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Guidelines
Treatment of chronic bacterial prostatitis 1Urologic Clinic, Justus-Liebig-University Gießen, Gießen, Germany2Department of Urology, University of Washington, Seattle, United States of America This manuscript was published originally in: Naber KG Schaeffer AJ, Heyns CF, Matsumoto T, Shoskes DA, Bjerklund Johansen TE (eds): Urogenital Infections.
European Association of Urology - International Consultation on Urological Diseases, 1st edition 2010, Arnhem, The Netherlands, ISBN:978-90-79754-41-0. Abstract: Bacterial infection of the prostate can be demonstrated by the Meares & Stamey 4-glass or the pre and post prostate massage (PPM)2-glass test in only about 10% of men with symptoms of chronic prostatitis/chronic pelvic pain syndrome. Chronic bacterial prostatitis ismainly caused by Gram-negative uropathogens. The role of Gram-positives, such as staphylococci and enterococci, and atypicals, such aschlamydia, ureaplasmas, mycoplasmas, are still debateable. For treatment, fluoroquinolones are considered the drugs of choice because oftheir favourable pharmacokinetic properties and their antimicrobial spectrum, with the best evidence supporting ciprofloxacin and levofloxa-cin. The optimal treatment duration is 28 days. Relapse and reinfection due to antimicrobial resistant pathogens are major problems in chro-nic bacterial prostatitis. The increasing resistance of E. coli against fluoroquinolones in many countries is of great concern in that respect. Inpatients with pathogens resistant to fluoroquinolones, but susceptible to trimethoprim-sulfamethoxazole, a three month course of treatmentwith trimethoprim-sulfamethoxazole can be administered. In patients with pathogens resistant to fluoroquinolones and trimethoprim-sulfame-thoxazole, currently no recommendation can be given. Clinical trials with other antibiotics are urgently needed in this patient population.
Key words: Chronic bacterial prostatitis; Refractory chronic bacterial prostatitis; Antibiotic treatment; Antimicrobial resistance; Chronic pel-vic pain syndrome.
Summary of recommendations: 1. The fluoroquinolone drug class is the first choice systemic treatment for chronic bacterial prostatitis, withthe best evidence supporting use of ciprofloxacin and levofloxacin (GoR A). 2. Other drugs with evidence of efficacy include: gatifloxacin(discontinued in the US), lomefloxacin, moxifloxacin (no clinical data), prulifloxacin (not available in the US), and trimethoprim-sulfametho-xazole (GoR B). 3. The optimal duration of therapy is at least 28 days, with some studies supporting treatment for up to eight weeks (GoRB). 4. The optimal length of clinical follow-up is at least six months (GoR A). 5. The main unresolved issue is the increasing rate of antimi-crobial resistance and lack of promising oral alternatives to the fluoroquinolones. In patients with pathogens resistant to fluoroquinolones andtrimethoprim-sulfamethoxazole, currently no recommendation can be given. Clinical trials with other antibiotics are urgently needed in thispatient population (GoR A). 6. In refractory chronic bacterial prostatitis repeated treatment or antimicrobial prophylaxis is recommendedusing antimicrobials to which the pathogen is susceptible. More studies of this important issue are however warranted (GoR C).
7. Interventions are only recommended in patients with chronic bacterial prostatitis who have proven bladder outflow obstruction (GoR C).
8. There are insufficient data on alternative and complementary medicine approaches for patients with chronic bacterial prostatitis (GoR D).
Acute bacterial prostatitis (NIH category I) is defined as Approximately 10% of men with symptoms of chronic an acute bacterial infection of the prostate, associated with prostatitis/chronic pelvic pain syndrome have bacteriuria severe prostatitis symptoms, signs and symptoms of sys- with pathogens that can be proven to originate from infec- temic infection and acute bacterial urinary tract infection.3 tion of the prostate using the Meares and Stamey four-glass Chronic bacterial prostatitis (NIH category II) is de- or the pre- and post-prostate massage two-glass test. These fined as a chronic (3 months) bacterial infection of the patients meet the criteria for chronic bacterial prostatitis prostate, proven by adequate microbiological tests, with (NIH category II) and represent the focus of this consulta- documented bacteriuria caused by the same bacterial tion. Most cases of chronic bacterial prostatitis are caused strain. Only about 10% of men with chronic prostatitis by Gram-negative uropathogens. The role of Gram-positive symptoms have chronic bacterial infection of the and atypical bacteria is still debateable. The purpose of this prostate that can be demonstrated by the four-glass test.4 guideline is to evaluate the evidence supporting current Other categories of prostatitis are not associated with treatment options for patients with chronic bacterial prosta- prostatic infection proven by standard microbiological titis, including treatment-refractory cases.
methods in patients with chronic symptoms, termedchronic prostatitis/chronic pelvic pain syndrome (NIH category III), or in patients who have no symptoms buthave proven prostatic inflammation, termed asympto- Prostatitis syndrome is one of the most common prob- matic prostatitis (NIH category IV).
lems encountered in urologic practice. Classification ofthe prostatitis syndrome is based on the clinical presenta- tion of the patient, the presence or absence of whiteblood cells in the expressed prostatic secretions (EPS), The incidence of bacterial prostatitis may be higher and the presence or absence of bacteria in the EPS.1 than previously reported.5 A recent study evaluated new Prostatitis is described as chronic when symptoms are physician-diagnosed prostatitis cases in a managed care population over a two-year interval.6 The incidence ofacute or chronic bacterial prostatitis was 1.26 cases per The internationally-accepted classification of the pro- statitis syndrome follows the National Institute of Dia - betes and Digestive and Kidney Diseases (NIDDK)/National Institutes of Health (NIH) recommendations We defined one major question, “What is the optimal an- (Table 2).2 There are four categories of prostatitis.
timicrobial therapy for patients with chronic bacterial pro- Pelviperineology 2011; 30: 17-26 http://www.pelviperineology.org Florian ME Wagenlehner, John N Krieger statitis?” This question was then divided into four issues: and one cost-effectiveness study.40 These studies included a 1. What is the first choice antimicrobial drug category and total of 652 participants with chronic prostatitis (Table 1).
which drugs have the best evidence for clinical efficacy? The committee identified 25 Level 4 studies including: 11 2. What is the optimal duration of therapy? articles based on expert opinion,41-51 one cost-effectiveness 3. What is the desired length of follow-up? study,52 and 14 in vitro, laboratory, or animal model stud- 4. What is the major outstanding issue for treatment? ies.53-66 These studies included no participants with chronicbacterial prostatitis (Table 1). Although the Delphi processcan be used to give ‘expert opinion’ greater authority, we identified no article that used this approach.
We searched the major databases covering the last 10 years (e.g., Medline, Embase, Cochrane Library, Biosis,Science Citation Index) using the search term bacterial pro- statitis in binary combinations with the terms: chronic, EVALUATION OF PATIENTS WITH CHRONIC BACTE- treatment, outcome, complications, antibiotic and antimi- crobial. Similar searches were also conducted using thesearch term chronic bacterial prostatitis in binary combina- Chronic bacterial prostatitis is characteristically associat- tions with the terms: trimethoprim, refractory, antibiotic re- ed with recurrent urinary tract infections caused by the same sistance, surgery, TURP and prostatectomy. To identify pa- bacterial strain. Chronic bacterial prostatitis represents the pers not yet indexed in the major databases, we reviewed the most frequent cause of recurrent urinary tract infections in tables of contents of the major journals of urology and oth- young and middle aged men. Chronic bacterial prostatitis er relevant journals, for the last three months. Papers pub- can be a devastating disease, characterized by relapsing lished in non-reviewed supplements were not included.
febrile episodes, if not treated adequately from the begin- There is also a microbiological rationale supporting restric- ning. Potential complications include: urosepsis, prostatic tion of the literature search to the last 10 years, because in most areas a minimal inhibitory concentration (MIC) shift Accurate diagnosis of chronic bacterial prostatitis (NIH has taken place in the pathogens causing chronic bacterial category II) depends on quantitative segmental bacteriolog- ical localization cultures and EPS microscopy. The classical The studies were rated according to the level of evidence four-glass procedure, first described by Meares and Stamey, and the strength of recommendations. The Oxford Centre remains the gold standard.67 Nickel et al validated a simpler for Evidence Based Medicine have produced a widely ac- test to assess inflammation/infection as a screening test in cepted adaptation of the work of the Agency for Health Care primary care patient populations. The two-glass test is a Policy and Research (AHCPR).7 The ICUD consultations reasonable alternative when EPS cannot be obtained or use a modified version of the Oxford system which can be when microbiological assistance is not available, because directly “mapped” onto the Oxford system.8 EPS should be examined expeditously. Interpretation of lo-calization test results can follow various definitions that have been evaluated, but the NIH definition is the most ac-cepted. These searches identified a total of 1,656 articles, includ- ing 1,014 articles published from 1999-2008. Review of the titles and abstracts of the 1,014 identified articles, identifieda total of 72 articles that met the criteria for detailed analy- A bacterial strain is considered a pathogen if the colony sis and rating. These 72 articles were reviewed in detail for forming unit (CFU) concentration in EPS or post-prostate how well each study was designed and carried out using a massage voided urine is at least 10 times higher than in mid- standard checklist adopted from the CONSORT statement stream or first-void urine. The bacterial spectrum of chronic (available at http: //www.consort-statement.org).
bacterial prostatitis has been carefully investigated in pa-tients from tertiary care institutions.4, 68 Similar to the expe-rience with acute prostatitis, these series report that faculta- tive Gram-negative bacilli (especially E. coli) were respon- Of the 72 articles reviewed in detail, in total 57 papers sible for the great majority of cases. Recent reports from met the criteria for rating (Table 1). According to the hierar- clinical series of patients have reported a preponderance of chy of study types these papers included: no systematic re- Gram-positive cocci.10, 39 In these latter series, the median views or meta-analyses, three randomized clinical trials, duration of patients’ symptoms was 3.5 weeks. One recent three non-randomized cohort studies, two case-control stud- report however describes that cultures suggesting localiza- ies, six case series, 27 articles incorporating expert opinion, tion of Gram-positive bacteria are not consistent in more two cost-effectiveness studies, and 14 in vitro, laboratory or than 90% of patients.69 Nevertheless, most reports suggest that the bacterial spectrum resembles that of complicatedurinary tract infections, with a preponderance of enterobac- teria. P. aeruginosa and Enterococci are found less fre- quently, but are more difficult to treat.
Three Level 1 studies (LoE 1b) were identified: three ran- domized clinical trials.9-11 These studies included a total of 3.2. Other issues related to clinical assessment The committee identified four Level 2 studies (two stud- ies with LoE 2a, two studies with LoE 2b): two non-ran- A comprehensive study of 40 men with E. coli chronic domized cohort studies12-13 and two case series.14-16 These bacterial prostatitis evaluated the role of semen analysis and studies included a total o 359 participants (Table 1).
cultures. Bacteriospermia (>103 CFU/ml) was documented The committee identified 25 level three studies including: in 21 (53%) of the 40 men prior to treatment.14 Therefore, one non-randomized cohort study,17 two case-control stud- semen culture is not sufficient to diagnose chronic bacterial ies,18-19 four case series,20-23 16 expert opinion reviews24-39 Treatment of chronic bacterial prostatitis TABLE 1. – Evidence Table: Studies of Chronic Bacterial Prostatitis Treatment that Include Original Data, Systematic Reviews or Meta-analy-sis, Expert Opinion, or Other Data (1999-2008).
Study Type
Lead author,
Subjects
Design Aspects
Critical Findings
Rating of
year, reference
Evidence
lomefloxacin group and 84, 81, 82,and 72% in the ciprofloxacin group. mg or levofloxacin 500 mg 71.11% for levofloxacin (p=0.86) once daily.
4%) after 6 months and 13/22(59.1%) after 9 months.
gatifloxacin twice daily for 4 weeks after treatment4-8 weeks mg once daily (p.o.) for 28 the continued eradication rate wasdays. Patients were cases) or intramuscularinjection (20 cases).
500 mg bid with 12-24months follow-up.
improvement,” similar to responsein patients with category III.
diminished, irrespective of whetherpositive cultures remained.
Antibiotic cocktails (based 68% of patients were “cured of chronic betamethasone by prostateprostatitis Florian ME Wagenlehner, John N Krieger Study Type
Lead author,
Subjects
Design Aspects
Critical Findings
Rating of
year, reference
Evidence
completed a second combinationtherapy cycle: 27 patients (75%)showed eradication. Thecumulative eradication rate was83.9%.
category of its own is proposedrather than using the generalcategory of complicated UTI.
Trimethoprim-sulfamethoxazole or, 4, Positivepreferably, a fluoroquinolone for 6to 12 weeks.
least 3 to 4 weeks, although somemen require treatment for severalmonths.
be effective. Newer quinolonesmay be more effective againstgram-positive pathogens andanaerobes.
for 2 to 4 weeks will cure about70%.
500mg daily achieved similar clinical and bacteriologicalresponse rates to oral ciprofloxacin500mg twice daily.
sufficient for treatment of suscepti-ble pathogens.
Of agents, beta-lactam drugs pene- 3. Positive netration into prostatic fluid andtissue has been demonstrated withmany antimicrobial agents, inclu-ding tobramycin, netilmicin, tetra-cyclines, macrolides, quinolones,sulfonamides and nitrofurantoin.
Pharmacokinetic studies of antimi-crobials use heterogenous metho-dology. Antibiotic concentrationsin prostatic fluid suitable for treat-ment of infections are only foundwith fluoroquinolones, macrolides,lincosamides and trimethoprim.
Treatment of chronic bacterial prostatitis Study Type
Lead author,
Subjects
Design Aspects
Critical Findings
Rating of
year, reference
Evidence
traprostatic injections) in the treat-ment of chronic prostatitis are nota standard of care.
especially levofloxacin andgatifloxacin.
fluoroquinolones possess both theappropriate bactericidal activityand the ability to diffuse into theprostate. Levofloxacin showsparticularly good penetration.
necessary. Most fluoroquinoloneswith this indication should besufficient for susceptiblepathogens.
The fluoroquinolones (2-4 weeks)are the first choice, in particular le-vofloxacin is as effective as cipro-floxacin but shows a better prosta-tic penetration and is given oncedaily. Kurzer, 200240 hypotheti- Model comparing 90 days In vitro, laboratory, oranimal model studies of prostate repeated administration ofpenetra- 2006, 200830-31 volunteers moxifloxacin in plasma, 1-positive uropathogenic E. colicaused more inflammation-mediated and histological damagethan isogenic CNF1-negativemutants despite similar bacterialcounts.
ve disease than susceptible E. coli.
Florian ME Wagenlehner, John N Krieger Study Type
Lead author,
Subjects
Design Aspects
Critical Findings
Rating of
year, reference
Evidence
Good penetration into prostatic and 4, Positive tions in serum and prostate prostatic capsule and > 1.6 intissue after 400 mg oral could be an efficacious therapeuticoption for treatment of chronicprostatitis 11 of 23 patients, developed quino- 4, Positive displaced by quinolone-susceptibleE. coli. and ciprofloxacin had synergisticeffect. chanisms in an E. coli clinical iso- tly than those causing other urinarytract infections and had a higherfrequency of hemolysin (p = 0.03and 0.0002, respectively). synergistic effect withciprofloxacin in prostatitis treat-ment.
diagnosing chronic bacterial prostatitis or in predicting re- The role of transrectal prostate ultrasound and urodynam- ic investigations was evaluated in a prospective study of 164men. This study found that these investigations had no role 3.2.3. National Institutes of Health Chronic Prostatitis in discriminating chronic bacterial prostatitis from chronic prostatitis/ chronic pelvic pain syndrome.70 The NIH-CPSI provides a standardized assessment of In one study magnetic resonance imaging of four acute prostatitis symptoms.73 The NIH-CPSI was designed as a bacterial prostatitis and five chronic bacterial prostatitis cas- tool for monitoring response in clinical trials of chronic pro- es were compared to prostate cancer, benign prostatic hyper- statitis/chronic pelvic pain syndrome rather than as a diag- plasia and chronic prostatitis/chronic pelvic pain cases.71 nostic tool. Only limited data are available to validate use of Bacterial prostatitis showed some features similar to carci- this instrument in assessing the clinical response to therapy noma suggesting that magnetic resonance imaging may pro- in patients with chronic bacterial prostatitis.
In another study 19 patients with chronic bacterial prosta- titis were compared to controls and patients with chronic pelvic pain syndrome.72 Hot uptake was found in 68% ofchronic bacterial prostatitis patients and 70% of patients with chronic pelvic pain syndrome. Therefore, the data sug- Appropriate antimicrobial therapy represents the corner- gest that imaging procedures are of limited or no benefit in stone of successful treatment for patients with bacterial pro- Treatment of chronic bacterial prostatitis statitis. For effective antimicrobial therapy the pathogens at comparative study. A cost effectiveness study comparing the site of infection must be exposed to a drug concentration different antibiotics and duration concluded that cipro floxa - sufficient to inhibit bacterial growth or even eradicate the cin 500 mg twice daily for 28 days was the most cost-effec- pathogens from that site. Although it remains unproven in tive treatment.40 Based upon these results in chronic bacteri- humans, evidence suggests that bacteria in prostatic tissue al prostatitis, an oral fluoroquinolone should be given for at may survive in a milieu protected by biofilms.62, 74 Although least four weeks after the initial diagnosis (LoE 2, GoR B).
the efficacy of antimicrobial therapy is markedly less Follow up in most clinical studies was at least 6 months,9- against biofilm-associated bacteria, fluoroquinolones and 14, 19-20 which therefore should also be performed in clinical macrolides are more active in biofilm than other antimicro- bials, e.g. beta-lactams or aminoglycosides.75 A rather extensive review on pharmacokinetic studies of antimicrobial agents and their penetration into the prostate One study investigated amikacin 400 mg daily adminis- has been performed by Charalabopoulos et al.24 If only stud- tered for 10 days via submucosal anal or intramuscular in- ies with a suitable methodology are used, e.g. assessment of jection.18 This study reported inferior results. Non-systemic antibiotic concentrations in prostatic fluid, than antibiotic application of antibiotics is therefore not recommended concentrations in prostatic fluid sufficiently high to treat chronic infections in the prostate are only found with fluoro- No published study from the last 10 years evaluated inter- quinolones, macrolides, lincosamides and trimethoprim.
ventions in chronic bacterial prostatitis. Expert opinions only Encompassing pharmacokinetic and pharmacodynamic as- recommend interventions in patients with chronic bacterial pects, the fluoroquinolones are considered the drugs of prostatitis who have proven bladder outflow obstruction al- choice for antimicrobial treatment of chronic bacterial pro- though this has not been validated in studies (LoE 4, GoR C).
statitis. All clinical studies within the last 10 years havebeen performed with fluoroquinolones. 4.4. Alternative and complementary medicine approaches Because clinical experience suggests that relapse and re- One animal study investigated catechin, a green tea ex- infection are common observed in patients with chronic bac- tract, in combination with ciprofloxacin in the treatment of terial prostatitis, only the results of clinical studies with a chronic bacterial prostatitis.58 The authors reported a statisti- follow-up of at least six months is recommended.76 Overall, cally significant decrease in bacterial growth and improve- it appears that 60-80% of patients with E. coli and other ments in prostatic inflammation compared with the Enterobacteriaceae can be cured with a four-week course of ciprofloxacin only group.58 Further studies are necessary to fluoroquinolone therapy (Table 1). However, clinical experi- ence suggests that prostatitis due to P. aeruginosa or entero- One retrospective clinical study evaluated results of a 6- cocci seem to cause more failures. Therefore fluoro- week course of combination therapy with ciprofloxacin, quinolones with a broad anti-bacterial spectrum, like lev- azithromycin, alfuzosin and a Serenoa repens extract in pa- ofloxacin, gatifloxacin, or moxifloxacin with improved ac- tients with chronic bacterial prostatitis.15 Microbiological tivity against Gram-positive pathogens might be a better op- eradication rates were between 75.5% and 82.3%, and clin- tion in case of enterococci, although comparative RCT data ical success rates between 78.8% and 85.7%, depending on suggest that these agents are equivalent to results of the pathogens isolated and were thus not higher than in ciprofloxacin treatment. Levofloxacin was investigated in those studies with antibiotics alone.10,13 Thus, there are in- two recent clinical studies. The study by Bundrick et al.10 sufficient data on alternative and complementary medicine was a randomized double-blind multicenter study compar- approaches for patients with chronic bacterial prostatitis ing levofloxacin 500mg once daily to ciprofloxacin 500mg (LoE 4, GoR D, no recommendation possible.) twice daily and found levofloxacin was equivalent tociprofloxacin. Microbiological eradication was however on- ly followed up to four weeks and patients were not requiredto have documented bacteriuria with the localizing bacterial There are limited data available on treatment outcomes “pathogens.” In this study, the microbiological eradication for patients who fail initial therapy for chronic bacterial pro- rate by patient at four weeks was 75% in the levofloxacin statitis. One study investigated 36 patients with relapsing group and 77% in the ciprofloxacin group. The specific chronic bacterial prostatitis. 16 Of these 36 patients, 27 eradication rate of E. faecalis was 72% with levofloxacin (75%) were cured by a second cycle of combination phar- and 76% with ciprofloxacin. The eradication rate of P. macological therapy with antibacterial agents (ciprofloxa - aeruginosa was not indicated in this study. The other recent cin/azithromycin), alpha-blockers (alfuzosin) and the phy- study by Naber et al.13 was a non-randomized patient cohort totherapeutic, Serenoa repens. No other study evaluated pa- study investigating levofloxacin 500mg once daily, patients tients with recurrent disease. More studies of this important were not required to have documented bacteriuria with the issue are therefore warranted, therefore currently no recom- localizing bacterial “pathogens.” The study also used differ- mendation can be given for refractory patients.
ent classification schemes for the diagnosis of chronic bac-terial prostatitis. The corresponding10 total eradication rate at four weeks was 79%, and at six months 92%. The specific eradicationrate of E. faecalis in the comparable classification scheme to Antimicrobial resistance to fluoroquinolones is increasing the Bundrick study10 was 56% (10/18) and of P. aeruginosa world-wide. The impact of fluoroquinolone resistance on the treatment of chronic bacterial prostatitis has not beenevaluated systematically. However, from a pharmacologicalviewpoint, treatment failure with increasing pathogen MICs 4.2. Duration of antibiotic treatment and clinical follow-up has been observed anecdotally in our patients with chronic We identified no clinical studies comparing different du- bacterial prostatitis, as we have seen with urinary tract infec- rations of antibiotic treatment. Almost all studies used a four tions and other urogenital infections, such as gonorrhea (for week treatment regimen.9-13,19 In one study treatment with which fluoroquinolones are no longer recommended in the gatifloxacin was four to eight weeks,17 but this was not a USA). In patients with pathogens susceptible to trimetho- Florian ME Wagenlehner, John N Krieger prim-sulfamethoxazole and resistant to fluoroquinolones, TABLE 2. – National Institutes of Health Prostatitis Syndrome expert opinion recommends a three-month course of treat- ment with trimethoprim-sulfamethoxazole LoE 4, GoR C).
In patients with pathogens resistant to fluoroquinolones andtrimethoprim-sulfamethoxazole, currently no recommenda- III Chronic Prostatitis/Chronic Pelvic Pain Syndrome Clinical trials with other antibiotics are therefore urgently needed in this patient population (LoE 4, GoR A).
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