The Woman with Dysuria KURT KUROWSKI, M.D., Finch University of Health Sciences/Chicago Medical School North Chicago, Illinois Bacterial cystitis is the most common bacterial infection occurring in women. Thirty percent of women will experience at least one episode of cystitis during their lifetime. About one third of patients presenting with symptoms of cystitis have upper urinary tract infections. A careful history to identify risk factors for subclinical pyelonephritis is important. Symptoms of chronic cystitis accompanied by sterile urine without pyuria may represent interstitial cystitis. Dysuria may also be the principal complaint of women with vaginitis (infectious, atrophic or chemical) or urethritis. A stepwise diagnostic approach, accompanied by inexpensive office laboratory testing, is usually sufficient to determine the cause of dysuria. An appropriate starting point in identifying the cause of dysuria is to attempt to classify the woman's symptoms by the specific anatomic site thought to be responsible. Table 1 lists disorders associated with symptoms of dysuria and their characteristic laboratory and physical findings. TABLE 1 Differential Diagnosis of Women with Dysuria Diagnosis Cystitis Associated symptoms Additional history Physical examination Laboratory and other test results Frequency, urgency, may have gross hematuria Recent sexual intercourse, risk factors present (see Table 2) 15 to 20% have suprapubic tenderness; no costovertebral angle tenderness Usually positive for pyuria and sometimes also positive for bacteriuria and nitrite Frequency, Subclinical urgency, may pyelonephritis have gross hematuria Usually positive for pyuria and sometimes also positive for bacteriuria May have and nitrite; Risk factors suprapubic positive renal present (see tenderness; no cortical Table 5) costovertebral scintigraphy, angle tenderness urine culture usually > 105 colonyforming units per mL of urine Nausea, emesis, fever, Acute sepsis, pyelonephritis back/flank pain Interstitial cystitis May have had concurrent or preceding cystitis symptoms (see Table 5) Often middleFrequency, aged; urgency, gross longstanding hematuria symptoms (20%) with negative cultures Costovertebral angle tenderness, deep right or left upper quadrant tenderness Pyuria usually present with casts of white blood cells; obtain urine culture and sensitivity Urinalysis negative for No costovertebral white blood angle tenderness; cells or may have bacteria; suprapubic positive for tenderness glomerulations on cystoscopy Vaginitis External irritation, vaginal discharge or pruritus, dyspareunia; no hematuria Premenstrual exaggeration of symptoms; sexual activity or recent antibiotic exposure or postmenopausal and not receiving estrogen replacement therapy Vaginal discharge, inflamed vaginal mucosa (absent in bacterial vaginosis), inflamed cervix (Trichomonas), vaginal atrophy (postmenopausal) Genital herpes Dysuria, fever, headache, myalgias, neck pain, vulvar pain, photophobia Sexually active; may have vaginal discharge Grouped vesicles usually on cervix or pubic area, but Viral culture may be vaginal; optional tender inguinal adenopathy Urethritis Usually asymptomatic; if symptoms develop, they are usually delayed (>1 week) History of unprotected sexual exposure No suprapubic pain unless associated with pelvic inflammatory disease; rarely, visible urethral discharge Positive potassium hydroxide or vaginal saline preparation elevated pH (bacterial vaginosis or Trichomonas) Urethral swab positive for white blood cells; obtain Gram stain to detect intracellular gram-negative diplococci and DNA probe for Chlamydia and gonorrhea Historical Differentiation Dysuria with frequency and urgency suggests cystitis.1 Women usually sense internal discomfort (located in the urethra and bladder) as opposed to external discomfort such as the labial irritation associated with vaginitis. Hematuria is common with urinary tract infections and is unlikely to occur with other potential etiologies.1 Sexual intercourse is associated with many causes of dysuria, but women with postcoital cystitis typically develop symptoms within a few days of intercourse, whereas women with urethritis develop symptoms one to two weeks later and women with vaginitis develop symptoms from weeks to months later. A history of recurrent urinary tract infections, use of a spermicide and diaphragm, and a higher frequency of intercourse within the previous week increases the risk for a urinary tract infection.2 Only about 15 to 20 percent of women with acute cystitis have suprapubic pain.1 Rarely, women with cystitis mention lower back pain or have a low-grade fever. Associated vaginal discharge suggests some type of vaginitis, although patients with urethritis can atypically have a discharge as well. Perimenstrual exacerbation of symptoms points to candidal or Trichomonas vaginitis. Dyspareunia and the sensation of the dysuria being external are typical of vaginitis. Dysuria associated with symptoms of pelvic inflammatory disease, occurring about one to two weeks after intercourse or noted just at the start of urination, suggests urethritis.3 Associated fever, myalgia and headache suggest acute pyelonephritis or primary genital herpes as the cause of dysuria. Nausea and emesis also typically accompany acute pyelonephritis. Bladder irritation from a distal urethral stone, compression from an adnexal mass, and radiation or chemical exposure can also produce dysuria. Examination Differentiation The physical examination is unremarkable in patients with cystitis, except in the 15 to 20 percent of patients who have suprapubic tenderness. Fever (greater than 38.5°C [101.3°F]), costovertebral angle tenderness or upper abdominal tenderness to deep palpation suggest acute pyelonephritis. Women with candidal or Trichomonas vaginitis may have vaginal discharge. Satellite vaginal pustules are sometimes present in patients with vaginal candidiasis, and grouped painful vesicles and tender inguinal adenopathy may be present in patients with genital herpes. Laboratory Differentiation If symptoms of cystitis are present, the finding of more than 102 colony-forming units per mL indicates true infection. Urine Analysis The most sensitive laboratory indicator for urinary tract infections is pyuria. A positive leukocyte esterase dipstick test is 75 to 95 percent sensitive in detecting pyuria secondary to infection.4 If no vaginal contamination occurs during collection, vaginitis does not produce pyuria. The presence of white blood cell casts suggests acute pyelonephritis. Bacteriuria and urine nitrite are also frequently present but are less sensitive indicators of urinary tract infection. Most of the subtypes of the known bacterial pathogens (with the exception of Staphylococcus saprophyticus and Enterococcus) can convert urinary nitrate to nitrite. Positive nitrite is over 90 percent specific for urinary tract infections, but sensitivity is usually only about 30 percent.5 This is secondary to the six-hour incubation time needed. Sensitivity increases to 60 percent with first-voided morning urine samples. Urine Culture Women with uncomplicated cystitis who are not pregnant do not usually require a urine culture. However, if a culture is performed and symptoms of cystitis are present, the finding of greater than 102 colony-forming units per mL of urine in a promptly cultured specimen is significant. Vaginal Smears/pH Testing Increased vaginal pH is characteristic of trichomoniasis and bacterial vaginosis; however, bacterial vaginosis does not typically produce dysuria. The replacement of vaginal lactobacillus with coliform bacteria also increases pH. This may occur in women with recurrent urinary tract infections. Potassium hydroxide and normal saline vaginal smears may reveal mycelia and motile trichomonads in patients with suspected vaginitis. Most women with urethritis are found to have greater than five white blood cells per high-power field on urethral smear. Cystitis Acute cystitis is the most common bacterial infection occurring in women. Of the more than 30 percent of women who will experience at least one episode of cystitis in their lifetime, 20 percent will have recurrent cystitis.3 Pathogenesis. The shorter urethra in women makes the ascension of bacteria more likely, especially during sexual intercourse. Urine is a natural bactericide with a low pH and a high osmolarity and urea content. Normal urine flow and voiding physically expel bacteria from the urinary tract. A protective mucin coating also inhibits the adherence of bacteria. Women normally have lactobacillus colonization of the vaginal mucosa. Vaginal secretions have a lower pH that inhibits coliform bacteria. TABLE 2 Conditions That Cause an Increased Incidence of Urinary Tract Infections in Women Condition Cause Obstruction or alterations in urine flow Tumors or stones in ureter or at ureterovesical junction; anomalies of tract anatomy/function such as cystocele, cystic kidneys, pregnancy Alterations in normal vaginal lactobacillus colonization Nonoxynol-9 in spermatocidal jellies selectively kills lactobacillus but not Escherichia coli2; certain antibiotics (especially beta-lactambased) alter vaginal flora; postmenopausal status is associated with a decrease in vaginal lactobacillus colonization1 Disruption of mucin layer Urinary tract instrumentation, including insertion of Foley catheter Some patients experience the disruption of some of these defense mechanisms. The conditions that increase the incidence of disruptions are listed in Table 2. Some women have genetically determined receptors on their uroepithelial cells that allow attachment by the glycolipid fimbriae of many fimbriated subtypes of bacteria. Women with these receptors who do not have mucosal secretion of a fucosyltransferase enzyme (which helps to block bacterial adherence) are more likely to have the lactobacillus in their vaginal mucosa replaced with Escherichia coli and other coliforms from their rectum and to have more frequent episodes of cystitis. Since these uroepithelial receptors are also found in the upper urinary tract, these women are also more prone to pyelonephritis.6,7 Table 3 lists the likely bacterial pathogens in uncomplicated and complicated urinary tract infections. TABLE 3 Incidence of Bacterial Pathogens in Lower Urinary Tract Infections Pathogen Uncomplicated infections Escherichia coli Staphylococcus saprophyticus Proteus mirabilis Klebsiella pneumoniae Enterobacter species Beta-hemolytic streptococci Complicated infections E. coli Enterococcus faecalis P. mirabilis Staphylococcus epidermidis K. pneumoniae Pseudomonas aeruginosa Staphylococcus aureus Enterobacter species Others* Incidence (%) 80 10 5 4 1 <1 35 16 13 12 7 5 4 3 5 *--Includes Serratia, Streptococcus, Acinetobacter and Citrobacter species. Adapted with permission from Sweet RL, Gibbs RS. Infectious diseases of the female genital tract. 3d ed. Baltimore: Williams & Wilkins, 1995. Treatment. Many episodes of bacterial cystitis resolve without treatment. The consumption of cranberry juice decreases the ability of the bacteria to attach to uroepithelial cells.8 Antibiotics hasten the resolution of symptoms and prevent the infection from spreading into the upper urinary tract. Adult nongravida women with uncomplicated cystitis may be treated empirically with a three-day course of antibiotics based on their clinical presentation and evidence of pyuria. Urine culture is not necessary in these women but should be performed if there is no pyuria despite a clinical picture of cystitis. Many antibiotics are effective in the treatment of cystitis, and most achieve high concentrations in the urine. Selection of the antibiotic should be determined by side effect profiles, drug interactions, cost and teratogenic effects. Drugs and dosages for antibiotic therapy for uncomplicated cystitis in women are listed in Table 4. Although fluroquinolones have been proved to be effective for the treatment of uncomplicated cystitis, their use should be avoided because of cost and potential teratogenic effects. About 30 percent of the bacteria that cause cystitis are currently resistant to amoxicillin or sulfamethoxazole. Only 15 to 20 percent of bacteria are resistant to nitrofurantoin (Macrobid, Macrodantin), and 10 to 15 percent are resistant to trimethoprim (Trimpex) or trimethoprim-sulfamethoxazole (Bactrim, Septra). Recurrent infections are usually reinfections separated by an asymptomatic interval of at least one month's duration. They are usually caused by vaginal and rectal colonization with uropathogens. Anatomic abnormalities in young women with recurrent cystitis are rare.9 The diffusion of trimethoprim into vaginal fluid to clear vaginal colonization of uropathogens is a key factor in its success in shorter-course therapy.10 Complicated Urinary Tract Infections. Complicated urinary tract infections are defined as those occurring in patients with anatomically or functionally abnormal urinary tracts, or in patients who are immunocompromised or have iatrogenic infections. Clinical recognition of complicated urinary tract infections is important because these patients are more likely to harbor resistant organisms (Table 3). Therapy consists of broader spectrum agents such as fluroquinolones. Cystitis should be treated for one week. Upper urinary tract infections should be treated for two weeks. A urine culture should be obtained to confirm sensitivity. TABLE 4 Empiric Oral Antibiotic Therapy for Uncomplicated Cystitis in Women Drug Dosage Trimethoprimsulfamethoxazole (Bactrim DS, Septra DS) One double-strength (160 mg/800 mg) tablet taken orally twice daily for three days Trimethoprim (Trimpex) One 100-mg tablet taken orally twice daily for three days Nitrofurantoin (Macrobid, Macrodantin) One 100-mg tablet taken orally four times daily for three days NOTE: Sulfamethoxazole is contraindicated in pregnant women near term. Sulfamethoxazole and nitrofurantoin are contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency. Trimethoprim is contraindicated in patients with folate deficiency. Nitrofurantoin has not been proved as effective as trimethoprim-sulfamethoxazole or trimethoprim in three-day clinical trials. Subclinical Pyelonephritis Appropriately named, subclinical pyelonephritis represents a diagnostic challenge to clinicians, because although patients with the condition have renal parenchymal involvement, they experience only the symptoms of cystitis.11 Estimates based on bladder washout studies show that 30 percent of women presenting with symptoms of cystitis actually have subclinical pyelonephritis.12 This finding has important therapeutic sequelae: infections are more difficult to eradicate and require a twoweek course of antibiotic therapy compared with the usual three-day course for cystitis,13,14 and since the renal parenchyma is involved, organism identification and confirmation of sensitivity are important. Subclinical pyelonephritis is distinguished from cystitis on the basis of risk factors and requires treatment with a two-week course of a broad-spectrum antibiotic. A urine culture and sensitivity should be obtained when an upper urinary tract infection is suspected based on clinical symptoms or risk factors. Table 5 lists the identifiable factors that increase a patient's risk for subclinical pyelonephritis. The clinician must suspect subclinical pyelonephritis in any patient with symptoms of cystitis who has one or more of the risk factors listed in Table 5. The physician should be aware that complicated urinary tract infections and subclinical pyelonephritis are not mutually exclusive and have overlapping risk factors. Patients with symptoms of cystitis and one or more risk factors for subclinical pyelonephritis should be treated for both conditions with empiric broader-spectrum antibiotics for two weeks. Most patients with subclinical pyelonephritis tend to have bacterial counts greater than 105 units per mL on quantitative culture, but the specificity of this culture is not high enough to be clinically useful. Many laboratory tests, such as the antibodycoated bacteria assay and erythrocyte sedimentation rates, have been used to help identify patients with subclinical pyelonephritis, but the specificity of these tests is too poor to make them clinically useful. Renal cortical scintigraphy has an 86 percent accuracy rate in distinguishing upper tract infections.15 Patients with upper tract involvement will show a focal asymmetric uptake. Treatment, however, is usually based on the presence of risk factors and is usually determined without using imaging studies. TABLE 5 Risk Factors for Subclinical Pyelonephritis in Women Symptoms present for more than one week before seeking treatment Diabetes mellitus Immunocompromised Pregnancy Anatomic anomaly of the urinary tract Vesicoureteral reflux Relapse of symptoms within three days of treatment for acute cystitis Ureteral obstruction History of acute pyelonephritis within one year Adapted with permission from Johnson CC. Definitions, classification and clinical presentation of urinary tract infection. Med Clin North Am 1991; 75:241-52. Interstitial Cystitis Interstitial cystitis is an inflammatory condition of the bladder of unknown etiology. It is much more common than was previously believed, affecting an estimated 450,000 persons in the United States.16 Ninety percent of affected patients are women. Some experts believe that men with prostatodynia, especially those with symptoms of cystitis, may actually have interstitial cystitis.17 Adding these men to the number of affected patients decreases the female predominance. Epidemiologic studies have shown that patients with interstitial cystitis have had their symptoms for an average of 4.5 years before they are correctly diagnosed, and that the median age of afflicted patients is 40 years (about one quarter of these patients are less than 30 years old) at the time of diagnosis. No clear genetic predisposition has been proved, but studies have revealed that about 15 percent of patients are of Jewish origin.18 Patients with interstitial cystitis are more likely to have had urinary tract infections both as adults and as children. The etiology of interstitial cystitis remains unclear. Many efforts have been made, without success, to culture a causative organism. In past decades, this disorder was considered to be a manifestation of an underlying psychiatric disorder and, indeed, many patients with this condition reported feelings of depression and anxiety, and a history of psychiatric care.18 Most authorities now believe that, at least in most patients, these feelings represent an understandable response to their disorder and are not the cause of it. Theories abound as to the true cause of interstitial cystitis. Presently, the most popular theory is that alterations occur in the glycosaminoglycan mucous layer, possibly in response to a previous bacterial urinary tract infection, allowing solutes in the urine to provoke a secondary inflammatory response.19 Diagnostic Evaluation Interstitial cystitis may be treated initially with an oral agent; however, intravesical or surgical therapy may eventually be necessary to control symptoms Interstitial cystitis remains a diagnosis of exclusion. Patients present with dysuria, urgency and frequency (some affected patients urinate from 60 to 80 times a day and from 10 to 30 times at night). The majority of patients have dyspareunia, and about 20 percent of patients have gross hematuria. Characteristic symptoms of interstitial cystitis are listed in Table 6. Patients who have this condition will have these symptoms along with evidence of Hunner's ulcers (mucosal ulcerations on the bladder wall with surrounding granulation tissue) or glomerulations (multiple petechial-like hemorrhages seen in the bladder mucosa with the bladder distended during cystoscopic examination). Most authorities recommend beginning the physical evaluation with a urodynamic study to demonstrate a reduced bladder capacity. Bladder biopsies may also be taken to rule out other potential etiologies such as carcinoma in situ. TABLE 6 Symptom Characteristics of the Patient with Interstitial Cystitis Symptoms of suprapubic pain with nocturia and frequency of at least eight times a day for at least nine months Patient older than 18 years of age Bladder capacity of less than 350 mL and urge to void if distended with 150 mL of urine No recent (within the last three months) diagnosis of bacterial cystitis or prostatitis No alternative explanation for the patient's symptoms (e.g., tuberculous cystitis, radiation cystitis, tumors of the genitourinary tract, chemical cystitis or active genital herpes or vaginitis) Adapted with permission from Hanno PM. Diagnosis of interstitial cystitis. Urol Clin North Am 1994;21(1):63-6. Treatment There is no known curative therapy for interstitial cystitis; consequently, efforts are directed at ameliorating symptoms and improving function. Patients usually begin with oral therapy and, if it is not successful, are changed to intravesical therapy. Transcutaneous electrical nerve stimulation (TENS) is effective in some patients.20 Patient response to any oral therapeutic agent is usually modest at best. While these agents have been shown to improve patients' symptoms relative to placebo, evidence from large double-blind, controlled studies is lacking. Pentosan polysulfate (Elmiron) was recently labeled by the U.S. Food and Drug Administration (FDA) as an oral therapy for interstitial cystitis. It is a heparin-like compound with anticoagulant and fibrinolytic effects. Its mechanism in interstitial cystitis is unknown; however, it has been postulated that it acts by augmenting the glycosaminoglycan mucous protective lining of the bladder wall. Given these serious limitations, the oral therapies most commonly prescribed appear in Table 7. Intravesical therapies include hydrodistention of the bladder during cystoscopic evaluation. This is believed to be therapeutic secondary to the ischemia produced to the submucosal nerve plexuses and stretch receptors. About 20 percent of patients report decreased pain and increased bladder capacity after this procedure, but unfortunately symptoms usually recur within three months. Intravesical dimethyl sulfoxide (DMSO; Rimso-50) has anti-inflammatory and analgesic properties and is the only intravesical agent labeled by the FDA for the treatment of interstitial cystitis. The patient's urine must be sterile and at least one month must have passed since any bladder biopsies have been taken. Patients often complain of a transient worsening of their symptoms due to the chemical cystitis produced in the first day or two after treatment and will also notice a garlic-like odor to their breath, but 50 to 70 percent of patients with classic interstitial cystitis and 50 to 90 percent of patients with nonulcer interstitial cystitis obtain significant relief from this treatment.22,23 Even though about 40 percent of treated patients relapse, they usually improve again after another instillation.23 Patients who do not respond to dimethyl sulfoxide alone should undergo a second course of treatment that includes 100 mg of hydrocortisone. Surgery should be reserved for use in severe cases that are refractory to medical treatment. The most common surgical procedure performed is a supratrigonal cystectomy with formation of an enterovesical anastomosis. In this procedure, a small cuff of residual bladder around the trigone is anastomosed to a portion of bowel segment. This procedure is effective in 60 to 90 percent of patients.24 It is more likely to be effective in patients with smaller bladder capacities (less than 400 mL).25 Patients with interstitial cystitis report great disability from their symptoms. About 50 percent of patients state that they are unable to work full time. Patients with interstitial cystitis score lower on self-assessment quality-of-life scales than do renal dialysis patients. Physicians or patients seeking more information about this condition can contact the following organization: The Interstitial Cystitis Association, P.O. Box 1553, Madison Square Station, New York, NY 10159-1553; telephone: 212979-6057; 800-HELP-ICA (800-435-7422). TABLE 7 Oral Therapy for Interstitial Cystitis Oral agent Dosage Pentosan polysulfate 300 mg per day Amitriptyline (Elavil) Starting at 25 mg per day at bedtime, increasing by 25 mg every two to four weeks up to 150 mg per day at bedtime Hydroxyzine (Atarax) 25 to 50 mg per day at bedtime Nifedipine (Adalat, Procardia) 30 mg (extended-release) every day, increasing to 60 mg per day in one month Cimetidine (Tagamet)21 200 mg three times per day *--Pentosan polysulfate is the only oral agent labeled by the U.S. Food and Drug Administration for the treatment of interstitial cystitis. Limited evidence supports the efficacy of the other agents in the treatment of this condition. Vaginitis When vaginitis causes a concomitant dysuria, the symptoms and physical findings usually are sufficient to make the diagnosis. Candida, Trichomonas and genital herpes produce dysuria either because of direct injury to the vaginal epithelium or because of an associated inflammatory response. On the other hand, bacterial vaginosis and some cases of urethritis are far less likely to cause dysuria because these infections produce less local inflammation. Candidal Vaginitis Dysuria, vaginal pruritus and discharge are the most common symptoms of candidiasis and usually worsen just before menstruation. Organisms originate in the perianal area and cause alterations in the normal vaginal environment. The alterations allow the yeast to multiply, change to its invasive mycelial form and cause symptoms. Table 8 shows several host factors that increase the risk of asymptomatic and symptomatic vaginal candidiasis. TABLE 8 Factors That Increase the Risk for Asymptomatic and Symptomatic Vaginal Candidiasis Factor Mechanism Pregnancy Higher vaginal glycogen content secondary to increased estrogen and progesterone levels; estrogen increases vaginal epithelial cell adherence by Candida Contraceptive use (including high-dose estrogen oral contraceptive pills, intrauterine devices, nonoxynol-9, diaphragm, contraceptive Elimination of normal protective flora sponge) Antibiotic use Elimination of normal protective flora (especially with the use of tetracyclines and broader spectrum betalactam antibiotics) Diabetes mellitus (especially if poorly controlled) Increased vaginal glycogen substrate Increased association with sexually transmitted diseases Increased exposure to antibiotics and contraceptives (see contraceptive use above); possible direct inoculation of organisms during intercourse Tight-fitting, synthetic underclothing Increased perineal moisture and temperature Corticosteroid therapy Altered cell-mediated immunity; increased serum glucose (see diabetes mellitus above) Human immunodeficiency virus Altered cell-mediated infection immunity Trichomonas Vaginitis Trichomonas vaginalis infection may be asymptomatic but usually causes an inflammatory vaginitis. There is a three-day to three-week incubation period. Trichomonads reproduce better at the higher vaginal pH in menstrual blood; consequently, a woman with Trichomonas vaginitis will usually note that her symptoms increase during and immediately following menstruation. Genital Herpes Eighty percent of patients with primary symptomatic genital herpes will have dysuria; however, dysuria is usually not present if the infection recurs.26 Most new cases of genital herpes are acquired from sexual contact with asymptomatic viral shedders. Primary herpetic infections typically produce dysuria, associated fever, headache, neck pain, photophobia and tender inguinal adenopathy. Seventy-five percent of patients with genital herpes will have vaginal discharge. Atrophic Vaginitis Dysuria occurs in women with atrophic vaginitis because of urine contact with the inflamed atrophic tissues themselves or because of the increased incidence of urinary tract infections in these women. Atrophic vaginitis is a common disorder, affecting from 20 to 30 percent of postmenopausal women. Decreased vaginal discharge, vaginal tenderness and dyspareunia are common in women with atrophic vaginitis. Women may also have bloody vaginal spotting, especially after intercourse. Atrophic vaginitis also increases the risk for urinary tract infections. Approximately 10 to 15 percent of women over 60 years of age have frequent urinary tract infections. Postmenopausal status is associated with a higher vaginal pH, a decrease in vaginal lactobacillus colonization and increased colonization with E. coli. Topical estriol vaginal cream is an effective treatment in postmenopausal women with recurrent infections. In one study,27 patients treated with the estriol cream averaged 0.5 infections per year, compared with about 6.0 infections per year in women who were not treated. Infectious Urethritis Infectious urethritis has not been studied as extensively in women as it has been in men. Chlamydia infection has long been thought to be responsible for many cases of dysuria in women with negative urine cultures.28 However, some authorities have been unable to show an association between dysuria and Chlamydia in women.29 A correlation between greater than five white blood cells per high-power field on a urethral swab and the presence of Chlamydia has been identified.29 A gonococcus may, less commonly, be asymptomatically present in the female urethra as well. About 75 percent of women with Chlamydia identified on urethral swabs have simultaneously had the organism isolated from their cervixes. The finding of intracellular, gram-negative diplococci on Gram's stain is 50 percent sensitive for gonorrhea infection in women.30 If either organism is suspected, the patient should undergo further testing such as a DNA probe to confirm the diagnosis. Miscellaneous Vaginal and urethral trauma, including sexual abuse and the insertion of a foreign body, can cause dysuria, as can irritant or topical allergic responses to soaps, douches, vaginal lubricants, spermicidal jellies, contraceptive foams and sponges, and tampons and sanitary napkins. Perfumed soaps and toilet paper are also common causes of dysuria. Avoidance of the irritative agent generally leads to the resolution of symptoms. The Author KURT KUROWSKI, M.D., is an assistant professor and predoctoral director in the Department of Family Medicine at the Finch University of Health Sciences/Chicago Medical School, North Chicago. He received a medical degree from the University of Wisconsin Medical School, Madison, and completed a family practice residency at Resurrection Hospital, Chicago. Urinary Tract Infections in Adults ROBERT ORENSTEIN, D.O. Hunter Holmes McGuire Veterans Affairs Medical Center Richmond, Virginia EDWARD S. WONG, M.D. Virginia Commonwealth University, Medical College of Virginia Richmond, Virginia Urinary tract infections remain a significant cause of morbidity in all age groups. Recent studies have helped to better define the population groups at risk for these infections, as well as the most cost-effective management strategies. Initially, a urinary tract infection should be categorized as complicated or uncomplicated. Further categorization of the infection by clinical syndrome and by host (i.e., acute cystitis in young women, acute pyelonephritis, catheter-related infection, infection in men, asymptomatic bacteriuria in the elderly) helps the physician determine the appropriate diagnostic and management strategies. Uncomplicated urinary tract infections are caused by a predictable group of susceptible organisms. These infections can be empirically treated without the need for urine cultures. The most effective therapy for an uncomplicated infection is a three-day course of trimethoprim-sulfamethoxazole. Complicated infections are diagnosed by quantitative urine cultures and require a more prolonged course of therapy. Asymptomatic bacteriuria rarely requires treatment and is not associated with increased morbidity in elderly patients. Urinary tract infections (UTIs) are a leading cause of morbidity and health care expenditures in persons of all ages. Sexually active young women are disproportionately affected, but several other populations, including elderly persons and those undergoing genitourinary instrumentation or catheterization, are also at risk. An estimated 40 percent of women report having had a UTI at some point in their lives.1 UTIs are the leading cause of gram-negative bacteremia. In the United States, these infections account for approximately 7 million office visits and more than 1 million hospitalizations, for an overall annual cost in excess of $1 billion.1,2 Recently published studies have added to the body of knowledge concerning the pathogenesis, diagnosis and management of UTIs. However, many practical issues have yet to be fully addressed. When should urine cultures be obtained? What diagnostic threshold should be used to define infection? What is the optimal duration of therapy and how should it be administered? Does bacteriuria in the elderly lead to adverse outcomes? Should trimethoprim-sulfamethoxazole (Bactrim, Septra) remain the initial therapy of choice for UTIs? This article clarifies these issues by reviewing the approach to the diagnosis and treatment of each patient group at risk for UTIs. In addition, a simple diagnostic approach to urinary tract infection in adults is presented in Figure 1. Adult Urinary Tract Infection FIGURE 1. Diagnostic approach to urinary tract infections in adults. (UTI=urinary tract infection) A recent categorization of UTIs is most helpful clinically because it divides patients into groups based on clinical factors and their impact on morbidity and treatment (Table 1).3 These categories are as follows: acute uncomplicated cystitis in young women; recurrent cystitis in young women; acute uncomplicated pyelonephritis in young women; complicated UTI and its subcategories; UTI related to indwelling catheters; UTI in men; and asymptomatic bacteriuria. Acute Uncomplicated Cystitis in Young Women Those most at risk for UTIs are sexually active young women. Their propensity to develop UTIs has been explained on the basis of anatomy (especially a short urethra) and certain behavioral factors, including delays in micturition, sexual activity, and the use of diaphragms and spermicides (both of which promote colonization of the periurethral area with coliform bacteria).4 Fortunately, most UTIs in this population are uncomplicated and are rarely associated with functional or anatomic abnormalities. In studies of women presenting with dysuria and increased frequency of urination, intravenous pyelography and ultrasonography have demonstrated low rates (less than 1 percent) of surgically correctable anatomic abnormalities of the urinary tract.5 Therefore, aggressive diagnostic work-ups are unwarranted in young women presenting with an uncomplicated episode of cystitis.3,6 TABLE 1 Urinary Tract Infections in Adults Category Diagnosti Principal c criteria pathogens First-line therapy Comments • • Urinalysis for pyuria Acute and uncomplicate hematuria d cystitis (culture not required) Recurrent cystitis in young women Symptoms and a urine culture with a bacterial count of more than • • • Escherichia coli Staphylococc us saprophyticus Proteus mirabilis Klebsiella pneumoniae • • • • • • Same as for acute uncomplicate d cystitis TMP-SMX DS (Bactrim, Septra) Trimethopri m (Proloprim) Ciprofloxaci n (Cipro) Ofloxacin (Floxin) If the patient has more than three cystitis episodes per year, treat • • Threeday course is best Quinolon es may be used in areas of TMPSMX resistanc e or in patients who cannot tolerate TMP-SMX Repeat therapy for seven to 10 days based on culture results 100 CFU per mL of urine Urine culture with a bacterial Acute cystitis count of in young 1,000 to men 10,000 CFU per mL of urine prophylactic ally with postcoital, patientdirected* or continuous daily therapy (see text) • Same as for acute uncomplicate d cystitis • Same as for acute uncomplicat ed cystitis • If gramnegative organism, oral fluoroquinol one If grampositive organism, amoxicillin If parenteral administrati on is required, ceftriaxone (Rocephin) or a fluoroquinol one If Enterococcu s species, add oral or IV amoxicillin • Urine culture Acute with a uncomplicate bacterial d count of pyelonephriti 100,000 s CFU per mL of urine • Same as for acute uncomplicate d cystitis • • Urine Complicated culture urinary tract with a infection bacterial count of • • • • E. coli K. pneumoniae P. mirabilis Enterococcus • If gramnegative organism, oral fluoroquinol and then use prophylac tic therapy • Treat for seven to 10 days • Switch from IV to oral administr ation when the patient is able to take medicatio n by mouth; complete a 14-day course • Treat for 10 to 14 days more than 10,000 CFU per mL of urine Urine culture with a bacterial Asymptomati count of c bacteriuria more than in pregnancy 10,000 CFU per mL of urine • • species Pseudomonas aeruginosa Same as for acute uncomplicate d cystitis • • • • one If Enterococcu s species, ampicillin or amoxicillin with or without gentamicin (Garamycin) Amoxicillin Nitrofuranto in (Macrodanti n) Cephalexin (Keflex) • • • • Symptoms and a urine culture Catheterwith a associated bacterial urinary tract count of infection more than 100 CFU per mL of urine • Depends on duration of catheterizatio n • If gramnegative organism, a fluoroquinol one If grampositive organism, ampicillin or amoxicillin plus gentamicin • TMP-SMX=trimethoprim-sulfamethoxazole; CFU=colonyforming unit; IV=intravenous. *--Patient is given a prescription for an antibiotic to take if symptoms develop. Information from Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J Med 1993;329:132834. Avoid tetracycli nes and fluoroqui nolones Treat for three to seven days Remove catheter if possible, and treat for seven to 10 days For patients with longterm catheters and symptom s, treat for five to seven days The diagnosis of UTI was once based on a quantitative urine culture yielding greater than 100,000 colony-forming units (CFU) of bacteria per milliliter of urine, which was termed "significant bacteriuria."7 This value was chosen because of its high specificity for the diagnosis of true infection, even in asymptomatic persons. However, several studies8-10 have established that one third or more of symptomatic women have CFU counts below this level (low-coliform-count infections) and that a bacterial count of 100 CFU per mL of urine has a high positive predictive value for cystitis in symptomatic women. Unfortunately, some clinical laboratories do not report counts of less than 10,000 CFU per mL of urine. As a result, low-coliform-count infections are not diagnosed by these laboratories. The microbiology of uncomplicated cystitis is limited to a few pathogens. As many as 90 percent of uncomplicated cystitis episodes are caused by Escherichia coli, 10 to 20 percent are caused by coagulase-negative Staphylococcus saprophyticus and 5 percent or less are caused by other Enterobacteriaceae organisms or enterococci.3 In addition, the antimicrobial susceptibilities of these organisms are highly predictable. Up to one third of uropathogens are resistant to ampicillin and sulfonamides, but the majority are susceptible to trimethoprim-sulfamethoxazole (85 to 95 percent) and fluoroquinolones (95 percent).3,11 TABLE 2 Diagnostic Tests for Urinary Tract Infections in Women with Dysuria Laboratory test Positive Negative Sensitivity Specificity predictive predictive value value Midstream culture Any coliforms 1.00 0.71 0.79 1.00 More than 100 coliforms 0.95 per mL of urine 0.85 0.88 0.94 More than 100,000 0.51 coliforms per mL of urine 0.59 0.98 0.65 0.91 0.50 0.67 0.83 More than 20 white blood 0.50 cells per mm3 0.95 0.94 0.54 0.95 0.50 0.92 Microscopy More than 8 white blood cells per mm3 Rapid tests Leukocyte esterase 0.75 to 0.90 dipstick Nitrite dipstick 0.35 to 0.85 0.95 0.96 0.27 to 0.70 Leukocyte 0.75 to esterase and 0.90 nitrite 0.70 0.75 to 0.93 0.41 to 0.95 Adapted with permission from Fihn SD, McGee SR. Outpatient medicine. Philadelphia, Pa.: Saunders, 1992. In view of the limited spectrum of causative organisms and their predictable susceptibility, urine cultures and susceptibility testing add little to the choice of antibiotic for the treatment of acute uncomplicated cystitis in young women. Therefore, urine cultures are no longer advocated as part of the routine work-up of these patients. Instead, these patients should undergo an abbreviated laboratory work-up in which the presence of pyuria is confirmed by traditional urinalysis (wet mount examination of spun urine), the cell-counting chamber technique or a dipstick test for leukocyte esterase.3,6 An estimated 40 percent of women report having had a UTI at some point in their lives. A positive leukocyte esterase test has a reported sensitivity of 75 to 90 percent in detecting pyuria associated with a UTI. Gram staining of unspun urine can be used to detect bacteriuria. In this semiquantitative test, one organism per oil immersion field correlates with 100,000 CFU per mL by culture.1 Because the procedure is timeconsuming and has low sensitivity, it is not routinely performed in most clinical laboratories unless it is specifically requested. In today's office practice, the dipstick test for nitrite is used as a surrogate marker for bacteriuria. It should be noted that not all uropathogens reduce nitrates to nitrite. For example, enterococci, S. saprophyticus and Acinetobacter species do not and therefore give false-negative results. The sensitivities and specificities of the tests commonly used to diagnose UTIs are given in Table 2.12 Treatment options for uncomplicated cystitis include single-dose antibiotic therapy and three- or seven-day courses of antibiotics (Table 3). Treatment of cystitis with seven or more days of antibiotics once was the standard of therapy. Although this regimen was highly efficacious, it was associated with a certain (albeit low) frequency of side effects. Single-dose therapy appears to offer the advantages of low cost, high compliance and comparable efficacy. Studies using 3 g of amoxicillin, 400 mg of trimethoprim (Proloprim), two to three double-strength trimethoprimsulfamethoxazole tablets, 800 mg of norfloxacin (Noroxin), 125 mg of ciprofloxacin (Cipro) or 200 mg of ofloxacin (Floxin) have confirmed that single-dose therapy is highly effective in the treatment of acute uncomplicated cystitis, with cure rates ranging from 80 to 99 percent.3 Fosfomycin tromethamine (Monurol) can be given as a single oral 3-g sachet for the treatment of acute uncomplicated UTIs. This drug is active against E. coli, enterococci and Citrobacter, Enterobacter, Klebsiella and Serratia species. The clinical cure rate is estimated to be as high as 99 percent. Fosfomycin may be safely used in pregnancy.13 Single-dose antibiotic therapy fell into disfavor when it was observed that women had a high risk of recurrence within six weeks of the initial treatment.14,15 The risk was attributed to the failure of single-dose antibiotics to eradicate gram-negative bacteria from the rectum, the source or reservoir for ascending uropathogens. TABLE 3 Antibiotic Therapy for Urinary Tract Infections Diagnostic group Duration Cost Route of of Empiric options (generic)* administration therapy Acute uncomplicated urinary tract Oral infections in women Three days Trimethoprimsulfamethoxazole $ 7.50 (Bactrim DS), one (2.00) double-strength tablet twice daily Trimethoprim (Proloprim), 100 mg twice daily 4.00 (1.00) Norfloxacin (Noroxin), 400 mg twice daily 18.50 Ciprofloxacin (Cipro), 250 mg twice daily 19.50 Lomefloxacin (Maxaquin), 400 mg per day 20.00 Ofloxacin (Floxin), 200 mg twice daily 21.00 Enoxacin (Penetrex), 200 mg twice daily 18.00 Sparfloxacin (Zagam), 400 mg 25.00 as initial dose, then 200 mg per day Levofloxacin (Levaquin), 250 mg per day 19.00 Nitrofurantoin (Macrodantin), 100 mg four times daily 17.00 (14.00) Cefpodoxime (Vantin), 100 mg 17.00 twice daily Cefixime 21.00 (Suprax), 400 mg per day Amoxicillinclavulanate 17.50 potassium (Augmentin), 500 mg twice daily Acute uncomplicated Oral pyelonephritis 14 days Trimethoprimsulfamethoxazole 36.00 DS, one double(11.00) strength tablet twice daily Ciprofloxacin, 500 105.50 mg twice daily Levofloxacin, 250 92.00 mg per day Enoxacin, 400 mg 191.00 twice daily Sparfloxacin, 400 mg initial dose, 104.50 then 200 mg per day Ofloxacin, 400 mg twice daily 124.50 Cefpodoxime, 200 mg twice daily 111.00 Cefixime, 400 mg 97.50 per day Parenteral Up to 3 days† Trimethoprim32.00 sulfamethoxazole (12.00) per 160/800 twice day daily Ceftriaxone (Rocephin), 1 g per day 41.00 per day Ciprofloxacin, 400 57.50 per mg twice daily day Ofloxacin, 400 mg twice daily 53.00 per day Levofloxacin, 250 21.00 per mg day Complicated urinary tract infections Oral Parenteral Aztreonam (Azactam), 1 g three times daily 48.50 per day Gentamicin (Garamycin), 3 mg per kg per day in 3 divided doses every 8 hours‡§ 12.50 (2.50 to 3.00) per day 14 days Fluoroquinolones Up to 3 days Ampicillin, 1 g 14.50 every six hours, (5.00 to and gentamicin, 3 5.50) per mg per kg per day day‡ Urinary tract infections in young men Oral Seven days Trimethoprimsulfamethoxazole, 18.00 one double(5.50) strength tablet twice daily Urinary tract infections in pregnant women Oral Three to seven days Amoxicillin, 250 mg three times daily 2.00 to 4.50 (1.00 to 5.00) Asymptomatic bacteriuria in Oral pregnant women Three to seven days Nitrofurantoin, 100 mg four times daily 12.00 to 28.00 (14.00 to 32.50 *--Estimated cost to the pharmacist based on average wholesale prices, rounded to the nearest half dollar, in Red book. Montvale, N.J.: Medical Economics Data, 1998. Cost to the patient will be higher, depending on prescription filling fee. †--The Sanford guide (1998) recommends intravenous therapy until patient is afebrile for 24 to 48 hours, then a two-week course of oral therapy. ‡--Same regimens as for pyelonephritis. §--Based on 70-kg (154-lb) patient. Unlike single-dose antibiotic therapy, a three-day regimen reduces rectal carriage of gram-negative bacteria and is not associated with a high recurrence rate. Thus, three-day regimens appear to offer the optimal combination of convenience, low cost and an efficacy comparable to that of seven-day or longer regimens but with fewer side effects.11 One randomized trial16 compared three days of trimethoprim-sulfamethoxazole therapy, one double-strength tablet twice daily, with three days of treatment using the following drugs: nitrofurantoin (Macrodantin), 100 mg four times daily; cefadroxil, 500 mg twice daily; and amoxicillin, 500 mg three times daily. Trimethoprim-sulfamethoxazole was found to be the most cost-effective treatment. Three-day regimens of ciprofloxacin, 250 mg twice daily, and ofloxacin, 200 mg twice daily, were recently compared with three-day trimethoprim-sulfamethoxazole therapy.3,11 The oral fluoroquinolones produced better cure rates with less toxicity, but at a greater overall cost. Quinolones that are useful in treating complicated and uncomplicated cystitis include ciprofloxacin, norfloxacin, ofloxacin, enoxacin (Penetrex), lomefloxacin (Maxaquin), sparfloxacin (Zagam) and levofloxacin (Levaquin).11 The newer fluoroquinolone, sparfloxacin, in a dosage of 400 mg per day as the initial dose and then 200 mg per day for two days, is equivalent to three days of therapy with ofloxacin or ciprofloxacin. However, sparfloxacin can cause phototoxicity, and it has also been associated with prolongation of the QT interval.17 As many as 90 percent of uncomplicated cystitis episodes are caused by Escherichia coli, 10 to 20 percent are caused by the coagulase-negative Staphylococcus saprophyticus, and 5 percent or less are caused by other Enterobacteriaceae organisms or enterococci. On the basis of cost and efficacy, trimethoprim-sulfamethoxazole remains the antibiotic of choice in the treatment of uncomplicated UTIs in young women. The use of fluoroquinolones as first-line therapy for uncomplicated UTIs should be discouraged, except in patients who cannot tolerate sulfonamides or trimethoprim, who have a high frequency of antibiotic resistance because of recent antibiotic treatment or who reside in an area in which significant resistance to trimethoprimsulfamethoxazole has been noted. Three days is the optimal duration of treatment for uncomplicated cystitis. A seven-day course should be considered in pregnant women, diabetic women and women who have had symptoms for more than than one week and thus are at higher risk for pyelonephritis because of the delay in treatment. Recurrent Cystitis in Young Women Up to 20 percent of young women with acute cystitis develop recurrent UTIs. During these recurrent episodes, the causative organism should be identified by urine culture and then documented to help differentiate between relapse (infection with the same organism) and recurrence (infection with different organisms). Multiple infections caused by the same organism are, by definition, complicated UTIs and require longer courses of antibiotics and possibly further diagnostic tests (see the discussion of complicated UTIs). Fortunately, most recurrent UTIs in young women are uncomplicated infections caused by different organisms. These infections are generally not associated with underlying anatomic abnormalities and do not require further work-up of the genitourinary tract.5,11,18 Women who have more than three UTI recurrences documented by urine culture within one year can be managed using one of three preventive strategies3,19: 1. Acute self-treatment with a three-day course of standard therapy. 2. Postcoital prophylaxis with one-half of a trimethoprim-sulfamethoxazole doublestrength tablet (40/200 mg) if the UTIs have been clearly related to intercourse. 3. Continuous daily prophylaxis with one of these regimens for a period of six months: trimethoprim-sulfamethoxazole, one-half tablet per day (40/200 mg); nitrofurantoin, 50 to 100 mg per day; norfloxacin, 200 mg per day; cephalexin (Keflex), 250 mg per day; or trimethoprim, 100 mg per day. Each of these regimens has been shown to decrease the morbidity of recurrent UTIs without a concomitant increase in antibiotic resistance. Long-term studies have shown antibiotic prophylaxis to be effective for up to five years with trimethoprim, trimethoprim-sulfamethoxazole or nitrofurantoin, without the emergence of drug resistance.3,19 Unfortunately, antibiotic prophylaxis does not appear to alter the natural history of recurrences because 40 to 60 percent of these women reestablish their pattern or frequency of infections within six months of stopping prophylaxis.19 Complicated UTI A complicated UTI is one that occurs because of anatomic, functional or pharmacologic factors that predispose the patient to persistent infection, recurrent infection or treatment failure. These factors include conditions often encountered in elderly men, such as enlargement of the prostate gland, blockages and other problems necessitating the placement of indwelling urinary devices, and the presence of bacteria that are resistant to multiple antibiotics. Although antibioticsusceptible E. coli is responsible for more than 80 percent of uncomplicated UTIs, it accounts for fewer than one third of complicated cases.1,3 Clinically, the spectrum of complicated UTIs may range from cystitis to urosepsis with septic shock. Accurate urine culture and susceptibility information are necessary to best target and eradicate the pathogens in complicated UTIs. These infections are usually associated with high-count bacteriuria (greater than 100,000 CFU per mL of urine). Occasionally, lower quantitative counts may be encountered in patients who are undergoing diuresis or who are in renal failure. The initial empiric therapy for these patients should include an agent with a broad spectrum of activity against the expected uropathogens. Treatment most often includes a fluoroquinolone, administered orally if possible. In patients who are unable to tolerate oral medication or who require hospitalization for concomitant medical problems, appropriate initial therapy may be parenteral administration of one of the following: a third-generation cephalosporin with antipseudomonal activity such as ceftazidime (Fortaz) or cefoperazone (Cefobid), cefepime (Maxipime), aztreonam (Azactam), imipenemcilastatin (Primaxin) or the combination of an antipseudomonal penicillin (ticarcillin [Ticar], mezlocillin [Mezlin], piperacillin [Pipracil]) with an aminoglycoside. Enterococci are frequently encountered uropathogens in complicated UTIs. In areas in which vancomycin-resistant Enterococcus faecium is prevalent, the investigational agent quinupristin-dalfopristin (Synercid) may be useful.20 Patients with complicated UTIs require at least a 10- to 14-day course of therapy. Follow-up urine cultures should be performed within 10 to 14 days after treatment to ensure that the uropathogen has been eradicated. Recent studies have shown that patients initially placed on parenteral therapy can be switched to oral therapy within 72 hours as long as they are clinically improving and able to tolerate the oral agent, and a regimen is available that covers the identified pathogen(s).11,21 Uncomplicated Pyelonephritis Women with acute uncomplicated pyelonephritis may present with one of the following: a mild cystitis-like illness and accompanying flank pain; a more severe illness with fever, chills, nausea, vomiting, leukocytosis and abdominal pain; or a serious gram-negative bacteremia. The microbiologic features of acute uncomplicated pyelonephritis mirror cystitis, except that S. saprophyticus is a rare cause. In most patients, uncomplicated pyelonephritis is caused by specific uropathogenic strains of E. coli possessing adhesins that permit ascending infection of the urinary tract. The diagnosis should be confirmed by urinalysis with examination for pyuria and/or white blood cell casts and by urine culture. Urine cultures demonstrate more than 100,000 CFU per mL of urine in 80 percent of women with pyelonephritis. Blood cultures are positive in up to 20 percent of women who have this infection. With the exceptions of white cell casts on urinalysis, and bacteremia and flank pain on physical examination, none of the physical or laboratory findings are specific for pyelonephritis.3 Oral therapy should be considered in women with mild to moderate symptoms who are compliant with therapy and can tolerate oral antibiotics but do not have other significant conditions, including pregnancy and gastrointestinal upset. Since E. coli resistance to ampicillin, amoxicillin and first-generation cephalosporins exceeds 30 percent in most locales, these agents should not be used empirically for the treatment of pyelonephritis.11 Even though trimethoprim-sulfamethoxazole is often considered the treatment of choice, resistance to this drug combination may exceed 15 percent in some regions. In those instances, empiric therapy using an oral fluoroquinolone should be considered. Patients who are too ill to take oral antibiotics or who are unable to take them should initially be treated with parenterally administered single agents, such as trimethoprim-sulfamethoxazole, a third-generation cephalosporin, aztreonam, a broad-spectrum penicillin, a quinolone or an aminoglycoside. The choice of antibiotic is largely empiric, but Gram staining of the urine may be helpful. Once these patients have improved clinically (usually by day 3), they can be switched to oral therapy based on the results of culture and sensitivity studies.11 The total duration of therapy need not exceed 14 days, regardless of the initial bacteremia. Patients with persistent symptoms after three days of appropriate antimicrobial therapy should be evaluated by renal ultrasonography or computed tomography for evidence of urinary obstruction or abscess. In the small percentage of patients who relapse after a two-week course, a repeated six-week course is usually curative.11 UTI in Men Urinary tract infections most commonly occur in older men with prostatic disease, outlet obstruction or urinary tract instrumentation. These infections occasionally occur in young men who participate in anal sex (exposure to E. coli in the rectum), who are not circumcised (increased E. coli colonization of the glans and prepuce) or whose sexual partner is colonized with uropathogens.22 In men (unlike in women), a urine culture growing more than 1,000 CFU of a pathogen per mL of urine is the best sign of a urinary tract infection, with a sensitivity and specificity of 97 percent.23 Men with urinary tract infections should receive a minimum of seven days of antibiotic therapy (either trimethoprimsulfamethoxazole or a fluoroquinolone). However, more extensive courses may be required in, for example, men with associated urinary tract infection and prostatitis. Consensus regarding the need for a urologic work-up in men with urinary tract infections is lacking. Among young men with acute cystitis who respond to seven days of treatment, diagnostic work-ups beyond cultures are generally unrewarding.24 Urologic evaluation should be performed routinely in adolescents and men with pyelonephritis or recurrent infections.11,25 When bacterial prostatitis is the source of a urinary tract infection, eradication usually requires antibiotic therapy for six to 12 weeks and in rare instances even longer. Catheter-Associated UTI Between 10 and 20 percent of patients who are hospitalized receive an indwelling Foley catheter. Once this catheter is in place, the risk of bacteriuria is approximately 5 percent per day. With long-term catheterization, bacteriuria is inevitable. Catheter- associated urinary tract infections account for 40 percent of all nosocomial infections and are the most common source of gram-negative bacteremia in hospitalized patients.26 Unlike single-dose antibiotic therapy, a three-day regimen reduces rectal carriage of gram-negative bacteria and is not associated with a high recurrence rate. Thus, three-day regimens appear to offer the optimal combination of convenience, low cost and an efficacy comparable to that of seven-day or longer regimens but with fewer side effects. The diagnosis of catheter-associated urinary tract infection can be made when the urine culture shows 100 or more CFU per mL of urine from a catheterized patient. The microbiology of catheter-associated urinary tract infections includes E. coli and Proteus, Enterococcus, Pseudomonas, Enterobacter, Serratia and Candida species. The bacterial distribution reflects the nosocomial origin of the infections because so many of the uropathogens are acquired exogenously via manipulation of the catheter and drainage device. Bacteriuria is often polymicrobic, especially in patients with long-term indwelling urinary catheters. Symptomatic bacteriuria in a patient with an indwelling Foley catheter should be treated with antibiotics that cover potential nosocomial uropathogens. Patients with mild to moderate infections may be treated with one of the oral quinolones, usually for 10 to 14 days. Parenteral antibiotic therapy may be necessary in patients with severe infections or patients who are unable to tolerate oral medications. The recommended duration of therapy for severe infections is 14 to 21 days. Treatment is not recommended for catheterized patients who have asymptomatic bacteriuria, with the following exceptions: patients who are immunosuppressed after organ transplantation, patients at risk for bacterial endocarditis and patients who are about to undergo urinary tract instrumentation.26 Bacteriuria is almost inevitable with long-term catheterization, and prevention strategies have largely been unsuccessful. In such patients, catheters should be changed periodically to prevent the formation of concretions and obstruction that can lead to infection. Prophylactic systemic antibiotics have been shown to delay the onset of bacteriuria in catheterized patients, but this strategy may lead to increased bacterial resistance.26 Prophylactic antibiotic therapy has been successful in reducing the frequency of bacteriuria only in patients who can be weaned from indwelling catheters to intermittent catheterization. Asymptomatic Bacteriuria Asymptomatic bacteriuria is defined as the presence of more than 100,000 CFU per mL of voided urine in persons with no symptoms of urinary tract infection. The largest patient population at risk for asymptomatic bacteriuria is the elderly. Up to 40 percent of elderly men and women may have bacteriuria without symptoms. Although early studies noted an association between bacteriuria and excess mortality, more recent studies have failed to demonstrate any such link.27 In fact, aggressively screening elderly persons for asymptomatic bacteriuria and subsequent treatment of the infection has not been found to reduce either infectious complications or mortality. Consequently, this approach currently is not recommended. Three groups of patients with asymptomatic bacteriuria have been shown to benefit from treatment: (1) pregnant women, (2) patients with renal transplants and (3) patients who are about to undergo genitourinary tract procedures.3 Between 2 and 10 percent of pregnancies are complicated by UTIs; if left untreated, 25 to 30 percent of these women develop pyelonephritis.28,29 Pregnancies that are complicated by pyelonephritis have been associated with low-birth-weight infants and prematurity. Thus, pregnant women should be screened for bacteriuria by urine culture at 12 to 16 weeks of gestation. The presence of 100,000 CFU of bacteria per mL of urine is considered significant. Pregnant women with asymptomatic bacteriuria should be treated with a three- to seven-day course of antibiotics, and the urine should subsequently be cultured to ensure cure and the avoidance of relapse.29 Although amoxicillin is frequently suggested as the agent of choice, E. coli is now commonly resistant to ampicillin, amoxicillin and cephalexin. Thus, treatment should be based on the results of susceptibility tests. Nitrofurantoin or trimethoprim-sulfamethoxazole may also be used; however, caution should be exercised in the third trimester because the sulfonamides compete with bilirubin binding in the newborn. Symptomatic urinary tract infections complicate 1 to 2 percent of pregnancies, usually in women with persistent bacteriuria.28,29 Most pregnant women with pyelonephritis should be hospitalized. Initially, these patients should receive intravenous antibiotic therapy. They should complete a 14-day course of acute antibiotic therapy followed by nightly suppressive therapy until delivery. Recent studies have shown that selected pregnant women with pyelonephritis can be treated with either outpatient intramuscularly administered ceftriaxone (Rocephin) or orally administered cephalexin.28 Ceftriaxone, a third-generation parenterally administered cephalosporin, is a suitable agent for inpatient treatment. Tetracyclines and fluoroquinolones should be avoided in pregnancy. The Authors ROBERT ORENSTEIN, D.O., is assistant professor in the Department of Internal Medicine at the Virginia Commonwealth University Medical College of Virginia, Richmond. He is also director of the HIV/AIDS Program at Hunter Holmes McGuire Veterans Affairs Medical Center, also in Richmond. Dr. Orenstein graduated from the University of Osteopathic Medicine and Health Sciences, Des Moines, Iowa. He completed a residency in internal medicine at Geisinger Medical Center, Danville, Pa., and a fellowship in infectious diseases at the Medical College of Virginia. EDWARD S. WONG, M.D., is associate professor in the Department of Internal Medicine at Virginia Commonwealth University Medical College of Virginia and chief of the infectious diseases section at Hunter Holmes McGuire Veterans Affairs Medical Center. Dr. Wong received his medical degree from Harvard Medical School, Boston. He completed a residency in internal medicine at Montefiore Hospital, New York, N.Y., and a fellowship in infectious diseases at the University of Washington Medical Center, Seattle.
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