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Urinary tract infection (UTI) probably affects about one-half of all people during their lifetimes. By some estimates, UTI accounts for more than 10 million office visits and 1 million hospitalizations each year in the United States at a total cost exceeding 1 billion dollars. Up to 10% of UTIs result in serious complications such as gram-negative sepsis or chronic pyelonephritis with loss of renal function. Understanding some key definitions and their limitations facilitates a knowledgeable approach to clinical management.
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Figure 1Epidemiology of clinically-apparent UTI (upper panel) and asymptomatic bacteriuria (lower panel) according to age and sex. |
Overview of the Epidemiology and Etiology UTI in Clinical Practice UTI affects males mainly during infancy and after the fifth decade of life. The higher incidence of UTI in male infants compared to female infants is attributed to males having more congenital abnormalities. Thereafter, symptomatic and asymptomatic UTI becomes mainly a disease of females until the sixth decade. During the reproductive years, women have a 50-fold increased incidence of UTI compared to males. After the fifth decade, the sex distribution of UTI is approximately equal between the sexes as both sexes develop problems with voiding and men develop prostatism (figure 1). In the past all UTIs in males have been considered “complicated.” It is now thought that some males without predisposing anatomic or functional abnormalities develop UTI as a result of sexual activity. Over 90% of UTIs are caused by a single microorganism. Most uncomplicated UTIs are caused by E. coli, which frequently colonizes the periurethral tissues. Staphylococcus saprophyticus, which is one of the coagulase-negative staphylococci, accounts for 10% to 15% of uncomplicated UTI, mainly during the summer months. Complicated UTI is caused by a more diverse group of microorganisms, which, compared to E. coli, are more difficult-to-treat. |
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Laboratory Diagnosis The ease of obtaining urine specimens from most patients and the availability of dipsticks, microscopes, and facilities for culture in most clinics make the laboratory diagnosis of urinary tract infection a relatively straightforward matter. Key findings pointing toward UTI include pyuria (which can, however, have other causes), hematuria (a finding helpful mainly in excluding alternative diagnoses such as urethritis and vaginitis), and significant bacteriuria (as defined above, again with the caveat that < 105 bacteria per mL can sometimes be significant). Recent studies have focused on the extent to which dipsticks can replace traditional microscopy and urine culture for patients with uncomplicated UTI. Patients with complicated UTI, however, deserve cultures because therapy tends to be more prolonged and difficult. Obtaining urine
specimens Gross inspection of
urine Dipstick analysis of
urine The leukocyte esterase test is used to screen for white blood cells in urine. The dipstick should be read at 1 minute. Some experts suggest that it be read again at 5 minutes to increase the sensitivity of the test, which detects the presence of the enzyme leukocyte esterase contained in white blood cells. This test has a reported 75% to 96% sensitivity and a 94% to 98% specificity for detecting pyuria. False-positive tests are usually caused by contamination, often by vaginal secretions. False-negative specimens can be caused by hypertonic urine (as determined by high specific gravity), glycosuria, and urobilinogen. Non-infectious causes of pyuria (sterile pyuria) are discussed below. The nitrite test is used to screen for significant bacteriuria. It is based on two observations: (1) normal urine contains nitrates but not nitrites; and (2) about 90% of bacterial species causing UTI can convert urinary nitrates to nitrites. The nitrite test has a 92% to 100% sensitivity for UTI but only a 35% to 85% specificity. It is most useful for detecting > 105 CFU/mL of aerobic gram-negative rods. The nitrite test is especially useful in patients with indwelling urinary catheters to determine whether or not they are infected. In children, the sensitivity of the nitrite test is high (up to 98%) but specificity is lower (29% to 44%) than in adults. False-positive tests can result from substances that cause red urine such as the ingestion of beets in susceptible subjects or the bladder analgesic phenazopyridine. False-negative nitrite tests can occur in “low-count” UTI (> 105 CFU of bacteria per mL of urine), infections caused by bacteria that do not produce nitrites (such as enterococci), short bladder dwell time, dilute urine specimens, or acid urine. Microscopic
examination of urine Examination of “unspun” (uncentrifuged) urine begins by placing a drop of urine on a glass slide, adding a coverslip, and using the high, dry objective of the microscope. Bacteria, recognizable as rod- or brick-shaped structures, are usually visible in patients whose urine contains > 105 CFU of gram-negative rods per mL. Finding one or more such bacterial structures in each high, dry magnification field carries high positive predictive value for significant bacteriuria due to gram-negative bacilli. Round or irregularly shaped structures, on the other hand, may represent non-specific debris or amorphous phosphates in the urine rather than gram-positive cocci. Observing white blood cells in unspun urine indicates pyuria. These observations on unspun urine can be made without the application of a stain, but require some experience for interpretation. The most accurate method for detecting pyuria is to look at an unspun midstream urine sample with a hemocytometer; 10 or more leukocytes per mL is abnormal. Examination of “spun” (centrifuged) urine entails centrifugation at 2,000 rpm for 5 minutes, discarding the supernatant, and placing a drop of the sediment on a glass slide. A coverslip is added and the specimen is examined with the high, dry objective of the microscope as described above. Alternatively, the drop of sediment is allowed to dry and is then stained with Gram's method. These two methods can be complimentary. The presence of > 5 leukocytes per high-powered field indicates pyuria. This finding is 90% to 95% sensitive for detecting significant bacteriuria. However, it is not specific since sterile pyuria can be caused by other types of infections (genitourinary tuberculosis is a classic cause; others include endocarditis, gonorrhea, and vaginitis) and also by non-infectious conditions such as glomerulonephritis, drugs (notably steroids and cyclophosphamide), trauma, and inflammation of structures abutting on the urinary tract (for example, diverticulitis or appendicitis). The absence of bacteria on Gram's stain of spun urine sediment has a high negative predictive value for significant bacteriuria. Urine culture Determining the number of bacteria in urine is accomplished by plating out cultures using a calibrated loop. A number of alternative methods have been developed such as dip-slides and pipettes coated with culture media. The definition of “significant bacteriuria” as the finding of >105 CFU/mL of urine (see above) derives in part from the bimodal frequency distribution of colony counts in urine cultures. Patients with symptomatic infection usually have counts significantly greater than 105 CFU/mL, (e.g., 106 or 107 CFU/mL) while contaminated cultures usually show fewer than 103 CFU/mL of urine. In other words, most urine cultures will show < 103 CFU/mL or > 105 CFU/mL with relatively few cultures falling in the gray zone in between (that is, 104 CFU/mL of urine). Colony counts less than < 105 CFU/mL of urine can be significant in at least 4 situations:
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Asymptomatic bacteriuria Asymptomatic bacteriuria is a relatively common finding. It is present in up to 5% of unselected medical outpatients, 10% of pregnant patients at term, 14% of hypertensive patients, and 20% of patients with diabetes mellitus. Anatomic obstruction of any kind markedly increases the incidence of asymptomatic bacteriuria. Thus, asymptomatic bacteriuria was found in 23% of women with cystocele, 57% of patients with congenital urologic disease, 85% of patients with hydronephrosis and nephrolithiasis, and in nearly all patients in whom an indwelling retention catheter has been left in place with open drainage for more than 48 hours. Issues in primary care include when and how to diagnose and treat patients with this laboratory finding. Asymptomatic bacteriuria affects mainly women until men develop prostatism. Bacteria colonize the vaginal introitus and then invade the urinary bladder. The mechanism of colonization by E. coli has been studied extensively. The organism adheres to uroepithelial cells by specific binding of bacterial surface molecules (adhesins) to complementary receptors on the host's epithelial cells. The ability of E. coli strains to adhere to uroepithelial cells correlates with the presence of pili or fimbriae. Many studies indicate a genetic susceptibility to colonization in some women. Estrogens increase the likelihood of colonization, and oral contraceptives increase the risk of bacteriuria, apparently by causing physiologic changes in the urinary tract. Most patients remain asymptomatic. In patients without anatomic factors predisposing to UTI, bacteriuria often resolves through normal host defense mechanisms including the mechanical flushing of the urinary stream. Complications such as pyelonephritis and sepsis are likely to occur in certain patient groups: (1) pregnant women; (2) patients undergoing genitourinary surgery; and (3) patients undergoing urethral catheterization in the presence of complicating disease. |
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Urinary Tract Infection in Children During the neonatal period, UTI affects mainly boys. Thereafter, UTI during childhood mainly affects girls. About 30% to 50% of children with UTI have vesicoureteral reflux, which can lead to permanent renal damage. Ultrasonography and voiding cystourethrography are generally recommended for boys who have had one episode of UTI and for pre-school girls who have experienced two episodes. Children with frequent recurrent UTIs and those with severe vesicoureteral reflux should be evaluated by a urologist.
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Uncomplicated Lower UTI (Cystitis) in Non-pregnant Adult Women Acute dysuria in adult women affects millions of women in the United States each year and usually reflects one of three conditions: acute bacterial cystitis, urethritis, or vaginitis. At the time of the initial evaluation, it is sometimes not possible to determine whether acute cystitis is complicated or uncomplicated. Subclinical involvement of the kidney (pyelonephritis) is present in up to 30% to 50% of these cases. Why some patients develop symptomatic inflammation of the bladder (acute cystitis) while others do not (asymptomatic bacteriuria) is poorly understood. Experimentally, 99.9% of a bladder inoculum of bacteria is promptly eliminated by voiding. Thus, establishment of infection is the exception rather than the rule. UTI in women is facilitated by sexual intercourse, during which the urethra often becomes intra-vaginal and bacteria are literally massaged from the periurethral mucosa into the bladder. Daily intercourse for one week increases the likelihood of cystitis by nine-fold. The risk is increased by the use of a diaphragm and by spermicidal contraceptives, which increase the vaginal pH, alter the microbial environment, and enhance the ability of E. coli to adhere to the mucosa. E. coli causes 70% to 90% of episodes of acute cystitis in sexually active younger women. Staphylococcus saprophyticus causes most other episodes, especially during the spring and summer months. Enterococci and various gram-negative rods explain most of the remainder of the cases.
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Acute Upper UTI (pyelonephritis) in Adult Women Acute pyelonephritis is a relatively common problem in adult women, accounting by some estimates for at least 250,000 hospitalizations per year. Many of these patients can be managed as outpatients, sometimes after brief observation in an acute-care facility. It is generally assumed that bacteria ascend from the bladder to the renal pelvis by way of the ureters. Some researchers suggest that bacteria first enter the bloodstream from the renal pelvis through pyelovenous communications and then recirculate to the kidney. Be that as it may, it is easiest to consider most cases of pyelonephritis to be the result of "ascending UTI" as defined above. The renal medulla has been called “an immunologic desert,” since host defenses are rendered relatively helpless by the low pH and high osmolality. Multiplying bacteria can enter the bloodstream, causing the sepsis syndrome. Pyelonephritis in patients with structurally-normal urinary tracts is usually caused by so-called uropathogenic strains of E. coli. Other aerobic gram-negative rods sometimes cause acute pyelonephritis especially in patients with complicated urologic histories. S. saprophyticus, although a common cause of acute cystitis, seldom causes pyelonephritis. Whether atypical microorganisms such as Ureaplasma urealyticum and Mycoplasma hominis cause acute uncomplicated pyelonephritis is unclear. Acute pyelonephritis occurs both with and without symptoms of lower UTI, such as frequency, urgency, and dysuria. The hallmark symptoms are fever and flank pain. However, nausea and generalized abdominal pain often dominate the clinical picture. Acute disease of the gastrointestinal tract (such as acute appendicitis, cholecystitis, or pancreatitis) and pelvis (pelvic inflammatory disease, ectopic pregnancy) must be considered in the differential diagnosis. Physical examination should focus on the vital signs, the abdomen, and the costovertebral angle (CVA). Careful measurement of temperature is important, since fever with UTI strongly suggests pyelonephritis. An increased respiratory rate can indicate respiratory compensation for metabolic acidosis. The abdomen should be examined especially for adnexal tenderness, which may suggest that the correct diagnosis is actually pelvic inflammatory disease. CVA tenderness is the classic physical finding in pyelonephritis. Pyuria is nearly always present. As already mentioned, it can be absent if the site of infection is excluded from the normal flow of urine, as is the case with complete ureteral obstruction or perinephric abscess. Hematuria may be present but does not help differentiate pyelonephritis from cystitis. Urine culture reveals > 105 CFU/mL in 80% to 95% of cases. Some patients, as discussed above, have lower colony counts. Between 10% and 20% of patients will have positive blood cultures. However, there is no evidence that patients with positive blood cultures do worse than patients whose blood cultures are sterile, and it is therefore reasonable to limit blood cultures to patients who require hospitalization. Many researchers have sought ways to discern between upper and lower UTI. These include ureteral catheterization (accurate but invasive), Fairley's bladder washout test (helpful but labor-intensive), the antibody-coated bacteria test (now generally out of favor because of questions about its accuracy), measurement of urinary concentrating ability, serum antibody levels, and urinary levels of various enzymes and β2-microglobulin. To date, none of these tests or procedures can be recommended for management of UTI in daily office practice. Patients with UTI and any combination of fever, flank pain, or CVA tenderness should be treated appropriately for pyelonephritis.
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UTI During Pregnancy Pregnancy markedly predisposes to pyelonephritis, which can harm both the mother and the fetus. Bacteriuria during pregnancy is associated with prematurity and low birth weight, although a cause-and-effect relationship is unclear. Urine culture should be obtained at the first prenatal visit. Dipstick methods are insufficiently sensitive for screening for bacteriuria in pregnancy. Patients with asymptomatic bacteriuria should be treated with a 3-day course of antibiotics and followed closely.
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Complicated UTI in Adults A minority of women with acute pyelonephritis experience complications that can potentially lead to chronic pyelonephritis and renal failure. UTI in men is often complicated and is likely to be associated with obstructive uropathy and/or prostatitis. Complicated UTI occurs in specific clinical settings. Renal abscess can result from hematogenous seeding of the renal cortex (most often due to S. aureus) or from ascending infection leading to severe pyelonephritis (most often due to gram-negative rods). Perinephric abscess usually occurs in the setting of structural or functional abnormalities of the urinary tract. Vesicoureteral reflux, although less common than in children, sometimes occurs in adults (and then generally in women). Struvite or infection stones result from UTI caused by urease-producing bacteria, most often Proteus species and especially Proteus mirabilis. The urine is typically alkaline (pH > 7). Large “staghorn” calculi that form casts of the renal pelvocalyceal system are sometimes apparent on plain x-ray. The range of causative bacteria is much more diverse than is the case in uncomplicated UTI. One frequently encounters aerobic gram-negative rods such as Klebsiella, Enterobacter, Serratia, or Providencia species, enterococci, and fungi. Complicated UTI is often polymicrobial (that is, urine culture reveals two or more species of microorganisms). Fungal UTI presents special problems.
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Prostatitis The term “prostatitis” encompasses a spectrum of disorders, some of which are infections and some of which are probably not. Among these disorders, acute bacterial prostatitis is by far the most serious but also the least common. Bacteria usually enter the prostate by reflux of urine from the urethra into the prostatic ducts. E. coli and Proteus species are the most commonly-isolated bacteria. Patients with acute bacterial prostatitis usually present with dramatic systemic and local symptoms. Fever, chills, malaise, and myalgia suggest acute infection. Dysuria, pelvic or perineal pain, and difficulty voiding suggest the site of infection. Laboratory findings include leukocytosis and pyuria. When all of these findings are present and the diagnosis seems straightforward, rectal examination should be avoided since it will be painful and may cause bacteremia. Compared to acute bacterial prostatitis, chronic bacterial prostatitis is more common and presents as a more subtle illness with recurrent urinary tract infections accompanied by a large, “boggy” prostate. A somewhat cumbersome procedure known as the four-cup test is the cornerstone to accurate diagnosis. Gram-negative rods such as E. coli are the most common causes. E. coli strains causing prostatitis have virulence factors similar to those that cause pyelonephritis in women. The disease can be caused by enterococci and perhaps by Staphylococcus saprophyticus. A few cases are polymicrobial. Evidence that Chlamydia trachomatis causes chronic prostatitis is inconclusive. Most men evaluated for prostatitis (>90% by some estimates) are given the diagnosis of chronic nonbacterial prostatitis or chronic pelvic pain syndrome. These overlapping syndromes are extremely common, poorly understood, and separated from each other mainly on the basis of examination of the prostate and microscopic examination of prostatic secretions.
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Epididymitis Epididymitis, which is usually but not always an infectious disease, accounts for more than 600,000 physician visits in the United States each year according to one estimate. In younger men, it is usually caused by sexually-transmitted pathogens. In older men it is usually a bacterial disease associated with prostatic enlargement. Epididymitis must be distinguished from testicular torsion, a urologic emergency. Microorganisms can enter the epididymis from the prostate by way of the ejaculatory duct. Healthy younger men with sexually-transmitted disease usually have no predisposing factors. The usual pathogens, in order of frequency, are Chlamydia trachomatis, Neisseria gonorrhoeae, and Ureaplasma urealyticum. In older men, the usual causes are aerobic gram-negative rods such as E. coli, other Enterobacteriacae, and Pseudomonas species, but gram-positive cocci are also common. Tuberculous epididymitis was formerly common, and epididymitis continues to be the most common manifestation of genitourinary tuberculosis in men. Predisposing factors to epididymitis include acute or chronic bacterial prostatitis, neurogenic bladder, indwelling urinary catheters, recent urologic surgery, and recent or remote prostatectomy or vasectomy.
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