AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Urinary tract infection (UTI) is defined as significant bacteriuria in the presence of symptoms. This common clinical entity accounts for a significant number of emergency department (ED) visits. It affects an estimated 20% of women at some time during their lifetimes.

Successful emergent management includes proper specimen collection, use of immediately available laboratory testing for presumptive diagnosis, appreciation of epidemiological and host factors that may identify patients with clinically inapparent upper UTI, and selection of appropriate antimicrobial therapy with recommendations for follow-up care.

Pathophysiology

The urinary tract is normally sterile. Uncomplicated UTI involves the urinary bladder in a host without underlying renal or neurologic disease. The clinical entity is termed cystitis and represents bladder mucosal invasion, most often by enteric coliform bacteria (eg, Escherichia coli) that inhabit the periurethral vaginal introitus and ascend into the bladder via the urethra.

Sexual intercourse may promote this migration, and cystitis is common in otherwise healthy young women. Urine is generally a good culture medium; factors unfavorable to bacterial growth include a low pH (5.5 or less), a high concentration of urea, and the presence of organic acids derived from a diet that includes fruits and protein. Organic acids enhance acidification of the urine.

Frequent and complete voiding has been associated with a reduction in the incidence of UTI. Normally, a thin film of urine remains in the bladder after emptying, and any bacteria present are removed by the mucosal cell production of organic acids. If the mechanisms of the lower urinary tract fail, upper tract or kidney involvement occurs and is termed pyelonephritis. Host defenses at this level include local leukocyte phagocytosis and renal production of antibodies that kill bacteria in the presence of complement.

Complicated UTI occurs in the setting of underlying structural, medical, or neurologic disease. Patients with a neurogenic bladder or bladder diverticulum and postmenopausal women with bladder or uterine prolapse have an increased frequency of UTI due to incomplete bladder emptying. This eventually allows residual bacteria to overwhelm local bladder mucosal defenses. The high urine glucose content and the defective host immune factors in patients with diabetes mellitus also predispose to infection.

Frequency

United States

UTI accounts for over 6 million patient visits to physicians per year in the United States. Approximately one fifth of those visits are to EDs.

International

As 1 in 5 adult women experience UTI at some point, it is an exceedingly common, clinically apparent, worldwide patient problem.

Mortality/Morbidity

• Although simple lower UTI (cystitis) may resolve spontaneously, effective treatment lessens the duration of symptoms and reduces the incidence of progression to upper UTI.
• Pyelonephritis is associated with substantial morbidity, including systemic effects such as fever, vomiting, dehydration, and loss of vasomotor tone resulting in hypotension. Complications include acute papillary necrosis with possible development of ureteral obstruction, septic shock, and perinephric abscess. Chronic pyelonephritis may lead to scarring with diminished renal function.
• Younger patients have the lowest rates of morbidity and mortality. Unfortunately, despite appropriate intervention, 1-3% of patients with acute pyelonephritis die. Factors associated with unfavorable prognosis are general debility and old age, renal calculi or obstruction, recent hospitalization or instrumentation, diabetes mellitus, sickle cell anemia, underlying carcinoma, intercurrent chemotherapy, or chronic nephropathy.

Race

No racial predilection exists.

Sex

The natural history of UTI varies with sex and age.

• Of neonates, boys are slightly more likely than girls to present with UTI as part of a gram-negative sepsis syndrome. The incidence in preschool children is approximately 2% and is 10 times more common in girls. Five percent of school-aged girls experience UTI. It is rare in school-aged boys.
• The largest group of patients with UTI is adult women. The incidence increases with age and sexual activity. Rates of infection are high in postmenopausal women because of bladder or uterine prolapse causing incomplete bladder emptying; loss of estrogen with attendant changes in vaginal flora; loss of lactobacilli, which allows periurethral colonization with gram-negative aerobes, such as E coli; and higher likelihood of concomitant medical illness, such as diabetes.
• UTI is unusual in males younger than 50 years, and symptoms of dysuria and frequency are usually due to urethral or prostatic infection. In older men, however, the incidence of UTI rises because of prostatic obstruction or subsequent instrumentation.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The classical symptoms of UTI in the adult are primarily dysuria with accompanying urinary urgency and frequency.
• A sensation of bladder fullness or lower abdominal discomfort is often present.
• Bloody urine is reported in as many as 10% of cases of UTI in otherwise healthy women; this condition is called hemorrhagic cystitis.
• Fevers, chills, and malaise may be noted, though these are associated more frequently with upper UTI (ie, pyelonephritis).
• Because of the referred pain pathways, even simple lower UTI may be accompanied by flank pain and costovertebral angle tenderness. In the ED, assume that the presence of these symptoms represents upper UTI.
• A history of vaginal discharge suggests that vaginitis, cervicitis, or pelvic inflammatory disease is responsible for symptoms of dysuria; therefore, a pelvic examination must be performed.
• Important additional information includes a history of prior sexually transmitted disease (STD) and multiple current sexual partners.

Physical

• Most adult women with simple lower UTI have suprapubic tenderness with no evidence of vaginitis, cervicitis, or pelvic tenderness (eg, cervical motion tenderness, which suggests pelvic inflammatory disease).
• The patient appears uncomfortable but not toxic.
• The patient with pyelonephritis usually appears ill and, in addition to fever, sweating, and prostration, is found to have costovertebral angle (flank) tenderness in the majority of cases.
• The clinician may appreciate signs of dehydration, such as dry mucous membranes and tachycardia, as well as poor vascular tone due to gram-negative bacteremia, which may be manifested by clammy extremities and profound orthostatic hypotension.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Cervicitis
Chlamydia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• If UTI is suspected, the initial test of choice is urinalysis.
• • An appropriate specimen must be collected.
  • The midstream-voided technique is as accurate as catheterization if proper technique is followed.
    • Instruct the woman to remove her underwear and sit facing the back of the toilet. This promotes proper positioning of the thighs.
    • Instruct patient to spread the labia with one hand and cleanse from front to back with povidone-iodine or soaped swabs with the other hand, then pass a small amount of urine into the toilet, and finally urinate into the specimen cup.
    • The use of a tampon may allow a proper specimen if heavy vaginal bleeding or discharge is present.
• Pyuria, as indicated by a positive result of the leukocyte esterase dip test, is found in the vast majority of patients with UTI. This is an exceedingly useful screening examination that can be performed promptly in any ED setting.
• However, appreciate that low-level pyuria (6-20 white blood cells [WBCs] per high power field [HPF] microscopy on a centrifuged specimen) may be associated with an unacceptable level of false-negative results with the leukocyte esterase dip test, as Propp et al found in an ED setting¹.
• • In the female with appropriate symptoms and examination findings suggestive of UTI, urine microscopy may be indicated despite a negative result of the leukocyte esterase dip test.
  • Current emphasis in the diagnosis of UTI rests with the detection of pyuria. As noted, a positive leukocyte esterase dip test suffices in most instances.
  • According to Stamm et al, levels of pyuria as low as 2-5 WBCs per HPF in a centrifuged specimen are important in the female with appropriate symptoms. The presence of bacteriuria is as significant.
  • A positive result on the nitrate test is highly specific for UTI, typically because of urease-splitting organisms, such as Proteus species and, occasionally, E coli; however, it is very insensitive as a screening tool, as only 25% of patients with UTI have a positive nitrite test result.
  • Low-level or, occasionally, frank hematuria may be noted in otherwise typical UTI; however, its positive predictive value is poor.
• Visual inspection of the urine is not helpful. Cloudiness of the urine is most often due to protein or crystal presence, and malodorous urine may be due to diet or medication use.
• Historically, the definition of UTI was based on the finding at culture of 100,000 colonies/mL of a single organism. However, this definition misses up to 50% of symptomatic infections, so the lower colony rate of greater than 1,000 colonies/mL is now accepted.
• • Obtain a urine culture in patients suspected of having an upper UTI and a complicated UTI as well in those in whom initial treatment fails.
  • If the patient has had a UTI within the last month, relapse is probably caused by the same organism. Relapse represents treatment failure.
  • Re-infection occurs in 1-6 months and usually is due to a different organism (or serotype of the same organism). Obtain a urine culture for patients who are re-infected.
• A complete blood count (CBC) is not that helpful in differentiating upper from lower UTI or in making decisions regarding admission. However, leukopenia in hosts who are older or immunocompromised is an ominous finding.
• Renal function testing is not indicated in most episodes of UTI. It may be helpful in patients with known urinary tract structural abnormality or renal insufficiency. Renal function testing also may be helpful in older, particularly ill-appearing, hosts or in hosts with other complications.

Imaging Studies

• In the vast majority of patients with UTI, no imaging studies are indicated.
• If findings are suggestive of nephrolithiasis complicating the presentation, an intravenous pyelogram (IVP) or renal ultrasound should be obtained to exclude the possibility of obstruction or hydronephrosis.
• Recent studies with dynamic computed tomography (helical CT scan) are proving that this study provides information similar to that yielded by IVP without the need for dye injection. Dynamic CT scans also can serve as a convenient screen for abdominal aortic aneurysm masquerading as UTI or renal colic.
• Additional testing may be indicated if the diagnosis is in doubt. For example, a pelvic ultrasound may be indicated in a young woman with pelvic tenderness, cervical discharge, and unilateral adnexal tenderness to evaluate for a tubo-ovarian abscess; a CT scan may be indicated in the elderly patient whose presentation is not typical for UTI but who has abdominal pain, lower abdominal tenderness, and pyuria.

Procedures

• Catheterization is indicated if the patient cannot void spontaneously, if the patient is too debilitated or immobilized, or if obesity prevents the patient from obtaining a suitable specimen.
• Although less common than in older men, postvoiding residual urine volume, measurable by catheterization, may reveal urinary retention in a host with a defective bladder-emptying mechanism.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

• With few exceptions, the vast majority of adult patients with UTI present to the ED on an ambulatory basis.
• Exceptions include the immunocompromised or elderly patient who has UTI manifesting as a sepsis syndrome with circulatory insufficiency. In this situation, mental status changes (eg, confusion) or profound weakness may prompt paramedical transport to the hospital.
• Findings of hypotension, tachycardia, and delayed capillary refill require intravenous (IV) fluid resuscitation in the field.

Emergency Department Care

• Ambulatory patients who have symptoms and findings consistent with UTI, who have stable vital signs, and who otherwise appear well may be treated on an outpatient basis.
• Oral therapy with an antibiotic effective against gram-negative aerobic coliform bacteria, such as E coli, is the principal treatment intervention in patients with UTI. The patient with an uncomplicated presumed lower UTI or simple cystitis who has symptoms of less than 48 hours' duration may be treated with one of the following agents for a total of 3 days:
• • Co-trimoxazole DS (double strength) (eg, Bactrim, Septra): The Infectious Disease Society of America recommends the use of Bactrim as first-line therapy in patients without an allergy and in areas where resistance if not high (>15%).
  • Ciprofloxacin or similar fluoroquinolone: Reserving the use of fluoroquinolones for complicated infections or cases with documented drug resistance may help decrease the incidence of bacterial resistance to drugs in the fluoroquinolone class. These drugs must be avoided in pregnancy.
  • Nitrofurantoin macrocrystals (eg, Macrodantin)
  • Amoxicillin/clavulanate (eg, Augmentin)
• If the patient has intense dysuria, offering a bladder analgesic, such as phenazopyridine (Pyridium), for 1-2 days is a considerate gesture on the part of the treating physician. Avoid use if the patient has a sulfa allergy. Many authors advise stressing the intake of plenty of fluids to promote a dilute urine flow.
• Pregnant, otherwise healthy women with no evidence of an upper UTI should be treated with a 14-day course of a cephalosporin, as most obstetrics authorities prefer prolonged treatment even in the absence of signs of upper tract disease. More recently, many authors have recommended a 10- to 14-day course of nitrofurantoin macrocrystals (eg, Macrodantin) as a preferred first-line agent due to increased resistance to cephalosporins. Pregnant patients should be treated for all episodes of pyuria or bacteriuria, regardless of whether they have symptoms. Successful outpatient treatment of a subset of pregnant patients with clinically evident pyelonephritis has been reported. They must be less than 24 weeks' pregnant, hemodynamically stable, and able to tolerate oral fluids and medications. A urine culture should be performed in all pregnant patients.
• Ambulatory younger women who present with signs and symptoms of pyelonephritis may be candidates for outpatient therapy. They must be otherwise healthy and must not be pregnant. They must be treated initially in the ED with vigorous oral or IV fluids, antipyretic pain medication, and a dose of parenteral antibiotics. Studies have shown that outpatient therapy for selected patients was as safe as, and much less expensive than, inpatient therapy for a comparable group of patients.
• A popular regimen for the outpatient treatment of young, otherwise healthy nonpregnant women at the authors' institution is referred to as "treatment by (the rule of) twos."
• • In the ED, patients receive 2 liters of fluid (IV or orally), 2 Tylenol #3, and 2 g of ceftriaxone IV.
  • The patient can go home if her temperature drops by 2°F and she is able to tolerate 2 glasses of water.
  • On discharge, the patient must take 2 co-trimoxazole DS 2 times per day for 2 weeks (or ciprofloxacin, 500 mg, 2 times per day for 1-2 wk). Establish follow-up in 2 days.
• The decision regarding admission of a patient with acute pyelonephritis is dependent on age; host factors, such as immunocompromising chemotherapy or chronic diseases, known urinary tract structural abnormalities, renal calculi, recent hospitalization, or urinary tract instrumentation; and the patient's response to ED therapy. Initial treatment should include the following:
  • IV antibiotic therapy using co-trimoxazole (eg, Bactrim, Septra), which is directed at coliform gram-negative bacteria, such as E coli; a third-generation cephalosporin, such as ceftriaxone (eg, Rocephin); a carbapenem beta-lactam, such as ertapenem (eg, Invanz); or an aminoglycoside, such as tobramycin. Most authors recommend monotherapy unless the urine Gram stain reveals gram-positive cocci; in this case, add ampicillin to the antibiotic regimen to cover enterococci (eg, Streptococcus faecalis).
  • Adequate fluid resuscitation restores effective circulating volume and generous urinary volumes.
  • Antipyretic pain medications may be administered, as appropriate.
  • Imaging studies are often helpful; consider while the patient is still in the ED.
  • Recognition of obstruction with hydronephrosis may require acute intervention by a consultant urologist to effect a bacteriologic cure.

Consultations

• Evidence of obstruction, hydronephrosis, perinephric abscess, or other structural abnormality requires urologic consultation.
• In the patient with a complicated UTI, coverage for unusual or multiple antibiotic resistant organisms (eg, Pseudomonas aeruginosa) must be considered. An infectious disease consultation may be helpful in selecting the appropriate antimicrobial agent.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Antibiotics are the principal medications needed in treatment of UTI. Adjunctive measures include bladder anesthetics, antipyretics, interventions for the control of pain or nausea, and correction of dehydration.

Drug Category: Antibiotics

Empiric antimicrobial therapy should cover all likely pathogens in the context of this clinical setting.

Drug Category: Analgesics, urinary

These agents relieve pain, discomfort, and spasms of the bladder.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• The necessity for admission is based on host factors, age, risk of complicated infection, and likelihood of morbidity associated with failed outpatient treatment.
• Admit all patients with complicated UTI. Complicating factors include the following:
• • Structural abnormalities (eg, calculi, tract anomalies, indwelling catheter, obstruction)
  • Metabolic disease (eg, diabetes, renal insufficiency)
  • Impaired host defenses (eg, HIV, current chemotherapy, underlying active cancer)
• The following patients with clinically apparent uncomplicated pyelonephritis also should be admitted:
• • Those patients who are unable to maintain adequate oral hydration or have evidence of vasomotor instability or unrelenting fever despite antipyretic therapy
  • Those with debilitating pain or dehydration that cannot be corrected promptly in the ED
  • Patients with inadequate home care or resources to fill prescriptions or comply with the medical regimen (eg, homeless patients, adolescents, elderly patients in an acute illness setting who are at risk for clouded judgment, patients with substance abuse issues or other issues that will prevent adequate compliance)

Further Outpatient Care

• The vast majority of patients with simple uncomplicated UTI may receive care as outpatients.

Transfer

• This is rarely an issue for patients with UTI.
• Exceptions would include patients with complicated pyelonephritis who may require operative intervention to relieve obstruction.

Deterrence/Prevention

• Sexually active women may attempt voiding immediately after intercourse to lessen the risk of coitus-related introduction of bacteria into the bladder.
• Some authors recommend large urinary flow volumes as a measure that will reduce the risk of UTI.

Complications

• Complications of simple lower UTI in otherwise healthy individuals are rare, chiefly revolving around issues of resistant organisms or re-infection with the same organism. Relapse of symptoms after a brief 3-day course of antibiotics suggests the presence of clinically unsuspected upper UTI and requires 10- to 14-day therapy.
• More serious complications of UTI include the following:
• • Acute papillary necrosis with potential ureteric obstruction
  • Overwhelming sepsis syndrome with septic shock due to loss of vasomotor tone, capillary leak, and impaired myocardial performance
  • Perinephric abscess

Prognosis

• Unfortunately, the morbidity from upper UTI, especially in the elderly or those patients with complicated disease, is substantial.
• Factors associated with an unfavorable prognosis include the following:
• • Old age
  • General debility
  • Renal calculi or obstruction
  • Recent hospitalization
  • Urinary tract instrumentation or antibiotic therapy
  • Diabetes mellitus
  • Chronic nephropathy
  • Sickle cell anemia
  • Underlying cancer
  • Intercurrent chemotherapy

Patient Education

• Proper adherence to the outpatient medical regimen, drinking fluids to enhance diuresis, frequent voiding, and drinking fruit juices to acidify the urine are helpful in reducing recurrent infection.
• Postintercourse voiding may be helpful in reducing recurrent infection.
• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education articles Urinary Tract Infections and Bladder Control Problems.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Do not assume that a sexually active female with dysuria has UTI without first excluding the possibility of STD-related cervicitis, vaginitis, or pelvic inflammatory disease.
• Pyuria and bacteriuria always are treated during pregnancy, regardless of whether symptoms are present.
• In all cases of upper UTI and in pregnant patients, obtain a urine culture. It may provide the physician or the follow-up physician with valuable information as to why things are not working out as planned for the patient.
• Short 3-day courses of antibiotics are appropriate for a patient who appears to have a simple uncomplicated UTI with very brief duration of symptoms. Otherwise, err on the side of longer courses of antibiotic treatment for outpatients (ie, 7-10 d).
• Admission for older patients with pyelonephritis is a good thing. Also admit young women with pyelonephritis who do not have the means to take care of themselves.
• The fluoroquinolones are well tolerated and quite effective. They are probably the outpatient antibiotic treatment of choice for pyelonephritis. A recent study of selected patients with pyelonephritis treated as outpatients demonstrated that 7 days of ciprofloxacin was more effective than 14 days of co-trimoxazole. Unfortunately, fluoroquinolones are quite expensive compared to co-trimoxazole.
• Older patients who appear toxic are more likely to have an obstructive picture complicating their UTI. Obtain a structural study to rule out this possibility.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Propp DA, Weber D, Ciesla ML. Reliability of a urine dipstick in emergency department patients. Ann Emerg Med. May 1989;18(5):560-3. [Medline].
2. Avorn J, Monane M, Gurwitz JH, et al. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA. Mar 9 1994;271(10):751-4. [Medline].
3. Bent S, Nallamothu BK, Simel DL, et al. Does this woman have an acute uncomplicated urinary tract infection?. JAMA. May 22-29 2002;287(20):2701-10. [Medline].
4. Bent S, Nallamothu BK, Simel DL, Fihn SD, Saint S. Does this woman have an acute uncomplicated urinary tract infection?. JAMA. May 22-29 2002;287(20):2701-10. [Medline].
5. Berger RE. The urine dipstick test useful to rule out infections. A meta-analysis of the accuracy. J Urol. Sep 2005;174(3):941-2. [Medline].
6. Dwyer PL, O'Reilly M. Recurrent urinary tract infection in the female. Curr Opin Obstet Gynecol. Oct 2002;14(5):537-43. [Medline].
7. Ellis AK, Verma S. Quality of life in women with urinary tract infections: is benign disease a misnomer?. J Am Board Fam Pract. Nov-Dec 2000;13(6):392-7. [Medline].
8. Fihn SD. Clinical practice. Acute uncomplicated urinary tract infection in women. N Engl J Med. Jul 17 2003;349(3):259-66. [Medline].
9. Griebling TL. Urologic diseases in America project: trends in resource use for urinary tract infections in women. J Urol. Apr 2005;173(4):1281-7. [Medline].
10. Handley MA, Reingold AL, Shiboski S, Padian NS. Incidence of acute urinary tract infection in young women and use of male condoms with and without nonoxynol-9 spermicides. Epidemiology. Jul 2002;13(4):431-6. [Medline].
11. Hooton TM, Scholes D, Hughes JP, et al. A prospective study of risk factors for symptomatic urinary tract infection in young women. N Engl J Med. Aug 15 1996;335(7):468-74. [Medline].
12. Hooton TM, Scholes D, Stapleton AE, et al. A prospective study of asymptomatic bacteriuria in sexually active young women. N Engl J Med. Oct 5 2000;343(14):992-7. [Medline].
13. Howes DS, Bogner MP. Urinary tract infections. In: Tintinalli, et al, eds. Emergency Medicine. A Comprehensive Study Guide. 6^th ed. New York: McGraw-Hill; 2004:606-612.
14. Kaiser J, McPherson V, Kaufman L, Huber T. Clinical inquiries. Which UTI therapies are safe and effective during breastfeeding?. J Fam Pract. Mar 2007;56(3):225-8. [Medline].
15. Mehnert-Kay SA. Diagnosis and Management of Uncomplicated Urinary Tract Infections. American Family Physician [serial online]. August 1, 2005;27/No.3:1-9. Accessed August 8, 2007. Available at http://www.aafp.org/afp/20050801/451.html.
16. Millar LK, Wing DA, Paul RH, Grimes DA. Outpatient treatment of pyelonephritis in pregnancy: a randomized controlled trial. Obstet Gynecol. Oct 1995;86(4 Pt 1):560-4. [Medline].
17. National Institutes of Health National Kidney Urologic Diseases Information Clearinghouse. Available at http://kidney.niddk.nih.gov. Accessed August 5, 2007.
18. Talan DA, Stamm We, Reuning-Scherer J, et al. Ciprofloxacin 7-day vs tmp/smx 14-day +/- ceftriaxone for acute uncomplicated pyelonephritis: A randomized double-blind trial. 8th International Congress on Infectious Diseases. 1998.
19. Weir M, Brien J. Adolescent urinary tract infections. Adolesc Med. Jun 2000;11(2):293-313. [Medline].

Article Last Updated: Jan 31, 2008