Health and Prostate

Prostatitis is one of the most perplexing disease entities with which the practicing urologist must contend. Also, the treatment of this disease is the least gratifying in that the patients often are labeled as “crazy” and have a poor response. In many ways, there are some significant similarities with interstitial cystitis, and perhaps some of the patients with complaints of prostatitis actually have interstitial cystitis, as has been suggested. Indeed, many of the symptoms and physical findings are similar and are outlined in Table 71-1. As in the case of interstitial cystitis, prostatitis has also been difficult to study, being a disease that lacked a formal and specific definition. Therefore, the National Institute for Diabetes, Digestive, and Kidney Diseases (NIDDKD) convened a consensus group to define prostatitis, expressly for the purpose of describing the different prostatitis syndromes in such a way that they could be investigated, and ultimately treated, in a more efficacious fashion. These new definitions, while not being radically different from the old criteria, serve the purpose of enabling urologists and primary care physicians to discuss and treat this disease in an organized way. Most of the controversy, with respect to treatment, centers on category III prostatitis. Category I and II are of bacterial origin, and the therapy is largely antimicrobial. Some of the ancillary treatments are not as widely accepted but most of the different regimens used for category III will also have efficacy in category II with respect to relieving the pain symptoms. As several authors have reported that category III constitutes the majority of patients suffering from this disorder, this chapter will focus on this group.

Antibiotics

Endocrine Therapy

Hormonal therapy for prostatitis has recently undergone a resurgence of interest. It was used many years ago in the treatment of abacterial prostatitis, especially using estrogens. The sex steroid, 17-beta estradiol, has been shown in certain species of rats to cause abacterial prostatitis. Wistar rats are more susceptible than Sprague-Dawley, indicating a genetic predisposition within the genus. This inflammation is known to occur spontaneously in the aging rat and has even been reported to be an autoimmune phenomenon. Furthermore, it appears that prolactin plays a role in the induction and propagation of this inflammatory reaction. The possible autoimmune nature of this entity was also studied in humans, and prostatic plasma proteins are implicated as the antigen. A few reports exist in the literature stating that estrogen reduced the symptoms of abacterial prostatitis; however, side effects such as vasomotor instability, painful gynecomastia, and erectile dysfunction limit the usefulness. The increased incidence of cardiovascular side effects is obviated by the fact that most therapeutic interventions for prostatitis are of short duration. Most recently, finasteride (Proscar, MSD) has been suggested in the treatment of category IIIA prostatitis. It has shown efficacy in limited studies. Because of its limited adverse events, this would be a logical alternative to the use of estrogen. As yet, no controlled studies on hormones in prostatitis exist but the preponderance of clinical reports support the initiation of a placebo-controlled trial. Since it is not yet widely used in this condition, patient accrual should not be a problem. The efficacy may be attributed to size reduction, the reported diminution of prostatic blood flow, or other mechanisms. Antiestrogens have not shown efficacy in prostatitis, and one report actually implicates clomiphene citrate in the induction of prostatic inflammation.

Alpha-Blockade Therapy

Several authors have suggested that the use of alpha-blockade therapy benefits patients with all forms of prostatitis as well as patients with benign prostatic hypertrophy. There has been use of nonselective agents such as phenoxybenzamine as well as the more selective, long-acting alpha-1 receptor antagonists such as prazosin, terazosin, and doxazosin. The theoretic reason that these agents would be beneficial is that there is an increase in the urethral resistance and tone in patients who have symptoms of prostatitis. The resultant increase in pressure causes turbulent urine flow. Since the prostatic urethra, bladder neck, and proximal urethra are richly innervated with alpha-receptors, and they, in turn, respond to alpha-blockade, it is reasonable to use these agents to lower the urethral resistance. The etiology of pain in this disease process is postulated to be not only prostatic or urethral spasm but also reflux of urinary products into the ejaculatory and prostatic ducts, thereby initiating a self-perpetuating inflammatory process. The turbulent flow of urine that results may also be contributory to the pain syndrome. The manifestations in a given patient may not be a diminished urinary flow rate or an elevated postvoid residual, as these findings imply some degree of decompensation, as seen in patients with benign prostatic hyperplasia. Another potential method of action for drugs of this nature in this disease is to diminish afferent stimulation. The alpha-adrenergic blockade not only decreases the smooth muscle contraction but also decreases sensory input traveling in the sameneurons, thereby relieving symptoms. Additionally, since category IIIB (similar to prostatodynia) has been treated with alpha-blockade with some degree of success, there is precedent for this form of therapy As there have been no completed studies that employed a randomized, placebo-controlled double-blind methodology, work remains to be completed. However, it does not appear that there is potential merit in their use. More recently, one group of researchers has used alpha-blockade in conjunction with antibiotics and showed that there was a positive response in both bacterial and nonbacterial prostatitis. Clearly, there is a dearth of good studies in the literature, not only for treatment but also for etiology. An instrument is needed to measure prostatitis symptoms and is under development at this time by an National Institutes of Health (NIH) committee.

Other Medications

Prostatic Massage

Urologists have used prostatic massage for many years in the management of prostatic congestion. It was thought that this relieved this condition and ameliorated symptoms. Little attention was given to this modality, and it was largely relegated to a historic role. More recently, interest in this area has surged, largely generated by the Internet and the mushrooming prostate/prostatitis websites.

TABLE. Investigation Agents

The most well-known institution for this treatment being Dr. Feliciano’s clinic in the Philippines. Dr. Feliciano indicates that repeated prostatic massage is indicated for the treatment of a wide array of prostate or pelvic floor symptoms. The theoretic effectiveness of this method is predicated on the presence of inspissated prostatic secretions, causing congested glands and ducts. This would further lead to a microenvironment that would be supportive of an infectious process. The regular prostatic massage, usually combined with an oral antibiotic, allows for manual drainage of the obstructed ducts, facilitating drainage of the infection that may be present. Relief of congestion would allow for greater penetration of antibiotics into the prostate and, possibly better antimicrobial activity. To date, there has been no other published report regarding the efficacy of this treatment. Until there is more information, claims of efficacy should be tempered. Furthermore, before widespread implementation of this method, more data analysis should be undertaken.

A treatment modality that has been offered for urge incontinence and the frequency/urgency syndrome in females is biofeedback. Considering its relative efficacy in these women, attention has turned to patients with prostatitis. Whereas no controlled trials exist, there are scattered reports of efficacy. It is an attractive alternative, largely because this technology is available in many urologists’ offices already and can be easily used. As they are as yet unproven there are concerns with respect to reimbursement with this and other treatments.

Surgery

The oldest surgical therapy for chronic prostatitis is the so-called radical transurethral resection of the prostate. There are reports of “cures” using this therapy but little has been reported lately. In fact, in most urology circles, there are only a handful of practitioners who have ever actually performed one of these surgeries for this indication. It is suggested that the entire transition zone, including the usual prostatic calculi seen at the junction of the peripheral zone, be resected, to remove all infected tissue. Another way of accomplishing this would be radical prostatectomy. Few urologists would suggest this therapy but theoretically it would remove all involved tissue. Since most patients do not have a demonstrable infection, this therapy should see very little use. Other less invasive procedures have been touted as therapy for chronic prostatitis as well. The first, and best studied is transurethral microwave thermotherapy. This method uses heat energy transmitted to the prostate gland by a special catheter. There are at least two of these devices available in the United States, where it is currently approved for the treatment of benign prostatic hyperplasia. Its efficacy in the latter condition has been documented to be satisfactory, if not as durable as transurethral resection of the prostate. For prostatitis, the advantages are less well studied. There are reports of improvement of pain in these patients but very few exist on following them up over a period. The mechanisms by which this method would work are not known. Theories exist about these reasons but most are speculation. Microwave energy is clearly bactericidal at temperatures greater than 42°C, which are easily achieved in this form of treatment. The afferent neurons supplying the prostate would be affected in a similar fashion as the rest of the gland. The tissues are heated to the point of protein and DNA degeneration. This effectively causes prostatic cell death in the treatment area. Involution and some sloughing of tissue occur and cause the potentially infected tissue to be removed. Whether symptom relief is achieved by the bacterial killing, the tissue removal, or differentiation remains obscure. More research in this area will be necessary before these issues are resolved.

Conclusion

The treatment of chronic prostatitis will continue to be as varied as the symptoms in the patients who suffer from this condition. In part, this is due to the fact that our understanding of the disease remains limited. It may be that the symptoms of category IIIA are the final outcome of a variety of processes, some infectious, some autoimmune, some of a nonspecific inflammatory nature, and others. Thus, treatment might depend on the precipitating event and the coincident etiology rather than the symptoms that are apparent at the outset. On the other hand, etiology may not be important at all, and symptom relief may be the only area of pertinence. Category IIIB may be the most ill-defined, so far, as there are no defining physical findings, laboratory tests, imaging studies, or even symptoms. If this is truly not a prostatic problem, as most would suggest, then the pelvic floor and its physiology must be explored. It also may be true that categories IIA and IIIB have no relationship to one another. One step in the right direction has been the attempt by the NIH to study this disease in a rational manner: first, to define the entities; second, to establish guidelines to standardize the study; and last, to begin an attempt at understanding the natural history. Only with these beginnings can we hope to gain an understanding of this disease. Future treatments of this disease will depend on the success of these ventures. One of the first advances will be a prostatitis symptom score sheet which will probably be similar to the benign prostatic hyperplasia scoring instrument. This will give everyone a common ground to begin to assess treatment efficacy by examining a common outcome. Perhaps when we understand the natural history, more effective treatments will be forthcoming.

Most urologists will treat prostatitis empirically with a course of antibiotics prior to receiving the results of any bacteriologic studies that are performed. Furthermore, most would continue the antibiotic for a full course (2 to 12 weeks), irrespective of the culture results. The only change, typically, would be considered if the antibiogram indicated that a particular organism was resistant to the antibiotic employed. The time course for treatment is highly variable. Most authors and research indicate that a period of 30 days is adequate but literature exists to support as long as 3 to 6 months of therapy. A number of antibiotics have been touted as the most appropriate for the treatment of classic chronic bacterial prostatitis or category II; these drugs should be used in category IIIA as well. Carbenicillin indanyl sodium (Geocillin-Roche) was probably the first antibiotic to have a specific indication for the treatment of prostatitis. It has an excellent spectrum of activity but it is cumbersome for patients as it is dosed four times a day. The tetracyclines as a group have an appropriately broad spectrum and also have the ability to penetrate the prostate well. More specifically, the derivatives doxycycline and minocycline have been shown to be efficacious and also have the added benefit of covering the more fastidious organisms such as Mycoplasma, Ureaplasma, and Chlamydia. It is not clear as to whether these organisms have a role in the etiology of category IIIA prostatitis as ample opinion exists for either side of the argument. They are, however, pathogenic for the urinary tract and may cause infections that are confused with category III prostatitis. The disadvantage with this class is that they are bacteriostatic and therefore rely, at least in part, on host defenses for bacterial clearance. Since the advent of the fluoroquinolones, the treatment of prostatitis of a known bacterial etiology has been simplified. These drugs freely penetrate into the prostate and may be found in the glandular tissue as well as the prostatic secretions.  Their dissociation constant (pKa) and lipid solubility facilitates this bioavailability but may also contribute to the neurologic side effects. This class of antibiotic is becoming the medication used most commonly either in the period after the initial physician visit but prior to receipt of the culture results or as empiric therapy. If the culture is negative, most clinicians still continue to treat for their prescribed time interval. Perhaps the most commonly employed agent worldwide for the treatment of “chronic” prostatitis is the sulfamethoxazole-trimethoprim combination.

TABLE. Common Symptoms in Prostatitis and Interstitial Cystitis

There are numerous references to support the theoretic reasons that these agents should be efficacious in these patients.” Most of the work in this area has used animal models, which may not be completely applicable to humans. On the other hand, many years of employing this combination in patients has lent credence to its efficacy.

There is some concern regarding delivery of certain antimicrobials to the prostate gland itself. Since bacteria may potentially be harbored in prostatic stones, prostatic ducts that are obstructed with inspissated secretions, or in their own protective glycoprotein matrix, it may be difficult to consolidate an agent in the prostate at a concentration sufficient to penetrate these adaptive defenses and eradicate the bacteria. There does not appear to be an appreciable difference between intravenous or oral routes of administration in the levels achieved, especially with the quinolones, which can dramatically affect the cost of therapy. Some authors have administered the antibiotics directly into the prostate. The secretory dysfunction of infected prostates has popularized this method. The results are variable for this method but there is potential for development of granulomatous prostatitis, using this route. The theoretic advantages appear to be superceded by the complexity of administration and the cost, not to mention potential adverse events.

The evidence for bacteria as an etiologic agent in category IIIA prostatitis is slowly accumulating, which, in turn, lends credence to empiric antibiotic therapy.” Since it was recognized that bacteria may construct a glycoprotein matrix in which they grow at a metabolically slowed rate while being relatively protected from the host defense mechanisms and antimicrobial agents,’ interest has increased in searching for bacteria that may be difficult to detect with conventional methodologies. This state may hamper the microbiologists’ efforts to isolate organisms using standard culture techniques. This holds true for the cell-wall-deficient/defective organisms like Mycoplasma, Chlamydia, and Ureaplasma, as well as L-forms. Where extended culture techniques are employed, unusual organisms have been isolated; the isolates are bacteria that so far had been assumed to be commensals and not actually involved in the infection itself. It remains to be seen whether these are the etiologic agents or not but this may explain why patients who have bacteriologically negative prostates may respond to antimicrobial therapy. The use of more sophisticated molecular biologic techniques has shown the presence of bacterial genetic material in many of these patients.’ Several problems exist with the use of molecular biologic techniques in the establishment of a bacterial diagnosis. First, they are so sensitive that very small amounts of contaminating bacteria may significantly affect the results. Second, the genes used occasionally make it daunting to identify the specific organism, and furthermore, information regarding sensitivity to antibiotics is little more than an empiric guess.

TABLE. Categorization of Prostatitis

The 16s ribosomal ribonucleic acid subunit has been found in a surprisingly large number of cases as has the m-Tet gene, which is a genetic sequence that is found in a modest number of uropathogens. In one study, bacteria were actually visualized in the prostate glands, using electron microscopy. The mere presence of bacterial genetic material (RNA or deoxyribonucleic acid [DNA]) or even organisms themselves does not prove unequivocally that the etiologic agents have been identified. It does, though, give a plausible explanation as to why a percentage of these patients respond to antibiotics and should suggest that further studies on a bacteriologic etiology for category III prostatitis should be conducted.

Clinical Trials

Few studies exist with respect to the use of antibiotics in category IIIA or chronic abacterial prostatitis. One of the problems is that this classification has only been adopted into use a short time ago, and its acceptance is not complete. Second, the degree to which the diagnosis is made differs from study to study. Last, patient accrual is difficult, owing to the fact that the great majority of patients, who come to the urologist with complaints similar to prostatitis, have usually already been treated with not one but several antibiotics, usually for a protracted time period. Most of these patients are actually seen by their primary care physician at the onset and are referred only after antibiotic failure.

In attempting therapy with empiric antibiotics, prior to knowing whether one is treating category II or category IIIA, it would seem prudent to use an agent that is best suited for penetration into the prostatic parenchyma. In general, the agent must be highly lipid soluble; it must have low protein binding, and have a high pKa, specifically on the order of 8.6.

TABLE. Antibiotics in the Treatment of Prostatitis

The spectrum of activity should be sufficiently broad while retaining a high degree of activity against gram-negative organisms as well as the known gram-positive uropathogens (group D streptococci, certain coagulase negative staphylococci, and others). No single antibiotic fits this description perfectly. As previously mentioned, the most widely used agent is the combination sulfamethoxazole-trimethoprim. It is inexpensive, has fair prostatic levels, and the spectrum of activity is excellent for the pathogens most commonly found. There have even been a few studies using sulfamethoxazole-trimethoprim in documented bacterial prostatitis with good results. Some questions, however, have arisen as to antibiotic levels in the human prostate.

The tetracycline group, specifically doxycycline and minocycline, has shown promise in the treatment of category II prostatitis. These drugs are more lipid soluble than tetracycline itself, and prostatic parenchymal levels are established. These drugs have been used extensively in the fertility literature as empiric treatment of leukocytospermia. This condition, in fact, possibly represents category IV prostatitis or perhaps category IIIA. It has been shown, in uncontrolled studies, to reduce leukocytes in both the semen and prostatic fluid. It does have the significant adverse effect of gonadotoxicity, which is, at least in part, reversible. Macrolide antibiotics such as azithromycin and clarithromycin are well concentrated in the prostate gland and are excreted slowly, enabling excellent levels of drug to be present for an extended period of time. The spectrum, however, does not include gram-negative organisms to a significant degree.

The 5-fluoroquinolones, such as ciprofloxacin, norfloxacin, and ofloxacin, are perhaps the agents of choice in category II prostatitis. This has led to clinicians using this drug as empiric therapy for category IIIA disease. These drugs reach abundant levels in the prostate and have a broad spectrum of activity. There are potential problems with theophylline toxicity, photosensitivity, and neurologic side effects as well as fertility concerns with ofloxacin. Lastly, as this group is more expensive than most other agents when therapy may take several weeks to complete, the cost may be substantial.

Many of the drugs that have been used in this disease have anti-inflammatory properties. Nonsteroidal anti-inflammatory agents are some of the most common agents used anecdotally These agents block prostaglandin synthesis and are able to reduce not only the inflammatory component but also the pain associated with prostatitis. Since pain is the primary manifestation of category IIIA prostatitis, these agents are highly likely to be efficacious. These medications also have a strong antispasmodic effect on smooth muscle. This would reduce the voiding pain and also presumably ameliorate the voiding dysfunction that is evident in this group of patients. These agents have been used extensively in the treatment of ureteral colic for the same reasons, and they have been shown to have this antispasmodic effect on the ureter.

Another type of anti-inflammatory agent that has been used in abacterial prostatitis is the free-radical scavenger, allopurinol. It is the most widely used agent in this class. The mechanism of action involves the reduction of urate in the urine and prostatic secretions. The theory is predicated on the assumption that there is urine reflux into the prostatic ducts, where the urate creates a nonspecific inflammation. The pain is correlated with the amount of urate in the urine and, potentially, this could be relieved by urate reduction. There is controversy in the literature with respect to the efficacy of this treatment. The results are mixed across a population but in individual patients that are well selected, there appears to be a good response.

Antihistamines may play a special role on the basis that there are many similarities between prostatitis and interstitial cystitis. These agents (hydroxyzine, in particular) have shown efficacy in the treatment of interstitial cystitis owing to their ability to stabilize most cell membranes. They also have sedative properties and may serve in an anxiolytic capacity as well as contribute anticholinergic effects, similar in their action are the tricyclic antidepressants. For those patients in whom there is a significant voiding dysfunction (specifically, obstruction), the anticholinergic effects coupled with the result of peripheral adrenergic stimulation might actually exacerbate the symptoms of voiding dysfunction and, therefore, pain. If depression is a significant part of this disease complex, other agents should probably be explored.

A variety of other medications have been sought but none has been sufficiently studied to ascertain whether they may be beneficial. They include pentosan polysulfonic acid (Elmiron®) , which is one agent mentioned in upcoming clinical trials. As yet, there is no information on this or other heparinoids of glycosaminoglycan surrogates.

Numerous other medications have been suggested anecdotally. Capsaicin, or pepper extract, has been used effectively by the intravesical route in patients with neurogenic bladders to reduce sensory input. Its action is on the C-fibers that transmit afferent information and on substance P. They are involved in pain transmission and are affected by capsaicin. Pressures are reduced and there is less uninhibited contraction. There is anecdotal information on the use of this agent in interstitial cystitis but there are no long-term studies. Recently, attention has turned to so-called alternative therapies. One such touted for the treatment of benign prostatic hyperplasia is phytotherapy, also referred to as “plant extracts.” These substances are classified by the Food and Drug Administration as food additives and as such are not well regulated as to their potency, bioavailability, or other quality control issues. The method of action has not been clearly elucidated and has variously been ascribed to an estrogen effect (some of the agents are phytoestrogen compounds), five alpha-reductase inhibitors, inhibition of testosterone binding, and anti-inflammatory, and others. There is little consensus amid a plethora of hyperbole. There are, however, a few studies that suggest that they are beneficial in relieving the symptoms of “prostatism” and benign prostatic hyperplasia. These studies are mostly from Europe, where there is prescription availability of “saw palmetto.” The magnitude of its use in the United States for benign prostatic hyperplasia is currently unknown, and there is no information on its use in prostatitis although there is some interest. Several compounds are available in addition to saw palmetto, including Pygeum africanum, Echi-naceae purpurea and a host of others. Since pain is a major component of prostatitis syndromes, interest is being generated in the long-term use of pain medications and pain-modulating agents. Some that are being considered are gabapentin, tizanidine, and others. These are typically used with methadone or other long-acting narcotics.

Prostatitis is a poorly understood syndrome. This lack of understanding may adversely affect outcomes in patients with all forms of prostatitis. To improve on the prognosis of prostatitis, the clinician requires an excellent understanding of its epidemiology, evaluation, etiology, pathophysiology, and therapy. The goal of this chapter is to illustrate some common misconceptions concerning prostatitis and provide an up-to-date review of prostatitis syndromes, with special emphasis on factors affecting prognosis.

The term prostatitis implies prostatic inflammation. Prostatitis, however, represents a number of disorders related to symptoms and/or signs referable to the lower urinary tract. Acute bacterial prostatitis, chronic bacterial prostatitis, nonbacterial prostatitis, and prostatodynia — or pelviperineal pain syndrome — represent the four categories of prostatitis. There is currently an emphasis on standardizing and reclassifying the various forms of the disorder to enhance physician understanding. The incidence of nonbacterial forms of the disease predominate — approximately 60% in the form of nonbacterial prostatitis and 30% as prostatodynia. With the exception of acute bacterial prostatitis, the various forms of prostatitis can not be distinguished solely on the basis of clinical symptomatology.

Epidemiology

Many physicians underestimate the prevalence of prostatitis. It is, in fact, a very common disorder. Prostatitis will affect approximately 50% of men at some point in their lives; in autopsy series, histologic evidence of inflammation is found in up to 44% of cases. In 1985, more men visited urologists for prostatitis than for prostate cancer or benign prostatic hypertrophy. The current estimate of its incidence is 5 to 8%; for men < 50 years of age, it is the most common urologic problem. For men older than 50 years of age, it is third in frequency. Prostatitis syndromes account for one-quarter of office visits to the average urologist. In a recent poll of primary care physicians and urologists, a significant over-estimation of the prevalence of bacterial forms of the disease was demonstrated, with seventy-five percent of primary care physicians and 50% of urologists believing that bacterial prostatitis represents 70 to 90% of cases. The truth is that bacteria are responsible for the minority of cases, approximately 5 to 10%. These misconceptions no doubt affect physician’s diagnostic and therapeutic decision making, possibly impacting negatively on the disease.

Evaluation

Localization

Pathogenesis and Pharmacodynamics

There appear to be three major mechanisms of infection in the prostate. Reflux of urine into intraprostatic ducts is the most common proposed mechanism and is supported by indirect and direct evidence. The indirect evidence comes from the chemical composition of some prostatic stones removed from men treated for Chronic bacterial prostatitis. While prostate stones are typically composed of tricalcium phosphate, the composition of some stones is similar to urinary stones, namely calcium oxalate, which suggests urinary reflux into the prostate. Persson and Ronquist demonstrated elevated prostate fluid creatinine and urate levels, adding more indirect evidence for the role of sterile reflux in pathogenesis. Reflux-induced prostatitis also has been demonstrated in animal models.

Another mechanism of infection includes prior urinary instrumentation, although the majority of afflicted men have no such history. Finally, typical prostate stones are frequently felt to harbor pathogens within their matrix, out of reach of antimicrobials. For pathogens to cause infection once inside the prostate, they must elude the prostate’s own natural defenses. Bacteria do this by forming microcolonies enclosed in a protective glycocalyx envelope. They are inaccessible to antimicrobials inside this envelope. In addition, zinc levels — a major component of prostatic antibacterial factor — are low in men with Chronic bacterial prostatitis Prostatic antibacterial factor is postulated to inhibit viral growth as well as growth of gram-negative rods, yeast, and fastidious organisms. Other host factors include an undefined role of immunoglobulins, interleukins, and the influence of androgen.”’ There is recent evidence that autoimmune phenomena may play a role in chronic pelvic pain syndrome.

Therapy and Prognosis

Conclusion

Prostatitis syndromes are a common occurrence for both patients and physicians and represent a diagnostic and therapeutic challenge to positively influence the lives of millions of people. While prognosis for patients with bacterial prostatitis is excellent with modern diagnostic methods and antimicrobial agents, these patients represent the minority of those with the syndrome. Unfortunately, the majority of patients suffer from nonbacterial prostatitis and prostatodynia. It is in these patients that improvements in diagnostic and therapeutic approaches will have the greatest impact on prognosis. The therapies discussed all play a role; if utilized in a rational, methodic, and analytic fashion, patients will likely benefit. Current research on prostatitis is exciting and hopefully the outlook for all patients suffering from prostatitis will improve.

The classic categorization of prostatitis into four main groups evolved in the 1960s and 1970s and has remained the standard. Patients don’t always fit neatly into one category or another, however, and guidelines for treating such patients do not exist. What should be done, for instance, with the patient whose prostatic fluid culture is positive for an atypical organism or with the asymptomatic patient with leukocytes in their prostatic fluid? What treatment type would most likely benefit the patient with perineal pain but no voiding symptoms? The National Institutes of Health Consensus Conference on Prostatitis has devised a new prostatitis classification system to help solve these types of problems. Category I and II refer to acute and chronic bacterial prostatitis. Category III refers to chronic pelvic pain syndrome in the presence of negative prostatic fluid cultures. Category IIIA identifies patients with significant inflammation in the prostatic fluid, that is nonbacterial prostatitis, and category IIIB identifies patients without significant prostatic fluid inflammation, that is, prostatodynia. Category IV defines asymptomatic patients with inflammatory cells in the prostatic fluid. The new system has yet to be clinically validated but it is currently the standard reference in research settings. Its goal is to promote a better understanding of the disease, with improvements in diagnosis, treatment, and ultimately prognosis.

Bacterial Prostatitis

Microbiologic etiologies are responsible for approximately 5 to 10% of cases of prostatitis. The term “bacterial prostatitis” refers to causative organisms cultured by routine methods. Currently, this definition is restricted to typical urinary pathogens, such as gram-negative bacilli, not fastidious organisms that would require advanced techniques, such as antibody immunofluorescence or polymerase chain reaction, to detect. The same bacteria infect the bladder and the prostate. Escherichia coli is the most common, followed by Klebsiella, Proteus, Serratia, Pseudomonas, and Enterobacter.’ The pathologic role of gram-positive species is controversial since most gram-positive isolates probably represent urethral flora. However, Enterococcus faecalis, Staphylococcus aureus, and Staphylococcus saprophyticus are all less common but definite pathogens. Diphtheroids, coagulase-negative Staphylococcus, and Streptococcus species are not believed to be pathogenic at this time. Chlamydia and Ureaplasma have been linked to prostatitis and are the subjects of ongoing investigations. Recent data, however, suggest these organisms are not responsible.

Category I:

Acute Bacterial Prostatitis Acute prostatitis is the most dramatic and life threatening form of the disease. Acute prostatitis is easily diagnosed and readily distinguishable from the other forms of prostatitis on clinical grounds. Patients present acutely to a health care provider with abrupt onset of chills, fever, and associated irritative and/or obstructive voiding difficulty Common additional complaints include perineal pain, especially when defecating, arthralgias, and myalgias. Patients will sometimes experience a prodrome of constitutional symptoms. Patients often appear toxic or septic and are generally febrile. The prostate is warm, swollen, and extremely tender. Prostate massage is absolutely contraindicated, as this maneuver can promote bacteremia. On laboratory analyses, a leukocytosis is common and urinalysis is suggestive of infection. Urine and blood cultures are usually positive for gram-negative organisms such as Escherichia coli? Acute bacterial prostatitis demands prompt evaluation and initiation of treatment to prevent serious morbidity or mortality. If adequately treated, however, most patients recover fully and have no long-term disability.

Category II:

Chronic Bacterial Prostatitis Chronic bacterial prostatitis appears to be the least common variety of prostatitis. While it has lower associated mortality and morbidity than does acute bacterial prostatitis, it is more difficult to adequately treat. The distinguishing characteristic of Chronic bacterial prostatitis is recurrent bouts of bacteriuria or symptomatic cystitis with the same bacterial pathogen. In fact, the most common cause of recurrent urinary tract infection in men is chronic bacterial prostatitis. Ten percent of men are infected with more than one organism. Some patients will have histories of antecedent acute prostatitis but most will not. Between active infections, the bacteria survive dormant in prostatic ducts and calculi.” The physical examination is much different from that for acute bacterial prostatitis. The patient will not appear septic or even in severe discomfort, and the general medical examination should be normal in the absence of other medical conditions. Digital rectal examination will usually reveal a normal or slightly indurated prostate. Blood chemistry and cell counts are normal. Prostatic fluid usually contains white blood cells and cultures localize uropathogens to the prostate. The outlook for complete recovery of patients with chronic bacterial prostatitis is good — with proper antimicrobials of appropriate duration, approximately 70% of patients may experience complete recovery.

Category III

Category III prostatitis accounts for approximately 90% of all cases of prostatitis and is a very challenging disorder to treat. With current treatment modalities, patients may expect dismal cure rates and high relapse rates.

Category IIIA: nonbacterial prostatitis. Nonbacterial prostatitis is the most common form of the prostatitis syndromes, accounting for approximately 60% of cases. It is the most common reason for patient visits to the urologist’s office and is eight times more common than either of the bacterial prostatidities. Despite continuous investigation, its etiology remains elusive. Several investigators have proposed that fastidious organisms such as Ureaplasma urealyticum and Chlamydia trachomatis, among others, are responsible but this has yet to be demonstrated. Prostate examination and microscopic analyses of urine and prostatic fluid from nonbacterial prostatitis and Chronic bacterial prostatitis patients are indistinguishable but urine and prostatic fluid cultures in nonbacterial prostatitis are continuously negative, characterizing the disorder. Like Chronic bacterial prostatitis, nonbacterial prostatitis has a relatively low morbidity; unlike Chronic bacterial prostatitis, it carries with it a high likelihood of inadequate treatment and long-term disability.

Category IIIB: prostatodynia. Prostatodynia may be said to occupy one end of the prostatitis continuum, opposite nonbacterial prostatitis. It is a chronic pelvic pain syndrome and an all-too-common disorder, accounting for approximately 30% of prostatitis syndrome cases. History and physical examination are essentially identical as in men with nonbacterial prostatitis, except that some of these men complain of extreme pain on digital rectal examination, despite normal findings. These men are often young to early middle age and their symptoms are localized to the perineum, prostate, scrotum, penis, rectum, anus, groin, and lower back. Pain is the most common complaint, followed by frequency and decreased stream. Pain is the sole complaint of a significant percentage of patients. There is often a marked psychiatric component to the disease. Some investigators have even referred to it as stress prostatitis. Forty percent of general physicians and 65% of urologists described a psychosomatic component to their nonbacterial prostatitis/Prostatodynia patients. Sixty percent of Prostatodynia patients are clinically depressed and suffer from anxiety disorder, and 50% exhibit clinical hypochondriasis and sexual dysfunction. These psychiatric diagnoses persist over time in roughly 40% of cases. Whether psychiatric issues are a cause or a function of the disease is not known. Urodynamic evaluation of some of these men has revealed low flow rates with elevated urethral closing pressure distal to the bladder neck and incomplete funneling of the bladder neck on videofluoroscopy. The implications of these findings are unclear but they may suggest a form of pelvic floor myalgia. The sine qua non of diagnosis rests in normal microscopic urine and prostatic fluid analyses with negative cultures. Treatments for the disorder have been nonspecific and often anecdotal. The prognosis for these patients often involves long-term disability.

The localization method is the most accurate and efficient method of distinguishing between urethral, bladder, and prostate sources of inflammation or infection. The localization technique was initially described by Meares and Stamey et al. in 1968 and has become the standard for a thorough and methodic evaluation of prostatitis syndromes. Surprisingly, few primary care physicians and only about 50% of urologists perform localization evaluations on patients. In fact, one study revealed that only 33 to 45% of urologists even cultured urine or prostatic fluid as part of their evaluation. Physicians cite several reasons for not performing this basic and important diagnostic measure: it is cumbersome, perceived to have a low yield, and perceived to possess high false negative and false positive rates with low predictive value. Such a low percentage of physicians utilizing these basic diagnostic measures may impact adversely on treatment outcomes.

Localization culture techniques have been described in detail elsewhere and will be briefly described here. The procedure involves analyzing aliquots of urine and pro-static fluid microscopically. The VB1, VB2, expressed prostatic secretions, and VB3 specimens refer to the initial 10 mL voided, the midstream urine, the expressed prostatic secretions, and the first 10 mL of urine after a prostate massage, respectively. The VB1 represents the urethral specimen, the VB2 the bladder specimen, and the expressed prostatic secretions and VB3 the prostatic specimens. The urethra may contain gram-positive bacteria in 95% of men and gram-negative bacteria in 5%. Since the VB2, expressed prostatic secretions, and VB3 also must traverse the urethra, the possibility of contaminating theses specimens exists. The expressed prostatic secretions is especially susceptible to contamination by urethral flora. Expressed prostatic secretions in most normal men will have low numbers of white blood cells, that is, < 4.22. The exact upper limit of normal for expressed prostatic secretions white blood cells has been somewhat controversial but 90 to 95% will have < 10 WBC per high-power field. Certain subsets of normal men will have somewhat elevated levels (10 to 20 WBC per high-power field), including men with benign prostatic hyperplasia or infertility. Ten percent of volunteers without any genitourinary complaints will have > 10 WBC per high-power field. Lipid-laden macrophages in expressed prostatic secretions are relatively sensitive indicators of prostatic inflammation.

Algorithm of Diagnosis

When patients are first seen in the office, they should undergo an initial localization routine. One cost-effective, quick approach entails obtaining a VB1, VB2, and expressed prostatic secretions on the first visit for analysis. IfVBl orVB2 shows inflammation or bacteriuria, patients should be cultured and treated empirically with an antimicrobial that achieves good urinary levels without penetrating the prostate and thus masking any prostatic microbiology. Nitrofurantoin, penicillin, and tetracycline all achieve adequate urinary bactericidal levels without entering the prostate. Fluoroquinolones, trimethoprim, or trimethoprim/sulfamethoxazole inhibit prostatic growth as well as urinary growth and should be avoided during the initial diagnostic evaluation. Treating the patients in this fashion prior to their second visit will amplify any difference between VB1 and expressed prostatic secretions. If VB1 or VB2 are negative on their first visit, quantitative culture of VB1, VB2, and expressed prostatic secretions should be obtained; a negative VB1 and VB2 and positive expressed prostatic secretions or > 10-fold difference in VB1 and expressed prostatic secretions bacterial counts indicate prostatic inflammation. Seminal fluid analysis has been used in the past but has since been abandoned due to its lack of sensitivity or specificity. It is not advocated at this time in the evaluation of prostatitis or lower urinary tract symptoms.

Radiographic Imaging

Unfortunately, there are currently no reliable radiographic modalities available to distinguish between the various forms of prostatitis. There are, however, techniques that can identify prostate pathology that may contribute to prostatitis. Approximately 75% of men older than 20 years of age and 100% older than 30 years of age will have prostatic stones. It is felt that these stones harbor the infectious agents from antimicrobials and the prostate’s own natural defense mechanisms. Plain radiography will detect stones in approximately 14% of patients, and ultrasound will detect them in 70% of patients. Except for imaging stones, ultrasound contributes little to the evaluation of the patient with prostatitis, despite initial reports of success. Similarly, computed tomography cannot distinguish between the various forms of prostatitis, although it is sensitive, like ultrasound, in detecting prostatic abscess. Magnetic resonance imaging is currently under investigation for its utility in men with prostatitis but anecdotal reports suggest it is no more effective than Computed tomography scan.

Immunologic Molecular Diagnosis

The search for etiologies of nonbacterial prostatitis has led researchers to develop antibodies to common bacterial and fastidious organisms such as Ureaplasma and Chlamydia. The basis of this rests in findings of increased prostate IgA and IgG levels in men with both chronic bacterial prostatitis and nonbacterial prostatitis compared to men without genitourinary complaints. Moreover, men adequately treated for their Chronic bacterial prostatitis respond with decreased IgA and IgG levels compared to untreated or inadequately treated men.

Shortliffe et al. examined prostatic fluid with antibodies against common epitopes of Ureaplasma and Chlamydia trachomatis as well as fastidious gram-negative organisms. No difference in antibody levels was found between men with and without prostate symptomatology. Investigations are currently underway using polymerase chain reaction technology on prostate tissue to search for messenger ribonucleic acid (MRNA) specific to various organisms.

Lactate dehydrogenase is an enzyme responsible for reversibly catalyzing the conversion of pyruvate to lactate. It has five isotypes and it is felt that epithelial damage results in an increased ratio of the various isotypes. Isotype 5 resides in the prostate. Schaeffer et al. demonstrated an increased lactate dehydrogenase and LDH5/LDH1 ratio in men with prostatitis compared to men without a genitourinary history. lactate dehydrogenase was not specific for Chronic bacterial prostatitis versus nonbacterial prostatitis.

Prostate-Specific Antigen Prostate-specific antigen levels have been extensively evaluated in prostatitis, mostly in an effort to distinguish prostate cancer from benign disorders. Whether or not prostatitis causes changes in prostate-specific antigen levels is controversial. Several investigators have noted a decrease in prostate-specific antigen levels in bacterial prostatitis compared to nonbacterial prostatitis or prostatodynia. They hypothesized a decrease in prostate-specific antigen production to account for the finding. In general, however, it does not appear that prostate-specific antigen can reliably differentiate between the various forms of prostatitis.

Tissue Microbiologic Culture Attempts have been made to obtain prostate tissue for microbial culture. This has met with limited success for several reasons. First, most biopsies are done transrectally or transurethrally and promote contamination of specimens. Cultures performed on radical prostatectomy specimens may also suffer contamination since these prostates would all have been biopsied prior to surgery to establish the diagnosis of cancer. Second, chronic bacterial prostatitis represents focal infections. As such, a high false negative culture rate is to be expected. In summary, prostate biopsy is seldom indicated in the diagnosis of prostatitis.

Antimicrobial Therapy

For an antimicrobial agent to be effective against prostatic infection, several properties of the agent must be met. First, the drug must achieve adequate bactericidal levels in both urine and prostate. Most commonly used agents today attain 50- to 100-fold greater urinary concentrations than serum concentration. Second, to enter the prostate under noninflammatory conditions, the agent should be lipid soluble and exist in the nonionized form. Once inside the prostate, the ideal agent should exist as a basic ion to trap itself within the prostate.”’ The fluoroquinolones meet most of the above criteria and are the first agents of choice in treating bacterial prostatitis. Some have questioned whether an inflamed prostate represents a similar environment to the uninflamed prostate with respect to pharmacodynamics. To address this question, a group of investigators induced prostatitis in rats and then treated the animals with norfloxacin, followed by assays for intraprostatic norfloxacin levels. The authors found no difference in levels or efficacy of the antimicrobial and concluded that the pathophysiology of the inflamed prostate does not adversely affect pharmacodynamics. They concluded that the protective bacterial glycocalyx, rather than altered pharmacodynamics, was probably responsible for most antimicrobial treatment failures. In addition, there is ample evidence that the inflamed prostate is more penetrable by antimicrobials than the uninflamed prostate.’ This explains why certain agents such as ampicillin and gentamicin are excellent choices for acute prostatitis but not for chronic bacterial prostatitis. Finally, the agent should have adequate activity against the offending pathogen. Most susceptibility panels reported in hospital laboratories note minimal inhibitory concentrations for serum drug levels. As previously stated, most agents achieve a much higher urinary than serum concentration and should be interpreted according to urinary concentration.

Acute Bacterial Prostatitis

Patients with acute prostatitis are usually systemically ill. Treatment should be instituted rapidly after diagnosis. For the medically stable patient, an oral fluoroquinolone should be used. This class of antimicrobials achieves good penetration into the inflamed prostate and covers most urinary pathogens. Response to treatment should be rapid and sustained; otherwise, complications such as prostatic abscess should be considered. The more severely ill patient, or the patient not tolerating an oral regimen, should be admitted to the hospital for intravenous antimicrobials and hydration. Ampicillin and gentamicin or vancomycin with gentamicin are excellent choices. These agents achieve excellent serum, urinary, and prostate levels and are effective against the vast majority of urinary pathogens. Fluoroquinolones are again a good choice but the intravenous forms offer little advantage to the oral forms in terms of bioavailability In addition to antimicrobials, patients suffering acute prostatitis should receive appropriate pain relief. Additional reports suggest that sitz baths, non-steroidal anti-inflammatory drugs, and stool softeners may provide symptomatic relief. In the patient with urinary retention, bladder drainage with a suprapubic cystostomy may be preferable to using a urethral catheter to avoid the risk of bacteremia.

Chronic Bacterial Prostatitis

Chronic bacterial prostatis does not carry the mortality or morbidity of acute prostatitis. It is considered an outpatient treatment. With current antimicrobials, most patients will respond to therapy, and cure rates of 50 to 90% can be expected. The antimicrobial selected must be efficacious against the pathogen isolated in expressed prostatic secretions and/or VB3 cultures. There have been a multitude of antimicrobials used in the past. Currently, fluoroquinolones are the preferred agents. Their broad spectrum against the majority of urinary pathogens, high lipid solubility, and low protein binding make them ideally suited for prostate penetration and antibacterial activity. Remarkably, only 25% of physicians use fluoroquinolones to treat prostatitis. The duration of therapy may be directly related to cure rates. Norfloxacin for 28 to 42 days cured 92% of Chronic bacterial prostatitis patients, compared to 75% of patients treated with the same drug at 14 days. Results with the other fluoroquinolones are similar and are superior to all other antimicrobial classes, including intraprostatic antimicrobial injection. In comparison, trimethoprim/sulfamethoxazole has been associated with maximal cure rates of 40 to 67% after 2 to 4 weeks of treatment. Only 53% of urologists and 37% of primary care physicians treat patients with therapy lasting longer than 4 weeks. After selecting an appropriate agent and duration of therapy, effectiveness should be monitored with repeat localization cultures after approximately 1 month. Ultimately, proof of success rests with an asymptomatic patient with no recurrent episodes of prostatitis.

Suppressive Therapy Several options exist for the significant group of individuals who fail antimicrobial therapy. The goal of suppressive therapy is to decrease the number of symptomatic urinary infections by preventing bacteriuria in spite of persistent infection in the prostate. Trimethoprim, trimethoprim/sulfamethoxazole, tetracycline, and nitrofurantoin are excellent choices for suppressive antimicrobial therapy. Each agent achieves excellent urinary levels, is inexpensive, and is well tolerated. In addition, these agents tend not to alter fecal flora, thus minimizing gastrointestinal problems associated with antimicrobials. The ultimate choice of antimicrobial, however, is governed by bacteria identification and antibiotic sensitivity panels from expressed prostatic secretions and VB3.

Surgical Therapy Transurethral resection of the prostate has been used for men who are refractory to more conventional therapy. Standard transurethral resection of the prostate resects only the transition zone, yet anatomic analyses have shown that the majority of infectious foci are peripheral.’ Therefore, a radical transurethral resection of the prostate with a much more extensive peripheral and distal resection is required. Improvements in cure have at best been moderate but at the cost of much higher rates of incontinence. Cure rates with this modality have approached 40 to 50%. Radical prostatectomy, a therapy that would probably result in cure, is not indicated for treatment of this disease except in extremely limited circumstances.

Nonbacterial Prostatitis and Prostatodynia

Predictably, effective treatment for nonbacterial prostatitis and prostatodynia does not exist. While it is reasonable to try a course of antimicrobial therapy with activity against usual uropathogens as well as C. trachomatis and Ureaplasma, chronic antimicrobial therapy is not justified at this time. While some patients report benefit from sitz baths, prostate massage, anticholinergic agents, anxiolytics, anti-inflammatory agents, and zinc, no large scale, randomized controlled studies demonstrating their utility exist. Anecdotal reports suggest disappointing therapeutic benefit. Some small, nonrandomized investigations of alpha-blocker therapy suggest moderate improvement in symptoms in as many as 50% of patients.°. No large, randomized controlled investigations for alpha-blockers exists. However, a trial of alpha-blocker therapy is probably warranted. Some recent studies have shown a beneficial effect of transurethral microwave thermotherapy, demonstrating improvement in 50 to 70% of patients. Long-term follow-up data are lacking and this procedure is considered investigational at this time.

Since nonbacterial prostatitis and prostatodynia have such pervasive psychiatric components, perhaps the best opportunity for long-term impact on prognosis rests with psychotherapy, psychopharmacy, and biofeedback. Indeed, several authors have shown a benefit of psychotherapy and biofeedback training. Berguis et al. recommended antidepressant medication to treat men who had prostatodynia combined with a major depressive component. Despite all available treatment options, however, the prognosis for these patients is poor. Several investigators recently performed sickness impact profile assessments on nonbacterial prostatitis and Prostatodynia patients. They revealed a level of disability in these unfortunate patients tantamount to that of patients suffering myocardial infarction, angina pectoris, or Crohn’s disease. An improved outlook for these patients may be gained by a multidisciplinary approach, eliciting advice and service from mental health providers.

Diagnosis and treatment of prostatitis requires diligence and persistence on the part of both the physician and the patient. Although diagnosis of acute bacterial prostatitis is easily made and its treatment straightforward, chronic bacterial prostatitis and other inflammatory prostatic syndromes are more difficult to define and differentiate. Diagnosis and documentation of specific infection is often elusive, despite careful evaluation. Clinical evaluation and diagnosis of prostatitis is variable. Family practice physicians and urologists do not routinely utilize a standard diagnosis protocol to evaluate patients with symptoms of prostatitis. Moon reviewed a questionnaire completed by primary care physicians and urologists diagnosing and treating prostatitis in Wisconsin. His study demonstrated that fewer than 50% of urologists and only 11 % of primary care providers evaluated expressed prostatic secretions to differentiate prostatic diseases. Similarly, few urologists or primary care physicians suggested nonantibacterial therapy to patients with prostatitis. While the nomenclature for prostatitis classification continues to be controversial, diagnosis is best separated into acute bacterial prostatitis and other nonacute inflammatory and bacterial syndromes.

Acute Bacterial Prostatitis

Diagnosis of Chronic Bacterial,Nonbacterial Prostatitis and Associated Inflammatory Prostatic Syndromes

Inflammatory prostatic syndromes are some of the most common genitourinary complaints of men. Lipsky reported in 1989 that 76 of 1000 primary care physician office visits for men were for genitourinary tract problems, of which 25% were for prostatitis. While chronic bacterial prostatitis accounts for a relatively small number of these patients, more than 90% of men with prostatitis-type symptoms are eventually diagnosed with nonbacterial prostatitis or other inflammatory syndromes such as prostatodynia. While the usual uropathogens associated with chronic bacterial prostatitis are the same as those associated with urinary tract infections and acute bacterial prostatitis, gram-positive organisms, especially Enterococci and Staphylococcus saprophyticus may also cause chronic inflammation in the prostate. Other unusual bacteria may be associated with the prostatic infections, especially in immune-compromised patients. These unusual bacteria include Mycobacterium tuberculosis, Neisseria gonorrhoeae, and fungi. Ureaplasma urealyticum (T-strain mycoplasma) and Chlamydia trachomatis have been widely studied as potential pathogens responsible for prostatitis; a variety of techniques, including antigen-specific immunoglobulins and immunoflourescent stains in patients with nonbacterial prostatitis, have been used. The results of these studies continue to be inconclusive, and both these agents continue to be unproven pathogens in chronic prostatic infectious disease.

Symptoms and Signs

Measurement of Immune Response

Changes in human prostatic fluid immunoglobulins (IgG and IgA) in prostatitis has suggested chemical methods for differentiating prostatic infection and inflammatory disease. Shortliffe and associates used solid phase radioimmunoassay to evaluate the immune response of patients with acute and chronic bacterial prostatitis. There was a prostatic fluid secretory IgA elevation observed in chronic bacterial prostatitis patients independent of serum responses. In patients with acute bacterial prostatitis, antigen-specific IgG levels in both serum and prostatic fluids were found to be elevated, with a slow decline for 6 to 12 months following curative antibiotic therapy. Prostatic fluid IgA levels, in contrast, became elevated following infection and began to decline approximately 1 year following successful treatment. Serum IgA levels, however, declined and disappeared within 4 weeks of successful treatment. Patients with chronic bacterial prostatitis had elevations in prostatic fluid IgA and IgG levels without associated serum IgA or IgG elevation. When chronic bacterial prostatitis was successfully treated with antibiotics, the prostatic fluid IgA levels remained elevated at 24 months while the IgG levels remained elevated for 6 months before decline. In patients inadequately treated with antibiotics, prostatic fluid IgA and IgG levels remained elevated. These same investigators were unable to document antigen-specific IgG or IgA elevations in prostatic fluid against Ureaplasma urealyticum or Chlamydia trachomatis in patients with nonbacterial prostatitis. These results clearly reflect the controversy surrounding the contention that these pathogens cause prostatitis.

Other prostatic seminal agents have been shown to change in the presence of chronic bacterial prostatitis. These include changes in the ratio of lactate dehydrogenase isoezyme 5 to isoezyme 1, prostatic antibacterial factor which probably represents zinc concentration) , citric acid concentration, cholesterol concentration, spermine concentration, and acid phosphatase concentration. While each of these has been demonstrated to change in chronic bacterial prostatitis studies, their use as diagnostic tools continues to be uncertain.

Radiographic Examination

Granulomatous Prostatitis

Granulomatous prostatitis is an uncommon chronic inflammatory condition of the prostate whose incidence is increasing with the use of intravesicle bacillus Calmette-Guerin (BCG) for superficial transitional cell carcinoma of the bladder. Patients frequently present with an abnormal prostatic examination characterized by significant prostatic induration and nodularity. In addition to BCG therapy, immune compromise such as human immunodeficiency virus infection may be associated with granulomatous prostatitis caused by tuberculosis, syphilis, brucellosis, viruses, fungi, eosinophilic changes, and Wegener’s granulomatosis. Granulomatous prostatitis is frequently a sequela of a urinary tract infection. Presenting symptoms are similar to acute prostatitis, with recurrent febrile episodes, rigors, irritative and even obstructive urinary symptoms. The patient’s prostate-specific antigen level is usually elevated with granulomatous prostatitis but normal levels have also been reported. Many of these patients will have hypoechoic lesions and prostatic calculi on transrectal ultrasound. In a study of 668 urologic patients biopsied for abnormal prostatic examination, 19 had granulomatous prostatitis (2.8%). Ultrasound abnormalities of these 19 patients included a hypoechoic peripheral zone nodule in nine patients, multiple nodular foci in two, and a diffuse abnormal ultrasound pattern in seven. One patient had an isoechoic bulging peripheral zone nodule. These abnormalities on transrectal ultrasound are indistinguishable from those of prostatic carcinoma, and biopsy is essential to eliminate the possibility of prostatic malignancy. Once the diagnosis of granulomatous prostatitis is confirmed, however, resolution is usually spontaneous and there may be no specific therapy required.

The diagnosis of acute bacterial prostatitis is usually straightforward and readily apparent on physical examination. Patients are frequently febrile and toxic with severe rigors, back pain, perineal pain, dysuria, urgency, and frequency with associated mild to moderate obstructive urinary symptoms. As many as one-third of patients with acute bacterial prostatitis will present in acute urinary retention as a result of prostatic edema and enlargement secondary to acute inflammation of an already enlarged and partially obstructed urethra. Once a diagnosis is presumed by history, physical examination usually supports the diagnosis, with a rectal examination demonstrating a severely swollen, extremely tender prostate. Expression of prostatic secretions in acute bacterial prostatitis should not be performed because of the potential for systemic spread of prostatic infection. If prostatic fluid is available for microscopic examination, multiple polymorphonuclear leukocytes, both singularly and in clumps, are demonstrated. Urine culture as well as prostatic fluid culture will reveal the infectious pathogen, which is also frequently seen on Gram’s stain of both urine and prostatic fluid. Massage of an acutely infected prostate should be proscribed as bacteremia and septicemia may result. Over-whelming prostatic infections in acute bacterial prostatitis are usually associated with positive urine cultures; bacteria enter the bladder and the infecting organism is often cultured from the midstream urine collection.

The most common uropathogens found in acute bacterial prostatitis are those most commonly seen in urinary tract infections, including: Escherichia coli, Proteus, members of the Klebsiella-Enterobacter group, and Enterococci. Once a history, physical examination, and Gram’s stain of the urine has established an acute urinary infection and blood and urine cultures have been collected, therapy can be begun empirically until specific culture and sensitivity information is available. Broad spectrum antibiotics, most of which usually penetrate the acutely infected prostate more efficiently than the chronically infected prostate, can be used until antibiotic therapy is tailored to the offending organism, based on definitive blood and urine culture sensitivity reports. These antibiotics should be targeted at gram-negative pathogens.

Since acute bacterial prostatitis may progress to prostatic abscess, this possibility should be explored when patients show continued systemic signs and unabated symptoms while on appropriate antibiotic treatment, bed rest, and fluids. These abscesses may be multiple and are often associated with painful prostatic enlargement and fluctuance on rectal examination. Patients with further acute prostatitis who have other associated risk factors such as diabetes, chronic renal failure on maintenance dialysis, and other causes of immune compromise (especially if associated with urethral instrumentation or indwelling Foley catheters) are at highest risk for prostatic abscess. The signs and symptoms of prostatic abscess are variable. They were reviewed by Weinberger et al. in 1988 and included prostatic enlargement in 75% of patients, prostatic tenderness in 35%, and palpable fluctuance in 16%. Meares reviewed 213 men with prostatic abscesses and reported acute urinary retention in 34%, fever in 33%, dysuria in 27%, urinary frequency in 23%, and perineal pain in 23%. An additional 7% had hematuria or urethral discharge.

Definitive diagnosis of a prostatic abscess may require more sophisticated imaging studies. Once a prostatic abscess has drained, a retrograde cystourethrogram or voiding cystourethrogram may demonstrate contrast filling of the abscess cavity. Initial diagnostic investigation with transrectal ultrasound is the most simple and effective method of identifying a prostatic abscess. Abscess cavities are clearly hypoechoic but contain some internal echoes that differentiate them from simple cysts. Central abscess debris produces these internal echoes. Similarly, prostatic abscesses, while frequently unilocular, may be complex, communicating, or multilocular in appearance. When multiple small cystic areas are present on transrectal ultrasound, confirmation of cavity communication is usually not possible. An abscess that is significant may extend into the seminal vesicles, producing unilateral or bilateral seminal vesicle dilatation, thickening, and asymmetry.

Computed tomography scan imaging may also be helpful in identifying prostatic abscesses, demonstrating low attenuation areas of the prostate with associated prostatic enlargement and asymmetry. Seminal vesicle enlargement and asymmetry may be also identified, with internal loculations of the seminal vesicles associated with seminal vesicle septal thickening. Computed tomography scanning may assist the urologist in identifying an optimal method for treating a prostatic abscess by defining the extent of the abscess and suggesting an appropriate surgical approach and subsequent management. Once a prostatic abscess has drained either spontaneously or surgically, the resultant cavity may fill with contrast administered either by retrograde urethrogram or voiding cystourethrogram, may epithelialize, or may remain indefinitely as open diverticuli. These cavities may produce a nidus for continued bacterial prostatitis or urinary infections. An abscess limited to the prostate may be drained transurethrally. An abscess that is multilocular or extends to the seminal vesicles may require more aggressive treatment with open surgical intervention.

Radiographic imaging of acute bacterial prostatitis without abscess is usually nonspecific. While voiding studies may demonstrate prostatic urethral narrowing during the acute phase with large residual urine volumes, such findings are nonspecific and are similar to those associated with benign prostatic enlargement and bladder outlet obstruction. Similarly, intravenous urogram or plain radiographs, while occasionally demonstrating associated prostatic calcifications, are nonspecific in patients with acute bacterial prostatitis or prostatic abscess. Cystoscopy as a diagnostic tool for prostatic abscess and acute bacterial prostatitis is usually nonspecific, with findings including elongation of the prostatic urethra and trigonal elevation or elongation. Thus, transrectal ultrasound and Computed tomography scan imaging are the best diagnostic tools and will be of assistance in differentiating acute prostatitis from prostatic abscess as well as in identifying appropriate treatment and guiding percutaneous drainage.

Most patients with nonacute inflammatory and infectious diseases of the prostate present with similar symptoms, including bladder inflammation with irritative voiding symptoms such as urinary frequency, urgency, and dysuria. Referred pain can occur to the low back, genitalia, supra-pubic area, and lower extremities; frequently perineal pain, scrotalgia, and postejaculatory discomfort occur alone or in combination in these patients. Obstructive symptoms are uncommon without coexistent prostatic hyperplasia. Obstructive symptoms may, however, occur in patients with associated bladder neck spasm and inflammatory prostatic conditions such as prostatodynia. Krieger and colleagues investigated the standardized evaluation of symptoms associated with chronic prostatitis. They compared a symptom index in 50 patients with prostatitis and 75 control patients. It was useful, reproducible, and helped in identifying symptoms. In their series, patients with prostatitis were more likely than control patients to complain of perineal, lower abdominal, testicular, penile, and postejaculatory pain as well as sexual dysfunction.

Since prostatitis is frequently associated with significant psychologic abnormalities, investigation of associated psychologic diagnoses, stress, and depression should be undertaken in selected patients presenting for treatment of chronic prostatitis. Many patients may require psychologic or psychiatric referral for these conditions. Use of depression inventories and other psychologic questionnaires or structured psychologic interviews may be helpful in patients suspected of having significant depression stress syndromes or associated conditions.

Differentiating the etiologies of inflammatory diseases of the prostate is difficult, time consuming, expensive, and, at best, only partially accurate. Identifying prostatic inflammation through inflammatory expressed prostatic secretions may be helpful. Clearly, the microscopic examination of expressed prostatic secretions can easily be done in a cost-effective fashion in most clinicians’ offices. This simple technique has been demonstrated to improve the diagnosis of prostatic inflammatory diseases. The definition of prostatic inflammation in expressed prostatic secretions is usually agreed upon as 10 or more white blood cells by high-power field with multiple lipid-laden macrophages. Wright et al. reviewed the diagnostic accuracy of leukocytosis in expressed prostatic secretions and found that 10 white blood cells by high-power field was diagnostic of prostatic inflammation and correlated well with leukocytes demonstrated in a spun-down postprostatic massage urinary specimen. These findings have been confirmed in a careful analysis by Weidner and Ebner. With these careful microscopic examinations and evaluations, patients with noninfectious prostatic inflammatory syndromes such as prostatodynia will demonstrate clear expressed prostatic secretions with few white cells on microscopic examination. These correlate well with patients who have negative selective prostatic cultures. Since many patients with chronic prostatitis have been on multiple antibiotics and are taking antibiotics when seen and examined, expressed prostatic secretions may be more accurate in these patients than selective cultures, which are difficult and quite expensive to obtain. More accurate methods of quantifying leukocytes in prostatic fluid specimens using a Fuchs-Rosenthal chamber have been suggested. Using this technique, 1000 polymor-phonuclear leukocytes per micrometer has been suggested as an indication of chronic bacterial prostatitis.

Other alterations in the composition of prostatic secretions have been suggested as diagnostic alternatives to leukocyte counts in evaluating chronic prostatitis. Weidner et al. have suggested that changes in expressed prostatic secretions acidity may correlate with chronic bacterial prostatitis and suggest that those patients most likely to respond successfully to antibiotic treatment have a high pH. His study suggests that an expressed prostatic secretions alkaline pH > 8.0 associated with chronic bacterial prostatitis significantly decreases the therapeutic success of antibiotics used in treating chronic bacterial prostatitis.

The presence of lipid-laden macrophages (oval fat bodies) on microscopic examination of expressed prostatic secretions has been the subject of some controversy. Both Meares and Stamey have reported that they rarely, if ever, occur in the prostatic secretions of men without prostatic inflammation and are absent from men whose urinary tract infections are caused by anterior urethritis. Lipid-laden macrophages in patients with prostatitis are increased as much as eightfold over those in patients without bacterial prostatitis. The position diagnosis of chronic bacterial prostatitis must be confirmed by quantitative, selected bacteriologic localization studies. These studies, first described by Meares and Stamey in 1968, continue to be the standard for bacteriologic localization, and standardized pharmacologic treatment studies, and are helpful in resolving diagnostic dilemmas associated with clinical prostatic infection. Since these studies are frequently expensive, difficult to perform, uncomfortable, and not always reproducible, controversy has continued about their value and of all quantitative localization techniques in patients with prostatitis.

De la Rossette and colleagues evaluated 409 patients with prostatitis syndromes. Their evaluation included urinalysis, renal ultrasonograms, plain films of the abdomen, and basic urodynamics. Urine cytology was not helpful in any patients while uroflometry was abnormal in 30% of patients investigated. Positive bacterial cultures were found in 10.4% of patients while urethral cultures were positive in 14.3% of patients. Prostatic fluid cultures did not provide significant additional information and semen cultures correlated poorly with either prostatic fluid or urine cultures. Since < 15% of most patients have bacterial prostatitis, the cost-effectiveness of this series of culture studies in all patients remains controversial.

The technique for collecting urine specimens and pro-static fluid is simple and can be performed in any clinical setting or private office. Patients are instructed to present with a full bladder and void 10 mL of urine into a sterile container. This specimen is the voided bladder #1 (VB1) specimen. The patient then voids 100 mL of urine, which is discarded and voids 10 mL of urine into a sterile container that is labeled VB2. The patient is instructed to cease voiding and a prostatic massage is undertaken. Prostatic secretions are collected, if possible, in a sterile container and labeled expressed prostatic secretions. These secretions can be used for culture or microscopic examination. The patient then voids the remaining urine into a fourth aliquot labeled VB3. These specimens are immediately inoculated onto culture media. The VB1 specimen represents those bacteria present in the urethra while the VB2 specimen is the classic midstream specimen reflecting bladder bacteria. The expressed prostatic secretions and VB3 specimens reflect the pro-static fluid and prostatic pathogens. For significant bacterial infection to be present, colony counts in the VB3 or expressed prostatic secretions specimens must be at least 10 times greater (one log) than those in the VB1 or VB2 specimens. If all three specimens reflect large numbers of bacteria, a urinary antiseptic such as Macrodantin may be administered for 3 to 5 days and the studies repeated to confirm prostatic bacterial colonization.

Because these studies are expensive, time consuming, and difficult, Nickel has suggested a pre- and postmassage test (PPMT). The pre- and postmassage test includes only the classic VB2 and VB3 specimens with the expressed prostatic secretions used for microscopic evaluation. Nickel compared a personal series of 53 patients with 59 patients reported in the literature, investigating for the accuracy of the two-culture technique, and found that sensitivity and specificity of the PPMT was 91%. Comparing the PPMT with the three-culture test, there was little difference in the additional (VB1 and expressed prostatic secretions) cultures in making the diagnosis of chronic bacterial prostatitis.

Bacterial evaluation of seminal ejaculate specimens has also been suggested for differentiating locations and causes of bacterial prostatitis. These ejaculate specimens do not appear to significantly improve the diagnostic accuracy and may be misleading in the absence of examination of expressed prostatic secretions and selective cultures. Since seminal fluid contains not only prostatic fluid but also seminal vesical, urethral, and accessory sex gland fluid, it produces a misleading mixture of fluids for study. Microscopic examination of this fluid is also misleading since the differentiation of leukocytes from immature sperm without specific selective staining techniques is difficult. While these results may suggest generalized infection of many of the male accessory glands, localization using ejaculate cultures is difficult.

Krieger and colleagues investigated seminal fluid specimens and expressed prostatic secretions results in a group of men with and without chronic bacterial prostatitis. They demonstrated a poor correlation between inflammation in prostatic secretions as an endpoint for the definition of prostatitis and semen changes. Similarly, sperm motility, clumping, and other parameters of inflammation in semen specimens did not correlate well with prostatic inflammatory conditions. Thus, ejaculate cultures are infrequently helpful in differentiating chronic bacterial prostatitis from other prostatitis syndromes.

Transperineal biopsy of the prostate for identifying prostatic infection has also been suggested. Since typical inflammation and infection of the prostate is not a global disease but only focal, these random biopsies are usually inaccurate. Currently, transrectal or perineal needle biopsy in diagnosing prostatitis remains controversial.