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Approach to the Patient with Urinary Tract Infection
Definitions
Urinary tract infection (UTI) is bacterial or fungal infection of urine with associated signs or symptoms. The clinical presentation varies from cystitis (bladder or lower tract infection) to pyelonephritis (renal or upper tract infection) and urosepsis (systemic inflammatory response syndrome or septic shock from a urinary source). Asymptomatic bacteriuria is best considered a state of colonization that requires treatment in only specific clinical circumstances. Urethritis caused by Chlamydia trachomatis , Ureaplasma urealyticum ( Chapter 264 ), or Neisseria gonorrhoeae ( Chapter 275 ), as well as prostatitis ( Chapter 114 ) and renal tuberculosis ( Chapter 299 ), are addressed elsewhere in this text.
UTIs should be classified by the site of infection, tendency to recur, and presence or absence of complicating factors. Uncomplicated UTI occurs mainly in women with normal genitourinary tracts. Most uncomplicated UTIs present as cystitis; acute nonobstructive pyelonephritis also occurs in these women but at a lower frequency. Complicated UTI, which is often associated with host factors that facilitate the establishment and persistence of bacteriuria or infection ( Table 263-1 ), typically refers to UTI occurring in patients with functional or structural abnormalities of the urinary tract. Uncomplicated UTI rarely occurs in young men, and any man who presents with a UTI should be assumed to have complicated infection until proven otherwise. Recurrent UTI is typically considered a reinfection when it is caused by a new bacterial strain and a relapse when the same strain that caused preceding infections is isolated, especially when the subsequent infection occurs within 30 days of completing therapy.
TABLE 263-1
HOST FACTORS ASSOCIATED WITH COMPLICATED URINARY TRACT INFECTION
| EXAMPLES | |
|---|---|
| Obstruction | Urethral or ureteric strictures Tumor Diverticula Pelvicalyceal junction obstruction Prostate enlargement Urolithiasis Extrinsic compression |
| Functional | Neurogenic bladder Vesicoureteral reflux Anatomic defects Pregnancy Turbulent urethral urine flow Cystocele |
| Urologic interventions | Urethral or suprapubic catheters Urologic surgery Ureteric stents Nephrostomy tubes Cystoscopy Neobladders |
| Metabolic or congenital diseases | Urethral valves Polycystic kidneys Nephrocalcinosis Medullary sponge kidney |
| Immunologic abnormalities | Renal transplantation |
Epidemiology
UTI is the most common bacterial infection. It is somewhat more common in boys than in girls in the newborn period because of the higher frequency of urethral malformations in boys. Later in childhood, UTIs are more common in girls, as is asymptomatic bacteriuria. More than half of all healthy women experience at least one symptomatic UTI in their lifetime, and each year, 2 to 10% of women experience at least one episode. The estimated annual rates of outpatient clinical UTI are 5.4/100 person-years based on antibiotic prescriptions and 2.6/100 person-years based on a positive urine culture.
UTI is uncommon in men with a normal genitourinary tract but increases after the age of 65 years, primarily attributable to prostatic hypertrophy and prostatitis ( Chapter 114 ). The frequency of infection in patients with complicating factors varies by the abnormality that promotes infection. For example, patients who have a neurogenic bladder have continuing high rates of infection, but patients whose abnormalities can be corrected will no longer be at an increased risk of infection after the issue is corrected. UTI is also one of the most common hospital-acquired infections; about 80% of these are a consequence of the use of an indwelling bladder catheter. However, many of these “catheter-associated” UTIs are actually asymptomatic bacteriuria detected via unnecessary urine cultures.
Asymptomatic bacteriuria is common. Its prevalence increases from 1 to 2% of schoolgirls to 3 to 5% of sexually active premenopausal women, 10 to 20% of healthy postmenopausal women, and 40 to 50% of elderly women in nursing homes. UTIs are infrequent in men until older ages, with 5 to 10% of elderly men in the community and 35 to 40% of men in nursing homes having bacteriuria. Patients with genitourinary complications also have a very high prevalence of bacteriuria. For example, 50% of patients with a neurogenic bladder and without an indwelling catheter and virtually 100% of patients with chronic indwelling catheters have bacteriuria.
Pathobiology
Acute uncomplicated UTI follows ascension of normal gut flora, which have colonized the vagina and periurethral mucosa, into the bladder or kidney. The ability of these uropathogenic organisms, usually Escherichia coli , to colonize and to persist within the urinary tract is dependent on an array of virulence factors that include adhesins, toxins, and iron-scavenging proteins. Uromodulin, which is the most abundant protein in human urine, forms filaments that antagonize the adhesion of uropathogens and allows their clearance by micturition. The organism’s virulence is a major determinant of whether symptomatic infection develops and whether it is manifested as cystitis or pyelonephritis. Bacterial strains that cause uncomplicated infection typically express the FimH adhesin, but this adhesin is not specific for UTI. E. coli isolated from uncomplicated pyelonephritis are characterized by the presence of the P fimbria adhesin Gal(α1-4) Galβ disaccharide globoside, which initiates mucosal inflammation. Adherence of organisms in the bladder or kidney activates the innate immune response, thereby leading to release of cytokines, particularly interleukin-6 and interleukin-8, and mobilizes leukocytes. This process results in pyuria as well as local or systemic symptoms, including fever in patients with pyelonephritis.
The occurrence of acute uncomplicated UTI in healthy premenopausal women is determined by both genetic and behavioral factors. A genetic predisposition is supported by observations that a history of prior UTI is consistently one of the strongest associations with recurrent uncomplicated UTI, and women who experience these infections report a higher proportion of first-degree female relatives with recurrent UTI than do those without infection. One established genetic association is being a nonsecretor of the ABH blood group antigen (being unable to secrete blood type antigens into body fluids), with more avid binding of uropathogenic organisms to the vaginal epithelium in nonsecretors. Genetic polymorphisms affecting innate immunity are correlated with increased frequency of infection as well as with specific presentations.
Behavioral risk factors are similar for women for cystitis, pyelonephritis, and asymptomatic bacteriuria. The strongest behavioral factors are sexual intercourse and spermicide use. For sexually active premenopausal women, 75 to 90% of episodes are attributed to intercourse. This association is primarily attributed to ascension of periurethral organisms into the bladder during intercourse, but unprotected vaginal sex may also reduce endogenous anti– E. coli activity. The normal lactobacillus flora of the vagina maintains an acid environment that prevents colonization by potential uropathogens, and spermicides suppress this normal flora. Despite popular perceptions, use of oral contraceptives or condoms, postcoital voiding, type of underwear, personal hygiene after voiding or defecating, and taking a bath rather than a shower are not associated with recurrent UTI. Sexual intercourse is not a major contributor to UTI in postmenopausal women, in whom the most important determinants of infection are a history of UTI at a younger age and nonsecretory status (see earlier).
The risk of complicated UTI is determined by the underlying abnormality. Genitourinary abnormalities facilitate infection by increasing the entry of organisms into the bladder, such as via intermittent catheterization or urologic procedures, and the persistence of organisms within the urinary tract because of incomplete voiding or their persistence in biofilms on urologic devices. The determinants that promote symptomatic infection rather than asymptomatic colonization are not well characterized. However, obstruction and mucosal trauma with bleeding are well-recognized antecedents for bacteremia and sepsis in patients with preexisting bacteriuria. Although it is generally accepted that patients with diabetes have an increased incidence of UTI, this risk correlates more with long-term complications of diabetes, such as neurogenic bladder, than with the diabetes itself. Patients with poorly controlled diabetes, however, are at risk for more severe manifestations of infection.
Acquisition of bacteriuria in individuals with indwelling urinary devices, including catheters, stents, and nephrostomy tubes, is primarily attributable to the development of biofilms along the device. Biofilms are composed of an extracellular polysaccharide material that is produced by the organisms and that incorporates urine components, including Tamm-Horsfall protein, as well as magnesium or calcium ions. After insertion of the device, a conditioning layer composed of proteins and other host components immediately coats the device. Organisms adhere to this conditioning layer and initiate the formation of biofilm. Colonization usually begins at the urethral orifice or in the drainage bag, and the biofilm then ascends the catheter. Organisms growing in the biofilm persist in an environment relatively protected from antibiotics or host defenses. For patients who have an indwelling catheter, the acquisition of bacteriuria occurs at a rate of 3 to 7% per day. Bacteriuria that follows insertion of an indwelling catheter initially is usually with a single organism, but polymicrobial flora, particularly including Proteus mirabilis , is typical in mature biofilms on chronic indwelling devices. P. mirabilis strains may produce copious biofilm, and the related production of urease creates an alkaline environment, thereby leading to precipitation of calcium and magnesium ions. The resultant “crystalline biofilm,” which is similar to what causes infection-related kidney stones, may obstruct an indwelling catheter. About 80% of episodes of obstructed urinary catheters are attributable to P. mirabilis .
Etiology
In all types of UTI, E. coli ( Chapter 280 ) is the dominant bacterial species, and it causes up to 85% of all symptomatic UTIs in women with community-acquired infections ( Table 263-2 ). The second most common species causing uncomplicated cystitis is Staphylococcus saprophyticus , which is isolated more frequently in later summer and early fall. In patients who have recurrent complicated UTIs, species such as Enterococcus faecalis ( Chapter 270 ), Enterococcus faecium , Klebsiella species ( Chapter 281 ), Proteus species ( Chapter 281 ), Providencia stuartii , and Morganella morganii become more common. In patients with very frequent recurrences or with bladder catheters, particularly patients in hospitals and nursing homes where antimicrobials are frequently used, E. coli accounts for less than 50% of UTIs, and patients instead may have infections caused by Pseudomonas aeruginosa ( Chapter 282 ), Acinetobacter baumannii , Serratia marcescens , and Stenotrophomonas maltophilia isolated. Urolithiasis attributed to infected stones is associated with urease-producing organisms; the alkaline urine created facilitates struvite formation. Repeated antimicrobial treatment administered to patients with recurrent complicated UTI often leads to increased antimicrobial resistance in the organisms isolated from recurrent infections. In health care facilities, the catheterized urinary tract is the most common site for the isolation of multiple drug–resistant gram-negative organisms, including extended-spectrum β-lactamase–producing and carbapenemase-producing Enterobacteriaceae. Candida sp is the most common cause of fungal UTI. Patients with Candida UTI often have diabetes or an indwelling urinary catheter, as well as prior exposure to broad-spectrum antimicrobial agents.
TABLE 263-2
MICROBIAL ETIOLOGY OF URINARY TRACT INFECTIONS
| ORGANISMS | CLINICAL CHARACTERISTICS |
|---|---|
| GRAM-NEGATIVE BACTERIA | |
| Escherichia coli | Typical |
| Klebsiella pneumoniae | Often reinfection |
| Enterobacter spp | Often reinfection or health care–associated infection ∗ |
| Proteus spp | May indicate calculi; frequent with devices |
| Providencia stuartii | Often reinfection or health care–associated infection ∗ |
| Morganella morganii | Often reinfection or health care–associated infection ∗ |
| Serratia marcescens | Often health care–associated infection ∗ |
| Acinetobacter baumannii | Often health care–associated infection ∗ |
| Burkholderia spp | Often health care–associated infection ∗ |
| Pseudomonas aeruginosa | Often health care–associated infection ∗ |
| Stenotrophomonas maltophilia | Often health care–associated infection ∗ |
| GRAM-POSITIVE BACTERIA | |
| Staphylococcus saprophyticus | Most common during late summer and fall |
| Staphylococcus aureus | May indicate focus outside the genitourinary tract |
| Enterococcus spp | Often reinfection |
| Other gram-positive bacteria | In most cases contaminants or colonizers |
| FUNGI | |
| Candida spp | May indicate focus outside the genitourinary tract |
Clinical Manifestations
The onset of cystitis is rapid, and symptoms ( Table 263-3 ) usually develop within 24 hours. Clinically, the lack of vaginal discharge can differentiate cystitis from urethritis ( Chapter 264 ) caused by chlamydia, ureaplasma, or gonococci. Women who experience recurrent episodes of acute uncomplicated UTI are more than 90% reliable for self-diagnosis.
TABLE 263-3
CLINICAL SYMPTOMS OF URINARY TRACT INFECTIONS
| TYPE OF URINARY TRACT INFECTION | TYPICAL SIGNS OR SYMPTOMS |
|---|---|
| Cystitis | Frequency Dysuria Urgency Stranguria (difficulty in micturition) Suprapubic pain Hematuria |
| Pyelonephritis | Costovertebral angle pain or tenderness Fever Chills Cystitis symptoms (may be absent) |
| Urosepsis | Fever Chills, rigors Sepsis syndrome |
Pyelonephritis may also have a rapid onset and may or may not be associated with symptoms of cystitis. Bacteremia occurs in 10 to 30% of patients but does not have prognostic significance. The typical flank pain and tenderness, which result from inflammation and edema of the renal parenchyma, may be masked by the intake of analgesic drugs such as acetaminophen, which may also reduce the fever. An important differential diagnosis is renal calculus ( Chapter 111 ), in which the pain may have a similar location but fever is not present unless the stone is complicated by infection.
Complicated UTI manifests across a clinical spectrum from minimal voiding abnormalities to symptoms consistent with cystitis, pyelonephritis, or severe sepsis. Urosepsis is a life-threatening condition, usually associated with bacteremia. Obstruction, which is more common in men with prostatic hypertrophy ( Chapter 114 ), or trauma to the mucosa from an indwelling catheter or urologic surgery may precipitate bacteremia. Patients who present with urosepsis typically have complicated UTI rather than nonobstructive pyelonephritis. Urosepsis can present with or progress to septic shock ( Chapter 94 ), which requires life-supporting treatment in addition to antibiotics.
Diagnosis
Laboratory Findings
The hallmark of the diagnosis of UTI is demonstration of bacteriuria in a urine sample. A pretherapy urine culture specimen should be obtained for all patients who present with pyelonephritis, urosepsis, or complicated UTI or when the diagnosis is uncertain. Routine culture is not generally recommended for acute uncomplicated cystitis because the clinical presentation is characteristic, and empiric short-course therapy often resolves symptoms by the time the culture is available. However, frequently recurrent cystitis raises the likelihood of bacterial resistance, so a culture should be obtained in this situation, in patients with an early recurrence post-therapy, and in patients with persistent symptoms despite appropriate empiric antimicrobial therapy.
Urine specimens for culture must be collected before institution of antimicrobial therapy because the urine is rapidly sterilized after initiation of systemic antimicrobials. The usual collection method is a midstream urine sample to limit contamination. For patients with indwelling catheters, specimens should be collected from the catheter port and not from the drainage bag. All specimens should be taken promptly to the laboratory to prevent growth of contaminants during transportation.
The interpretation of the quantitative urine culture varies with the clinical presentation and collection method ( Table 263-4 ). Significant bacteriuria is usually 10 5 CFU/mL or more, where one colony-forming unit (CFU) is one or more bacterial cells forming a colony when growing on an agar plate. In women with symptoms of uncomplicated cystitis, 10 2 CFU/mL or more in midstream urine of E. coli or S. saprophyticus is consistent with infection. Other gram-positive organisms at any quantitative count should be interpreted as contaminants, except for Staphylococcus aureus , which may be identified in the urine owing to renal filtration in patients who have S. aureus bacteremia or endocarditis.
TABLE 263-4
INTERPRETATION OF THE QUANTITATIVE URINE CULTURE
| QUANTITATIVE BACTERIAL COUNT | |
|---|---|
| Asymptomatic bacteriuria | ≥10 5 CFU/mL in two consecutive specimens for women |
| Acute uncomplicated cystitis | ≥10 2 CFU/mL of Escherichia coli or Staphylococcus saprophyticus |
| Acute uncomplicated pyelonephritis | ≥10 4 CFU/mL (95% have ≥10 5 CFU/mL) |
| Complicated urinary tract infection | ≥10 5 CFU/mL (lower counts may occur with diuresis) |
| Intermittent or in and out catheter collection | ≥10 2 CFU/mL |
| Suprapubic or percutaneous aspiration | Any organisms isolated |
CFU = colony-forming unit.
Pyuria is present in most patients with symptomatic UTI or asymptomatic bacteriuria. Many other abnormalities are, however, associated with pyuria, and the presence of pyuria does not diagnose infection or differentiate symptomatic from asymptomatic infection. The absence of pyuria has a high negative predictive value to exclude UTI for most patients. However, the absence of pyuria in a urine specimen from a woman with symptoms compatible with cystitis is not an indication to withhold empiric antimicrobial therapy.
For rapid screening for possible bacteriuria, identification of nitrite by dipstick urine testing may be useful, with a sensitivity of about 90%. Gram-negative bacteria, with the exception of P. aeruginosa , will metabolize nitrate to nitrite, which can be demonstrated by a color reaction on a dipstick. Gram-positive bacteria and fungi do not metabolize nitrate. The technique is rapid (<1 minute) and inexpensive. It has a high degree of specificity but is insensitive because it does not detect infections caused by gram-positive organisms.
Conversely, some patients with evident pyuria will have negative urine cultures. Infectious causes of sterile pyuria include tuberculosis ( Chapter 299 ), gonorrhea ( Chapter 275 ), chlamydia ( Chapter 294 ), mycoplasma ( Chapter 293 ) and ureaplasma ( Chapters 293 and 264 ), genital herpes ( Chapter 345 ), trichomoniasis ( Chapter 324 ), fungal infections ( Chapter 314 ), and schistosomiasis ( Chapter 326 ).
Blood culture specimens should be obtained in all patients with suspected urosepsis. Patients with acute pyelonephritis, but not those with acute cystitis, have increased serum levels of C-reactive protein.
Imaging
Early imaging should be performed in any patient with urosepsis to identify abnormalities that require immediate source control. The optimal imaging modality is a computed tomography scan with intravenous contrast. Magnetic resonance imaging may not identify gas in tissues or small stones. Ultrasound may provide a rapid examination to exclude significant obstruction. Investigations are also indicated for patients with delayed response or failure to respond to appropriate antimicrobial therapy or with early relapse of pyelonephritis after completion of therapy. Because the optimal management of a complicated urinary infection requires characterization and potential correction of any underlying anatomic abnormalities, selected patients may require imaging studies for the diagnosis of vesicoureteral reflux ( Chapter 113 ) or to characterize differential renal function.
Differential Diagnosis
Clinical manifestations will usually differentiate acute cystitis and acute pyelonephritis ( Table 263-5 ). New-onset frequency, dysuria, and urgency without accompanying vaginal discharge or pain have a positive predictive value of 90% for acute cystitis. The differential diagnosis for women presenting with acute irritative lower tract symptoms includes sexually transmitted infections, vulvovaginal candidiasis, and noninfectious causes such as interstitial cystitis. Some patients who present with only lower tract symptoms may have renal infection, referred to as occult pyelonephritis. Patients with appendicitis ( Chapter 128 ) and cholecystitis ( Chapter 141 ) can present with flank pain similar to right-sided pyelonephritis, and pelvic inflammatory disease ( Chapter 264 ) may be misdiagnosed as urinary infection.
TABLE 263-5
DECISION PROCESS FOR DIAGNOSIS AND TREATMENT OF UPPER (PYELONEPHRITIS) VERSUS LOWER (CYSTITIS) URINARY TRACT INFECTIONS
| CYSTITIS | PYELONEPHRITIS | |
|---|---|---|
| SIGNS AND SYMPTOMS | ||
| Fever | No | Yes |
| Dysuria | Yes | May be present |
| Frequency | Yes | May be present |
| Flank pain | No | Yes |
| DIAGNOSIS | ||
| Pyuria | Yes | Yes |
| Nitrite test result | Normally positive | Normally positive |
| Bacteriuria | Yes | Yes |
| C-reactive protein | Normal | Increased |
| Blood cultures | Negative | Positive in ≈10-30% |
| TREATMENT | ||
| First line | Short-term oral therapy ( Table 263-6 ) | Oral: fluoroquinolone for 7 days; parenteral: cephalosporin, fluoroquinolone, or aminoglycoside for 7-14 days ( Table 263-7 ) |
| Second line | Fluoroquinolone for 3 days or cephalosporin for 7 days | Injectable cephalosporin until afebrile, followed by oral step-down for total of 2 weeks |
| Pregnant women | Nitrofurantoin or cephalosporin for 5-7 days | Injectable cephalosporin until afebrile, followed by oral cephalosporin for 14 days |
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