Review of Urinary Tract Infection

US Pharm . 2006;6:HS-26-HS-36.

Urinary tract infection (UTI)--a broad term used to describe bacterial infection of the urethra, bladder, and kidneys--is a problem frequently encountered by health care providers today. In addition to bacteria, viruses and fungi are other infectious agents that colonize the urinary tract. Traditionally, UTIs are categorized as uncomplicated or complicated, or by site of infection. Infections may be symptomatic or asymptomatic. Lower UTIs include urethritis and cystitis, and upper tract infections include pyelonephritis and renal abscesses. Acute infections are usually associated with a single pathogen; chronic infections are usually polymicrobial.

The economic impact of bacterial UTIs is a major factor affecting health care expenses today. Both outpatient and inpatient treatment contribute to overall costs. The urinary tract is the most common site of hospital infection, accounting for more than 40% of nosocomial infections (estimated to be 600,000 patients per year) reported by acute care hospitals.¹ The vast majority of hospital-acquired infections are due to indwelling catheters. On average, a hospital-acquired UTI increases length of stay by one day, resulting in nearly one million extra hospital days. The economic impact is between $424 million and $451 million annually. ² UTI accounts for approximately eight million health care provider visits in the United States. More than 100,000 hospitalizations per year are due to infections of the urinary tract. Uncomplicated cystitis is by far the most common outpatient infection, while pyelonephritis accounts for the majority of inpatient visits.³ Diagnosis of UTIs accounts for an estimated $6 billion in health care expenditures.⁴

Epidemiology
Nearly half of all women will have a UTI once in their lives.⁵ It has been reported that one third of women will have had at least one UTI by age 24 years.⁶ Simple, uncomplicated UTIs are quite common in women ages 20 to 50. The geriatric community is frequently affected by these infections. Notably, these infections often do not cause symptoms.⁷ UTIs are the second most common type of infection in the geriatric population, accounting for nearly 25% of all infections in the elderly.⁶ Fifty percent of elderly women are affected by asymptomatic bacteriuria. In many cases, bladder catheriterization is a contributing factor; 38% of chronic care residents require bladder catheterization, a cause for the increasing incidence of UTIs in the elderly.⁸

The pediatric population is also affected by UTIs. Bacteriuria is present in 2.7% of boys and 0.7% of girls.⁹ Uncircumcised males have a higher incidence of infection. Uncircumcised infants younger than 6 months have a higher incidence of gram-negative uropathogens.⁶ The rate of hospital admission is higher in uncircumcised boys, since this population has a 12-fold increased UTI risk. ¹⁰ A study by Nuutinen and Uhari found that 35% of boys and 32% of girls who had their first UTI before age 1 contracted a recurrent UTI during the next three years.¹¹ Other risk factors for exposure in infants are hospitalization and catheterization. Children between ages 1 and 5 years have a 4.5% increased incidence of bacteriuria.

Pathophysiologic Considerations
Transitional epithelium transports urine from the kidneys to an elastic bladder. The bladder stores large volumes of urine at low pressures.¹² The incidence of cystitis is greater in women, primarily due to the proximity of the urethral opening to the vagina and perianal area. Risk factors for UTIs in women include fecal contamination, recent UTI, decreased fluid intake, irregular emptying, sexual intercourse, diaphragm and/or spermicide use, a symptomatic partner, pregnancy, menopause, low vaginal pH or dryness of mucosa, neurogenic bladder, renal disease, urologic anatomic abnormalities, instrumentation, immunosuppression, hospitalization, nephrolithiasis, and diabetes.⁵

UTIs are less likely to occur in men under 50 years of age. Unlike female anatomy, the male urethra is separated from the rectum by several centimeters and is keratinized by squamous epithelium. The incidence of UTI becomes similar in men and women at age 65, given the increased proportion of men with benign prostatic hypertrophy.¹² Approximately one fifth of men in their 70s have experienced a UTI.¹³ Other risk factors for men include urologic abnormalities, neurogenic bladder, instrumentation, anal intercourse, and immunosuppression.⁵

Immunosuppressed states in males and females include age, diabetes, multiple sclerosis, HIV, and other chronic illnesses that may impair the immune system. For the diabetic patient, the risk of UTI is greater in females than in males. Diabetic patients generally seem to have a twofold to fourfold increased incidence of bacteriuria,¹³ leading to a higher incidence of pyelonephritis.

Symptoms of UTI are similar among the sexes: Dysuria (painful urination), urgency, hesitancy, polyuria, and incomplete voiding may all be associated with acute cystitis. Urinary incontinence, hematuria, and suprapubic or low back pain may also be present. Typically, females with acute dysuria have one of three types of infections: acute cystitis; acute urethritis due to Chlamydia trachomatis, Neisseria gonorrheae, or herpes simplex virus; or vaginitis due to Candida or Trichomonas.

Symptoms that indicate pyelonephritis include fever, costovertebral angle pain, nausea, and vomiting. Hematuria may occur in any UTI, but it is more suggestive of nephrolithiasis when accompanied by flank pain.

In the pediatric population during the first 8 to 12 weeks of life, UTI may be associated with bacteremia. Symptoms in infants up to 2 years old may include difficulty with feeding, nausea and vomiting, or failure to thrive. Children ages 2 to 5 may demonstrate fever and abdominal pain. Children under 5 are at risk for renal scarring.¹⁴ Children older than 5 may have the same symptomatology as adults. As many as 25% of young children without pyelonephritis have renal bacteriuria.¹⁵ As in other age groups, urine culture is the goal standard for diagnosis of UTI. However, an adequate sterile urine culture is often difficult to obtain in the pediatric patient. The urinalysis will support the presumptive diagnosis of UTI. Markers for infection in a urinalysis are the presence of nitrites, leukocytes esterase, bacteria, or white blood cells.¹⁶ An infant who is evaluated for fever may require lumbar puncture, in addition to blood cultures, to evaluate UTI with secondary bacteremia.

Diagnosis
The diagnoses for acute pyelonephritis, cystitis, and asymptomatic bacteriuria are made by the presence of bacteria in the urine, usually based on a clean midstream urine sample. There must be a minimum of 10⁵ colony-forming units per milliliter (cfu/mL) of uropathogens for diagnosis of acute pyelonephritis and asymptomatic bacteriuria but only 10³ cfu/mL for the diagnosis of cystitis. Up to one third of cystitis cases would be missed if the criterion for diagnosis were the same as that for upper tract infections.¹⁷

Uncomplicated UTI refers to cystitis and pyelonephritis that occurs in young, healthy, nonpregnant, or ambulatory postmenopausal women--all of whom have an anatomically and functionally normal urinary tract. Patients with complicated UTIs are those who have an associated risk for infection in the urinary tract (e.g., those with neurogenic bladder, nephrolithiasis, hospital-acquired infection, diabetes, indwelling catheters, or who are immunosuppressed). Resistant organisms can be seen in either complicated or uncomplicated UTIs.¹⁷

Because UTIs occur in young healthy men infrequently, there is debate whether to consider these infections complicated or uncomplicated, given the paucity of studies in this patient group. The organisms and sensitivity patterns seem to be the same as in women with uncomplicated cystitis. Empiric treatment for cystitis would utilize the same antibiotic choices used in women, but three-day regimens are not recommended because of the lack of supporting data. A pretreatment urine culture should be obtained in all men with UTI; however, a posttreatment culture is usually not necessary. Recurrent infections require evaluation for prostatitis, and if negative, an evaluation for anatomic abnormalities should ensue.¹⁷

In practicality, using bacteriuria for the diagnosis of cystitis can be cumbersome, since urine culture is not performed in many cases of uncomplicated cystitis. Urine microscopy has a low sensitivity (40% to 70%) but a high specificity (85% to 95%) for the diagnosis of UTI. Pyuria is present in most cases of pyelonephritis--estimated to be about 90%. Presence of pyuria increases the sensitivity (95%) and specifity (71%) for the diagnosis of acute pyelonephritis. White cell casts always point to an upper tract infection.¹⁸ Urine culture is positive in 90% of cases of pyelonephritis, and 20% of hospitalized cases have positive blood cultures. The cultures were obtained prior to antibiotic therapy in these cases. There is no evidence that positive blood cultures indicate a more complicated course in immunocompetent individuals.¹⁹

Dipstick urinalysis has become the most frequently used test due to its cost and fast results. Studies have shown that dipstick urinalysis, in combination with clinician judgment, greatly improves diagnostic accuracy in the patient with nonspecific symptoms. Urine dipstick is positive if there is a presence of nitrate and/or if there is a positive reaction greater than or equal to trace leukocyte esterase.²⁰

Patients should be screened for asymptomatic bacteriuria in cases of pregnancy or prior to a urologic procedure or surgery. Urine culture is the method of choice, since the other types of studies lack the sensitivity and specificity in these cases. During pregnancy, UTIs are common in the sixth week and peak during weeks 22 to 24. Pregnant women have a prevalence of asymptomatic bacteriuria of 2% to 7%. If untreated, 20% to 30% of these women will develop acute pyelonephritis later in pregnancy. When pyelonephritis occurs late in pregnancy, there is an association with preterm labor. Treatment has been shown to decrease this risk by 90%. The current recommendation by the Infectious Diseases Society of America is to obtain a urine culture at the end of the first trimester, and if positive, to treat the bacteriuria. Intrauterine growth retardation and neonatal death have also been linked to asymptomatic bacteriuria. There are no indications for screening elderly patients in the community or in institutions for asymptomatic bacteriuria, as treatment has not been shown to benefit these individuals. ²¹

Imaging
The diagnosis of pyelonephritis can usually be made by history, physical examination, and laboratory tests. Imaging may be necessary when the diagnosis is in question, when there are recurrent infections, or if the patient responds poorly to appropriate antibiotic therapy after three days. Computed tomography (CT) with intravenous (IV) contrast is the test of choice when evaluating the urinary tract. The most common CT finding in pyelonephritis is wedge-shaped lesions of decreased attenuation with or without swelling. Anatomic abnormalities and perinephric abscesses can also be seen on contrast-enhanced scans. Renal ultrasound is also used to evaluate the collecting system and pyelonephritis and may show ureteral dilation, suggesting obstruction. Although renal ultrasound is helpful, a CT scan is more sensitive. Magnetic resonance imaging may be used in patients who are allergic to iodinated contrast.²²

Diagnostic studies for UTI in pediatric patients are important, given the potential long-term sequelae associated with undiagnosed or recurrent UTIs. Recurrence may be a marker for genitourinary abnormalities, and imaging is recommended after the first infection with concomitant fever. Vesicoureteral reflux encompasses a variety of conditions that represent the most common abnormality observed in infants and young children. This condition can lead to recurrent UTIs, resulting in secondary scarring that causes an increased risk of progression to renal disease into adulthood. Children with poor clinical response to appropriate treatment should have immediate renal and bladder ultrasound (RBUS) and voiding cystourethrography (VCUG).²³

Treatment
Prevention of UTI is always the goal of clinicians. There are many proven and unproven strategies to accomplish this task (see table 1). Most UTIs will clear spontaneously if untreated, but symptoms may persist for a significantly longer period of time. Tables 2 and 3 review first-line and alternative treatments for UTI, outlining the adverse effects of each agent.

In one study, one in 38 women progressed from uncomplicated cystitis to pyelonephritis without treatment.¹⁷ The most common organisms by far are gram-negative bacilli. Escherichia coli causes 80% of all community-acquired UTIs among otherwise healthy individuals, and roughly half of UTIs occur in hospitalized patients and diabetic patients.² Other bacteriuria include gram-negative rods such as Proteus, Klebsiella, and Enterobacter. Antibiotic resistance has become an important factor to consider in the treatment of infections. Resistance may occur in ambulatory, institutionalized, and hospitalized infections. E. coli resistance has been progressing for more than a decade.²⁴

E. coli Resistance: The resistance pattern is not uniform in the U.S.; in 2000, it ranged from 10% in the Northeast to 22% in the West.²⁵ The resistance to trimethoprim-sulfamethoxazole (TMP-SMX) has been significant, and therefore, it is no longer the first therapeutic choice in complicated UTI or pyelonephritis. Given the concern of resistance progressing with the fluoroquinolones, TMP-SMX remains first-line therapy for the most common uncomplicated cystitis.²⁴ Fluoroquinolones are the primary therapy for complicated cystitis and acute pyelonephritis. There is still relatively low resistance to fluoroquinolones for E. coli, but resistance is significantly emerging with enterococci. Tendonitis and, rarely, Achilles heel rupture in the geriatric population have been noted with the quinolones.²⁶ Nitrofurantoin is associated with low levels of E. coli resistance, which is theorized to be due to its multiple mechanisms of action, but the agent has poor tissue and plasma concentration. Thus, nitrofurantoin has no use beyond the urinary tract.²⁴ Beta-lactams have significant problems with resistance--up to 40% in 2002. Fosfomycin is indicated only for uncomplicated cystitis and has low reported resistance.²⁴

Urinary Catheters: Any catheterization of the bladder increases the risk of infection, but indwelling has a higher risk than intermittent catheterization. Treatment of asymptomatic bacteriuria in patients with chronic indwelling catheters has shown no benefit.²¹ When a patient becomes symptomatic, blood and urine cultures should be obtained prior to treatment. Antibiotics should be initiated immediately after cultures and should be tailored to the patient, institution, and susceptibility patterns.

Cystitis: For uncomplicated cystitis in women, a three-day course of TMP-SMX is recommended; if the patient is older, a longer course of therapy (seven to 10 days) should be considered. This recommendation applies to areas where E. coli resistance is less than 20%. Studies have examined three-day courses of ciprofloxacin versus TMP-SMX, and the results of bacteria eradication were similar in uncomplicated cystitis. If the patient is allergic to sulfa, alternative therapies are nitrofurantoin for seven days or single-dose fosfomycin. Fluoroquinolones are first-line therapy in areas where E. coli resistance is greater than 20%.²⁷ In pregnant patients with cystitis, a seven-day duration is preferred for nitrofurantoin or cephalexin. However, fosfomycin in a single dose is another alternative.²⁷ Women with recurrent bouts of cystitis may need to consider an alternative form of contraception. Spermicides and diaphragms may predispose women to infection. Postcoital prophylaxis should be instituted only after the current infection is treated and a negative urine culture is obtained. Single-dose TMP-SMX, nitrofurantoin, or fluoroquinolones can be used after intercourse. ¹⁸

Complicated Cystitis: In complicated UTIs, a wide range of bacteria can cause infection. Fluoroquinolones are effective first-line treatment, given their broad spectrum of coverage for mild to moderate infections. For more seriously ill, hospitalized patients, initial empiric therapy includes ampicillin and gentamicin. Alternative choices of antimicrobials are third-generation cephalosporins, pipercillin-tazobactam, meropenem, or ciprofloxacin, based on sensitivities. The expected length of treatment for complicated UTIs is 10 to 14 days. Switching from IV to postoperative coverage largely depends on clinical improvement. Pseudomonas and Enterococcus are difficult to treat and may require a longer course of IV antibiotics. Repeat cultures are recommended one to two weeks after the completion of therapy. If a patient fails to respond to treatment, repeat cultures should be attained along with imaging studies to rule out persistent infection secondary to anatomic abnormalities or stone disease.²⁸

Most complicated UTIs are nosocomial in origin. The most common pathogens are gram-negative bacteria, which have been shown to colonize the meatus.  Hand washing and good aseptic technique are imperative in preventing infection. Practitioners must be cautious when determining the need for indwelling Foley catheters. Intermittent catheterization reduces the risk of bacteriuria. If a chronic indwelling Foley catheter is indicated, then the catheter should be changed at least once every 30 days. 

Perinephric abscess is considered a complicated UTI. The most common causative organism is Staphylococcus aureus . First-line treatment is IV nafcillin or a third-generation cephalosporin. Vancomycin may be used as an alternative. In most cases, patients will need surgical intervention or aspiration of the infected fluid collection.²⁹

Acute Pyelonephritis: Many patients with pyelonephritis need to be hospitalized. (See Table 4 for indications.) Patients who do not meet absolute indications for hospitalization are treated successfully in about 90% of cases with outpatient oral regimens. After the urine culture is obtained, empiric therapy consists of an oral fluoroquinolone for outpatient treatment. Patients requiring hospitalization should receive an IV fluoroquinolone or an aminoglycoside alone or in combination with an extended-spectrum cephalosporin or ampicillin. Oral treatment may be instituted once the patient is afebrile, clinically improved, and able to tolerate oral medications and hydration.¹⁹ The duration of therapy in pyelonephritis is controversial. In acute, uncomplicated pyelonephritis, therapy duration ranges from seven to 14 days. Beta-lactams generally require 10 to 14 days, while the more common fluoroquinolones or TMP-SMX can require a duration of seven to 10 days. Complicated pyelonephritis may require a longer course of treatment, especially if the patients are immunocompromised. Generally, these patients require 14 to 21 days of therapy or even longer depending on their clinical course.¹⁷

Pediatric Population
Group B streptococcus is the most common organism seen in neonates. Overall, E. coli is the most typical organism found in the pediatric population, accounting for 75% to 90% of all cases. Hospitalized children may require frequent catheterizations, making Enterococcus and Pseudomonas a possible consideration.³⁰

Management of UTI in the neonatal population is largely geared toward preventing bacteremia, given the high risk of meningitis in this age group. Another goal in the treatment of pediatric patients is prompt diagnosis and empiric treatment to prevent progression of renal disease and to identify any urinary tract abnormalities.¹⁵ Infants and children younger than 5 years of age should be hospitalized if the clinical suspicion is high for systemic infection. According to the American Academy of Pediatrics (AAP), hospitalization should also be considered if noncompliance is a concern, if outpatient treatment has failed, or if the patient is immunocompromised. A hospitalized patient who remains afebrile for 48 hours and tolerates oral antibiotics may be discharged with continued therapy on oral antibiotics. Once the infection has cleared, additional tests may be required to rule out abnormalities of the urinary tract (RBUS and VCUG). ²³

The choice of antimicrobial depends on a number of different factors, such as the patient's clinical status, age (which may be associated with specific pathogens), and local sensitivity patterns in the area of practice.¹⁵ For neonates with a diagnosis of UTI and hydronephrosis, amoxicillin is recommended at one third of the normal dosage. ³¹ Sulfamethoxazole, TMP-SMX, or cephalosporins are beneficial first-line choices for children who are able to tolerate oral medications. ³² In children who have failed oral therapy, ceftriaxone or gentamicin administered intramuscularly has been shown to be effective in treating UTI. ²³ The AAP recommends seven to 10 days of treatment for uncomplicated UTIs. For febrile infants with a UTI and children with presumed pyelonephritis, a 14-day course of therapy is recommended.

Prophylactic antimicrobials may be used in children with symptomatic UTIs with anatomic abnormalities. There are few data to support the use of antibiotics in children without anatomic anomalies. ³³

References
1. Centers for Disease Control and Prevention. Guideline for the Prevention of catheter-associated Urinary Tract Infections. Available at: www.cdc.gov/ncidod/dhqp/gl_catheter_assoc.html.  
2. Brown P, Foxman B. Epidemiology of urinary tract infections transmission and risk factors, incidence and costs. Infec Dis Clin N Am. 2003;17: 227-241.
3. IDSA Practice Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Available at: www.uptodateonline.com.
4. Stamm WE, Norrby SR. Urinary tract infections: Disease panorama and challenges. J Infec Dis. 2001;183:S1.
5. Green MB, Bailey PP. Infectious processes: Urinary tract infections and sexually transmitted diseases. In: Buttaro TM, Trybulski J, Bailey PP, Sandberg-Cook J, eds. Primary Care: A Collaborative Practice. St. Louis, MO: Mosby; 2003.
6. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity and economic costs. Am J Med. 2002;113:5-13.
7. NCHS: Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, 1997. Vital and Health Statistics Series 1999:13(143).
8. Warren, JW, Steinberg, L, Hebel, JR, et al. The prevalence of urinary catheterization in Maryland nursing homes. Arch Intern Med. 1989:149:1535.
9. Wettergren B, Jodal U, Jonasson G. Epidemiology of bacteriuria during the first year of life. Acta Paediatr Scand. 1995;74:925.
10. To T, Agha M, Dick PT, Feldman W. Cohort sudy on the circumcision of newborn boys and subsequent risk of urinary tract infection. Lancet. 1998;352:1813-1816.
11. Nuutinen M, Uhari M. Recurrence and follow-up after urinary tract infection under the age of 1 year. Pediatric Nephrology. 2001;16:69-72.
12. Hooten TM, Scholes D, Hughes JP, et al. A prospective study of risk factors from symptomatic urinary tract infections in young women. N Engl J. Med. 1996;335:468-474.
13. Ronald A, Ludwig E. Urinary tract infections in adults with diabetes. Int J Antimicrobial Agents. 2001;17:287-292.
14. MacNeily AE. Pediatric urinary tract infections: current controversies. Canadian J Urol. 2001;8:18-23.
15. Schlager TA. Urinary tract infections in infants and children. Infec Dis Clin N Am. 2003;17:353-365.
16. Layton KL. Diagnosis and management of pediatric urinary tract infections. Clin Fam Practice. 2003;5:367-382.
17. Hooten T. The current management strategies for community-acquired urinary tract infection. Infect Dis Clin N Am. 2003;17:303-332.
18. Fihn S. Acute uncomplicated urinary tract infection in women. N Engl J Med. 2003;349:259-266.
19. Ramakrishnan K, Scheid D. Diagnosis and management of acute pyelonephritis in adults. Am Fam Physician . 2005;71:933-942.
20. Sultana R, Zalstein S, Cameron P, Campbell D. Dipstick urinalysis and the accuracy of the clinical diagnosis of urinary tract infection. J Emerg Med. 2001;20:13-19.
21. Nicolle L. Asymptomatic bacteriuria: When to screen and when to treat. Infec Dis Clin N Am. 2003;17:367-394.
22. Kawashima A, Leroy A. Radiologic evaluation of patients with renal infections. Infec Dis Clin N Am. 2003;17:433-456.
23. Shortliffe L, McCue J. Urinary tract infection at age extremes: pediatrics and geriatrics. Am J Med. 2002;133:55-65.
24. Gupta K. Emerging antibiotic resistance in urinary tract pathogens. Infec Dis Clin N Am. 2003;17:243-259.
25. Gupta K, Sahm DF, et al. Antimicrobial resistance among uropathogens that cause community acquired urinary tract infections in women: a nationwide analysis. Clin Infec Dis . 2001;33:89.
26. Gold L, Igra H. Levofloxacin-induced tendon rupture: A case report and review of the literature. J Am Board Fam Practice 2003;16:458-460.
27. Mehnert-Kay S. Diagnosis and management of uncomplicated urinary tract infections. Am Fam Physician. 2005;72:451-456.
28. Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J Med. 1993;329:1328-1334.
29. Sanford Guide for Microbiology; Perinephric Abscess, 2005:22-23.
30. Elder JS. Urinary tract infections. In: Behrman RE, Kliegman FM, Jenson HB, eds. Nelson Textbook of Pediatrics. Philadelphia, PA: W.B. Saunders; 2000:1624-1625.
31. Caldemone A. Antibiotic prophylaxis for infants with congenital hydronephrosis [letter]. Pediatric Infec Dis J. 1999;18:398-399.
32. American Academy of Pediatrics. Subcommittee on Urinary Tract Infection. Practice parameter: diagnosis, treatment, and evaluation of urinary tract infection in infants and young children. Pediatrics. 1999;103:843-852.
33. Dagan R, Phillip M, Watemberg NM, et al. Outpatient treatment of serious community-acquired pediatric infections using once daily intramuscular ceftriaxone. Pediatric Infec Dis J. 1987;6:1080-1084.
34. UrologyHealthChannel. Available: www.urologychannel.com/uti/alternativetreatment.shtml.
35. Lynch D. Cranberry for prevention of urinary tract infections. Am Fam Physician. 2004;70:2175-2177.

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