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The term prostatitis is applied to a series of disorders, ranging from acute bacterial infection to chronic pain syndromes, in which the prostate gland is inflamed. Patients present with a variety of symptoms, including urinary obstruction, fever, myalgias, decreased libido or impotence, painful ejaculation and low-back and perineal pain. Physical examination often fails to clarify the cause of the pain. Cultures and microscopic examination of urine and prostatic secretions before and after prostatic massage may help differentiate prostatitis caused by infection from prostatitis with other causes. Because the rate of occult infection is high, a therapeutic trial of antibiotics is often in order even when patients do not appear to have bacterial prostatitis. If the patient responds to therapy, antibiotics are continued for at least three to four weeks, although some men require treatment for several months. A patient who does not respond might be evaluated for chronic nonbacterial prostatitis, in which nonsteroidal anti-inflammatory drugs, alpha-blocking agents, anticholinergic agents or other therapies may provide symptomatic relief. (Am Fam Physician 2000;61:3015-22,3025-6.)

Prostatitis is inflammation of the prostate gland. In clinical practice, the term prostatitis encompasses multiple diverse disorders that cause symptoms related to the prostate gland. One author has described prostatitis as "a wastebasket of clinical ignorance"(1) because so many poorly characterized syndromes are diagnosed as prostatitis. The spectrum of prostatitis ranges from straightforward acute bacterial prostatitis to complex conditions that may not even involve prostatic inflammation. These conditions can often be frustrating for the patient and the clinician.

Prostatitis is a common condition. In a survey of National Guard members (20 to 49 years of age) using a self-reported diagnosis of prostatitis, a 5 percent lifetime prevalence was noted.(2) A population-based study of men (40 to 79 years of age) in Olmstead County, Minn., suggests a lifetime prevalence close to 9 percent. The latter study used a medical record review to confirm physician diagnosis of prostatitis. Patients with a previous episode of prostatitis were at significantly increased risk for subsequent episodes.(3) In a nationwide review of data from outpatient physician visits, it was noted that 15 percent of men who saw a physician for genitourinary complaints were diagnosed with prostatitis.(4) Every year, approximately 2 million physician visits include the diagnosis of prostatitis. Despite its widespread prevalence, prostatitis remains a poorly studied and little understood condition.

Diagnosis

Prostatitis is not easily diagnosed or classified. Patients with prostatitis often present with varied, nonspecific symptoms, and the physical examination is frequently not helpful. The traditional diagnostic test for differentiating types of prostatitis is the Stamey-Meares four-glass localization method.(5) It includes bacterial cultures of the initial voided urine (VB1), midstream urine (VB2), expressed prostatic secretions (EPS), and a postprostatic massage urine specimen (VB3). The VB1 is tested for urethral infection or inflammation, and the VB2 is tested for urinary bladder infection. The prostatic secretions are cultured and examined for white blood cells (more than 10 to 20 per high-power field is considered abnormal). The postmassage urine specimen is believed to flush out bacteria from the prostate that remain in the urethra.

Although widely described as the gold standard for evaluation for prostatitis, this diagnostic technique has never been appropriately tested to assess its usefulness in the diagnosis or treatment of prostatic disease. The expression of prostatic secretions can be difficult and uncomfortable. In addition, the test is somewhat cumbersome and expensive, which may explain its infrequent use by primary care physicians and urologists.(3,6)

An alternative diagnostic test, called the pre- and postmassage test (PPMT) has been proposed. Although easier to carry out, this test has also not been validated; in retrospective studies, it performed about as well as the four-glass method.(7)

The technique is straightforward. The patient retracts the foreskin, cleanses the penis and then obtains a midstream urine sample. The examiner performs a digital rectal examination and vigorously massages the prostate from the periphery toward the midline. The patient collects a second urine sample, and both specimens are sent for microscopy and culture. See Table 1 for interpretation of results of the four-glass test and the PPMT.

Categorizing Prostatitis

Traditionally, prostatitis has been divided into four subtypes based on the chronicity of symptoms, the presence of white blood cells in the prostatic fluid and culture results. These subtypes are acute bacterial prostatitis, chronic bacterial prostatitis, chronic nonbacterial prostatitis and prostadynia.(5) Although this classification system has been widely used, it has never been validated for diagnostic or therapeutic utility.

At a recent National Institutes of Health (NIH) conference, a new classification system was proposed that could account for patients who do not clearly fit into the old system.(3,8) The subgroups of acute and chronic bacterial prostatitis remain essentially unchanged. Chronic nonbacterial prostatitis and prostadynia have been merged into a new category called chronic nonbacterial prostatitis/ chronic pelvic pain syndrome (CNP/CPPS). This category can be subdivided further based on the presence or absence of white blood cells in prostatic secretions. A fourth and final category of asymptomatic prostatitis was added to the classification system. A large-scale study is in progress in an attempt to validate the new classification system. Table 2 compares the two classification systems.

ACUTE BACTERIAL PROSTATITIS

Acute bacterial prostatitis (ABP) may be considered a subtype of urinary tract infection. Two main etiologies have been proposed. The first is reflux of infected urine into the glandular prostatic tissue via the ejaculatory and prostatic ducts. The second is ascending urethral infection from the meatus, particularly during sexual intercourse.(1) The causative organisms are primarily gram-negative, coliform bacteria. The most commonly found organism is Escherichia coli. Other species frequently found include Klebsiella, Proteus, Enterococci and Pseudomonas. On occasion, cultures grow Staphylococcus aureus, Streptococcus faecalis, Chlamydia or anaerobes such as Bacteriodes species.(9-13)

Because acute infection of the prostate is often associated with infection in other parts of the urinary tract, patients may have findings consistent with cystitis or pyelonephritis. Patients with ABP may present with fever, chills, low back pain, perineal or ejaculatory pain, dysuria, urinary frequency, urgency, myalgias and varying degrees of obstruction.(9,13)

Typically, the prostate gland is tender and may be warm, swollen, firm and irregular. A standard recommendation is to avoid vigorous digital examination of the prostate, because, theoretically, that may induce or worsen bacteremia. Although no test is diagnostic for acute bacterial prostatitis, the infecting organism can often be identified by culturing the urine.(13) Initially, antibiotic selection is empiric, but the regimen can be modified once pathogen susceptibilities are available. Patients respond well to most antibiotics, although many cross the blood-prostate barrier poorly. The inflammation caused by ABP may actually allow better penetration of antibiotics into the organ.

It is difficult to interpret the few controlled trials of antibiotic treatment for bacterial prostatitis because of poor case definition, low rates of follow-up and small numbers. Based on case series and laboratory studies of antibiotic penetration in animal models, standard recommendations usually include the use of a tetracycline, trimethoprim-sulfamethoxazole (TMP-SMX [Bactrim, Septra]) or a quinolone. Men at increased risk for sexually transmitted disease might benefit from medications that also cover Chlamydia infection. The most commonly recommended regimens are listed in Table 3. Other medications that are labeled for treatment of prostatitis include carbenicillin (Miostat), cefazolin (Ancef), cephalexin (Keflex), cephradine (Velosef) and minocycline (Minocin).

The duration of therapy has also not been well studied. If the patient is responding clinically and the pathogen is sensitive to treatment, most experts recommend that antibiotic therapy be continued for three to four weeks to prevent relapse, although a longer course is sometimes necessary.(13) In a limited survey(7) of primary practitioners and urologists, it was found that most of them use TMP-SMX as the first-line agent in treating prostatitis (of any type). About 40 percent of urologists and 65 percent of primary care physicians treated patients for only two weeks.

Extremely ill patients, such as those with sepsis, should be hospitalized to receive parenteral antibiotics, usually a broad-spectrum cephalosporin and an aminoglycoside. Supportive measures, such as antipyretics, analgesics, hydration and stool softeners, may also be needed.(13) Some urologists place suprapubic catheters in patients who have severe obstructive symptoms from an acutely inflamed prostate gland.

The possibility of a prostatic abscess should be considered in patients with a prolonged course that does not respond to appropriate antibiotic therapy. The examiner can often detect an abscess as a fluctuant mass on rectal examination. Computed tomography, magnetic resonance imaging or transrectal ultrasonography usually provide an adequate image of the prostate to evaluate for abscess. Transurethral drainage or resection is usually required.

CHRONIC BACTERIAL PROSTATITIS

Chronic bacterial prostatitis (CBP) is a common cause of recurrent urinary tract infections in men. Patients typically have recurrent urinary tract infections with persistence of the same strain of pathogenic bacteria in prostatic fluid or urine. Symptoms can be quite variable, but many men experience irritative voiding symptoms, possibly with pain in the back, testes, epididymis or penis, low-grade fever, arthralgias and myalgias. Many patients are asymptomatic between episodes of acute cystitis. Signs may include urethral discharge, hemospermia and evidence of secondary epididymo-orchitis.(13) Often the prostate is normal on digital rectal examination. No single clinical finding is diagnostic, although urine or prostatic secretion cultures can aid in the evaluation.

Classically, CBP presents with negative premassage urine culture results, and greater than 10 to 20 white blood cells per high-power field in both the pre- and the postmassage urine specimen. Significant bacteriuria in the postmassage urine specimen suggests chronic bacterial prostatitis (Table 1).

The efficacy of antibiotic treatment is probably limited by the inability of many antibiotics to penetrate the prostatic epithelium when it is not inflamed. Because the prostatic epithelium is a lipid membrane, more lipophilic antibiotics can better cross that barrier. In laboratory studies of dogs, the antibiotics that reached the highest concentrations in the prostate were erythromycin, clindamycin (Cleocin) and trimethoprim (Proloprim).(13) Unfortunately, erythromycin and clindamycin have little activity against gram-negative organisms, which are the bacteria most likely to cause CBP.

Based on highly limited studies, TMP-SMX is considered a first-line antibiotic for CBP caused by gram-negative bacteria. The cure rate (over variable periods) has been reported to range from 33 to 71 percent.(14,15) It is thought that the treatment failures are caused by poor antibiotic penetration of the prostate rather than by resistant organisms. In one case series,(16) 400 mg of norfloxacin (Noroxin) taken twice a day for 28 days achieved a cure rate in 64 percent of patients who had failed treatment with TMP-SMX, carbenicillin, or both. In a limited randomized trial of patients with acute and chronic prostatitis, it was found that ofloxacin (Floxin) had a higher cure rate than carbenicillin five weeks after therapy.17 In a randomized controlled trial with a very short follow-up period, it was shown that norfloxacin had a higher cure rate (92 percent) than TMP-SMX (67 percent) in patients with recurrent urinary tract infections.(11) In another randomized controlled trial(12) it was found that minocycline may be more effective than cephalexin. The results of this study were limited because those evaluating clinical outcomes were not blinded to the drug, and the follow-up rate was only 50 percent.(12)

Because of the expense of an extended course of the newer antimicrobial agents, it may be reasonable to try TMP-SMX as a first agent, changing to a fluoroquinolone in the event of antibiotic failure. Some men probably require long-term antibiotic suppression to prevent recurrent urinary tract infections. No studies adequately address how to select these patients or what agent (or dosage) to use, although TMP-SMX and nitrofurantoin (Furadantin) are often recommended.

Rarely, transurethral prostatectomy can be curative if all of the infected prostatic tissue is removed; however, infection often is harbored in the more peripheral tissues. In extreme cases, total prostatectomy may provide a definitive cure, although the potential complications of surgery limit its application in this benign but troublesome disease.(13)

Chronic Nonbacterial Prostatitis/Chronic Pelvic Pain Syndrome

It has been widely reported that more than 90 percent of men with prostatitis meet the criteria for chronic nonbacterial prostatitis/ chronic pelvic pain syndrome (CNP/ CPPS).(10) However, these estimates come from urologic referral centers and are likely to over-represent more complex cases and under-represent more straightforward cases of acute and chronic bacterial prostatitis. Because of these referral biases, the true incidence and prevalence of these syndromes are unknown.

The etiology of CNP/CPPS is not understood. It is likely that multiple disorders are being lumped together in this diagnosis. At least some cases represent chronic bacterial prostatitis not diagnosed as such because of limited sampling techniques. In a study(18) using transperineal needle biopsy for culture of prostate tissue, it was found that there is frequently an occult bacterial prostatitis, especially in men with leukocytes in prostatic secretions (52 percent had positive culture of organisms). A variety of other possible etiologies have been proposed in the medical literature. Some authors have noted increased uric acid levels in prostate secretions in men with chronic nonbacterial prostatitis. It has also been proposed that men with CNP/CPPS may have an extra-prostatic cause, such as bladder outflow or pelvic floor muscle disorder. Others have pointed out the similarity between CNP/CPPS and interstitial cystitis or even fibromyalgia. There may well be an overlap of symptoms and etiologies between CNP/CPPS and benign prostatic hypertrophy.(4) Most of these hypotheses have not been validated and, in general, have not resulted in clinically useful therapies.

Like many such poorly understood conditions, CNP/CPPS remains a challenging syndrome. Patients usually have symptoms consistent with prostatitis, such as painful ejaculation or pain in the penis, testicles or scrotum. They may complain of low back pain, rectal or perineal pain, or even pain along the inner aspects of the thighs. They often have irritative or obstructive urinary symptoms and decreased libido or impotence. As a rule, these patients do not have recurrent urinary tract infections. The physical examination is usually unremarkable, but patients may have a tender prostate.

This syndrome can be differentiated from other types of prostatitis by using the Stamey-Meares localization method. No bacteria will grow on any culture, but leukocytosis (more than 10 to 20 white blood cells per high-power field) may be found in the prostatic secretions. When the PPMT is used, all cultures are negative. The premassage urine has fewer than 10 white blood cells per high-power field, and the postmassage urine contains more than 10 to 20 white blood cells per high-power field (Table 1). The possibility of bladder cancer, which can also cause irritative symptoms, bears consideration.

The treatment of this condition is challenging, and there is limited evidence to support any particular therapy. Given the high rate of occult prostatic infection, an antibiotic trial is reasonable, to see if the patient responds clinically. Because Chlamydia trachomatis, Ureaplasma urealyticum and Mycoplasma hominis have been identified as potential pathogens, treatment should cover these organisms.

Options for treatment are 100 mg of doxycycline (Vibramycin) or minocycline (Minocin) twice daily for 14 days, or erythromycin at 500 mg four times daily for 14 days.(13)

A small, randomized controlled trial19 of allopurinol (Zyloprim) found potential benefit, but the study did not have either enough study subjects or adequate design to demonstrate a convincing benefit. Other therapies, such as thrice weekly prostate massage, have been proposed, although the supportive data are limited.(20) Transurethral microwave thermotherapy did relieve symptoms in a small, randomized controlled trial.(21) Diazepam (Valium) worked about as well as minocycline in one small trial(22); however, patients taking diazepam received more courses of antibiotics in follow-up. Other reported, but untested, therapies include biofeedback, relaxation techniques and muscle relaxants.

Hot sitz baths and nonsteroidal anti-inflammatory drugs (NSAIDs) may provide some symptom relief. Some men may notice aggravation of symptoms with intake of alcohol or spicy foods and, if so, should avoid them. In men with irritative voiding symptoms, anticholinergic agents (such as oxybutynin [Ditropan]) or alpha-blocking agents (such as doxazosin [Cardura], prazosin [Minipress], tamsulosin [Flomax] or terazosin [Hytrin]) may be beneficial.(13) Reassurance can be helpful for these men, and it is important that they know their condition is neither infectious nor contagious and is not known to cause cancer or other serious disorders. Some men benefit from counseling and other approaches helpful in chronic pain syndromes.

Asymptomatic Prostatitis

Information presented at the NIH consensus conference added asymptomatic prostatitis as a new category, partly because of the widespread use of the prostate-specific antigen (PSA) test.

Clearly, symptomatic bacterial prostatitis can elevate the PSA test to abnormal levels.(23) Asymptomatic prostatitis may also elevate the PSA level. In addition, patients who are being evaluated for other prostatic disease may be found on biopsy to have prostatitis. There are no studies elucidating the natural history or appropriate therapy of this condition. It does appear that PSA levels return to normal four to six weeks after a 14-day course of antibiotics.(23) Treatment is routinely recommended only in patients with chronic asymptomatic prostatitis known to elevate the PSA level. In these patients, it may be prudent to treat before drawing subsequent PSA samples.

Recommendations for a General Approach

Although evidence to support them is scarce, the following recommendations are offered. If the history and physical examination suggest prostatitis, physicians may consider a diagnostic test, such as the four-glass test or the PPMT. In most cases, empiric antibiotic therapy is reasonable whether or not the diagnostic test proves a bacterial cause. Common choices include TMP-SMX, doxycycline or one of the fluoroquinolones. Treatment is often recommended for four weeks, although some clinicians use shorter courses. Physicians should encourage hydration, treat pain appropriately and consider the use of NSAIDs, an alpha-blocking agent, or both. If symptoms persist, a more thorough evaluation for CNP/CPPS should be pursued. Some patients may need several trials of different therapies to find one that alleviates their symptoms.

The term prostatitis describes a wide spectrum of conditions with variable etiologies, prognoses and treatments. Unfortunately, these conditions have not been well studied, and most recommendations for treatment, including those given here, are based primarily on case series and anecdotal experience. For these reasons, many men and their physicians find prostatitis to be a challenging condition to treat.

Members of various medical faculties develop articles for "Practical Therapeutics." This article is one in a series coordinated by the Department of Family and Community Medicine at the University of Missouri-Columbia School of Medicine. Guest editor of the series is Robert L. Blake Jr., M.D.

JAMES J. STEVERMER, M.D., M.S.P.H., is an assistant professor in the Department of Family and Community Medicine at the University of Missouri-Columbia School of Medicine. He graduated from Washington University School of Medicine in St. Louis and completed a residency in family practice and an academic medicine fellowship in the Department of Family and Community Medicine at the University of Missouri-Columbia.

SUSAN K. EASLEY, M.D., is currently a resident in the Department of Family Medicine at the University of Maryland School of Medicine, Baltimore. She received her medical degree at the University of Missouri-Columbia School of Medicine.

Address correspondence to James J. Stevermer, M.D., University of Missouri-Columbia School of Medicine, Ma303 Medical Sciences Building, Columbia, MO 65212. Reprints are not available from the authors.

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