Am Fam Physician. 1998;57(9):2155-2164
See related patient information handout on the causes of painful urination, written by the author of this article.
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.
| Diagnosis | Associated symptoms | Additional history | Physical examination | Laboratory and other test results |
|---|---|---|---|---|
| Cystitis | 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 |
| Subclinical pyelonephritis | Frequency, urgency, may have gross hematuria | Risk factors present (see Table 5) | May have suprapubic tenderness; no costovertebral angle tenderness | Usually positive for pyuria and sometimes also positive for bacteriuria and nitrite; positive renal cortical scintigraphy, urine culture usually > 105 colony-forming units per mL of urine |
| Acute pyelonephritis | Nausea, emesis, fever, sepsis, back/flank pain | May have had concurrent or preceding cystitis symptoms (see Table 5) | Costovertebral angle tenderness, deep right or left upper quadrant tenderness | Pyuria usually present with casts of white blood cells; obtain urine culture and sensitivity |
| Interstitial cystitis | Frequency, urgency, gross hematuria (20%) | Often middle-aged; longstanding symptoms with negative cultures | No costovertebral angle tenderness; may have suprapubic tenderness | Urinalysis negative for white blood cells or bacteria; positive for glomerulations on cystoscopy |
| Vaginitis | External irritation, vaginal discharge or pruritus, dyspareunia; no hematuria | Premenstrual exaggeration of symptoms; sexual activity or recent antibiotic exposure or post-menopausal and not receiving estrogen replacement therapy | Vaginal discharge, inflamed vaginal mucosa (absent in bacterial vaginosis), inflamed cervix (Trichomonas), vaginal atrophy (postmenopausal) | Positive potassium hydroxide or vaginal saline preparation; elevated pH (bacterial vaginosis or Trichomonas) |
| 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 may be vaginal; tender inguinal adenopathy | Viral culture optional |
| 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 | 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
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.
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.
| 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-lactam–based) 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 |
| Drug | Dosage |
|---|---|
| Trimethoprim-sulfamethoxazole (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 |
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.
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 two-week 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.
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 antibody-coated 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.
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 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.
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.
| Oral agent | Dosage |
|---|---|
| Pentosan polysulfate (Elmiron)* | 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 |
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, 110 N. Washington St., Ste. 340, Rockville, MD 20850; telephone: 800-435-7422; Web site: http://www.ichelp.org.
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.
| 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 sponge) | Elimination of normal protective flora |
| Antibiotic use | Elimination of normal protective flora (especially with the use of tetracyclines and broader spectrum beta-lactam 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 infection | Altered cell-mediated 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 lacto-bacillus 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.