Prostatitis and Related Conditions

Microbiologic

Altered Prostatic Host Defense

Risk factors that allow bacterial colonization or infection of the prostate with potentially pathogenic bacteria include intraprostatic ductal reflux (Kirby et al, 1982); phimosis (VanHowe, 1998); specific blood groups (Lomberg et al, 1986); unprotected penetrative anal rectal intercourse; UTI; acute epididymitis (Berger et al, 1987); indwelling urethral catheters and condom catheter drainage (Meares, 1998); and transurethral surgery, especially in men who have untreated, infected urine (Meares, 1989). Secretory dysfunction of the prostate characterized by an alteration in the composition of prostatic secretions can be diagnostic of patients with prostatitis: there is a decrease in the levels of fructose; citric acid; acid phosphatase; the cations zinc, magnesium, and calcium; and the zinc-containing prostatic antibacterial factor; but pH, the ratio of isoenzymes lactate dehydrogenase-5 to lactate dehydrogenase-1, levels of inflammatory proteins such as ceruloplasmin, and complement C3 are increased (Meares, 1989). These defined alterations in the prostate secretory function have also been blamed for adversely affecting the normal antibacterial nature of prostatic secretions. A decrease in prostatic antibacterial factor may reduce the intrinsic antibacterial activity of the prostatic fluid (Fair et al, 1976), whereas the alkaline pH may hamper diffusion of certain basic antimicrobial drugs into the prostatic tissue and fluid (Fair and Cordonnier, 1978). However, caution is warranted because it is not known whether these compositional changes are a cause or a consequence of inflammation.

Dysfunctional Voiding

Anatomic or neurophysiologic obstruction resulting in high-pressure dysfunctional flow patterns has been implicated in the pathogenesis of the prostatitis syndrome. Blacklock (1974, 1991) demonstrated that bladder neck, prostatic, and urethral anatomic abnormalities predisposed some men to developing prostatitis. Urodynamic studies confirm that many patients, particularly those with prostatodynia, have decreased maximal urinary flow rates and obstructive-appearing flow patterns (Barbalias et al, 1983; Ghobish, 2002). On video-urodynamic studies, many patients with prostatitis syndromes show incomplete funneling of the bladder neck as well as vesicourethral dyssynergic patterns (Kaplan et al, 1994, 1997; Hruz et al, 2003). Investigators (Dellabella et al, 2006) have described ultrasound alterations of the preprostatic sphincter in men with chronic prostatitis. In a study of 48 treatment refractory chronic prostatitis patients with no associated infection, Hruz and associates (2003) determined that 29 (60%) had bladder neck hypertrophy diagnosed by endoscopic and urodynamic criteria. This dyssynergic voiding may lead to an autonomic overstimulation of the perineal-pelvic neural system with subsequent development of a chronic neuropathic pain state. Alternatively, this high-pressure, dysfunctional voiding may result in intraprostatic ductal reflux in susceptible individuals (see the next section).

Intraprostatic Ductal Reflux

Reflux of urine and possibly bacteria into the prostatic ducts has been postulated as one of the most important etiologic mechanisms involved in the pathogenesis of chronic bacterial and nonbacterial prostatic inflammation. Anatomically, the ductal drainage of the peripheral zone is more susceptible than other prostatic zones to intraprostatic ductal reflux (Blacklock, 1974, 1991). Kirby and associates (1982) instilled a carbon particle solution into the bladders of men diagnosed with nonbacterial prostatitis. Carbon particles were found in the EPS macrophages and prostatic acini and ductal system after surgery in men with nonbacterial prostatitis. Persson and Ronquist (1996) noted high levels of urate and creatinine in EPS, which they postulated was caused by urine reflux into the prostatic ducts. Terai and coworkers (2000) provided molecular epidemiologic evidence for ascending infection in acute bacterial prostatitis.

Prostatic calculi are composed of substances found only in urine, not in prostatic secretions (Sutor and Wooley, 1974; Ramiraz et al, 1980), further evidence that urinary intraprostatic reflux occurs and likely contributes to the formation of prostatic calculi. If pathogenic bacteria reflux into the prostate gland, they may exist in protected aggregates within prostatic calculi themselves. High culture counts of pathogens encrusted in prostatic calculi have been demonstrated by Eykyn and colleagues (1974). This type of bacterial colonization in protective bacterial aggregates or biofilms associated with prostatic calculi may lead to recalcitrant chronic prostatitis and subsequent recurrent UTIs despite what seems to be adequate antibiotic therapy. Ludwig and coworkers (1994), employing transrectal ultrasonography, showed that men with chronic inflammatory prostatitis had a significantly increased frequency of prostatic calculi compared with men without prostate inflammation (prostatodynia). It appears that prostatic calcification is common in patients with nonbacterial chronic prostatitis and is associated with greater inflammation, bacterial colonization, pelvic floor spasm, and symptom duration (Shoskes et al, 2007). The inflammation resulting from chemical, bacterial, or immunologic stimulation has been shown to possibly cause an increase in intraprostatic pressures, measurable with transperineally inserted pressure transducers (Mehik et al, 2002).

Immunologic Alterations

The local prostatic immune system is activated by infection in bacterial prostatitis. In acute bacterial prostatitis, serum and prostatic fluid antigen-specific (i.e., bacterial antigen) IgG and IgA can be detected immediately after the onset of infection, and after successful antibiotic therapy they decline to normal levels over the next 6 to 12 months (Fowler and Mariano, 1984a; Meares, 1977, 1998; Kumon, 1992). Prostate-specific antigen (PSA) levels can be markedly elevated during an acute episode of bacterial prostatitis (Dalton, 1989; Moon et al, 1992; Neal et al, 1992) and slowly resolve to normal levels over the course of 6 weeks, provided there is no recrudescence of the infection. In chronic bacterial prostatitis, no serum immunoglobulin elevation is detected, whereas prostatic fluid IgA and IgG levels are both increased (Shortliffe and Wehner, 1986; Kumon, 1992). After successful antibiotic therapy, IgG levels return to normal after several months but the IgA (particularly secretory IgA) levels remain elevated for almost 2 years (Shortliffe et al, 1981a, 1981b; Fowler and Mariano, 1984a). Antibody-coated bacteria detected in urine, EPS, and semen is another prominent feature of chronic bacterial prostatitis (Riedasch et al, 1984, 1991).

Noninfectious inflammation (nonbacterial prostatitis) might also be secondary to immunologically mediated inflammation due to some unknown antigen or perhaps even related to an autoimmune process. IgA and IgM antibody levels (not microorganism-specific) are elevated (Shortliffe and Wehner, 1986; Shortliffe et al, 1989, 1992), and similar antibodies as well as fibrinogen and complement C3 (Vinje et al, 1983; Doble et al, 1990) have been identified in prostatic biopsy specimens from patients with chronic prostatitis. Both animal model studies (Donadio et al, 1998; Ceri et al, 1999; Lang et al, 2000) and human studies (Alexander et al, 1997; Batstone et al, 2002; Maake et al, 2003; Motrich et al, 2007) have suggested that prostatitis may be an autoimmune process. A number of candidates have been suggested for the self-antigen, including PSA (Ponniah et al, 2000). Other specific immunologic and neuroendocrine alterations such as cytokine production (Alexander et al, 1998; Jang et al, 2003) and nerve growth factor (Miller et al, 2002) have a subsequent role to play in the process of inflammation. Specifically, interleukin-10 has been implicated in the etiology and clinical manifestations in chronic prostatitis (Miller et al, 2002; Shoskes et al, 2002) but other cytokines such as interleukin (IL)-1β and tumor necrosis factor-α have also been implicated (Nadler et al, 2000). IL-8 is the most common cytokine localized to the semen in men with chronic prostatitis (Khadra et al, 2006; Penna et al, 2007). There may be a genetic phenotype that promotes specific immunologic parameters that predispose to immunologically induced prostatic inflammation (Riley et al, 2002; Shoskes et al, 2002). These immunophenotypic patterns have even been observed in noninflammatory category IIIB chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) (Barghorn et al, 2001). Whatever the initiating event, the immunologic cascade appears to have an important role in the development of prostatitis in those patients who develop prostatic inflammation (Moon, 1998; Kumon, 1999).

Chemically Induced Inflammation

Investigators have demonstrated that urine and its metabolites (e.g., urate) are present in the prostatic secretion of patients with chronic prostatitis (Persson and Ronquist, 1996). These investigators have hypothesized that the prostatic inflammation and subsequent symptoms may be simply due to a chemically induced inflammation secondary to the noxious substances in the urine that have refluxed into the prostatic duct.

Pelvic Floor Muscle Abnormalities

Some investigators (Zermann et al, 1999) propose that the sensory or motor disturbances or both consistent with neural dysregulation of the lower urinary tract may be a consequence of acquired abnormalities in the central nervous system. Certainly, extraprostatic tenderness is identified in many patients with chronic prostatitis (Berger et al, 2007; Shoskes et al, 2008). Zermann and Schmidt (1999) describe 103 patients with chronic pelvic pain whom they evaluated at a specialized neurourologic unit. They showed that a majority of the men had insufficient conscious control of their somatically innervated striated pelvic floor muscles. The patients showed various levels of identity with their pelvic floor muscles, but none was able to demonstrate the full range of pelvic floor contraction and relaxation repetitively and effortlessly. This was true whether or not there was evidence of inflammation. They conclude that their findings reflect a functional disassociation between the central nervous system and the peripheral target, the pelvic floor muscles.

Other clinicians (Anderson, 1999; Potts, 2003) believe that the source of the pain is specifically at the pelvic musculature attachment area at the sacrum, coccyx, ischial tuberosity, pubic rami, and endopelvic fascia. These areas are immediately adjacent to the prostate and bladder and can be recognized by the demonstration of a hyperirritable spot or myofascial trigger point that is painful on compression. It is hypothesized that the formation of myofascial trigger points in this area results from mechanical abnormalities in the hip and lower extremities, chronic holding patterns such as those that occur during toilet training, sexual abuse, repetitive minor trauma and constipation, sports that create chronic pelvic stimulation, trauma or unusual sexual activity, recurrent infections, and surgery (Anderson, 1999). More recently, it has been hypothesized that the pain experienced in some men with CPPS may be explained by pudendal nerve entrapment, which causes subsequent neuropathic pain (Antolak et al, 2002). Unfortunately, all these studies examining pelvic floor muscle abnormalities did not compare findings to a control group (a criticism that can apply to many of the studies cited in this etiology section).

Neuroendocrine Mechanisms

The pain associated with the chronic prostatitis syndromes is similar in many respects to neuropathic pain. Objective autonomic nervous system changes can be observed in men with a chronic prostatitis, suggesting that altered autonomic nervous system responses may be responsible for the pain associated with this chronic pelvic pain syndrome (Yilmaz et al, 2007). Pain that may have originated in the prostate or pelvic floor muscles, through mechanisms of cross-sensitization, may have spread to adjacent organs and/or structures. We are only recently beginning to understand the complexity of overlapping neuropathways and possible mechanisms underlying pelvic organ crosstalk (Malykhina, 2007).

It has been shown that men with chronic prostatitis showed evidence of dysfunctional hypothalamic-pituitary-adrenal axis function reflected in augmented awakening cortisol responses (Anderson et al, 2008). Another study evaluating the adrenocortical hormone abnormalities in men with chronic prostatitis suggested that some men with this condition may even meet the diagnostic criteria for nonclassic congenital hyperplasia (Dimitrakov et al, 2008).

Psychological Factors

Psychological factors have always been considered to play an important role in the development or exacerbation of the chronic prostatitis syndromes. Some researchers who have investigated the psychopathology in these patients concluded that this syndrome should be viewed as a psychosomatic disorder (Mendlewich et al, 1971; Mellan et al, 1973; Keltikangas-Jarvinen et al, 1982). De la Rosette and associates (1993b) compared a group of 50 patients with chronic prostatitis with a group of 50 patients seen for vasectomy and showed that, although there were significant statistical differences between the groups (with patients with chronic prostatitis scoring consistently higher personality disorder scores), these differences in scores were quite small compared with those between patients with prostatitis and psychiatric patients. Berghuis and coworkers (1996) compared 51 prostatitis patients with a group of 34 men without any chronic pain condition and concluded that depression and psychological disturbances are common among prostatitis patients. Egan and Krieger (1994) compared prostatitis patients with those seeking treatment for chronic low back pain. Major depression was more common in prostatitis patients, but back pain caused more somatically focused depression and anxiety. Ku and coworkers (2002) suggested that depression and weak masculine identity may be associated with an early stage of chronic prostatitis. A large case-control study confirmed that depression and panic disorders are significantly more common in men with chronic pelvic pain conditions than in control subjects (Clemens et al, 2008). These more recent studies demonstrate that psychological factors are involved in the disease, but it seems unjustified to label this group of patients as neurotic or as having a psychopathologic condition. However, recent analyses of the large prostatitis cohorts showed that psychological variables, such as depression, maladaptive coping techniques (e.g., pain catastrophizing and pain contingent resting), poor social support, and stress are important in chronic prostatitis outcomes (Tripp et al, 2004, 2005, 2006; Ulrich et al, 2005; Nickel et al, 2008b). Factors such as catastrophizing are particularly important because they have been found to be stronger predictors of patient pain reports than depression (Tripp et al, 2006), indicating that negative cognitive appraisals of pain experience may be a primary target for psychosocial interventions. This may be especially important given the strong association that pain catastrophizing has shown with elevations in depression, disability, and lower quality of life manifest in patients with chronic prostatitis (Tripp et al, 2005, 2006; Nickel et al, 2008b).

Association with Interstitial Cystitis (Painful Bladder Syndrome)

Interstitial cystitis, now referred to many as painful bladder syndrome or bladder pain syndrome, is an ill-defined CPPS occurring primarily in females, and a number of investigators have hypothesized that chronic nonbacterial prostatitis may have a similar cause (Pontari, 2006; Forrest et al, 2007). Unfortunately the cause of interstitial cystitis remains unknown, but the pathogenic mechanisms are theorized to be very similar to those that cause chronic prostatitis in men (Sant and Nickel, 1999; Eisenberg et al, 2003; Parsons 2003). Some researchers have proposed that in some patients diagnosed with prostatitis, a bladder-orientated interstitial cystitis mechanism actually accounts for the symptoms and that the prostate is only indirectly involved (Sant and Kominski, 1997). Certainly, the pain and voiding symptoms of interstitial cystitis and chronic prostatitis overlap to some extent (Miller et al, 1995; Novicki et al, 1998; Sant and Nickel, 1999; Forrest and Schmidt, 2004), and men with prostatitis diagnoses have findings on cystoscopic (Berger et al, 1998), urodynamic (Siroky et al, 1981), and potassium sensitivity testing (Parsons et al, 2002, 2005) very similar to those of patients with interstitial cystitis. However, Yilmaz and associates (2004) did not confirm positive potassium sensitivity testing in prostatitis patients and Keay and colleagues (2004) have shown that men diagnosed with chronic prostatitis (pain only) have normal antiproliferative factor activity whereas men diagnosed with interstitial cystitis (pain and irritative voiding symptoms) have detectable levels of urine antiproliferative factor.

An Interrelated, Pluricausal, Multifactorial Etiology

It is likely that the nonbacterial prostatitis syndromes have a multifactorial etiology, either a spectrum of etiologic mechanisms or, more likely, a progression or cascade of events after some initiating factor. In an important review on mechanisms involved in the pathogenesis of chronic prostatitis, Pontari and Ruggieri (2004) concluded that, “the symptoms of chronic prostatitis/chronic pelvic pain syndrome appear to result from an interplay between psychological factors and dysfunction in the immune, neurological and endocrine systems.” Figure 11–2 describes a hypothetical scenario that could potentially involve most of the proposed and interrelated causes described in this section.

Figure 11–2 It is very likely that the etiology and pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (category III CPPS) involves a pluricausal, multifactorial mechanism. An initiating stimulus such as infection, reflux of some “toxic” or “immunogenic” urine substance, perineal/pelvic “trauma,” and/or psychological stress starts a cascade of events in an anatomically or genetically susceptible man, resulting in a local response of either inflammation or neurogenic injury (or both). Further immunologic or neuropathic (possibly interrelated) mechanisms mediated by neuroendocrine pathways propagate or sustain the chronicity of the initial (or ongoing) event. The final outcome is the clinical manifestation of chronic perineal/pelvic pain–associated symptoms associated with local and central neuropathic mechanisms.

Traditional Classification

The traditional classification system is based on the landmark paper by Meares and Stamey (1968) describing the differential diagnosis of the prostatitis syndromes. This classic paper described in great details the serial cultures (and treatment) in four patients with chronic prostatitis and introduced the so-called Meares-Stamey four-glass test. This localization test, which segmentally assesses inflammation and cultures of the male lower urinary tract, is described later in this chapter (see Lower Urinary Tract Evaluation). Based on 10 years of clinical experience with this test, a classification system describing four categories of prostatitis was described by Drach and colleagues in 1978. Differentiation of the four categories depended on an analysis of prostatic fluid, which included microscopy (examination for white blood cells [WBCs], inflammatory cell clumps, mucus debris, oval fat bodies, and macrophages) and culturing (identifying traditional uropathogens).

Acute bacterial prostatitis was diagnosed when prostatic fluid was clinically purulent, systemic signs of infectious disease were present, and bacteria were cultured from prostatic fluid. Chronic bacterial prostatitis was diagnosed when pathogenic bacteria were recovered in significant numbers from a purulent prostatic fluid in the absence of a concomitant UTI or significant systemic signs. Nonbacterial prostatitis was diagnosed when significant numbers of bacteria could not be cultured from prostatic fluid but the fluid consistently revealed microscopic purulence. Prostatodynia was diagnosed in the remaining patients who had persistent pain and voiding complaints as in the previous two categories but who had no significant bacteria or purulence in the prostatic fluid. This clinical differentiation of the prostatitis syndromes is now referred to as the “traditional” classification system (Table 11–1).

Table 11–1 Classification System for the Prostatitis Syndromes

The significant limitations of this classification system included the abandonment by most physicians of the rigorous Meares-Stamey four-glass test (Moon, 1997; Nickel et al, 1998a; McNaughton Collins et al, 1999, 2000a), the realization that only the very rare patient would be subsequently diagnosed with chronic bacterial prostatitis, the perception that patients responded to specific therapy (e.g., antibiotics) independent of this classification system, and the dawning realization that, in many cases, patients presenting with prostatitis syndromes were not easily classified into one of these categories (e.g., patients in whom specific cultures were negative because of previous antibiotic therapy or those thought to have a cause other than the prostate gland) (Nickel, 1998a).

National Institutes of Health Classification

The limitations of the traditional diagnostic algorithm and traditional classification system led to the development of the National Institutes of Health (NIH) classification system (see Table 11–1) (Krieger et al, 1999). The new definition recognized that pain is the main symptom in “abacterial chronic prostatitis” (with variable voiding and sexual dysfunction), and it was the optimal criterion to differentiate chronic prostatitis patients from control patients or patients experiencing other genitourinary problems (e.g., BPH). This classification differed from the traditional system in two main areas: the descriptions of category III CP/CPPS and category IV asymptomatic inflammatory prostatitis.

Category I is identical to the acute bacterial prostatitis category of the traditional classification system. Category II is identical to the traditional chronic bacterial prostatitis classification, except that it now usually refers to patients with recurrent lower urinary tract infections (with a prostate nidus of infection) (Schaeffer, 2006). Category III is defined as the “presence of genitourinary pain in the absence of uropathogenic bacteria detected by standard microbiologic methodology.” This syndrome is further categorized into category IIIA, or inflammatory CP/CPPS (based on the presence of excessive leukocytes in EPSs or post–prostatic massage urine or semen), and category IIIB, or noninflammatory CP/CPPS (no significant leukocytes in similar specimens). Category IV, or asymptomatic inflammatory prostatitis, addressed one of the major problems and omissions of the traditional classification system. Patients are classified as having category IV prostatitis by the presence of significant leukocytes (or bacteria or both) in prostate-specific specimens (EPS, semen, and tissue biopsies) in the absence of typical chronic pelvic pain.

The NIH International Prostatitis Collaborative Network met in Washington in 1998 and confirmed the value of this classification system, not only in clinical research studies but also in clinical practice (Nickel et al, 1999c).

Category I: Acute Bacterial Prostatitis

Acute bacterial prostatitis, category I, is a rare but important lower urinary tract infectious disease. It is characterized by an acute onset of pain combined with irritative and obstructive voiding symptoms in a patient with manifestations of a systemic febrile illness. The patient typically complains of urinary frequency, urgency, and dysuria. Obstructive voiding complaints including hesitancy, poor interrupted stream, strangury, and even acute urinary retention are common. The patient complains of perineal and suprapubic pain and may have associated pain or discomfort of the external genitalia. In addition, there are usually significant systemic symptoms including fever, chills, malaise, nausea and vomiting, and even frank septicemia with hypotension. The combination and severity of symptoms in category I, acute bacterial prostatitis, vary from patient to patient. Approximately 5% of patients with acute bacterial prostatitis may progress to chronic bacterial prostatitis (Cho et al, 2005).

Category II: Chronic Bacterial Prostatitis

The most important clue in the diagnosis of category II, chronic bacterial prostatitis, is a history of documented recurrent UTIs. From 25% to 43% of patients diagnosed with chronic bacterial prostatitis employing a four-glass test had a history of recurrent UTIs (Weidner and Ludwig, 1994; Wright et al, 1994). Patients may be relatively asymptomatic between acute episodes, or they may present with a long history of a CPPS, which is described extensively in the next section. The prevalence of bacterial prostatitis ranges from 5% to 15% of prostatitis cases (Schaeffer et al, 1981; Krieger and Egan, 1991; Weidner and Ludwig, 1994). In one of the largest and most comprehensive clinical series, Weidner and associates (1991b) found significant bacteriuria (with uropathogenic organisms) in 4.4% of patients with symptoms of chronic prostatitis.

Category III: CP/CPPS

The presenting symptoms of inflammatory category IIIA CP/CPPS (similar to the previous category of chronic nonbacterial prostatitis) are indistinguishable from those of patients with noninflammatory category IIIB disease (previously referred to as prostatodynia). The symptoms experienced by patients with CP/CPPS have been studied extensively by Krieger and colleagues (1996a). They evaluated 50 patients with CP/CPPS seen in a prostatitis clinic (compared with 75 control patients). Alexander and Trissel (1996) surveyed a cohort of 163 prostatitis patients on the Internet. These symptoms were best defined in the development of prostatitis symptom scores by Neal and Moon (1994), Krieger and colleagues (1996a), Nickel and Sorensen (1996b), and Brahler and coworkers (1997). The predominant symptom in all these studies was pain, which was most commonly localized to the perineum, suprapubic area, and penis but can also occur in the testes, groin, or low back. Pain during or after ejaculation is one of the most prominent, important, and bothersome features in many patients (Shoskes et al, 2004). Irritative and obstructive voiding symptoms including urgency, frequency, hesitancy, and poor interrupted flow are associated with this syndrome in many patients. Erectile dysfunction and sexual disturbances have been reported in patients with CPPS (Mehik et al, 2001; Liang et al, 2004; Zaslau et al, 2005; Muller and Mulhall, 2006; Marzalek et al, 2007; Smith et al, 2007a, 2007b; Lee et al, 2008a) but are not pathognomonic features of this syndrome. The best description of the CP/CPPS patient was provided by the NIH Chronic Prostatitis Cohort Study (Schaeffer et al, 2002). A detailed description of 488 men with CP/CPPS noted that the most frequently reported pain/discomfort was in the perineum, followed by pain/discomfort in the suprapubic area. Over half of the men had pain/discomfort during or after sexual climax (ejaculatory pain may be the most discriminatory symptom).

By definition, the syndrome becomes chronic after 3 months’ duration. The symptoms tend to wax and wane over time; approximately one third of patients improve over 1 year (usually patients with shorter duration and fewer symptoms) (Nickel et al, 2002; Turner et al, 2004; Propert et al, 2006). An age-matched case-control study of risk factors in men with CP/CPPS (Pontari et al, 2005) showed that compared with asymptomatic controls, men with CP/CPPS reported a significantly greater life time prevalence of nonspecific urethritis (12% vs. 4%), cardiovascular disease (11% vs. 2%), neurologic disease (41% vs. 14%), psychiatric conditions (29% vs. 11%), and blood or infectious disease (41% vs. 20%).

The impact of this condition on health status is significant. The quality of life of many patients diagnosed with CP/CPPS is greatly diminished. Wenninger and associates (1996), employing a generic health status measure, the Sickness Impact Profile, showed that the mean scores were within the range of scores reported in the literature for patients with a history of myocardial infarction, angina, or Crohn disease. McNaughton Collins and coworkers (2001b) employed similar quality of life assessment instruments in the NIH Chronic Prostatitis Cohort Study of almost 300 patients and confirmed this finding. These investigators noted that the mental health component was affected more than the physical component of the quality of life assessment. CP/CPPS patients’ quality of life was lower than those observed in the most severe subgroups of men with congestive heart failure and diabetes mellitus. This significant impact on quality of life has also been reported in a cohort of CP/CPPS men evaluated in a primary care setting (Turner et al, 2002). Patients with a diagnosis of CP/CPPS may present with depression (Tripp et al, 2005, 2006), stress (Ulrich et al, 2005), or a history of abuse (sexual, physical, or emotional) (Hu et al, 2007). Depression, maladaptive coping techniques (e.g., catastrophizing and pain contingent resting) and poor social support are associated with a poorer quality of life (Nickel et al, 2008b).

Category IV: Asymptomatic Inflammatory Prostatitis

Category IV, asymptomatic inflammatory prostatitis, by definition, does not cause symptoms. The patients present with BPH, an elevated PSA level, prostate cancer, or infertility. Subsequent microscopy of EPS or semen and/or histologic examination of BPH chips, prostate cancer specimens, or prostate biopsy specimens disclose evidence of prostatic inflammation.

Physical Examination

Physical examination is an important part of the evaluation of a patient with prostatitis, but it is usually not helpful in making a definitive diagnosis or further classifying the disorder. It assists in ruling out other perineal, anal, neurologic, pelvic, or prostate abnormalities and is an integral part of the lower urinary tract evaluation by providing prostate-specific specimens.

In category I, acute bacterial prostatitis, the patient may be systemically toxic, that is, flushed, febrile, tachycardic, tachypneic, and even hypotensive. The patient usually has suprapubic discomfort and perhaps has clinically detectable acute urinary retention. Perineal pain and anal sphincter spasm may complicate the digital rectal examination. The prostate itself is usually described as hot, boggy, and exquisitely tender. The expression of prostatic fluid is believed to be totally unnecessary and perhaps even harmful.

The physical examination of a patient with category II, chronic bacterial prostatitis and category III CPPS is usually unremarkable (except for pain). Careful examination and palpation of external genitalia, groin, perineum, coccyx, external anal sphincter (tone), and internal pelvic floor and side walls may pinpoint prominent areas of pain or discomfort. The digital rectal examination should be performed after the patient has produced preprostatic massage urine specimens (see later). The prostate may be normal in size and consistency, and it has also been described as enlarged and boggy (loosely defined by the author as softer than normal). The degree of elicited pain during prostatic palpation is variable and is unhelpful in differentiating a prostatitis syndrome. The prostate should be carefully checked for prostatic nodules before a vigorous prostatic massage is performed to produce prostate-specific specimens (EPS and post–prostatic massage urine sample).

Lower Urinary Tract Cytologic Examination and Culture Techniques

In patients presenting with category I, acute bacterial prostatitis, a urine culture is the only laboratory evaluation of the lower urinary tract required. It has been suggested that the vigorous prostatic massage necessary to produce EPS can exacerbate the clinical situation, although such fears have never been substantiated in the literature. A midstream urine specimen will show significant leukocytosis and bacteriuria microscopically, and culturing usually discloses typical uropathogens. Blood cultures may show the same organism.

In 1968, Meares and Stamey described the classic four-glass urine collection technique to distinguish urethral, bladder, and prostate infections in men with chronic prostatitis, and for 3 decades this has remained the “gold standard” for the evaluation of this lower urinary tract syndrome. The voided bladder-1 (VB1) specimen includes the first 10 mL of urine and represents the urethral specimen. The voided bladder-2 (VB2) specimen is similar to a midstream urine collection and represents the bladder urine. EPS should be collected directly into a sterile container during prostatic massage. The voided bladder-3 (VB3) specimen, the first 10 mL of urine voided after prostatic massage, includes any EPS trapped in the prostatic urethra. The three urine specimens are centrifuged for 5 minutes and the sediment examined under high power for leukocytes (including aggregates of leukocytes), macrophages, oval fat bodies, erythrocytes, bacteria, and fungal hyphae. A wet mount of a drop of EPS can be examined under a coverslip in a similar manner. Some researchers (Muller et al, 2001; Krieger et al, 2003) point out that quantitative determination of the EPS WBC concentration by a counting chamber method is superior to the standard wet mount method but probably only indicated in research studies. In fact, the NIH Chronic Prostatitis Cohort Study (Schaeffer et al, 2002; Nickel et al, 2003a) suggested that leukocyte determination did not appear to add significant clinical information to the assessment of a patient with CP/CPPS. All four specimens are sent to the laboratory for quantitative culturing. Figure 11–4 illustrates the technique and interpretation of the four-glass test.

Figure 11–4 Technique and interpretation of the Meares-Stamey four-glass lower urinary tract localization test for CP/CPPS.

Category II, chronic bacterial prostatitis, is diagnosed if there is a 10-fold increase in bacteria in the EPS or VB3 specimen compared with the VB1 and VB2 specimens. In a patient who has acute cystitis this localization is impossible, and in this case the patient can be treated with a short course (1 to 3 days) of therapy with an antibiotic such as nitrofurantoin, which penetrates the prostate poorly but eradicates the bladder bacteriuria. Subsequent localization of bacteria in the post–prostatic massage urine or EPS is then diagnostic of category II prostatitis. Category IIIA CP/CPPS is diagnosed when no uropathogenic bacteria are cultured, but excessive leukocytosis (usually defined as more than 5 to 10 WBCs/high-power field [hpf]) is noted in the prostate-specific specimens (EPS or VB3 or both). Category IIIB CP/CPPS is diagnosed when no uropathogenic bacteria are cultured and there is no significant leukocytosis noted on microscopic examination of EPS or the sediment of VB3.

Although the four-glass test remains the gold standard diagnostic evaluation of prostatitis patients, numerous surveys (Moon, 1997; Nickel et al, 1998a; McNaughton Collins et al, 1999, 2000a) have confirmed that clinicians have more or less abandoned this time-consuming and expensive rigorous evaluation. The pre-massage and post-massage test (or two-glass test), originally suggested by Weidner and Ebner (1985) and popularized by Nickel (1995, 1996, 1997a), is a simple, cost-effective screen to categorize patients with chronic prostatitis. The patient provides a midstream pre-massage urine specimen and a urine specimen (initial 10 mL) after prostatic massage. Microscopy (sediment) and culturing of these two screening urine specimens allows categorization of the majority of patients presenting with a chronic prostatitis syndrome. Figure 11–5 illustrates the technique and interpretation of the two-glass pre-massage and post-massage test.

Figure 11–5 Technique and interpretation of the pre- and post-massage two-glass lower urinary tract localization test for CP/CPPS.

In a retrospective personal series and a review of series in the literature, Nickel (1997a) noted that this test had 91% sensitivity and specificity compared with the gold standard Meares-Stamey test. Its limitations were thought to be due to the exclusion of the urethral and EPS specimen. However, in patients without clinical urethritis, Krieger and associates (2000) demonstrated that urethral swabs are more efficient in picking up urethral inflammation than the VB1 specimen. But in this series of 235 patients only 3% had more than 1 WBC/hpf. Therefore the urethral specimens rarely detected significant urethral inflammation, and in this series rarely did cultured organisms change the direction of clinical therapy in patients with prostatitis (without clinical urethritis). In the same study (Krieger et al, 2000) comparing EPS with post–prostatic massage urine, the investigators demonstrated that EPS examination detected 76%, whereas post-massage urine examination detected 82% of the patients who had inflammation on one or both tests. Ludwig and associates (2000), in a series of 328 patients in whom both EPS and a VB3 specimen were obtained, demonstrated that VB3 is almost as accurate as EPS (92% sensitivity; 99% specificity) in detecting prostate-specific inflammation. Seiler and associates (2003) came to the same conclusion in their study of 143 chronic prostatitis patients. Nickel and colleagues from the NIH CPCRN (2006) examined a cohort of 353 CP/CPPS men with complete four-glass data and noted that the two-glass test predicted a positive four-glass result with clinically acceptable accuracy (over 95% of men would have had the same diagnosis if the four-glass test was performed). This test, however, is only a screening test, and in patients in whom it is important to localize bacteria to the prostate versus the urethra (e.g., patients with recurrent UTIs, suspicion of urethral abnormality), a follow-up VB1 specimen or urethral swab may be very helpful. If typical urethral organisms are localized to the prostate when the pre-massage and post-massage test is used and the clinician is inclined to consider them pathogenic and subsequently treat the patients, urethral and EPS specimens to definitively localize the specific bacteria to the prostate are appropriate. As a general rule, it is always best to examine the EPS (if obtainable) microscopically.

Cytologic Considerations

The differentiation of the two subtypes of category III CP/CPPS depend on cytologic examination of the urine or EPS or both. The urine specimens are centrifuged for 5 minutes, and the sediment is resuspended under a coverslip and examined at high power (×300 to ×400) while the wet mount of a drop of EPS is examined under a coverslip at the same power. WBCs have traditionally been reported as numbers of leukocytes per high-power field (Fig. 11–6). There is no validated cutoff point for the level of WBCs per high-power field that is required to differentiate an inflammatory from a noninflammatory CP/CPPS. Although the suggested limits have ranged from as low as 2 (Anderson and Weller, 1979) to as high as 20 (Blacklock and Beavis, 1978) the consensus appears to favor 5 to 10 WBCs/hpf in EPS as the upper level of normal (Meares and Stamey, 1968; Pfau et al, 1978; Schaeffer et al, 1981). But inflammatory cells in the EPS fluctuate over time (Anderson and Weller, 1979; Schaeffer et al, 1981) and with the frequency of ejaculation (Jameson, 1967; Yavascaoglu et al, 1999). A disadvantage of looking at a drop of prostatic fluid or urine sediment is that the cells may clump or aggregate, which renders quantifying them virtually impossible. Also, an unstained specimen does not allow differentiation of the type of WBC present (e.g., polymorphonuclear leukocytes, lymphocytes, monocytes, macrophages). If accuracy is required (i.e., research), then the WBCs can be counted in a glass hemacytometer (so they may be quantified as cells per square millimeter) and subsequently stained to differentiate the inflammatory cell subtype (Anderson and Weller, 1979).

Figure 11–6 A and B, Unstained photomicrographs showing individual white blood cells, clumps of white blood cells, and lipid-laden macrophages in the expressed prostatic secretion (EPS) of a patient with category IIIA CPPS (A, ×250; B, ×400).

The clinical relevance of adding cytologic examination of semen specimens (which is difficult without special staining techniques) is unknown. Certainly, semen examination increases the percentage of patients identified as inflammatory category IIIA CP/CPPS (Krieger et al, 2000).

Nickel and colleagues (2003a) compared the number of WBCs in the EPS in patients with CP/CPPS to EPS specimens from normal asymptomatic control men and noted that while there was a statistically significant difference in WBC counts in the CP/CPPS men the clinical significance was not apparent (e.g., 50% of CPPS men had >5 WBCs/hpf compared with 40% of control men). The relevance of examining urine and EPS for white cells in routine clinical practice has been challenged (Nickel et al, 2003a). In fact, we have not been able to confirm the association between histologically proven prostate inflammation and prostatitis symptoms (Nickel et al, 2007), further confusing the issue of whether we really need to determine prostate-specific specimen inflammation, which is really just a surrogate for prostate inflammation. However, some investigators (Nickel, 2002d) have recommended that urine cytology (for malignant cells) become a standard diagnostic test for men presenting with prostatitis-like symptoms, particularly if the symptom-complex includes irritative voiding symptoms, dysuria, and/or suprapubic/bladder pain.

Urodynamics

Pain is the dominant symptom in patients presenting with CP/CPPS, but a wide constellation of irritative and obstructive voiding symptoms are associated with this syndrome. Proposed causes to account for the persistent irritative and obstructive voiding symptoms include detrusor vesical neck or external sphincter dyssynergia, proximal or distal urethral obstruction, and fibrosis or hypertrophy of the vesical neck (Blacklock, 1974, 1986; Bates et al, 1975; Orland et al, 1985; Theodorou et al, 1999). These abnormalities can often be clarified and diagnosed by urodynamics, particularly video-urodynamics. Others have suggested that men with defined primary voiding dysfunction have been misdiagnosed with chronic prostatitis (Webster et al, 1980; Siroky et al, 1981; Murnaghan and Millard, 1984). Siroky and associates (1981) noted that urodynamics revealed that 50% of 47 men with recurrent voiding symptoms, perigenital pain, or both previously diagnosed as chronic prostatitis had bladder acontractility during a study with nonrelaxing perineal floor (striated muscle spasm) and that another 36% had detrusor overactivity with appropriate striated sphincter relaxation. Barbalias (1990) and Barbalias and colleagues (1983) noted decreased peak and mean urinary flow rates, a significantly elevated maximal urethral closing pressure, and incomplete funneling of the bladder neck accompanied by urethral narrowing at the level of the external urinary sphincter during voiding with urodynamic evaluation of men diagnosed with chronic prostatitis. Hellstrom and colleagues (1987) also noted elevated urethral pressures, “hyperreflexia” of the external urethral sphincter, and intraprostatic reflux in three patients with unremitting symptoms of chronic nonbacterial prostatitis.

Kaplan and associates (1994, 1996, 1997) postulated that chronic lower urinary tract symptoms in young men are often misdiagnosed as chronic nonbacterial prostatitis when in fact they indicate a cohort of men with undiagnosed chronic voiding dysfunction. This conclusion is based on the video-urodynamic studies of 137 consecutive men 50 years of age or younger diagnosed with chronic prostatitis (Kaplan et al, 1996). These researchers demonstrated a variety of urodynamic abnormalities, including 54% of patients with primary vesical neck obstruction, 24% with functional obstruction localized to the membranous urethra (pseudodyssynergia), 17% with impaired bladder contractility, and 5% with an acontractile bladder. They noted detrusor overactivity in 49% of the men. Simple documentation of uroflowmetry and residual urine bladder scan abnormalities may suggest proceeding to more sophisticated urodynamics (Ghobish, 2000). Other groups dispute the benefits of urodynamics and have noted very few urodynamic abnormalities in patients presenting with classic chronic prostatitis symptoms (Mayo et al, 1998).

Endoscopy

Clinical experience (rather than controlled clinical studies) suggests that lower urinary tract endoscopy (i.e., cystoscopy) is not indicated in the majority of men presenting with CP/CPPS. However, cystoscopy is indicated in patients in whom the history (e.g., hematuria), lower urinary tract evaluation (e.g., VB1 urinalysis), or ancillary studies (e.g., urodynamics) indicate the possibility of a diagnosis other than CP/CPPS. In these patients, occasionally lower urinary tract malignancy, stones, urethral strictures, bladder neck abnormalities, and so forth that can be surgically corrected are discovered. Cystoscopy can probably be justified in men refractory to standard therapy.

Transrectal Ultrasonography

Transrectal ultrasonography has become one of the best radiologic methods to evaluate prostate disease and has become an especially helpful clinical tool for the assessment of prostate volume and ultrasound guidance of biopsy needles. The diagnostic value of ultrasonography in differentiating benign from malignant prostate disease is controversial, and the further differentiation of the various benign conditions of the prostate is even more so. Di Trapani and colleagues (1988) described inhomogeneous echo structures, constant dilatation of periprostatic venous plexus, elongated seminal vesicles, and thickening of the inner septa in patients with prostatitis. Doble and Carter (1989) described seven ultrasound signs associated with the presence of symptoms of chronic prostatitis compared with controls, and although the sensitivity increased with higher leukocyte counts the signs were not sufficiently specific to differentiate clinical groups.

Peeling and Griffiths (1984) describe the heterogeneity of the echo pattern and prostatic calculi as ultrasound features related to prostatitis. Ludwig and coworkers (1994) described the ultrasound features such as prostatic calcifications and seminal vesicle abnormalities that appear to be indicative of signs of inflammation but not proof of the presence of chronic prostatitis. Harada and associates (1980) concluded that the presence of stones is not related to a specific prostate disease process. De la Rosette and colleagues (1992b) performed ultrasonography in 22 patients with nonbacterial prostatitis and compared the results with those of a control group of 22 patients without lower urinary tract symptoms. This study indicated that there were no significant differences in ultrasound patterns of patients with nonbacterial prostatitis and the control group. Others have employed color Doppler ultrasonography (Veneziano et al, 1995) and automated computer analysis (de la Rosette et al, 1995) in an attempt to improve the value of transrectal ultrasonography in the evaluation of prostatitis patients; however, the results are not conclusive enough to indicate that this is a clinically useful tool.

Transrectal ultrasonography can be valuable in diagnosing medial prostatic cysts in patients with prostatitis-like symptoms (Dik et al, 1996), diagnosing and draining prostatic abscesses (Granados et al, 1992), or diagnosing and draining obstructed seminal vesicles (Littrup et al, 1988). It is not required in all cases of acute bacterial prostatitis but rather only in those patients who are failing appropriate antimicrobial therapy (Horcajada et al, 2003).

Prostate Biopsy

Occasionally, because of an elevated PSA level or abnormal digital rectal examination, prostate biopsy is indicated (Kawakami et al, 2004). Some clinicians will consider starting patients with elevated screening PSA levels and a history of prostatitis or symptoms of CPPS on antibiotics, but this practice is really only rational in patients with acute or chronic bacterial prostatitis (Nickel, 2002c), conditions that invariably lead to elevated PSA levels. The diagnosis of CP/CPPS should be used only as a reason against a prostate biopsy if the clinician is looking for an excuse not to biopsy (Nickel, 2002c). A comprehensive review on PSA and prostatitis is available (Kawakami et al, 2004).

Out of desperation, urologists sometimes resort to prostate biopsy in an attempt either to demonstrate histologic evidence of prostatic inflammation or to culture an organism that cannot be cultured employing the standard approach. The importance and interpretation of prostate biopsies in prostatitis performed for reasons other than prostate cancer screening is unclear. Doble and associates (1990) demonstrated immune complexes in the prostate of patients with prostatitis but found culture of the prostatic tissue unhelpful (Doble et al, 1989a). Nickel and Costerton (1993) were able to confirm the presence of potentially uropathogenic bacteria in patients with a documented history of chronic bacterial prostatitis in whom EPS cultures became sterile after antibiotic therapy. Berger and associates (1997) also confirmed the presence of potential uropathogenic bacteria in prostate biopsy specimens (which correlated to some extent with prostatic inflammation in EPS) in patients in whom the same bacteria did not grow standard prostatic specimens (e.g., EPS). Krieger and colleagues (1996b) demonstrated the possible presence of microorganisms in the prostate gland of a majority of men with chronic prostatitis syndrome using the molecular biologic technique of polymerase chain reaction. At this time, histologic, culture, and molecular biologic evaluations of prostate biopsy specimens in patients with CP/CPPS remain research tools only.

Seminal Vesiculitis

Occasionally, seminal vesiculitis can occur as a consequence of local bacterial infection in acute and chronic bacterial prostatitis (Zeitlin, 1999) and patients can present with seminal vesicle abscesses (Stearns, 1963; Kennelly and Oesterling, 1989). Seminal vesicle abscesses were traditionally diagnosed clinically by a positive ejaculate culture and seminal vesiculography (Dunnick et al, 1982; Baert et al, 1986) but is now imaged with computed tomography (Patel and Wilbur, 1987), transrectal ultrasonography (Littrup et al, 1988), magnetic resonance imaging (Sue et al, 1989) or recently with technetium-99m ciprofloxacin radioisotope scan (Choe et al, 2003).

Other Possible Markers

Wishnow and associates (1982) found that control patients (10 patients) and men with chronic abacterial prostatitis (4 patients) had no antibodies to gram-negative bacterial antigens, in contrast to men with bacterial prostatitis (6 patients). They hypothesized that immunologic analysis may provide a better diagnostic tool than culturing and microscopy. Shortliffe and coworkers (1981a, 1981b, 1986, 1989, 1992) found that the total IgA and IgG levels in the prostatic fluid in men with chronic abacterial prostatitis were higher than those of controls. They also discovered that prostatic fluid from control or abacterial prostatitis patients did not contain specific antibodies to gram-negative urinary pathogens (in contrast to men with bacterial prostatitis). Nickel and colleagues (2001a) used a similar antibody screening procedure in evaluation of 102 men with CP/CPPS who were subsequently treated with quinolone antibiotics. However, “antibody-positive” patients did not have a better response to antibiotic therapy than “antibody-negative” patients after 12 weeks of therapy. Li and associates (2001) demonstrated increased endotoxin concentrations in EPS and VB3 of men with bacterial prostatitis and inflammatory category IIIA CPPS and suggested that endotoxin levels might be used to identify these categories of patients with chronic prostatitis.

Alexander and colleagues (1998) discovered that men with chronic abacterial prostatitis had higher mean levels of the proinflammatory cytokines IL-1α and TNF-α in seminal plasma compared with controls. Ruggieri and coworkers (2000) noted that levels of both IL-1α and IL-8 were significantly higher in semen in category IIIA patients (leukocytes) than in category IIIB patients, but there was no statistically significant difference in levels of TNF-α, IL-1α, or IL-6. This group found no correlation between cytokine levels and the number of leukocytes in EPS. The increased IL-8 levels in the semen of patients with prostatitis symptoms has recently been confirmed by Khadra and coworkers (2006) and Penna and associates (2007), suggesting that this could be a surrogate marker for CP/CPPS. Nadler and colleagues (2000) found that mean levels of IL-1α in EPS were higher in men with inflammatory chronic abacterial prostatitis and noninflammatory chronic bacterial prostatitis compared with controls. Hochreiter and associates (2000a) did find a direct significant correlation between the number of leukocytes in EPS and IL-1α levels in EPS. One of the most intriguing possible biomarkers includes monocyte chemoattractant protein-1 and macrophage inflammatory protein-1α detected in EPS. Both of these chemokines are elevated in category IIIA and IIIB CP/CPPS, whereas macrophage inflammatory protein-1α may be a further marker for clinical pain in these patients (Desireddi et al, 2008). The sensitivity, specificity, and, more importantly, the clinical applicability of all these immunologic tests is really unknown and none of them is yet indicated in clinical practice.

Marmar and associates (1980) hypothesized that zinc levels in EPS would be a useful marker for prostatitis and found that, indeed, zinc levels in men with chronic abacterial prostatitis and bacterial prostatitis were significantly lower than zinc levels in control patients and men with prostatodynia. However, Zaichick and colleagues (1996) found no differences in zinc levels between patients with chronic abacterial prostatitis, BPH, and controls. At this time the measurement of zinc levels in prostatic or semen specimens is clinically unhelpful.

Tanner and associates (1999) detected positive signals (rRNA-based molecular technique with prostatic fluid) in 65% of patients with chronic prostatitis. Seven of 11 patients with bacterial signals but none of 6 patients without bacterial signals was improved on antibiotic therapy. The same group (Shoskes and Shahed, 2000) subsequently confirmed this finding with a larger cohort of patients. These results are intriguing, and controlled studies evaluating the potential clinical significance of differentiating patients based on molecular biologic techniques are required.

An Approach to Diagnosis and Classification

A diagnostic algorithm that provides a practical approach to the workup of the majority of men presenting with CP/CPPS is shown in Figure 11–7. Table 11–2 shows the tests recommended by the NIH Third International Prostatitis Collaborative Network (Nickel, 2003).

Figure 11–7 A suggested diagnostic algorithm for the evaluation of patients presenting with CP/CPPS. UTIs, urinary tract infections; TRUS, transrectal ultrasonography; CT, computed tomography; MRI, magnetic resonance imaging; DRE, digital rectal examination; PSA, prostate-specific antigen.

Table 11–2 Suggested Evaluation of a Man with Chronic Pelvic Pain Syndrome*

* See text for explanation, rationale, and description of each test.

Antimicrobial Agents

Clinical Trial Data

Unless the patient has a significant anatomic abnormality of the lower urinary tract or develops a prostate abscess, antimicrobial therapy is universally successful in eradicating the bacteria and curing the patient presenting with acute bacterial prostatitis (Nickel and Moon, 2005). In the acutely inflamed prostate gland the pharmacokinetic considerations described in the previous section probably do not play a significant role in antibiotic penetration, and it is believed that most antibiotics achieve reasonable intraprostatic concentrations in the acute phase of the disease. Although prospective clinical trial data are unavailable, most experts suggest therapy initially with parenteral antibiotics (depending on the seriousness of the infection) followed by oral antibiotics with wide-spectrum antimicrobial activity (Becopoulos et al, 1990). The most common drugs suggested for initial therapy (Neal, 1999; Ludwig, 2008; Benway and Moon, 2008) are a combination of penicillin (i.e., ampicillin) and an aminoglycoside (i.e., gentamicin), second- or third-generation cephalosporins, or one of the fluoroquinolones. Once the acute infection has settled down, therapy should be continued with one of the oral antimicrobial agents appropriate for the treatment of chronic bacterial prostatitis (e.g., trimethoprim or fluoroquinolones). The duration of optimal therapy is unknown; between 2 and 4 weeks has been suggested (Nickel, 1998b; Bjerklund-Johansen et al, 1998; Wagenlehner et al, 2007; Ludwig, 2008).

In the 1970s to 1990s the most commonly used antimicrobial agent in the treatment of chronic prostatitis was trimethoprim-sulfamethoxazole (co-trimoxazole) (Moon, 1997; Nickel et al, 1998a) and, to a lesser extent, trimethoprim alone. In patients with chronic bacterial prostatitis, eradication of pathogens (the only objective measurement in most chronic prostatitis studies) with trimethoprim-sulfamethoxazole or trimethoprim alone ranged from a low of 0% (Smith et al, 1979) to a high of 67% (Paulson and White, 1978), with most studies demonstrating an efficacy rate of between 30% and 50% (Meares, 1973, 1975, 1978; Drach, 1974b; McGuire and Lytton, 1976). It appears that longer-duration therapy (90 days) provides the best clinical results. Trimethoprim-sulfamethoxazole is less effective both in bacterial eradication and cost-effectiveness when compared with the newer fluoroquinolones (Kurzer and Kaplan, 2002).

Except for the well-studied fluoroquinolones, most antibiotics (including minocycline, cephalexin, and carbenicillin) do not demonstrate significant clinical efficacy in clinical studies in which patients were observed for sufficient time (Paulson and White, 1978; Oliveri et al, 1979; Mobley, 1981). One notable exception has been the macrolides, erythromycin (Mobley, 1974), azithromycin (Skerk et al, 2003), and clarithromycin (Skerk et al, 2002b), particularly when C. trachomatis is implicated.

The fluoroquinolones have demonstrated improved therapeutic results, especially in prostatitis caused by E. coli and other members of the Enterobacteriaceae but not necessarily in prostatitis due to P. aeruginosa or enterococci. Naber (1999) analyzed the many studies available in the literature evaluating fluoroquinolones in the treatment of chronic prostatitis and found eight comparable studies in which the diagnosis was obtained by localization studies and in which the patients were observed for a sufficient time after completion of therapy (Weidner et al, 1987; Pust et al, 1989; Schaeffer and Darras, 1990; Heidler, 1990; Weidner et al, 1991a; Pfau, 1991; Ramirez et al, 1994; Koff, 1996); in these studies the researchers evaluated norfloxacin, ciprofloxacin, ofloxacin, and lomefloxacin. In 2005 Naber (reported at the Sixth International Consultation on New Developments in Prostate Cancer and Prostate Disease, Paris, June, 2005) added three more recent studies that met these strict criteria (Naber et al, 2000, 2002; Bundrick et al, 2003). These studies are outlined in Table 11–3. A subsequent study has suggested that levofloxacin may also be effective in treating chronic bacterial prostatitis (Naber et al, 2008). For chronic prostatitis caused by E. coli, treatment duration of 1 month for the fluoroquinolones seems to be superior to the usual 3-month treatment with trimethoprim-sulfamethoxazole. It has been suggested that antibiotics should be continued only for 4 to 6 weeks if pretreatment cultures are positive and/or the patient has reported positive effects from treatment (Wagenlehner et al, 2007). Some clinicians have observed that as many as 20% of patients who fail an initial treatment period could be rescued with a second cycle of treatment with another antibiotic (Magri et al, 2007). In microbiologically diagnosed chronic bacterial prostatitis, eradication of bacteria is associated with both short-term and long-term clinical success (Nickel and Xiang, 2008). This appears to be true in men with recent onset of prostatitis associated with bacterial localization with the traditional uropathogens (gram-negative uropathogens and enterococci species) as well as nontraditional bacteria (gram-positive such as coagulase-negative staphylococcal and streptococcal species) (Magri et al, 2007; Nickel and Xiang, 2008). A number of investigators (Baert and Leonard, 1988; Jimenez-Cruz et al, 1988; Yamamoto et al, 1996; Guercini et al, 2005b) have advocated direct injection of antibiotics into the prostate gland, but this method has never been rigorously evaluated or become popular among urologists.

Table 11–3 Clinical Trials of Fluoroquinolone Treatment of Chronic Bacterial Prostatitis*

Many studies evaluating physicians’ practice patterns in prostatitis syndromes (de la Rosette et al, 1992a; Moon, 1997; Nickel et al, 1998a; McNaughton Collins et al, 1998, 2000a) have confirmed that most patients diagnosed with chronic prostatitis, irrespective of culture results, are treated with antimicrobial therapy. Older studies have generally indicated that approximately 40% of patients with nonbacterial chronic prostatitis have some symptomatic improvement with antimicrobial therapy (Berger et al, 1989; Weidner, 1992; de la Rosette et al, 1993a; Ohkawa et al, 1993b; Bergman, 1994; Bjerklund-Johansen et al, 1998; Tanner et al, 1999; Nickel et al, 2001a). Antibiotic therapy may benefit CP/CPPS patients by three different mechanisms: a strong placebo effect, the eradication or suppression of noncultured microorganisms (Nickel et al, 2001a), or the independent anti-inflammatory effect of some antibiotics (Yoshimura et al, 1996; Galley et al, 1997). It has been suggested by a European consensus group evaluating the role of antibiotics in the treatment of chronic prostatitis (Bjerklund-Johansen et al, 1998) that antibiotics should be considered empirical treatment for category IIIA CP/CPPS but the benefits should be appraised after a minimum of 2 to 4 weeks of therapy. The antibiotics could be continued for 4 to 6 weeks if the patient has reported positive effects from treatment (Wagenlehner et al, 2007). These recommendations remain controversial, particularly because new data appear to provide conflicting interpretations. Two multicenter randomized placebo controlled studies have assessed the efficacy of 6 weeks of levofloxacin (Nickel et al, 2003b) and ciprofloxacin (Alexander et al, 2004) in men with CP/CPPS. In these trials the participants had chronic symptoms for a long duration (many years) and had been heavily treated (including treatment with antibiotics). In the study by Nickel and associates (2003b), 80 patients were randomized to levofloxacin or placebo whereas in the NIH-sponsored study reported by Alexander and colleagues (2004) 196 men with CP/CPPS were randomized in a 2 × 2 factorial design to ciprofloxacin, tamsulosin, the combination of ciprofloxacin and tamsulosin, or placebo. In both of these prospective-designed controlled multicenter trials, no significant difference was reported between the fluoroquinolone and placebo in terms of symptom amelioration. Antibiotics should not be prescribed for previously treated men with CP/CPPS of long duration. However, two recent prospective trials comparing the effect of 4 to 6 weeks of antibiotics (Magri et al, 2007; Nickel and Xiang, 2008) in men with localization of both traditional uropathogens and organisms not usually believed to be uropathogenic (and therefore classified as category III CP/CPPS) showed similar eradication and clinical success rates (75% to 80%). Furthermore, in the study by Nickel and Xiang (2008), the eradication of those organisms, whether or not they were considered to be uropathogens, correlated with both short- and long-term clinical success. Because the majority of patients in Nickel and Xiang’s study (2008) had a short history of prostatitis and were antibiotic naive for that episode, it was concluded that antibiotic treatment may be considered for antibiotic-naive patients with recent diagnosis of prostatitis, regardless of culture status.

α-Adrenergic Blocker Therapy

Anti-Inflammatory Agents and Immune Modulators

Muscle Relaxants

Hormone Therapy

Phytotherapeutic Agents

Neuromodulator Therapy

Allopurinol

Prostatic Massage

Prostatic massage has been the principal therapy for prostatitis since the turn of the 20th century (O’Conor, 1936; Campbell, 1957). With the introduction of the scientific approach advocated by Meares and Stamey in 1968, prostatic massage became important only as a diagnostic tool, but as a therapy it was abandoned by urologists. Currently it is regaining some popularity, primarily because of the failure of standard medical therapy in patients with refractory symptoms of chronic prostatitis. Its benefits are believed to arise from draining theoretically occluded prostatic ducts and improving circulation and antibiotic penetration (Hennenfent and Feliciano, 1998). Independent but uncontrolled studies (Nickel et al, 1999a; Shoskes and Zeitlin, 1999) describe clinical benefits in one third to two thirds of patients treated with repetitive prostatic massage (two to three times per week) for 4 to 6 weeks along with antibiotic therapy. However, another trial indicated that prostatic massage does not significantly improve the response of men with CP/CPPS treated with antibiotics (Ateya et al, 2006). It appears that some patients may improve with prostatic massage, but a panel of North American “prostatitis experts” (Nickel et al, 1999) could not come to a consensus on the potential overall benefit or even the mechanism of achieving that benefit if it does occur. A subsequent systematic review of the literature concluded that evidence for a role of repetitive prostatic massage as an adjunct in the management of chronic prostatitis is at most “soft” but could be considered as part of multimodal therapy in selected patients (Mishra et al, 2008). Frequent ejaculation may achieve the same function as prostatic massage (Yavascaoglu et al, 1999).

Perineal or Pelvic Floor Massage and Myofascial Trigger Point Release

Most clinicians recognize that men with prostatitis syndromes, especially the noninflammatory category or prostatodynia, have specific anatomic areas that cause discomfort. Anderson (1999) believes that prolonged or chronic tension, distention, or distortion in the muscle bands (e.g., in the perineum) leads to a painful trigger point that is responsible for the pain. Predisposing factors leading to the formation of myofascial trigger points in the perineum or pelvis may include mechanical abnormalities in the hip and lower extremities, chronic urinary holding patterns (dysfunctional toilet training), sexual abuse, repetitive minor trauma, constipation, trauma, unusual sexual activity, recurrent infections or surgery, and perhaps stress and anxiety. Treatment of these trigger points includes heat therapy, physiotherapy massage, ischemic compression, stretching, anesthetic injections, acupuncture, electroneural modulation, and mind-body interactions such as progressive relaxation exercises, yoga, and hypnosis (Potts, 2003). Anderson and associates (2005) report that employing these techniques with a team consisting of a urologist, physiotherapist, and psychologist results in more than half of patients having or demonstrating a clinically detectable improvement. A case study analysis indicates that this may be an effective therapeutic approach in some patients (Anderson et al, 2005) and may result in improvement not just in pain but also in sexual function (Anderson et al, 2006). A recently reported NIH pilot study of men and women with chronic pelvic pain treated with either relaxation massage or specific pelvic massage therapy demonstrated improvement in women but could not corroborate these findings in men (Peters K, presented at AUA annual meeting, May 19, 2008).

Pudendal Nerve Entrapment Therapy

It has been hypothesized that the symptoms of CPPS could be caused by entrapment of the pudendal nerve, perhaps between the sacrotuberous and sacrospinous ligaments, in the canal of Alcock or by the falciform process of the sacrotuberous ligament (Robert et al, 1998). Pudendal nerve blocks (Thoumas et al, 1999; McDonald and Spigos, 2000; Peng and Tumber, 2008) and neurolysis surgery (Robert et al, 1993; Mauillon et al, 1999) have been suggested for treatment. The role of the pudendal nerve in chronic perineal pain deserves more scientific scrutiny.

Biofeedback

It is possible that the voiding and pain symptoms associated with CP/CPPS may be secondary to some form of pseudodyssynergia during voiding or repetitive perineal muscle spasm; biofeedback has the potential to improve this process. Kaplan and associates (1997), Nadler (2002), Ye and colleagues (2003), and Cornel and coworkers (2005) have demonstrated in small uncontrolled studies that biofeedback does ameliorate specific prostatitis-like symptoms in some men. Controlled clinical trials will be necessary to evaluate this mode of therapy.

Acupuncture

Acupuncture is an accepted traditional Chinese therapy for chronic pain, including prostatitis (Ge et al, 1988; Katai, 1992; Ikeuchi and Iguchi, 1994). Chen and Nickel (2003) determined in a pilot study of 12 treatment-refractory men that acupuncture was safe and provided effective and durable symptom improvement. A subsequent study comparing 10 weeks of acupuncture versus sham acupuncture treatment indicated that the active acupuncture proved to be almost twice as likely as sham treatment to improve CP/CPPS symptoms (Lee et al, 2008).

Psychological Support

Data from the NIH Prostatitis Cohort (Tripp et al, 2005, 2006; Nickel et al, 2008b) support a biopsychosocial model that associates the chronic pain and poor quality of life of CP/CPPS with depression and suggests that physicians may be able to advise patients to avoid certain pain coping strategies that can be associated with greater depression. Nickel and colleagues (2008) have developed an evidence-based cognitive behavioral treatment program for men with CP/CPPS. This program specifically targets empirically supported biopsychosocial variables (e.g., pain catastrophizing, depressive thinking, social support) and encourages patients to critically evaluate their patterns of thinking and to entertain novel thinking and behavioral responses to their troublesome symptoms, with an end objective to improve overall quality of life.

Studies also show that the maladaptive pain coping technique of employing “pain contingent resting” (using rest rather than more active behaviors to control pain) is reported by CP/CPPS patients in response to their pain (Tripp et al, 2006; Nickel et al, 2008b). It was suggested by Tripp and coworkers (2006) that such sedentary behaviors in the presence of pain may be associated with elevated disability in men with CP/CPPS. A double-blind randomized study showed that men participating in aerobic exercise were significantly better than those who were randomized to stretching and motion exercise, suggesting that increased physical activity is a valid option in men with CP/CPPS (Giubilei et al, 2007). The results of a study examining perceived helpfulness of medical and self-management strategies suggested that clinicians may find it useful to support patients’ use of safe, inexpensive, self-management approaches, such as warm baths, increased water intake, exercise, and avoidance of prolonged sitting (Turner et al, 2006).

Minimally Invasive Therapies

Surgery

In acute bacterial prostatitis (category I), urinary obstruction is a very common symptom. Traditionally, it has been suggested that the insertion of a suprapubic cystotomy tube is the optimal therapy because an indwelling Foley catheter may further obstruct urethral ducts, resulting in the potential to develop prostate abscesses (Dajani and O’Flynn, 1968; Pai and Baht, 1972; Weinberger et al, 1988). In most patients, however, an in-and-out catheterization to relieve the initial obstruction or short-term (12 hours) indwelling catheterization with a small-caliber Foley catheter is appropriate. A developing prostate abscess, best detected with transrectal ultrasonography or computed tomography (Rovik and Doehlin, 1989), in patients who fail to respond quickly to antibiotics is optimally drained by the transurethral incision route (Pai and Baht, 1972). However, transperineal incision and drainage (Granados et al, 1992) must be considered when the abscess has penetrated beyond the prostatic capsule or penetrated through the levator ani muscle. More recently it has been suggested that percutaneous drainage of the abscess is the most effective and less morbid procedure (Varkarakis et al, 2004).

Surgery does not have an important role in the treatment of most chronic prostatitis syndromes unless a specific indication is discovered during the evaluation of the patient (Kirby, 1999). These indications are usually noted during specific and ancillary investigations such as cystoscopy, transrectal ultrasonography, urodynamics, or computed tomography/magnetic resonance imaging. Certainly, patients with urethral strictures benefit from surgical correction. Kaplan and associates (1994) have suggested that men with chronic nonbacterial prostatitis-like symptoms and urodynamic evidence of vesical neck obstruction benefit from endoscopic incision of the bladder neck.

Seminal vesicle abscesses can be managed with antibiotic therapy, transrectal aspiration, and, if necessary, an operation to remove the seminal vesicles. Traditionally seminal vesiculectomy was performed as a difficult open procedure, but recently laparoscopic excision of the seminal vesicles was reported to be the least morbid procedure (Nadler and Rubenstein, 2001).

Radical transurethral resection of the prostate (Barnes et al, 1982; Sant et al, 1984) has been advocated in patients who have either relapsing or refractory chronic bacterial prostatitis (category II) secondary to bacterial persistence within the prostate gland. Although prostatic calculi are not pathognomonic of prostatitis (Harada et al, 1980), it has been clearly shown that bacteria can persist in protective biofilms or aggregates within the interstices or on the surface of the calculus material (Meares, 1974; Nickel et al, 1994). Theoretically, removal of all the infected material, including potentially infected calculi, can be achieved (with appropriate intraoperative radiographs or ultrasound studies), but except for small anecdotal case series (Barnes et al, 1982; Sant et al, 1984) there is no substantial proof in the literature as to the efficacy of major prostate surgery in category II chronic prostatitis. Radical transurethral resection of the prostate has not been advocated for category III CP/CPPS, but open radical prostatectomy has been shown anecdotally to benefit a few patients with symptoms of nonbacterial prostatitis or prostatodynia or both (Davis and Weigel, 1990; Frazier et al, 1992). No definitive clinical series or long-term follow-up has ever been presented, and this type of surgery should not be encouraged or recommended at this time.

Treatment Summary

Acute bacterial prostatitis is relatively simple to treat; eradicate the bacteria with appropriate antibiotic therapy. The objective for chronic bacterial prostatitis is similar—eradication of bacteria, but long-term symptom amelioration sometimes eludes us. Our standard therapies for CP/CPPS, when used as monotherapy, offer only modest improvement in symptoms (Nickel et al, 2004a; Nickel, 2008b). Multimodal therapy employing multiple concurrent treatment strategies may offer the best results at this time (Shoskes et al, 2003; Shoskes and Katz, 2005). However, a number of well-controlled prospective studies did not demonstrate increased efficacy by combining α-adrenergic blockers and antibiotics (Alexander et al, 2004) or α-adrenergic blockers and anti-inflammatory agents (Batstone et al, 2005). The explanation for this difficulty in treating chronic prostatitis may be that the patients become peripherally and centrally sensitized and that treatment targeted to the initiators of the process may not work as well when the condition becomes chronic (Yang et al, 2003; Pontari and Ruggieri, 2004; Pontari, 2007). Table 11–4 is a list of the various standard medical therapies that are currently recommended. Further investigations should focus not only on the mechanisms inducing the symptoms, including the pain, but also on the mechanisms maintaining the pain.

Table 11–4 Suggested Medical Therapy for CP/CPPS

To evaluate and compare the many clinical trials assessing the various therapies advocated for CP/CPPS it is important to clearly define and classify the patient population (NIH classification system), determine results by employing a standardized outcome index (NIH-CPSI), prospectively compare a treated group to a similar group randomized to placebo, and fulfill the requirements of peer review for publication in a reputable journal (Nickel et al, 1999c; Propert et al, 2002). In the past several years the results of a significant number of such trials have been published (Nickel, 2004, 2008a; Schaeffer, 2006), allowing the reader to assess and compare the efficacy of antibiotics, α-adrenergic blockers, anti-inflammatory agents, phytotherapies, and hormonal agents in CP/CPPS (Table 11–5). A suggested treatment algorithm based on these assessments is presented in Figure 11–8.

Table 11–5 Clinical Trials Evaluating Therapy for CP/CPPS That Met the Evidence-Based Criteria Established by Nickel (see text)

Figure 11–8 A suggested therapeutic algorithm for the treatment of patients presenting with CP/CPPS. TUMT, transurethral microwave thermotherapy.