximized by ensuring that the patient has not recently
voided; by palpating, percussing, or transilluminating the bladder;
and by digital compression of the urethra to prevent reflex voiding.
++
Strait catheterization follows gentle cleansing of the anterior
urethra with soap and water. The catheter is advanced through the
urethra into the bladder until urine flows into the catheter. Because
the urethra cannot be sterilized, the first aliquot of urine that
flows should be discarded to avoid collecting bacteria that have
been pushed into the bladder. A later aliquot should be sent for
culture.91
++
A midstream clean-catch urine collection should be preceded by
disinfection of the area about the urethral meatus, then rinsed
clean prior to urination. Girls can straddle the toilet seat to
minimize contamination by urethral-vaginal reflux. Collections in
younger children should be supervised by a professional.
++
Unfortunately, there are no direct comparative studies of the
sensitivity and specificity of these methods in children. A negative
culture of a clean-catch specimen would obviate the need for catheterization
or suprapubic aspiration. Random urine samples and urine collected
as bag specimens should not be used as a basis for the diagnosis
of UTI. Screening for asymptomatic bacteriuria is not usually indicated.
++
The likelihood of UTI as detected by culture is a function of
the epidemiologic setting, the method of collection, and the prior
probability of infection. Organisms in any number are considered
significant when obtained by suprapubic aspiration. When urine is
collected by catheterization, a colony count greater than 1000 per
milliliter of urine is usually considered diagnostic. However, for
infants, counts of 10,000 colony-forming units (cfu)/mL
or greater have been obtained from catheterized specimens in the
absence of other findings of UTI.92 Infections
should be defined by a colony count greater than 50,000 cfu/mL
and pyuria of at least 10 leukocytes/mm3 in
samples collected by straight catheterization of children.89 If
the quantitative culture from a midstream sample reveals 100,000
bacteria or more per milliliter of urine, it also indicates the
presence of significant bacteriuria. In males, greater than 10,000
bacteria per milliliter suggests infection, but is equivocal in
females and thus should be repeated if symptoms have persisted.
A count of less than 10,000 bacteria per milliliter suggests probable
contamination. The specificity of this technique is enhanced from
80% to 95% if significant bacteriuria is demonstrated
on repeat testing.93 In the presence of pyuria
and symptoms, a single culture indicating significant bacteriuria
is considered diagnostic in adolescents and adults. The specific
bacterium recovered by culture should be identified as a guide to
appropriate therapy.
++
False-positive cultures may be due to contamination or prolonged
incubation of urine before culture. False-negative results may reflect
the following: prior antimicrobial therapy, the presence of a fastidious
organism that grows slowly or is difficult to culture, rapid flow
of urine, inactivation of bacteria by an extremely acid pH, or a
break in technique such as spilling soap or other cleansing agents into
the urine. Therefore there are clinical situations in which colony
counts of less than 100,000 may indicate significant bacteriuria.
++
Quantitative urine cultures should be performed. Commonly this
is done using a 0.001-mL calibrated loop inoculated onto blood agar and
MacConkey agar for Gram-negative rods and onto chocolate agar for H
influenzae. The culture is incubated overnight, counted,
and multiplied by 1000. In certain circumstances, special media
(eg, Sabouraud dextrose agar for fungi and human embryonic kidney,
HeLa, or HEp-2 tissue culture for viral isolation) are required.
When suprapubic aspiration is performed, 0.1 mL of urine should
be spread over the plate, incubated overnight, and counted.
++
Successful treatment is followed by negative culture results
within 24 to 72 hours after institution of therapy. Because of increasing reports
of antibiotic resistance and of failure of eradication of the offending
organism, antibiotic susceptibilities should also be requested at
the time of culture.
+++
Localization
of Infection
++
Localization of the anatomical site of infection remains difficult. Although
pyelonephritis is classically associated with fever, flank pain
or tenderness, decreased renal concentrating ability, and an elevated
erythrocyte sedimentation rate, the absence of these findings does
not reliably exclude upper tract disease. Collection of urine by
ureteral catheterization for quantitative culture is the most reliable
method of localizing the site of infection; however, it is an invasive test
and may require general anesthesia. Therefore its role in children
is limited to research applications. When 95 females and 26 males
with urinary tract infection were evaluated by this method, the
site of infection was limited to the bladder in 50% of
the group, but the site could not be predicted by history and physical
examination.94 Localization by bladder washout
(Fairley technique) is less invasive and does not require anesthesia;
however, this is a cumbersome test and is not routinely performed.
++
The use of technetium (Tc-99m), dimercaptosuccinic
acid (DMSA), or glucoheptonate scanning is gaining favor in the
early diagnosis of upper UTIs,95 as it appears
to be more sensitive than other easily available methods of localization.95-97 In
experimental studies, the sensitivity and specificity of scanning
were 91% and 99%, respectively, with overall 97% agreement
with histopathologic findings, although there may be substantial
interobserver variability in the detection and classification of
renal cortical defects.96,98 When scintigraphy
is performed for localization, an abnormal finding suggests the
need for voiding cystourethrogram to detect vesicoureteral reflux.
Again, however, the absence of vesicoureteral reflux does not rule
out pyelonephritis.
++
The detection of antibody coating of bacteria is a sensitive,
reliable, noninvasive indicator of renal bacteriuria in adults.99,100 Unfortunately,
when this immunofluorescence technique was applied to children with
bacteriuria, it was neither sensitive nor specific.101,102 After
addition of fluorescein-conjugated antihuman globulin to urine,
the demonstration of fluorescence of the antibody-coated bacteria indicates
upper tract involvement. Urinary lactic dehydrogenase (LDH) isoenzyme
5 is more accurate for localizing the site of infection in infants
and children. Elevations of urinary lactic dehydrogenase greater
than 150 units/L and elevations of fractions 4 and 5, C-reactive
protein (CRP; > 30 μg/mL) and increased
urinary IL-1-β are markers for pyelonephritis.105
++
C-reactive protein is also useful for distinguishing upper (>
30 μg/mL) from lower urinary tract infection
and has a sensitivity and specificity of approximately 90% when
compared to bladder washout.102 A C-reactive protein
value greater than 30 μg/mL suggests upper
tract disease. In differentiating upper versus lower urinary tract
infection, with dimercaptosuccinic acid scanning as the comparator,
a C-reactive protein value greater than 66 μg/mL
suggests upper tract disease if there has been more than 2 days
of fever, and a C-reactive protein value greater than 27 μg/mL suggests
upper tract disease if there has been less than 2 days of fever.104 Increased
urinary IL-1-β may be a marker for pyelonephritis
in febrile infants.105 Excretion of β-2-microglobulin
and N-acetyl-glucoseaminidase are also used as
adjuncts in some centers.
++
Finally, response to therapy is a clinical indicator of the site
of infection in adults. Studies in women indicate that more than
90% of patients with lower urinary tract infection but less
than 50% of those with upper urinary tract infection are
cured by a single dose of antibiotic if the organism is susceptible.106,107 In children,
however, recurrences of infection after short-duration therapy occur
in approximately 5% to 30% of those treated.108,109 This does
not differ from the frequency of recurrences following conventional
therapy.
+++
Differential Diagnosis
++
The differential diagnosis of urinary tract infection depends
in great part on the age of the patient. The clinical manifestations
in newborn infants and in infants under 2 years of age are nonspecific.
The findings of irritability, failure to thrive, vomiting, diarrhea,
and jaundice suggest the possibility of bacterial sepsis, acute
gastroenteritis, or hepatitis. The appropriate blood, stool, and
urine cultures should provide a clue to the correct diagnosis. Clinical
findings in infants can be due to a wide range of other infectious
and noninfectious processes. In older children and adults, various
conditions that may simulate cystitis or pyelonephritis should be
considered, including urinary calculi, dysfunctional elimination
and diabetes, vaginal foreign body nonspecific vulvovaginitis gonorrheal
or chlamydial urethritis may simulate urinary tract infection. A
right-sided pyelonephritis could be confused with acute appendicitis,
gallbladder disease, or hepatitis. In older children and adults,
various conditions that may simulate cystitis or pyelonephritis should
be considered, including urinary calculi, dysfunctional elimination
and diabetes. Vaginal foreign body and nonspecific vulvovaginitis
may simulate urinary tract infection. Similarly, the symptoms of
gonorrheal or chlamydial urethritis may suggest a lower urinary
tract infection. A right-sided pyelonephritis could be confused
with acute appendicitis, gallbladder disease, or hepatitis. When
the presenting complaint is hematuria and bacterial cultures are
negative, viral cultures may reveal the diagnosis. Careful history and
physical examination in conjunction with appropriate cultures and
serologic tests should help identify the true diagnosis.
+++
Radiologic Evaluation
++
Imaging strategies are addressed in Figure 238-1.
Radiologic evaluation for anatomic abnormalities is indicated in
all infants, children, and adolescents except in girls > 2 years
of age. In girls > 2 years of age, imaging is indicated in the presence
of symptomatic infection, physical examination findings suggestive of
possible renal or collecting system abnormalities, abnormal voiding,
hypertension, or poor physical development.110 Clinical
factors associated with an increased likelihood of finding an anatomic
abnormality include recurrent infection, poor urinary stream, palpable
kidneys, unusual organisms, invasive infection, prolonged clinical
course, failure to respond to antibiotics in 2 to 3 days, and patients
with unexpected demographics such as older boys.111 If
radiographic studies are not performed in older girls after the
primary infection, they are indicated if there is a recurrence.
Acute imaging is indicated in children who do not have the expected
clinical response to therapy in order to investigate the role of
obstruction. Ultrasonography should be performed acutely for disease
that is complicated or fails to resolve promptly. Routine radiologic
studies need only be delayed until infection and the resultant bladder irritability
is resolved.
++
++
Information obtained by imaging may or may not alter acute management,
but the information has implications for long-term management. In
uncomplicated, rapidly resolving disease, the results of renal ultrasound
and dimercaptosuccinic acid scan at the time of acute infection
have not modified management, suggesting that selective performance
of ultrasound, interval voiding cystourethrogram at 1 month, and
dimercaptosuccinic acid scan at 6 months may be more useful to identify vesicoureteral
reflux and scarring.
++
Vesiculoureteral reflux is the most commonly occuring abnormality.
Voiding cystourethrogram (VCUG) better characterizes reflux and
can demonstrate bladder and urethral abnormalities. Voiding cystourethrogram
is preferred in boys and in girls with evidence of voiding dysfunction
while uninfected. Radionuclide cystography has the advantage of
less radiation exposure and is the preferred method for following
the degree of reflux in those previously diagnosed. Radionuclide
cystography may be most useful in older children in whom reflux
is considered unlikely.114 One of the confounding
issues with renal scintigraphy is whether an abnormal area represents
an area of scarring due to vesicoureteral reflux–associated
pyelonephritis or a congenital renal lesion with hypoplasia or dysplasia
and associated urinary tract infection without secondary renal damage
is unknown.115
++
Children with no reflux or grade I reflux require only follow-up
examination. Children with grade II or III reflux may be candidates for
suppressive therapy. If grade III or IV reflux is detected, it probably
will be persistent and not be the result of acute infection. Children
with grade IV reflux are also candidates for suppressive therapy, and
urologic consultation should be obtained.
++
Radionuclide scanning appears to have increased sensitivity in
detecting renal scars following acute pyelonephritis. Approximately
two thirds of abnormalities demonstrated acutely resolve over time.98,121 New scarring
occurs at sites corresponding to the localization of acute inflammation
and appears to be unrelated to vesicoureteral reflux.122
++
When detailed anatomic information is required, computed tomography
or magnetic resonance imaging should be performed.
++
A problem with all modalities used for imaging the urinary tract
is that there is little data to link them with improved patient
outcomes. Routine imaging is not associated with a decrease in recurrences
or a decrease in renal scarring.124 Neither medical
nor surgical treatment of vesicoureteral reflux have been demonstrated
to be beneficial for long-term outcome.
++
Urologic referrals are appropriate for patients with obstruction,
urethral valves, renal scarring, anatomic abnormalities, and dysfunctional
voiding; however, there is no strong evidence to link medical or
surgical interventions for vesicoureteral reflux with improved long-term
outcome.
++
The objectives of treatment of children with urinary tract infections
(UTIs) are fivefold: (1) to eliminate the infection, (2) to detect
and correct functional or anatomic abnormalities, (3) to prevent
recurrences, (4) to preserve renal function, and (5) prevent late
sequelae such as hypertension. The achievement of these goals requires successful
identification of the causative microorganism, selection of optimal
antimicrobial drugs and patient compliance in their use, roentgenographic
evaluation of the urinary tract, screening for recurrent infections
with periodic urine cultures, and use of general hygienic measures
to prevent reinfections.
++
Antimicrobial therapy is a mainstay of intervention. Suggested
treatment regimens for patients with UTI are shown in Table
238-1. Parenteral administration of antibiotics is appropriate
in patients who are toxic, dehydrated, or incapable of accepting
or retaining oral intake, or when compliance is not assured. Newborn
infants with UTIs and children suspected of having pyelonephritis
should be treated empirically at the time of diagnosis because of
the frequency of associated bacteremia. Empiric therapy for newborn
infants with urinary tract infection and suspected sepsis should
include cefotaxime (100 mg/kg/day divided q 12
hours for infants < 1 week of age and 150 mg/kg/day
divided q 8 hours for infants > 1 week of age) and ampicillin (100
to 200 mg/kg/day). Alternatively, cefotaxime alone
is satisfactory for treatment of susceptible enteric Gram-negative
bacillary UTI.
++
++
Older children with mild symptoms and those with lower UTIs may
not require antimicrobial therapy until the results of urine culture
are available. If therapy is indicated before the results of culture
become available, oral cefixime is suggested because E coli and other
Gram-negative bacilli are the most common pathogens. Older children
and young adults may be treated with ciprofloxacin, which is labeled
for use down to 1 year of age, or another fluoroquinolone.
++
Older children with suspected pyelonephritis can be treated empirically
with ceftriaxone 50 to 75 mg/kg/day intravenously
or intramuscularly, possibly with the addition of an aminoglycoside.
Recent data indicate that orally administered cephalosporin drugs
with activity against Gram-negative rods are as effective
in the time to defeverescence (approximately 25 hours), ability
to eradicate the organism from the urine, prevention of recurrences,
and prevention of renal scarring at 6 months135 as
parenterally administered agents. Trimethoprim/sulfamethoxazole
or amoxicillin may be used as an alternative where resistance is
not a problem. Older children and young adults may be treated with
ciprofloxacin, which is labeled for use down to 1 year of age, or
another fluoroquinolone. Many fluoroquinolone antibiotics are not
labeled for use in patients < 18 years of age.
++
In selecting antibiotic therapy the history of first-versus-recurrent
infection, the prior use of antibiotics, and any history of drug allergy
should be considered. When the results of urine culture and antibiotic
sensitivities are known, the antimicrobial therapy can be changed
if necessary. Because many antibiotics are eliminated by glomerular
filtration and tubular secretion and achieve high concentrations
in the urine, infection may be eradicated even if organisms are
resistant. For those treated parenterally, a switch to oral therapy
can be considered if symptoms have abated and an oral agent to which
the pathogen is susceptible is available. For patients who remain
symptomatic, repeat culture should be performed and the results
of the sensitivity tests should be used as a basis for changing
the antimicrobial therapy.
++
A large number of antibiotics have been found
useful in the management of urinary tract infection. Some antibiotics
useful for parenteral administration include ceftriaxone, cefotaxime,
ceftazidime, cefazolin, tobramycin, ticarcillin, and ampicillin.
Aztreonam, meropenem, and ciprofloxacin are appropriate choices
for the treatment of urinary tract infection in children with urinary
tract anomalies, among whom there is a higher likelihood of antibiotic-resistant E
coli and Klebsiella infections. Nitrofurantoin
and nalidixic acid are appropriate for children with and without
urinary anomalies.136 Oral agents, for therapy
of mild to moderate disease, and for sequential therapy following
initial improvement with parenteral drugs, include cefixime, cefpodoxime,
cefprozil, cephalexin, trimethoprim/sulfamethoxazole, sulfisoxazole,
amoxicillin, and ciprofloxacin. Appropriate antibiotic therapies
for acute pyelonephritis in children include cefixime, ceftibuten,
or amoxicillin with clavulanic acid for children who do not require
parenteral, or a single dose or three-times-daily intravenous dose
of an aminoglycoside followed by the preceding oral regimen.123
++
In adolescents with acute obstructive, persistent, or frequently
recurrent urinary tract infections and for those with nosocomially acquired
organisms, fluoroquinolones, imipenem-cilastatin, ticarcillin-clavulanate,
or extended-spectrum cephalosporins are acceptable alternative drugs.
++
The use of single-dose or short-term regimens is problematic
for children. Pooled analysis of children indicates that long-course therapy
of 7 to 14 days is required because of fewer treatment failures
and less reinfection.132 As a result of the difficulty
in localizing infection and cost considerations, it may be more
appropriate to complete 7 to 14 days of therapy than to risk the
need to reevaluate and treat a recurrence. Reexamination of the patient
and reculture of the urine after short-term therapy is mandatory.
Cefixime, amoxicillin, cefadroxil, nitrofurantoin, and trimethoprim-sulfamethoxazole
have all been used successfully as short-term regimens in older patients
with lower tract disease. Short-course therapy of 3 days may be
appropriate for adolescent females with lower UTI.
++
A “cure” is determined by clinical improvement. Therapeutic
failures after short-course or conventional antibiotic treatment
of susceptible organisms suggest upper-tract disease. Consideration should be given to a 6-week regimen in
patients who do not respond to conventional therapy. Follow-up cultures
are usually indicated only for symptomatic recurrences. If reinfection
occurs, the susceptibility of the organism should be determined,
and the appropriate therapy should be instituted. Reinfection is
differentiated from recurrence by typing the causative agent.
++
Failure to recognize and treat acute urinary tract infections
may result in recurrent infections and progression to chronic pyelonephritis.
Children with chronic pyelonephritis associated with ureteral reflux
and obstructive uropathy may develop chronic renal failure with
anemia, hypertension, growth failure, and metabolic abnormalities.
Nephrolithiasis and stricture formation may also develop and further
complicate management. A rare complication is renal abscess, which
may rupture into the perirenal space. Another complication of chronic
or recurrent infection is follicular cystitis (cystitis cystica),
manifesting as nodular collections of lymphocytes in the bladder wall.
It is usually diagnosed by imaging or direct visualization at cystoscopy.
The changes resolve with treatment of the underlying infection.
++
Abscesses also result from infection ascending via the collecting
system, followed by renal seeding and localized liquefaction. Ultrasonographic
exam, reveals a mass effect, has been termed lobar nephronia. Abscesses also
occur in the medulla. The natural methods of extension include rupture
into the renal pelvis and extension through the renal capsule, producing
a perinephric (perirenal) abscess. A more chronic destructive process, associated
with lipid-laden macrophages and often stone formation, is termed
xanthogranulomatous pyelonephritis. It is associated with a high
tissue expression of monocyte chemotactic protein, suggesting a
role for recruited circulating monocytes or cells present in the
interstitium during inflammation.125
++
The prognosis depends on the site of involvement, the presence
or absence of obstructive uropathy, and vesicoureteral reflux and
is therefore related to the age of the patient. Young patients with
obstructive uropathy and infection are much more likely to have
serious long-term sequelae. Most single, uncomplicated episodes
of infection respond to specific antimicrobial therapy. However,
approximately one third of these patients may relapse within 1 year.
Relapses decrease in frequency beyond this time; however, 1% of patients
may relapse up to 6 years after initial infection. The prognosis
is less favorable for patients with obstructive lesions and for
those with chronic pyelonephritis. In spite of specific antimicrobial
therapy, most of these patients have repeated recurrences, and those with
bilateral renal involvement may progress to chronic renal insufficiency.
Recurring bouts of febrile urinary tract infection are strongly
associated with renal scarring. Therapeutic delay is thought to
be associated with renal damage.124
++
Risks for recurrence include vesicoureteral reflux, bladder instability,
and a history of prior infection, in addition to the greater rate
of recurrence among females. Up to 40% of children with
febrile recurrences have transient kidney damage, with permanent
damage demonstrated in approximately 5% of patients.125 Thirty
percent to 40% of children will have a renal signal on
scintigraphy following a febrile urinary tract infection, with or
without vesicoureteral reflux. Hypertension develops in approximately
10% of children who have a persistent signal.75
++
Pyelonephritis leading to renal failure in the absence of vesicoureteral
reflux is very rare if it occurs at all.128
++
In a multivariate analysis, vesicoureteral reflux was an independent
risk factor for renal scarring, but urinary tract infection was
not. In the same study, a univariate analysis found decreased bladder
capacity, urine residuals, a trabeculated thick bladder, and urinary
tract infection each associated with vesicoureteral reflux.132 These
results reinforce the concept that vesicoureteral reflux is the
main risk factor; however, causality for renal scarring may be multifactorial
and complex.
++
Suppressive therapy is used in children after the first urinary
tract infection awaiting diagnostic workup for evidence of obstruction
or anatomic abnormalities. Intermediate-term (3–6 months)
suppression is used for children with recurrent but uncomplicated
infection. Longer-term (1 year or more) suppressive therapy is used
in children with recurrent pyelonephritis, as well as in children
with functional or anatomic obstruction, dysfunctional voiding,
bladder mucosal thickening, reflux, renal abnormalities, and other
urinary tract structural abnormalities. Antibiotics for suppression
include: Trimethoprim/sulfamethoxazole (TMP/SMX;
2 mg TMP/10 mg SMX) as a single bedtime dose, or 5 mg TMP/25
mg SMX twice per week; nitrofurantoin (1–2 mg/kg
as a single daily dose); sulfisoxazole (10–20 mg/kg
divided q 12 hours); nalidixic acid (30 mg/kg divided q
12 hours); and methenamine mandelate (75 mg/kg divided
q 12 hours) have all been used for prophylaxis for urinary tract
infections (UTIs). Long-term antibiotic prophylaxis for recurrent
UTI reduces recurrence from 63% to 22%. Nitrofurantoin
is more effective than trimethoprim-sulfamethoxazole, but has more associated
side effects. However, only 17% of children prescribed
antibiotic prophylaxis for vesicoureteral reflux are compliant with the
regimen, which may explain, in part, the 58% failure rate
of prophylaxis within a year of starting.137 In
one large study, antimicrobial prophylaxis did not decrease the
risk of UTI but did increase the risk of infection with resistant
organisms.138
++
Although low-dose ampicillin interferes with adherence of E
coli to bladder mucosa, the clinical relevance of this
finding has not been determined. Postcoital urinary tract infection
may also be reduced by prophylaxis and by voiding after intercourse.139
++
Various other nonspecific general preventive measures may be
helpful in preventing recurrences of urinary tract infections. Nonspecific
preventative measures include adequate fluid intake; frequent voiding,
especially before bedtime; proper perineal hygiene, particularly
after defecation; and avoidance of chronic constipation, which could
produce rectal distention that might distort the bladder. Uncircumcised
males with phimosis may benefit from circumcision. Physical and chemical
irritants of the urethra should be identified and minimized or eliminated.
Individuals with functional abnormalities of the bladder benefit
from intermittent catheterization programs. No evidence-based conclusions
can be made regarding the equipment, techniques, or other interventions
to reduce UTI in patients who require intermittent bladder catheterization.140 Acidification
programs and long-term treatment with methenamine are occasionally
effective; however, they are difficult to maintain.141,142