Prostatitis
Authors: Deirdre L. Church MD, PhD FRCPC
Prostatitis is defined as painful inflammation of the prostate gland although this collective clinical term is used for several complex diseases that may or may not be associated with the presence of polymorphonuclear cells (PMNs) in the prostatic fluid secretions. This chapter focused on acute and chronic bacterial prostatitis with an emphasis on the microbiology, diagnosis and antimicrobial therapy of these challenging conditions in the face of increasing antibiotic resistance.
DEFINITION
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH held a workshop in 1995 to create a unified working definition and classification of prostatitis syndromes that is shown in Table 1 (12, 20). Prostatitis syndromes may be divided into four broad categories including: 1) Type I or acute bacterial prostatitis is an acute infection of the prostate. Although acute bacterial infection of the prostate is rare and diagnosed in less than 0.02% of all men the potential serious outcomes of this infection constitutes a medical emergency, 2) Type II of chronic bacterial prostatitis occurs in 2-10% of men with acute infection whose symptoms persist for a period of more than 3 months, 3) Type III is a condition called chronic pelvic pain syndrome (CPPS) which is the most common type of prostatitis found in 90% of men in the absence of detectable infection (31). Two subgroups are designated within CPPS, those men who have evidence of inflammation [i.e. PMNs are found in the semen, expressed prostatic secretion (EPS) or urine obtained after prostatic massage (voided bladder urine or VB-3)] and those that have non-inflammatory disease where no evidence of leukocytes are found in any of these samples, and 4) Type IV is asymptomatic inflammatory prostatitis where there are no clinical symptoms but PMNs are found in prostatic secretions at the time of surgery, biopsy or autopsy.
EPIDEMIOLOGY
Population-based estimates of the prevalence of prostatitis in the general male population in North America indicate that this condition affects 5% to 16% of men during their lifetime (10). Reports from international studies show comparable estimated prevalence rates of prostatitis in men in Europe and Asia. Despite the enormous burden prostatitis places on the healthcare system, it has been difficult to determine the precise epidemiology of the various prostatitis syndromes because of the differing definitions used to describe these conditions, and the heterogeneity of various diagnostic criteria including the lack of specificity of genitourinary tract inflammatory localization. Acute bacterial and chronic bacterial prostatitis only account for a small proportion of all cases. Acute bacterial prostatitis accounts for less than 0.02% of all patients diagnosed with prostatitis making this type of infection rare. In contrast, chronic bacterial prostatitis accounts for 5-10% of prostatitis cases due to infection. However, most men with prostatitis (~90%) have the CP/CPPS type that has not been shown to be due to infection (11, 14, 17).
Prostatitis is the most common urologic condition in men younger than 50 years of age. The age incidence rates for men with a diagnosis of acute prostatitis and prostatitis (not otherwise specified by type) or chronic prostatitis show a different pattern. For men with acute prostatitis, rates are highest between the 3rd and 5th decades from 3.2 to 3.6 per 1000 person-years, but increase in elderly men to 5.4 per 1000 person-years. In contrast, the incidence of chronic prostatitis remains low until after age 50 when the rates begin to steadily rise in elderly men. Data from the Chronic Prostatitis Cohort study determined that the cumulative incidence of acute prostatitis or prostatitis (not otherwise specified by type) increased from 0% at 18 years to 17% at 85 years while that of chronic prostatitis increased from 0% at 23 years to 9% at 85 years (41). This study also showed that race was not associated with the development of CP/CPPS. However, lower education level, lower income and unemployment were associated with more severe CP/CPPS symptoms.
Chronic prostatitis/CPPS is also associated with substantial costs and lower quality of life scores, which predicts healthcare resource consumption. Men in the United States with chronic prostatitis accounts for 2-5 million ambulatory physician visits per year including 8% of all appointments with a urologist and 1-2% of visits to primary care physicians (17). Prostatitis patients incur direct and indirect costs that average more than $4,000 per annum which is much greater that the costs associated with management of other common pain-related conditions.
PATHOGENESIS
Aside from acute bacterial prostatitis, the precise etiology and pathogenesis of the other types of prostatitis outlined in the NIH classification remain to be fully elucidated. Acute bacterial prostatitis is most likely caused by reflux of urine from the urethra into the intraprostatic ducts, which promotes ascending infection of the urinary tract and prostate. Animal models of bacterial prostatitis in the rat have demonstrated that the infection is mainly located along the base of the prostatic glands. Once infected, bacteria may chronically colonize the prostate gland in an asymptomatic manner after acute infection, but persist and cause recurrent episodes of chronic infection. Prostatic calculi may also play a role in inducing chronic infection, but obstruction of the intraprostatic ducts primarily promote and potentially maintains low grade glandular infection. Most acute and chronic prostatitis episodes are therefore due to the uropathogenic aerobic Gram-negative bacteria outlined in Table 2 (19, 25, 26). E. coli causes more than one-half of all cases of bacterial prostatitis since it is the most commonly isolated bacteria recovered from urine cultures. Certain Gram-positive bacteria that are part of the skin microbiota in the genital tract (i.e., coagulase-negative Staphylococciand Corynebacterium spp.) have also recently been implicated as pathogens in chronic bacterial prostatitis through detection of bacterial 16S RNA in prostatic secretions or tissue although localization of these organisms is often inconsistent and their unique role needs to be further delineated (4, 15, 16, 39,43). Atypical bacterial pathogens that may be sexually acquired and transmitted have also recently been recognized as having a critical role in bacterial prostatitis. Prostatitis may also occur due to ascending infection fromurethritis due to sexually acquired pathogen including Neisseria gonorrhoeae,Chlamydia trachomatis or Mycoplasma genitalium. Although U. parvum andM. hominis are part of the normal microbiota of the genital tract, these organisms may be opportunistic pathogens that cause urethritis and secondary prostatitis since they have been shown to infect the semen of infertile men (23,24, 44). Trichomonas vaginalis has also been isolated from the genitourinary tract of men diagnosed with prostatitis and this flagellate may be another overlooked cause of acute and chronic infection (13). Atypical sexually transmitted pathogens have all been isolated from the male genitourinary tract of men suffering from acute and chronic prostatitis but their role in causing infection needs to be further elucidated.
Once bacterial infection of the prostate is established, it is likely maintained due to the formation of a micro-organism biofilm. Biofilms are defined as tightly adherence colonies of bacteria that are enveloped in a gelatinous matrix that serves as a barrier to immune and antibacterial responses. Recent studies have demonstrated that E. coli strains associated with bacterial prostatitis have an increased ability to forma biofilm that strains associated with cystitis and pyelonephritis (5, 42). E. coli strains responsible for bacterial prostatitis also exhibit more virulence factors than other uropathogenic E. coli such as hemolysin and cytotoxic necrotizing factor (8). Bacterial biofilm formation may therefore promote the persistence of infection and lead to chronic bacterial infection and inflammation.
Although patients with underlying immunosuppression including those that are HIV seropositive or have AIDS may be susceptible to acquiring bacterial prostatitis due to the common bacterial uropathogens and atypical organisms found in healthy patients, this patient subgroup presents unique diagnostic challenges since unusual pathogens may cause infection due to bacteria, M. tuberculosis and M. avium-intracellulare (MAI), yeasts and fungi have been found (Table 2). Granulomatous prostatitis is also a rare complication of military tuberculosis in otherwise healthy men.
Risk factors for developing acute or chronic bacterial prostatitis are similar and include recent catheterization, cystoscopy or other instrumentation of the urinary tract as precipitating events. Urethral strictures caused by prior gonococcal urethritis may also increase the risk of prostatic infection. Immunocompromised patients including those with diabetes and human immunodeficiency virus infection are at increased risk. Spinal cord injury or the presence of a neurological disorder that impairs the detrusor or pelvic floor musculature may also be at higher risk. Clinical studies have not shown a role for other factors such as urogenital trauma, dehydration or sexual abstinence.
CLINICAL MANIFESTATIONS
Prostatitis due to bacterial infection is often associated with lower urinary tract symptoms such as dysuria, and urinary frequency. However, unlike urinary tract infection alone, men with prostatitis typically have suprapubic, rectal, testicular, scrotal and penile pain, and sexual dysfunction or discomfort, including erectile dysfunction, painful ejaculation and postcoital pelvic discomfort.
Acute bacterial prostatitis is uncommon but must be urgently diagnosed because it is a medically emergent illness that can be life-threatening due to the development of bacteremia and secondary septic shock. This condition typically presents as an acute urinary tract infection with fever (60%), chills and rigors, dysuria, urinary frequency and retention (80%), and perineal discomfort or pain (38%). Digital rectal examination should be performed in all men with symptoms of prostatitis, but prostatic massage should not be done during acute prostatic infection. The prostate gland is tender and enlarged during an episode of acute infection. Patients with acute bacterial prostatitis may present with bacteremia and septic shock (i.e. hypotension, coagulopathy and end organ dysfunction). Urinary outflow obstruction must be urgently identified and rectified by placement of a suprapubic catheter. Prostatic abscess may also be present or develop during the course of the infection. Immunocompromised patients including diabetics and those with underlying complicated urinary tract infections (i.e. spinal cord injured patients) that require permanent indwelling catheterization are more likely to present with this serious secondary infection. Patients with severe pain or fluctuance on digital prostate exam should have an urgent transrectal ultrasound or computerized tomography scan of the prostate gland.
Chronic bacterial prostatitis is a relapsing subacute illness that presents with persistent symptoms that mimic a urinary tract infection but wax and wane. Table 3 outlines the common symptoms in patients with chronic prostatitis syndromes. Patients usually have dysuria and urinary frequency and urgency along with lower back pain, perineal or scrotal pain, and painful ejaculation that have been present for more than 3 months. Men with chronic bacterial prostatitis do not present with systemic symptoms of infection (fever, chills and rigors). The physician exam including the digital rectal exam of the prostate do not reveal any abnormalities. Inflammation in the prostatic fluid occurs episodically and recurs in a course that waxes and wanes along with the patient’s symptoms. Chronic pain and sexually dysfunction occur as complications of chronic prostatic infection and inflammation.
DIFFERENTIAL DIAGNOSIS
Acute and chronic bacterial prostatitis must be primarily differentiated from both lower (cystitis) and upper (pyelonephritis) urinary tract infections since all of these infections present with lower urinary tract symptoms. Table 4 outlines the most common clinical manifestations that should be used to differentiate these types of genitourinary infection. Since simple cystitis is a localized urinary infection of the bladder, men with this infection will not have systemic symptoms of infection including fever, chills and rigors. Although patients with pyelonephritis manifest systemic symptoms of infection, they typically also have costovertebral angle tenderness (flank pain), and a digital rectal exam will reveal a normal prostate gland. Men with urinary tract infection with and without bacterial prostatitis may also have findings of an acute epididymitis and/or orchitis.
Older men with CP/CPPS are more likely to be confused with having benign prostatic hypertrophy or prostate cancer since many of the symptoms and clinical signs of the former condition mimic these diseases.Table 5 outlined the most common clinical manifestations of CP/CPPS compared to BPH and prostate cancer that should be used to differentiate these inflammatory genitourinary diseases. BPH is extremely common in ageing men with an estimated 70% of men aged 60-71 years and 90% of those aged 80-90 years having pathological BPH. BPH is defined as prostate gland enlargement secondary to hyperproliferation of stromal and glandular cells, with predominance of mesenchymal cells (32). BPH presents with progressive lower urinary tract symptoms including voiding dysfunction (urinary frequency and retention). Progressive prostatic inflammation appears to be an important factor in the pathogenesis and progression of BPH. Intraprostatic inflammation in men with BPH who required a TURP has recently been shown to be a significant indicator of progressive disease compared to men with BPH who had lesser or absent inflammation. A prior episode of prostatitis is also more common in ageing men who develop BPH although both conditions may co-exist. Asymptomatic inflammatory prostatitis (Type IV) has been shown to be present in 43-98% of surgically resected prostate glands removed for BPH. Further research is needed to delineate an association between the earlier presence of different types of prostatitis, chronic glandular inflammation and the development of BPH in ageing men.
Prostate cancer must also be ruled out in men with chronic prostatitis and persistently elevated prostate specific antigen (PSA) levels (i.e., >4 ng/ml), particularly if the level remains in the median range of 11-16 ng/ml after specific antimicrobial treatment and resolution of symptoms.
DIAGNOSTIC TESTS
Table 6 outlines the recommended laboratory and radiological tests that should be performed to diagnose acute and chronic bacterial prostatitis and to rule out complications (29).
Laboratory Testing
Urinalysis
Urinalysis should be done on all patients suspected of having prostatitis to pyuria and bacturiuria as indicators of urinary tract infection. The ratios from combined specific urinary proteins have also recently been shown to assist in diagnosing renal and urological disorders. Full urinalysis consists of three procedures including test strip analysis, urinary flow cytometry, and determination of specific urinary proteins [albumin, total protein, a1-microglobulin (A1M), a 2-macroglobulin (A2M)]. A recent study of 407 men with renal or urological disorders demonstrated that presence of two specific urinary proteins (A2M and urinary albumin) was diagnostic of acute prostatitis (35).
Cultures
Acute bacterial prostatitis is readily diagnosed by submitting a mid-stream urine sample for culture and sensitivity testing (C&S). The mid-stream portion of the urine stream should be collected after retracting the foreskin and cleansing the head of the penis and voiding the sample into a sterile container. The urine specimen is then aseptically transferred in a sterile tube containing a preservative such as Boric acid or inoculated onto a Dipslide for transportation to the microbiology laboratory. EPS need not be cultured during acute infection episodes since the microorganisms can be recovered from an MSU culture and a prostatic massage should not be done. Blood cultures should also be done on all patients with acute bacterial prostatitis to detect bacteremia. A minimum of two sets should be ordered to ensure an adequate volume of blood is cultured to achieve an optimal sensitivity.
Localizaton Tests
The Meares-Stamey 4Glass segmented urine/EPS 4-sample (VB1-first-void urine, VB2-mid-stream urine, VB3 -EPS, and VB4 - post-prostate massage urine) culture test has historically been used to diagnose chronic bacterial prostatitis and differentiate it from nonbacterial prostatitis (Types III and IV) and Prostadynia (Table 7). The Meares-Stamey 4-Glass test is performed by sequentially collecting four separate segmented urine samples into separate sterile containers as follows: 1) VB1 (10-15 mls of first-void urine sample) is initially collected after retracting the foreskin and cleansing the head of the penis with a soapy solution, 2) VB2 (20-30 mls of the mid-stream portion of voided urine) is next collected, 3) VB3 (EPS fluid is collected after the physician performs prostatic massage), and 4) VB4 (5-10 mls of post-massage urine is collected). All segmented urine/EPS sample are analyzed for the presence of PMNs/macrophages and are cultured to recover bacteria. Prostatitis is considered to be present if there are PMNs/macrophages and bacteria are found in the EPS/VB4 while the VB2 (bladder) sample is sterile. However, many clinicians including urologists infrequently perform this procedure because it is difficult to perform, particularly collection of the EPS sample and the results are difficult to interpret. The segmented urine/EPS 3-sample test also lacks sensitivity and has been shown in more recent studies to have a lower sensitivity for diagnosis of chronic bacterial prostatitis than either a pre-massage and post-massage urine culture or a semen culture. One recent study compared collection of a pre- and post-massage urine culture to the Meares-Stamey 4-segmented urine/EPS culture technique and showed strong concordance for the diagnosis of chronic bacterial prostatitis (33). Another recent study of 895 patients presenting with clinical manifestations of CBP/CPPS studied the sensitivity of distinguishing chronic bacterial prostatitis from nonbacterial prostatitis using the Meares & Stamey segmented urine/EPS technique compared to a semen culture (1). A total of 182 vs. 283 men had positive cultures from Gram-negative and Gram-positive micro-organisms respectively. The diagnostic performance of semen compared to EPS cultures showed a much higher sensitivity of a semen culture for recovery of Gram-negative pathogens (97% compared to only 82.4% for EPS culture) and Gram-positive pathogens (100% compared to only 16.1% for EPS cultures). Overall, only 5 patients in this study were diagnosed with chronic bacterial prostatitis based on a positive culture of the EPS/VB3 urine fraction that had a negative semen culture. A mid-stream urine (VB2) culture and a semen sample are currently considered the only culture tests necessary to diagnose chronic bacterial prostatitis/CPPS. Clinical laboratories are not routinely performing molecular analysis on EPS/semen samples to detect uncultivatable pathogens (i.e., according to current routine urine culture methods) but the future application of universal bacterial 16S RNA and real-time polymerase chain reaction tests may be able to identify a microbial cause for CP/CPPS.
Diagnosing EPS Inflammation
Prostate secretions expressed (EPS) by digital manipulation should be tested for the presence of PMNs/macrophages is an indication of inflammation, which is considered a key diagnostic finding the NIH classification of prostatitis syndromes although the definitions of each type of inflammatory prostatitis do not include a standard threshold for the critical number of PMNs/macrophages to diagnose inflammation in EPS samples. Since distinguishing inflammatory from non-inflammatory prostate diseases depends on accurately identifying of a critical of significant number of PMNs/macrophages in EPS, the accuracy of diagnosis reflects the accuracy of this laboratory test. However, various prostatitis studies use different thresholds for PMN levels in EPS because the methods used to perform PMN/macrophage quantitation on EPS samples, and likewise, the threshold level for diagnosing a critical increase in EPS inflammation has not been standardized. Few studies have evaluated available methods for detecting expressed prostatic secretion inflammation, although many clinical laboratories continue to rely on the traditional coverglass wet mount slide method. One study evaluated different laboratory methods for determining the number of PMNs/macrophages in EPS secretion samples from 159 men with CP/CPPS (30). Several laboratory methods were compared including traditional wet mounts, hemocytometer derived concentrations and EPS smears stained with Gram’s or DiffQuick stain (Dade International Inc., Miami, FL). This study showed that hemocytometer concentration at 500 PMNs/macrophages per mm3 or greater detected inflammation in 59% of the EPS samples compared to only 33% by the traditional wet mount method (P<0.001). When inflammation was defined at 1,000 PMNs per mm3 or greater the hemocytometer still identified significantly more EPS specimens and patients with inflammation. PMNs and macrophages were the most commonly observed cells on stained smears, and the DiffQuick stain detected more specimens (59%) than the traditional Gram stain. Further evaluation and standardization of clinical laboratories methods for EPS inflammation detection need to be done. In the meantime, laboratories should adopt a hemocytometer concentration method using a DiffQuick stained smear and use a threshold of 500 PMNs/macrophages per mm3 as the cut-off for reporting critical numbers of inflammatory cells in a specimen.
STD Pathogens
Men at risk of acquiring an STD should have a first-void urine submitted for detection of both Neisseria gonorrhoeae and Chlamydia trachomatis using a nucleic acid amplification method. Molecular testing for genital Mycoplasmas (M. genitalium, M. hominis and U. ureaplasma) is currently not available but a urethral and/or first-void urine sample should be sent to a reference laboratory for genital Mycoplasma testing in men with non-gonococcal, non-chlamydial urethritis who also have symptoms of prostatitis and negative urine/semen/EPS cultures. Trichomonas vaginalis has historically been diagnosed by culture and wet mount examination of urethral, semen or EPS samples, but these methods suffer from low sensitivity due to loss of viability of this flagellate parasite with delayed transportation. Newer molecular methods for detection of T. vaginalis will provide a highly sensitive method for detection of this important parasite in urethral and urinary tract samples.
Unusual Pathogens
Urine, semen and/or EPS specimens may be cultured for yeast, fungi and acid-fast bacilli if specifically ordered by the physician. Although routine culture media used to detect bacteria will also allow growth of most yeasts (Candida spp. and Cryptococcus neoformans), fungi (systemic mycoses, Aspergillus spp.) and Mycobacterium spp. will not be recovered unless specialized media are inoculated. Anaerobic bacteria are also not routinely isolated from urinary tract specimens and required inoculation of special pre-reduced media and incubation under anaerobic environmental conditions. An anaerobic culture of urine, semen or EPS should only be requested in patients suspected of having a vesiculo-enteric fistula.
Markers of Inflammation
Prostate-specific antigen (PSA) is an important inflammatory marker for detecting and monitoring prostate cancer. However, the specificity of the prostate-specific antigen level is not high when the level is intermediate (i.e., between 4 and 10 ng/ml) because ~70% of men with persistently elevated tests will not have cancer detected on prostate biopsy. The association between chronic prostate inflammation due to prostatitis and elevated prostate-specific antigen levels has however been controversial. Serum prostate-specific antigen and percent free prostate-specific antigen values changes were recently studied before and after antibiotic treatment in a study of 65 asymptomatic men with persistently elevated intermediate prostate-specific antigen levels (9). Of the 51 men who had laboratory tests consistent with prostatitis before antibiotic therapy, 30% had a treatment response defined as a decrease in the prostate-specific antigen levels >20% of baseline. In addition, the rage of variations of prostate-specific antigen and percent free prostate-specific antigen values also decreased significantly. Subclinical prostatic inflammation may contribute to an elevated prostate-specific antigen level and its variation amongst men with prostate cancer. Prostate-specific antigen should therefore be measured in patients with chronic prostatitis/CPPS (TYPE II/III) even if they are asymptomatic (Type IV). If PSA remains elevated (>4 ng/ml) despite a course of antibiotic treatment then the patient should have a prostate biopsy to rule out the presence of prostate cancer.
Other inflammatory markers may be increased during acute or chronic bacterial prostatitis episodes but both an erythrocyte sedimentation rate (ESR) or C-reactive protein elevation are non-specific markers of inflammation. No studies have been done evaluating the use of these inflammatory markers for therapeutic monitoring of prostatic inflammation. These tests only have the potential to be useful in monitoring resolution of prostatic inflammation in patients with no other foci of ongoing inflammation.
Radiologic Imaging
Patients with difficulty voiding of incomplete voiding should have further studies to diagnose urinary obstruction. Evaluation of bladder emptying by flow rate analysis measured by ultrasonography may be used voiding efficiency. A voiding cystourethrogram may also reliably detect urodynamic changes including reflux. Urethrocystoscopy may detect inflammation in the posterior urethra during prostatitis. Transrectal ultrasound (TRUS) of the prostate should be used to detect prostatic calculi and the presence of a prostatic abscess. Sonographic changes of acute prostatitis are manifestations of tissue edema, venous engorgement and increased blood flow to the gland. Acute inflammation causes a generalized enlargement and change in shape of the gland from triangular or ovoid shape to a more rounded symmetrical shape. There is also a generalized decrease in parenchymal echogenicity due to edema and inflammatory infiltrate. Prostatic abscess has a variable sonographic appearance depending on the stage of the infection. Early on TRUS will only show multifocal hypoechoic areas in the peripheral and transition zones of the gland representing edema and inflammatory infiltrates which is non-diagnostic (47). Later on TRUS will demonstrate progression to the distinctive appearance of a 1.5 to 4.0 cm anechoic lesion, which may show septation or nonhomogeneous internal echoes from central debris (47). Longitudinal imaging may therefore be necessary to obtain the most accurate picture of the evolution of complex abscesses in the prostate including extracapsular extension and involvement of the seminal vesicles. Since TRUS may underestimate the extraglandular extent of an abscess, patients with sonography showing extension to the prostatic capsule, apex or base should have a CT scan to better delineate the extent of the infection, which dictates the approach to medical and surgical management.
TRUS imaging of patients with chronic bacterial or nonbacterial prostatitis/CPPS provide essentially the same images. The findings include hypoechoic peripheral changes, calcification, and periprostatic venous engorgement and seminal vesicle abnormalities (47).
EMPIRIC ANTIBIOTIC THERAPY
Acute or chronic bacterial prostatitis is by definition a complicated urinary tract infection due to the sequestered nature of the prostate gland due to the poor penetration of many drugs into this site. Selection of an appropriate antimicrobial agent that has optimal pharmacokinetics for prostatic tissue is important to prevent treatment failure. Antibacterial diffusion into prostate tissue depends upon the lipid solubility, molecular size and pKa of the agent. Prostatic fluid is typically somewhat alkaline with a pH of 7.4 during chronic bacterial prostatitis, so that antibiotics that are also basic won’t have adequate tissue levels. Fluoroquinolones have the best penetration into prostatic tissue of all currently available antibiotic classes of drugs. Since these drugs exist in their zwitterion form with a pKa in both acidic and alkaline environments, these drugs penetrate and achieve prostatic fluid levels that are similar to those in plasma with ratios ranging from 0.12 to 0.48 (22). The concentration of ciprofloxacin in alkaline seminal fluid has been shown to exceed that in plasma. Ciprofloxacin attains nearly 2-fold higher concentrations in the prostate than in the plasma, whereas levofloxacin attains levels in the prostate that are approximately 3-fold higher than in plasma.Levofloxacin is excreted unchanged in the urine in concentrations that far exceed the MIC of most uropathogens. Other antibiotic agents that penetrate well into prostatic and seminal fluids include macrolides, trimethoprim-sulfamethoxazole (TMP-SMX) and tetracyclines including tigecycline.
Selection of an effective empiric antibiotic treatment regimen for acute or chronic bacterial prostatitis is further complicated by the increasing antimicrobial resistance of uropathogens to conventional antibiotic regimens. Recent research demonstrates that in vitro resistance patterns predict the therapeutic efficacy of antimicrobials against urinary tract infections including bacterial prostatitis. Although several published treatment guidelines for urinary tract infection currently recommend that initial therapy may includeampicillin plus an aminoglycoside, TMP-SMX or a fluoroquinolone (27, 46), uropathogens are developing increased resistance to many of the commonly used agents through acquisition of an integron that confers broad-spectrum resistance to several classes of antimicrobials (6, 7, 37, 40). Physicians therefore need to know the local resistance patterns of specific uropathogens to aid in initially choosing the most effective regimen prior to urine, EPS and blood culture results being available.
Table 8 outlines the typical antibiotic susceptibility patterns found in the United States for common uropathogens causing complicated urinary tract infections. TMP-SMX resistance is approaching 25-30% and much higher rates have been reported from other parts of the world (2, 21). In addition, 40-60% of E. coli strains isolated from urine culture are resistant to commonly prescribed B-lactam drugs including ampicillin and the first generation cephalosporin drugs (cephalothin and cefazolin). In contrast, fluoroquinolone resistance in gram-negative uropathogens currently remains low (i.e., 5-10%).
Table 9 summarizes the current recommended approach of initial therapy for acute and chronic bacterial prostatitis. Because of the low resistance profile and superior penetration into prostatic fluid and tissue, a fluoroquinolone agent should be used as the initial drug of choice for acute or chronic bacterial prostatitis. However, it should be noted that fluoroquinolones have only modest in vitro activity against the most common gram-positive pathogens causing prostatitis, including enterococci and coagulase-negativeStaphylococci. Older fluoroquinolones such as ciprofloxacin have limited gram-positive activity, so that one of the newer drugs such as levofloxacin with better efficacy potential against all organisms should be initially used for men with acute on chronic episodes of infection. Patients with acute bacterial prostatitis should be admitted to the hospital and given parenteral antibiotics if comorbid illness (cardiac disease or diabetes), immunosuppression or urinary outflow obstruction are present. Parenteral antibiotic therapy should also be used when symptoms of bacteremia (i.e., fever, chills and rigors) and/or clinical signs of septic shock (i.e. hypotension, coagulopathy and end organ dysfunction) are present.
Patients with acute bacterial prostatitis should receive a long enough course of antibiotic therapy to treat urinary tract infection in a sequestered tissue site. Patients should receive a minimum 14 day course of antibiotic therapy and single dose and short course therapy should not be used because of the high rate of relapsing infection. Uncomplicated acute prostatitis may be treated with a minimum 14 day course of an appropriate oral antibiotic agent based on the resolution of symptoms and sterilization of the urine. However, oral antibiotic therapy may be extended for an additional 2-4 weeks if the patient remains symptomatic and/or infection is documented to be caused by a highly antibiotic organism (See Micro-organism Specific Antibiotic Therapy). Patients with severe complicated episodes of acute bacterial prostatitis (i.e., men with an underlying co-morbid illnesses, bacteremia and sepsis and/or documented prostatic abscess) should receive a prolonged therapeutic antibiotic course. Therapeutic parenteral doses of bactericidal antibiotics such as a broad-spectrum penicillin, a third-generation cephalosporin, a carbepenem or a fluoroquinolone may be used (Table 9) and should be continued until there has been resolution of fever, acute urinary tract symptoms and pain before changing to an appropriate oral agent to complete 4-6 weeks of therapy (3).
MICRO-ORGANISM-SPECIFIC ANTIBIOTIC THERAPY
Many studies have documented that failure to prescribe adequate bactericidal therapy for common infections is not only expensive, it has the potential to drive increasing antibiotic resistance. Prospective clinical trials of acute urinary tract infection including prostatitis episodes have consistently demonstrated that the in vitro antibiotic susceptibility of the specific micro-organisms isolated from the urine, semen and/or EPS correlate with in vivotreatment results. Among patient treated with TMP-SMX for acute urinary tract infection, clinical and bacteriological cure rates were significantly lower in patient with a TMP-SMX resistant E. colistrain than in those with TMP-SMX susceptible E. coli strains (p<0.0001) (45). Physicians also need to prescribe antibiotic therapy that will eradicate infection as the main treatment strategy to prevent the further development of resistance in commonly isolated uropathogens (2).
Although patients hospitalized with complicated urinary tract infections associated with neurogenic bladder, reflux, obstruction, azotemia, and those who have had a transplant are at increased risk of being colonized and infected with multi-drug resistant bacteria, increasing antibiotic resistance is also being acquired in ambulatory patients. Despite the worldwide use of B-lactam antibiotics, the distribution of the B-lactamase enzymes responsible for resistance to oxyamino-cephalosporins and carbapenems is highly geographically dependent (7). For example, 40% of K. pneumoniae isolates in some hospitals in the United States are ESBL-producers while other facilities have reported no problems. Extended-spectrum B-lactamase (ESBL)-producing E. coli has recently been shown to cause urinary tract infection in ambulatory patients and these strains may cause community-based outbreaks (18). In addition, travel to India and SE Asia has been associated with acquisition of an ESBL-producing enteric strain of E. coli (36). Similarly, reports of hospital outbreaks due to MBL-producing P. aeruginosa strains have so far been localized to particular geographic regions in North America, andK. pneumoniae KPC-producing strains are mainly recovered in hospitalized patients in the NE United States (34, 38). However, given the propensity of bacteria to rapidly transfer genetic information that confers resistance information it is expected that these types of resistant strains may spread to other healthcare jurisdictions. In addition, new types of antibiotic resistance including new as yet undetected B-lactamases will undoubtedly be found.
Table 10 provides an outline of the major types of broad-spectrum antibiotic resistance being encountered amongst common uropathogens with suggested treatment regimens. However, clinical trials have not been done to determine the most effective antibiotic regimens to treat many types of evolving antibiotic resistance, and for specific pathogens such as extended-spectrum B-lactamase (ESBL)-producing E. coli or Klebsiella spp., carbepenemase-producing K. pneumoniae (KPCs) or metallo-B-lactamase-producing P. aeruginosa there are currently extremely limited treatment options for these types of infections. Because there are no effective oral antibiotic choices for treatment of many of these types of broad -spectrum resistance, patients must be treated with parenteral bactericidal antibiotic therapy for the entire duration of treatment. Although initial parenteral antibiotic treatment may occur in the hospital, patients may be treated in the community if home parenteral antibiotic therapy can be arranged. Because prostatitis caused by uropathogens with broad-spectrum antibiotic resistance are more difficult to eradicate, patients may need to be given a prolonged course of therapy and complete 4-6 weeks of parenteral therapy if no effective oral antibiotic agents are available.
OTHER NON-ANTIBIOTIC MANAGEMENT
Alpha-blocker therapy has become an important adjunctive measure in the treatment of chronic nonbacterial prostatitis-like syndromes, particularly for the amelioration of chronic symptoms and improvement in quality of life. Recently published randomized placebo-controlled trials using Tamsulosin, Terazosin or Alfuzosin have confirmed that alpha-blockers results in clinically significant decrease of lower urinary tract symptoms and pain/discomfort and improvement in the quality of life in men with CP/CPPS and should be routinely prescribed for this condition (28). At present, similar clinical trials have not been done in men with bacterial prostatitis so that there is only anecdotal or uncontrolled evidence for the use of alpha-blockers for Type I or II prostatitis patients. Alpha-blockers may relieve the severe obstructive symptoms of acute bacterial prostatitis (Type I) and combined with antibiotics may also ameliorate chronic obstructive and pain symptoms and reduce the risk of recurrence when compared to antibiotics alone in patients with chronic bacterial prostatitis (Type II). One uncontrolled study of a small number of men with chronic bacterial prostatitis supports this contention, but confirmation of the clinical efficacy of alpha-blockers requires further study.
Pain during acute prostatitis may be managed most effectively using a NSAID such as naproxen in regular doses. Regular prostatic massage to drain residual foci of infection has also been used in patients with chronic bacterial prostatitis to decrease symptoms and try and reduce the potential for recurrence, but there is no evidence from clinical trials that this is effective.
ENDPOINTS FOR MONITORING THERAPY
Patients with acute or chronic bacterial prostatitis should be treated with the aim of permanently eradicating infection of the urinary tract so that the potential for persistent relapsing infection is minimized. Clinical and bacteriological outcomes should be routinely monitored while on a course of antibiotic therapy. Patients with acute bacterial prostatitis should be clinically assessed each day from the time of initiation of antibiotic therapy for resolution of fever, urinary tract symptoms and pain. Once the patient has become asymptomatic on therapy, clinical assessment may be done on a weekly basis throughout the treatment course. Bacteriological sterilization of the urinary tract should also be routinely monitored by repeating a urinalysis and urine culture within 48 hours of initiating antibiotic therapy and then weekly thereafter while on therapy. Blood cultures should also be repeated every 48 hours after initiating antibiotic therapy in patients with bacteremia and sepsis until bloodstream sterilization has occurred.
Relapsing infection with the same uropathogen may occur because of persistent prostatic colonization because of antibiotic treatment failure. Patient with infection due to a highly resistant uropathogen or one where available antibiotic agents may not penetrate prostatic fluid/tissue in adequate levels (P. aeruginosa, enterococci) are particularly susceptible to repeated infection episodes. In order to detect relapsing bacturiuria indicative of relapsing infection a urinalysis and urine culture should be routinely done within 2 and 4 weeks after stopping a course of antibiotic therapy. Recurrent infection episodes usually occur more than a month apart and may be due to an entirely different uropathogens than the prior one. Patients with complicated urinary tract infections associated with neurogenic bladder, reflux, obstruction, azotemia, and those who have had a transplant are predisposed to have recurrent problems with urinary tract infection including acute and chronic bacterial prostatitis episodes due to an inability to mechanical drainage problems and immunosuppression. Patients with permanent mechanical urinary tract problems typically have permanent colonization with multiple uropathogens (2 or more) and these organisms become highly antibiotic resistant to one or more classes of drugs because of repeated antibiotic exposure due to multiple antibiotic treatment courses for acute infection episodes. Patients with complicated urinary tract problems should be routinely monitored by repeating urine cultures at least once per quarter for changing bacturiuria including the types of uropathogens and their resistance profiles so effective antibiotic therapy can be immediately started when they become symptomatic.
COMPLICATIONS AND MANAGEMENT
Prostatic abscess formation occurs in l.5% to 2.5% of patients hospitalized for acute bacterial prostatitis. Predisposing conditions include diabetes mellitus, immunosuppression and chronic dialysis. Uncommonly, hematogenous spread of a distant focus of infection (i.e., endocarditis with bacteremia) via septic emboli to the prostate may cause an acute infection of the gland, particularly S. aureus (MSSA and MRSA). Abscess limited to the prostate may be drained be transurethral resection, whereas more extensive disease may require open surgical drainage. TRUS may also be used to follow the resolution of small prostatic abscesses where antibiotic therapy without drainage is used. Patients presenting with acute bacterial prostatitis symptoms who report having pneumaturia may have a vesiculo-enteric fistula and should also have a CT scan of the abdomen and pelvis. Adenocarcinoma of the bowel or prostate may present with this complication. 12) Prevention: Activities such as bicycling, jogging and horseback riding may irritate the prostate and should be avoided in men with a history of prostatitis. Appropriate safe sexual practices should be consistently used to avoid acquisition of an STD that may result in a genitourinary infection. Condoms should be used during sexual intercourse with partners of unknown risk for acquiring an STD. Sexual contact should be avoided or minimized with partners known to have an active STD.
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Tables
Table 1. NIH Classification of Prostatitis Syndromes According to Voided Urine (VB-3)/Expressed Prostatic Secretions (EPS) Results
NIH Type |
Prostatitis Syndromes |
VB-3 PMNs* |
VB-3 Culture** |
EPS PMNs* |
EPS Culture** |
|---|---|---|---|---|---|
I |
Acute bacterial prostatitis (ABP) |
+ |
+ |
+ |
+ |
II |
Chronic bacterial prostatitis (CBP) |
+ |
+/- |
+ |
+/- |
III (Subgroup 1) |
Chronic prostatitis/chronic pelvic pain syndrome with inflammation (CP/CPPS-1) |
_ |
_ |
+ |
_ |
III (Subgroup II) |
Chronic prostatitis/chronic pelvic pain syndrome without inflammation (CP/CPPS-2) |
_ |
_ |
_ |
_ |
IV |
Asymptomatic inflammatory prostatitis (AIP) |
+ |
+/- |
+ |
+/- |
* Presence of polymorphonuclear cells (PMNs) in voided urine collected post-prostatic massage (VB-3) and expressed prostatic secretions
** Presence of one or more bacteria recovered on culture of voided urine collected post-prostatic massage (VB-3) and expressed prostatic secretions
Table 2. Microbial Etiology of Acute and Chronic Bacterial Prostatitis
Patient Type |
Common Pathogens |
|---|---|
1) Healthy |
Aerobic Gram-negative bacteria:
|
|
Aerobic Gram-positive bacteria: · Staphylococcus aureus (MSSA) · Staphylococcus aureus (MRSA) · Coagulase-negative Staphylococcus (CoNS) |
|
STD Pathogens: |
2) Vesiculoureteral Prostatic Fistula |
Culture positive for aerobic enteric bacteria + anaerobes |
3) Immunocompromised (HIVseropositive/AIDS or other medical conditions)
|
Unusual bacteria:
|
|
Yeasts: Candida albicans and other Candida spp. |
|
Fungi: |
|
Viruses: · HIV |
Table 3. Common Symptoms in Patients with Chronic Prostatitis (Types II and III)
Non-specific lower urinary tract symptoms |
|
Prostatitis specific symptoms |
|
Sexual dysfunction |
|
General symptoms |
|
++ Patients with pneumaturia (air or gas passed during or after urination) should be investigated for a vesiculo-enteric fistula
Table 4. Common Clinical Manifestations of Acute and Chronic Prostatic Infections Compared to Urinary Tract Infection
Clinical Manifestation |
Acute Bacterial Prostatitis |
Chronic Bacterial Prostatitis |
Cystitis |
Pyelonephritis |
|---|---|---|---|---|
Dysuria |
+ |
+/- |
+ |
+
|
Urinary frequency |
+ |
+/- |
+ |
+
|
Urinary retention |
+ |
+/- |
_ |
_
|
Change in urine smell, color or consistency |
+ |
_ |
+ |
+ |
Suprapubic pain |
_ |
_ |
+ |
+/-
|
Perineal pain |
+ |
_ |
_ |
_
|
Flank pain |
_ |
_ |
_ |
+
|
Tender, enlarged prostate |
+ |
+/- |
_ |
_ |
Fever |
+ |
_ |
_ |
+
|
Chills, rigor |
+ |
_ |
_ |
+
|
Hypotension |
+ |
_ |
_ |
+
|
PMNs in EPS |
+ |
+ |
_ |
+
|
PSA >4 ug/ml |
+ |
+ |
_ |
_
|
Table 5. Clinical Manifestations of Chronic Bacterial Prostatitis(CBP) Compared to CBP/Chronic Pelvic Pain Syndrome (CPPS), Benign Prostatic Hypertrophy (BPH) and Prostate Cancer
Clinical Manifestation |
CBP |
CBP/CPPS |
BPH |
Prostate CA |
|---|---|---|---|---|
Dysuria |
+/- |
|
_
|
_ |
Urinary frequency |
+/- |
_
|
_ |
_ |
Urinary retention |
+/- |
+/- |
+ |
+/- |
Nocturia |
_
|
_ |
+ |
+ |
Change in urine smell, color or consistency |
_ |
_ |
_ |
_ |
Urine dribbling |
_
|
_ |
+ |
+/- |
Difficulty stopping urine stream |
_ |
_ |
+ |
+/- |
Hematuria |
_ |
_ |
_ |
+
|
Chronic pelvic pain (prostodynia) |
_ |
+ |
_ |
+/- |
Enlarged, smooth prostate |
+ |
+/- |
+ |
_
|
Enlarged, firm, irregular prostate |
+/- |
_ |
_ |
+ |
Prostate tenderness |
+/- |
+/- |
_
|
_ |
PMNs in EPS |
+ |
+ |
_
|
_ |
Malaise, involuntary weight loss |
_ |
_ |
_ |
+
|
PSA >10 ug/ml |
_ |
_ |
_ |
+
|
Table 6. Diagnostic Investigations for Differential Diagnosis of Prostatitis Syndromes
Investigations |
Acute Bacterial Prostatitis |
Chronic Bacterial Prostatitis |
CP/CPPS |
|---|---|---|---|
Urinalysis (Routine test strip/Flow cytometry) |
+ |
+ |
+ |
Determination of urinary specific proteins |
+ |
_ |
_ |
MSU Urine culture |
+ |
+ |
+ |
Voided Post-Prostatic Massage Urine Culture (VB3) |
_ |
+ |
+ |
EPS PMN Level (Inflammation) |
_ |
+ |
+ |
Blood Cultures |
+ |
_ |
_ |
TRUS |
+ |
+/- |
_ |
Pelvic/Prostate CT Scan |
+ |
+/- |
+ |
PSA* |
+/- |
+ |
+ |
Inflammatory markers (ESR, CRP)++ |
- |
+ |
- |
*Prostate cancer should be suspected if PSA remains persistently elevated (≥4 ug/ml) after resolution of prostatitis
++ both ESR and CRP are nonspecific markers of inflammation but may be useful in monitoring resolution of prostatitis infection provided no other underlying inflammatory co-morbid conditions co-exist in a given patient
Table 7. Laboratory Differentiation of Chronic Bacterial Prostatitis
Condition |
EPS Inflammation (PMNs/macrophages)++ |
Positive Post-massage urine/Semen Culture |
Positive MSU Culture |
Digital Rectal Prostate Examination |
|---|---|---|---|---|
Chronic Bacterial Prostatitis (Type II) |
≥500 cells per mm3 |
+ |
+/- |
Normal or enlarged, tender and may be nodular |
CP/CPPS (Nonbacterial) |
≥500 cells per mm3 |
- |
- |
Normal or enlarged but not tender |
Prostodynia |
None |
- |
- |
Normal |
++ Hemocytometer concentration method using a DiffQuick stained smear
Table 8. Percentage Susceptibility of Common Uropathogens Causing Prostatitis in the United States++
Pathogen |
Ampicillin |
TMP-SMX |
Ciprofloxacin |
Levofloxacin |
|---|---|---|---|---|
60 |
82 |
99 |
99 |
|
1 |
92 |
99 |
99 |
|
92 |
94 |
99 |
98 |
|
3 |
95 |
96 |
99 |
|
N/A |
N/A |
74 |
72 |
|
98 |
N/A |
67 |
83 |
|
29 |
93 |
99 |
100 |
|
16 |
97 |
90 |
95 |
++ Adapted from references (2) and (21)
Table 9. Recommended Empiric Antibiotic Therapy for Acute and Chronic Bacterial Prostatitis++
Diagnosis |
Typical Microbial Etiologies |
Primary Empiric Regimen |
Alternative Agents |
Other Considerations |
|---|---|---|---|---|
Acute Bacterial Prostatitis (≥35 yo) (Uncomplicated with no risk of STD pathogens) |
Enterobacteriaceae (coliforms) |
Ciprofloxacin 500 mg po BID or Levofloxacin 500-750 mg po OD |
Treat as acute complicated urinary tract infection x 14 d. Single dose therapy should not be used. Initial antibiotic therapy should be modified based on the results of midstream urine and/or semen cultures. If remains symptomatic after 14 d of therapy, treatment may need to be extended to complete 4 weeks. Do follow-up urine cultures 2 and 4 weeks after therapy finished. |
|
Acute Bacterial Prostatitis (≤ 35 yo) (Uncomplicated with risk of STD pathogen) |
Ceftriaxone 250 mg I.M orCefixime 400mgs po x 1 dose. + Doxycycline 100 mg po BID x 14 days orAzithromicin 500 mgs po OD x 14 days |
Fluoroquinolone no longer recommended for gonococcal infection |
Patients should have urine nucleic-acid amplification test for detection of N. gonorrhoeae and C. trachomatis |
|
Acute Bacterial Prostatitis (Complicated by bacteremia and/or suspected prostatic abscess) |
Enterobacteriaceae (coliforms), enterococci |
Ciprofloxacin 400 mg IV q12h or Levofloxacin 500 mg IV q24h |
Ceftriaxone 1-2 g IV q24h + Levofloxacin 500-750 mg po OD, or Ertapenem 1 g IV q24h or Piperacillin-tazobactam 3.375 gms IV q6h |
Patients should have midstream urine, semen and blood cultures as well as radiologic imaging (Ultrasound or CT scan of the prostate gland). Change IV to oral regimen based on isolate susceptibility testing once blood cultures are sterile or abscess drained. Treat for 4 weeks based on resolution of symptoms and sterilization of the urine and bloodstream infection. |
Table 10. Recommended Treatment Regimens for Acute and Chronic Bacterial Prostatitis by Specific Pathogen Resistance Profile
Specific Pathogen |
Resistance Profile |
Primary Therapy |
Alternative |
Treatment Course and Comments |
|---|---|---|---|---|
Enterobacteriaceae (E. coliand other coliforms) |
TMP-SMX (R), FQ (S) |
Ciprofloxacin 500 mg po BID or levofloxacin 500 mg po OD |
Macrolide or Doxycycline100 mg po BID |
14 days (Acute) 4-6 weeks (Chronic) |
Enterobacteriaceae (E. coliand other coliforms) |
TMP-SMX (R) + Nalidixic acid (R), FG (S/I) (First-step gyrase mutation) or FQ (R) |
Macrolide or Doxycycline 100 mg po BID |
Ceftriaxone 1-2 g IV q24h or Ertapenem 1 g IV q24h |
14 days (Acute) FQ should not be used for treatment of isolate with first-step gyrase mutation since resistance may develop on therapy. |
Enterobacteriaceae (E. coli/Klebsiella spp. and other coliforms)++ |
Multi-drug resistant [(TMP-SMX (R), FQ (R), extended-spectrum B-lactamase (ESBL) producer and/or AmpC B-lactamase producer] |
Ertapenem 1 g IV q24h |
Meropenem 1 g IV q8h orTigecycline 100 mg IV x 1 dose and then 50 mg IV q12h |
14 days (Acute) 4-6 weeks (Chronic) Serratia spp., indole-positive Proteus spp.,Citrobacter spp. andEnterobacter spp. have inducible chromosomalAmpC B-lactamases are inherently resistant to most B-lactam) |
What's New
Etienne M, et al. Should blood cultures be performed for patients with acute prostatitis? J Clin Microbiol. 2010 May;48(5):1935-8