Supriya Koya, MD Resident UAB Internal Medicine Residency Program Montgomery, Ala W. J. Many, Jr, MD Professor of Medicine Program Director UAB Internal Medicine Residency Program Montgomery, Ala Jewell H. Halanych, MD, MSc Assistant Professor Division of Preventive Medicine University of Alabama at Birmingham Birmingham, Ala

Urinary tract infections are one of the most common bacterial infections encountered in primary care practice. These infections constitute a spectrum ranging from asymptomatic bacteriuria to complicated conditions involving significant systemic toxicity. Our understanding of the pathogenesis and management of urinary tract infections has undergone a myriad of changes during the past few decades. This article presents a comprehensive overview of the epidemiology and etiology of urinary tract infections and details current cost-effective, evidence-based management strategies for the various types of such infections.

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It is estimated that 150 million episodes of urinary tract infections (UTIs) occur each year globally, at an annual cost of $6 billion.¹ In the United States alone, UTIs account for about 9.9 million physician visits annually2 and are responsible for almost $3.5 billion in health care costs.^3,4 These infections are more common in women, with more than 50% of women having at least 1 UTI in their lifetime.³ Only about 20% of all cases occur in men,⁴ but this gender disparity lessens in the elderly and infant populations. An average of 250,000 episodes of pyelonephritis occur annually.¹ Catheter-associated UTIs account for 40% of all nosocomial infections.⁵

Pathophysiology
The urinary tract is normally sterile tract and is made up of the kidneys, ureters, bladder, and urethra. Infections typically occur when bacteria that have entered through the urethra multiply in the urinary tract. A descending spread of infection from the bloodstream, such as bacteremia from severe sepsis, is a less common route.

Risk Factors
Any structural or functional abnormality that slows the flow of urine from the ureters to the bladder sets the stage for infection. In women it is thought that the proximity of the urethra to the source of infection (anus, vagina) provides easy access to the bladder. Sexual intercourse or diaphragm use increases the risk for UTI.⁶ The lower incidence of UTI in men is believed to be the result of their longer urethra, lower rates of colonization, drier periurethral environment, and resistant prostatic secretions.⁷

Diagnostic Testing
When combined with clinical features, laboratory tests aid in the diagnosis of UTI (Table 1). Tests can also identify the specific etiologic organism and its antibiotic susceptibility, allowing for sensitivity-directed treatment.

Table 1

Laboratory tests for UTI in adults

Sensitivity,*

Specificity,*

Test

Indications

%

%

Comment

Leukocyte esterase

Rule in/rule out infection

48-86

17-93

Contamination of urine from vaginal bacteria can cause false-positive results

Nitrite

Detect conversion of nitrate to nitrite due to Enterobacteriaceae and other gram-negative bacteria

45-60

85-98

Requires a sample from thefirst urine in the morning

Nitrite + leukocyte

Detect bacteriuria and pyuria simultaneously

68-88

70-87

2 tests usually better thanesteraseeither alone; can rule outbacteriuria

Urine culture/sensitivity

Outpatients with recurrent UTIs, treatment nonresponse, or complicated UTI; hospitalized patients with UTI; pathogen-directed treatment

NA

NA

Presence of bacteriuriagenerally considered to be>105 CFU/mL

Urine microscopy

Typical UTI symptoms but negative leukocyte esterase test; pathogen identification; detection, quantification of pyuria

89-94

98-99

Bacteriuria/pyuria detectedby Gram’s stain or directobservation

CFU = colony-forming unit; NA = not applicable; UTI = urinary tract infection.

*Reference 8 for all, except urine microscopy: Hiraoka M, Hida Y, Mori Y, et al. Scand J Clin Lab Invest. 2005;65:125-132.

Urinalysis is the initial study when UTI is suspected clinically. The test includes analysis of the physical characteristics of the urine, measurements of urinary nitrite and leukocyte esterase enzymes, microscopic examination, Gram’s stain, and urine culture and sensitivity. A midstream specimen should be collected after thorough cleansing of the periurethral area. Samples may be centrifuged at 2000 rpm for 5 minutes before examination under high-power magnification.

Urine leukocyte esterase testing evaluates for the presence of the leukocyte esterase enzyme in white blood cells (WBCs), which indicates pyuria and thus UTI. A recent meta-analysis of 70 well-designed trials found that the sensitivity of this test ranged from 48% to 86% and specificity from 17% to 93%.⁸ False-positive results may occur when the urine specimen is contaminated with vaginal secretions; false-negative results are possible when the sample contains high levels of protein or glucose.

Urine nitrite testing evaluates for nitrite that has been converted from nitrate by the enzyme reductase produced by various species of gram-negative bacteria. Compared with the leukocyte esterase test, its sensitivity is lower (45%-60%), but the specificity is higher (85%-98%) for bacteriuria and UTI.⁸ When both tests are combined, sensitivity increases to anywhere from 68% to 88%.⁸ False-negative results can occur when the infection is caused by organisms that do not produce the reductase enzyme, dietary nitrate intake is low, urine does not remain in the bladder long enough for the reduction of nitrate to occur, or the bacteriuria count is low (ie, 102 to 104 colony-forming units [CFU]/mL).⁹

Microscopic urine examination is performed when a patient has typical UTI symptoms but the leukocyte esterase test is negative. From 5 to 10 WBCs per high-power field represents 50 to 100 cells/mm3, which is considered the upper limit of normal. The presence of epithelial cells indicates sample contamination and may warrant repeat urinalysis.

Urine Gram’s stain, which can be performed with an uncentrifuged sample, is used when uncommon pathogens (eg, gram-positive bacteria) are suspected in certain patients, such as those with diabetes, those who are immunocompromised, or those who have upper urinary tract symptoms. One organism per high-power oil-immersion field is equivalent to 105 CFU/mL.

Urine culture determines the presence of bacteriuria in the normally sterile bladder environment. A finding of 105 CFU/mL is no longer considered the standard indicator of significant bacteriuria; approximately one third to one half of patients with symp­tom­atic urinary tract infection will have less than 105 CFU/mL.¹⁰

The Infectious Diseases Society of America (IDSA) has recently issued guidelines for the interpretation of urine culture results.¹¹ The consensus definition of cystitis is the presence of symptoms and at least 1000 CFU/mL of a single species of bacteria in a urine culture. Pyelonephritis is defined as the presence of symptoms, which include fever, chills, nausea, vomiting, and flank pain, and at least 105 CFU/mL of a single species of bacteria.

Imaging studies are not required routinely in the evaluation of UTI. Indications for diagnostic imaging include severe and recurrent pyelonephritis, complicated UTI in a patient in whom structural abnormalities are suspected, UTI in a patient who does not respond to treatment, and suspicion for abscess or obstruction. Useful imaging studies may include ultrasound, computed tomography (CT), magnetic resonance imaging, nuclear scanning, voiding cystourethrography, or intravenous pyelography.

Classification of Infections in the Urinary Tract
Asymptomatic bacteriuria
As its name implies, asymptomatic bacteriuria is defined as bacteria in the urine of a patient who does not have clinical symptoms.

Diagnosis. In women, diagnosis of asymptomatic bacteriuria is based on 2 separate clean-catch midstream-voided specimens that contain more than 105 CFU/mL of the same organism. In asymptomatic men, bacteriuria is defined as a single clean-catch midstream urine specimen with 1 bacterial species in a quantitative count of more than 105 CFU/mL. There are no data showing that treatment improves patient outcomes in most cases.¹¹

Treatment. Screening for and treatment of asymptomatic bacteriuria is indicated in pregnant women (at 12-16 weeks gestation), renal transplant recipients, individuals with granulocytopenia, and patients scheduled for urologic surgery, because the presence of bacteriuria has adverse outcomes in these populations.¹¹ Treatment is similar to that used for acute uncomplicated cystitis.

Acute uncomplicated cystitis
This type of UTI consists of an infection or inflammation of the bladder characterized by a burning sensation during micturition. Fever; increased urinary frequency; lower abdominal pain; and foul-smelling, blood-tinged, or cloudy urine may be presenting features. Physical examination may reveal suprapubic tenderness. Acute uncomplicated cystitis usually affects young, healthy women who are not pregnant.¹ Risk factors include sexual intercourse, vaginal spermicide use, history of recurrent UTI, delayed postcoital voiding, and recent antibiotic exposure.⁶ In postmenopausal women, additional risk factors are diabetes and a lifetime history of UTIs.¹² Urethritis and vaginitis must be considered in the differential diagnosis, since they may also present with dysuria.

Diagnosis. Microscopic analysis of the urine is indicated in symptomatic individuals who have a negative leukocyte esterase test. Urine culture is generally not required, except in the following situations¹⁰:

• Suspicion for complicated infection
• Recurrent infection with treatment nonresponse
• Infection that develops during hospitalization.

Pelvic examination is required for women whose history suggests urethritis or vaginitis. The absence of pyuria usually indicates a noninfectious etiology.¹³

Treatment. The primary microbe of concern is Esch­erichia coli, which is isolated in about 85% of cases.¹⁴ Pathogens identified in approximately 5% to 15% of cases include Staphylococcus saprophyticus, Klebsiella, Proteus, Enterobacter, and Enterococcus faecalis.¹⁴ The ideal medication is one that is excreted in the urine and has a high vaginal secretion concentration, because recurrent UTI is usually the result of contamination of the periurethral region by vaginal secretions. Fluoroquinolones and trimethoprim/sulfamethoxazole (TMP/SMX; Bactrim, Septra) achieve high concentrations in both urine and vaginal secretions and thus are considered first-line therapy. Beta-lactams and nitrofurantoin (Macrodantin) achieve lower vaginal secretion levels but can still be used when fluoroquinolones are contraindicated, as in the case of pregnant women. As a result of the increasing resistance of E coli to TMP/SMX, the IDSA recommends reserving this agent for communities where less than 20% of E coli strains causing cystitis are resistant to TMP/SMX; a quinolone or nitrofurantoin should be used in other areas.¹⁵

When Enterococcus or group B Streptococcus is suspected, amoxicillin (Amoxil, Trimox) or a cephalosporin should be used for 7 days, although neither is considered first-line therapy for acute uncomplicated cystitis.¹⁶ Nitrofurantoin is indicated only for acute uncomplicated cystitis and not for pyelonephritis or complicated UTIs, since it does not achieve adequate tissue levels.

Complicated UTI
Complicated UTI is defined as a lower or upper UTI in a setting where the risk of treatment nonresponse is increased, for example, in the presence of anatomic or structural abnormalities of the urinary tract or multiple-drug–resistant pathogens17 (Table 2).

Diagnosis. Urine culture, sensitivity, and imaging studies are usually recommended for the evaluation of complicated UTI.

Treatment. Infection can be caused by either gram-negative or gram-positive organisms. E coli (53%-65%) and Klebsiella (10%-13%) are the most common gram-negative organisms; others include Pseudomonas, Providencia, Enterobacter, and Proteus.^18,19 Enterococcus is the most frequently isolated gram-positive organism (10%), followed by group B Streptococcus, Staphylococcus aureus, and Candida.²⁰ S saprophyticus is an uncommon microbe in complicated UTI.¹⁷

Management includes the empiric use of broad-spectrum antibiotics until culture data are available. Previous culture and sensitivity data can be invaluable for guiding initial therapy. If an underlying abnormality is present, such as renal stones or nephrostomy stents, it should be corrected, since therapy cannot succeed until the predisposing process is corrected.²¹

A 14-day course of treatment is recommended, but longer courses may be required in patients with underlying factors that may delay cure. Follow-up urine culture and sensitivity are indicated in all cases of complicated UTI.⁷ The course of management after repeat culture and sensitivity results become available depends on patient characteristics. Treatment should be continued until the infection has resolved in patients with an uncorrected urologic abnormality.

Acute pyelonephritis
This is an inflammation of the kidney and upper urinary tract, usually resulting from an ascending spread of bacteria. It presents with fever, chills, flank pain and tenderness, nausea, and vomiting.

Diagnosis. Pelvic examination can be helpful when the history suggests a pelvic inflammatory disease or acute appendicitis. Urinalysis frequently reveals WBCs and WBC casts. Gram’s stain of an unspun urine sample helps determine initial antibiotic therapy. Evaluation with urine culture and antimicrobial susceptibility is mandatory in patients with acute pyelonephritis, although blood cultures are needed only when hospitalization is required. Imaging studies are usually unnecessary in the initial stages.⁷

Treatment. Microbes of concern include E coli (80%-90%), Proteus (5%), Enterococcus (5%), S saprophyticus (3%), and Klebsiella (3%).^22-24 The IDSA guidelines for the treatment of acute pyelonephritis in adherent outpatients with mild-to-moderate symptoms recommend 7 to 14 days of quinolone or TMP/SMX therapy.¹⁵ Amoxicillin is preferred for gram-positive infections.

Hospitalization is indicated if the diagnosis is uncertain, the patient is pregnant or severely ill, or the individual may be nonadherent.⁷ Treatment for inpatients begins with parenteral antibiotic therapy, which is continued until the patient is afebrile. Quinolones or a third-generation cephalosporin with or without an aminoglycoside are preferred. Ampicillin (Principen) or ampicillin sodium/sulbactam sodium (Unasyn) with an aminoglycoside is used for suspected or confirmed gram-positive organisms.

Persistently positive blood cultures, lack of clinical improvement within 72 hours after treatment initiation, and symptom recurrence within 2 weeks of starting therapy are indications for imaging studies in patients with acute pyelonephritis.⁷ Ultrasonography or CT can be helpful in identifying a stone, obstruction, or abscess that may be causing persistent bacteremia or preventing clinical improvement. Routine posttreatment urine cultures are not recommended in asymptomatic nonpregnant patients who have completed therapy.⁷

Catheter-associated bacteriuria
Bacteriuria in association with a catheter is common, because the catheter represents a foreign body that allows bacteria that have migrated from the perineum or periurethral area into the urinary tract to be colonized there. Catheter-associated bacteriuria may be delayed or prevented by using sterile insertion techniques, maintaining a closed system, and prompt catheter removal.⁷ Intermittent catheterization is preferred to an indwelling suprapubic or urethral catheter to reduce the risk of infection.²⁵ Scheduled replacement of the catheter does not appear to offer any benefits, and some evidence suggests that the type of catheter has little effect on the incidence of bacteriuria.²⁶ A recent review, however, found that newer silver alloy–coated or nitrofurazone-coated antimicrobial catheters reduce the risk of nosocomial bacteriuria, with an absolute risk reduction ranging from 0.5% to 32%.²⁷

Diagnosis. Routine monitoring of urine cultures is of no proven benefit in asymptomatic catheterized patients.⁷ In catheterized patients who have persistent bacteriuria for more than 48 hours after removal of a bladder catheter that has been in place for less than 7 days, the IDSA recommends screening followed by treatment for those with positive urine cultures.¹¹

Treatment. Therapy is not indicated for asymptomatic patients with catheter-associated bacteriuria or funguria¹¹ but is recommended when there are systemic manifestations suggestive of infection. The catheter should be replaced before initiating therapy because of biofilms (Tamm-Horsfall protein, struvite, apatite, and bacterial glycoprotein) that form along the surface of the catheter7 and harbor microorganisms that protect against the effects of antimicrobial agents. For patients with lower urinary tract symptoms, single-dose therapy with TMP/SMX can be as effective as a 10-day course.²⁸ In patients with upper urinary tract symptoms who are infected by gram-positive organisms, treatment is similar to that used for acute pyelonephritis.

UTI in Men: Additional Considerations
In men, UTI is often associated with intercourse with an infected woman, lack of circumcision, or homosexuality.⁷ Uncomplicated acute cystitis in men usually presents with typical features of dysuria, urinary frequency, and suprapubic tenderness. However, UTI in boys and elderly men often presents with atypical signs and symptoms, such as secondary incontinence, confusion, anorexia, or fever.

Diagnosis
Urine samples should be obtained for culture in all men with suspected UTI. Routine referral for imaging studies or cystoscopy is not supported by current evidence.²⁹ Physicians must differentiate acute uncomplicated cystitis from prostatitis (based on the presence of a tender, swollen prostate on examination), urethritis (risk factors for and history of sexually transmitted diseases or sterile pyuria), and pyelonephritis (high fever and toxic appearance).

Men with recurrent UTIs should be evaluated for structural abnormalities of the urinary tract (such as prostatic enlargement), urethral strictures, stones, neurogenic bladder, vesicoureteral reflex, immunocompromised states, anal intercourse, and previous surgeries on the urinary tract.³⁰

Treatment
Pathogens responsible for UTI are similar in both men and women, and thus treatment is also similar. However, a 7-day course of treatment is usually recommended for men with uncomplicated cystitis instead of the 3-day course used in women, since these infections are less common in men and may be caused by resistant organisms. Follow-up evaluation is usually not beneficial in young men who respond to treatment but is needed in older men.⁷

Conclusion
UTIs are common infections that must be differentiated from other conditions with a similar presentation. Atypical symptoms and signs add to the diagnostic challenge. Although uncomplicated UTI may be diagnosed based solely on clinical findings, laboratory tests are often needed to confirm the diagnosis. In complicated UTI, laboratory tests are also used to identify the responsible pathogen and its antimicrobial susceptibility. Imaging studies are usually reserved for patients with severe or recurrent pyelo­nephritis, those with an underlying structural abnormality, or those who do not respond to treatment. Treatment of uncomplicated UTI may include a fluoroquinolone or TMP/SMX or, if the organism is gram-positive, amoxicillin. The definitive treatment for complicated UTI is correction of the underlying condition.

Self-assessment test
1. A 25-year-old sexually active woman presents to your clinic with a 3-day history of dysuria, polyuria, and suprapubic tenderness but no comorbid conditions. Which one of the following steps is NOT indicated?
A. Urinalysis
B. Urine culture
C. Treatment with TMP/SMX
D. Encouraging postcoital voiding

2. Treatment for asymptomatic bacteriuria is indicated for the following patients, except:
A. A pregnant woman
B. A patient before cardiac surgery
C. A patient with renal transplant
D. A patient scheduled for transurethral resection of the prostate

3. Which of the following statements about catheter-associated bacteriuria is true?
A. When treatment is indicated, the catheter should be replaced before initiating antibiotic therapy
B. Replacing an indwelling catheter every week reduces the risk for UTI
C. Indwelling urethral catheters lower the risk of infection compared with intermittent catheterization
D. 7-14 days of antibiotic treatment is required for asymptomatic catheter-associated bacteriuria

4. A 40-year-old black man with a history of renal stones and benign prostatic hyperplasia presents with symptomatic UTI. Which one of these statements about management is true?
A. Urine culture and sensitivity are not essential
B. Outpatient treatment with a 3-day course of antibiotics is sufficient
C. Urine culture and sensitivity follow-up are not necessary
D. Old culture and sensitivity data can be used to initiate treatment

5. Urine culture is indicated in all the following situations, except:
A. An 18-week pregnant 29-year-old woman with no other medical conditions
B. A 60-year-old man with symptomatic obstructive renal stones
C. A 40-year-old hospitalized man who has uncomplicated cystitis
D. A 20-year-old sexually active woman with no other medical conditions

References
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18. Cox CE, Marbury TC, Pittman WB, et al. A randomized, double-blind, multicenter comparison of gatifloxacin versus ciprofloxacin in the treatment of complicated urinary tract infection and pyelonephritis. Clin Ther. 2002;24:223-236.

19. Wells WG, Woods GL, Jiang Q, et al. Treatment of complicated urinary tract infection in adults: combined analysis of two randomized, double-blind, multicentre trials comparing ertapenem and ceftriaxone followed by appropriate oral therapy. J Antimicrob Chemother. 2004; 53(suppl 2):ii67-ii74.

20. Hummers-Pradier E, Koch M, Ohse AM, et al. Antibiotic resistance of urinary pathogens in female general practice patients. Scand J Infect Dis. 2005;37:256-261.

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Practice points • Urinary tract infections are more common in women than in men, but the gender disparity lessens in elderly and infant populations. • Any structural or functional abnormality that slows the flow of urine from the ureters to the bladder sets the stage for infection. • Laboratory tests aid in the diagnosis and can also identify the specific etiologic organism and its antibiotic susceptibility. • Imaging studies are usually reserved for patients with severe or recurrent pyelonephritis, those with an underlying structural abnormality, or those who do not respond to treatment.