Chapter 238. Urinary Tract Infections

Keith M. Krasinski

Urinary Tract Infections: Introduction

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.

Epidemiology

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

Host Defense Factors

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.

Humoral Immaturity

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

Host Flora

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.

Predisposing Factors

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.

Genetic Factors

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.

Clinical Features

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 Tests

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.

eTable 238.1. Screening and Diagnostic Testing for Symptomatic Urinary Tract Infection88,89,92,93

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eTable 238.1. Screening and Diagnostic Testing for Symptomatic Urinary Tract Infection88,89,92,93

Method

Estimated/Approximate % (range)

Sensitivity

Specificity

Microscopy

Pyuria (>20 WBC/hpf)

73 (32–100)

81 (45–98)

Bacteriuria

81 (16–99)

83 (11–100)

Dipstick

Nitrite positive

53 (15–82)

98 (90–100)

Leukocyte esterase positive

83 (67–94)

78 (64–92)

Nitrite or leukocyte esterase positive

93 (90–100)

72 (58–91)

Microscopy or dipstick positive

99.8 (99–100)

70 (60–98)

Culture

Estimated/Approximate Probability of Infection (%)

Suprapubic

Gram-negative bacilli

Any positive

> 99

Gram-positive cocci

> 2,000–3,000

> 99

In-and-out catheterization

> 100,000

50,000

< 1000

Unlikely

Midstream, clean catch

> 100,000 × 1

100,000 × 2

100,000 × 3

10,000

Suspicious

< 10,000

Unlikely

Bag or random

Do not send for culture for diagnosis of urinary tract infection

Data from: Bachur R, et al. Arch Pediatr Adolesc Med. 2001;155:60-65; Shaikh, N, et al. JAMA. 2007;298:2895-2904; Hoberman A, et al. J Pediatr. 1994;124:513-519; Hellerstein S. Pediatr Infect Dis J. 1982;1:271-281.

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.

Urine Culture

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.

Figure 238-1.

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Management approach to urinary tract infection (UTI). UA, urinalysis; VCUG, voiding cystourethrogram.

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.

Treatment

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.

Table 238-1. Antibiotic Therapy for Urinary Tract Infection*

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Table 238-1. Antibiotic Therapy for Urinary Tract Infection*

Age

Site

Organism

Comment

Recommended Antibiotic

<1 month

All sites

Identification pending or unknown

Little ability to restrict spread of infection or to localize site of infection. Treat UTI as pyelonephritis with generalized sepsis and consider the possibility of meningitis

Ampicillin PLUS cefotaxime

Ampicillin PLUS gentamicin

Gram-negative bacilli

Cefotaxime OR aminoglycoside

OR ampicillin (if susceptible)

Pseumonads

Ceftzidine PLUS tobramycin OR meropenem OR cefipine

Enterococci

Ampicillin susceptible

Ampicillin (add gentamicin if demonstrated synergy)

Ampicillin resistant

Vancomycin (add gentamicin if demonstrated synergy)

Staphylococcus aureus

Methicillin sensitive

Oxacillin OR nafcillin

Methicillin resistant

Vancomycin OR clindamycin OR linezolid

1 to 3 months

All sites

All pathogens except E. coli

Treat as for < 1 month old

E. coli

If E. Coli most likely, or confirmed, there is an increased likelihood of bactermia and meningitis versus older children

Ceftriaxone IV for 7 to 10 days

> 3 months

Cystitis

Identification pending or unknown

Mild

Trimethoprim/sulfamethoxazole (rate of resistance to TMP/SMX is 20 % in some areas) OR ciprofloxacin (above 1 yr) OR amoxicillin (if susceptible)

Moderate

Cefixime OR ciprofloxacin

Severe

Ceftriaxone IV

Pyelonephritis

Identification pending or unknown

E. coli most common

Ceftriaxone IV or IM then switch to amoxicillin or trimethoprim/sulfamethoxazole cefixime based upon susceptibilities

Adolescents

Cystitis

Identification pending or unknown

If risk factors for STD, assess for gonococcal and/or C. trachomatis infection

Ceftriaxone IV OR nitrofurantoin OR fosfomycin (single dose)

Pyelonephritis

Identification pending or unknown

Mild

Ciprofloxacin OR other fluoroquinolone

Moderate, severe, or hospitalized

Fluoroquinolone IV OR ampicillin PLUS gentamicin OR antipseudomonal penicillin

All ages

Complicated or obstruction or catheter related

Usually gram-negative enteric bacilli, pseudomonads, enterococci, staphylococci

Ampicillin PLUS gentamicin OR piperacillin/tazobactam OR ticarcillin/clavulanic acid OR imipenem OR meropenem OR fluoroquinolone (for adolescents)

<3 mo

Prophylaxis

While waiting anatomic evaluation following acute urinary tract infection

Ampicillin

Children and adolescents

Prophylaxis

Recurrent/symptomatic infection

Trimethoprim/sulfamethoxazole OR nitrofurantoin

*Recommendations based upon references 1, 2, 135, 136, 141, 142.

DS, double strength; TMP/SMX, trimethoprim/sulfamethoxazole; UTI, urinary tract infection.

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.

Complications

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

Prognosis

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.

Prevention

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

References

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Chapter 238. Urinary Tract Infections

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Urinary Tract Infections: Introduction

Epidemiology

Pathophysiology and Genetics

Microbial Virulence Factors

Host Defense Factors

Urine Flow and Chemisty

Urine Antibacterial Activity

Humoral Immaturity

Host Flora

Predisposing Factors

Vesicoureteral Reflux and UTI

Genetic Factors

Clinical Features

Diagnostic Evaluation

Laboratory Tests

Urine Culture

Localization of Infection

Differential Diagnosis

Radiologic Evaluation

Figure 238-1.

Treatment

Complications

Prognosis

Prevention

References

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