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. NIH-category II chronic bacterial prostatitis (CBP) is mainly caused by Gram-negative uropathogens, whereas the role of certain Gram-positive and sexually-transmitted pathogens is still discussed. For treatment, fluoroquinolones are considered the drugs of choice because of their favorable pharmacokinetic properties and their broad antimicrobial spectrum, with the best evidence supporting ciprofloxacin and levofloxacin. The optimal duration of treatment and follow-up is at least 28 days and 6 months, respectively. Relapse and reinfection due to antimicrobial resistant pathogens are major problems in chronic bacterial prostatitis, and the increasing resistance of E. coli against fluoroquinolones in many countries is of great concern. In patients with pathogens resistant to fluoroquinolones, currently no evidence-based recommendation can be given, though antibacterial therapy may be attempted, based on the results of antibiograms. A three month course of treatment with trimethoprim-sulfamethoxazole may be be tentatively administered, though eradication rates with these agents are relatively low, and strong and modern evidence-based foundations for this recommendation are missing. Quality randomized trials are urgently needed to validate the usage of a number of non-fluoroquinolone antibacterial agents whose efficacy in chronic bacterial prostatitis has been reported in the frame of noncomparative single-cohort studies or case series.

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Summary of recommendations

1. The fluoroquinolone drug class is the first choice systemic treatment for chronic bacterial prostatitis, with the best evidence supporting the use of ciprofloxacin and levofloxacin (Grade of Recommendation [GoR] A).
2. Other fluoroquinolones with evidence of efficacy include lomefloxacin (GoR A), prulifloxacin (GoR A), gatifloxacin (discontinued in the US, GoR B), and moxifloxacin (only case reports available, GoR C).
3. The optimal duration of therapy is at least 28 days, with some studies supporting treatment for up to eight weeks (GoR B).
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 antimicrobial resistance and lack of oral alternatives to the fluoroquinolones. In patients with pathogens resistant to fluoroquinolones, no high-graded recommendation can be currently given. Quality clinical trials (double-blinded, randomized-controlled setting) with non-fluoroquinolone antibacterial agents are urgently needed in patient populations with fluoroquinolone-resistant CBP. In refractory or fluoroquinolone-resistant chronic bacterial prostatitis, repeated courses of treatment, or long-term antimicrobial treatment is recommended using antimicrobials to which the pathogen is susceptible, based on careful analysis of the antibiogram. As aminopenicillins derivatives and several cephalosporins do not distribute efficiently to the prostatic sites of infection, preference may be given to agents that were reported to be effective on CBP patients as the result of cohort studies, published case series, or small randomized trials (e.g., co-trimoxazole, tetracyclines, macrolides, fosfomycin, aminoglycosides) (GoR C).
6. Prostate surgery is only recommended in patients with chronic bacterial prostatitis who have proven bladder outflow obstruction, with prostatitis likely complicating a concomitant condition of benign hyperplasia (GoR C).
7. Therapy of prostatitis may include agents aimed at reducing pain and inflammation (paracetamol, NSAIDS, or neuropatic pain medications in selected cases) and at facilitating urinary flow in case of pronounced voiding symptoms (alpha-adrenergic blockers) (GoR C).
8. There are insufficient data on alternative and complementary medicine approaches for patients with chronic bacterial prostatitis (GoR D).
9. Non-systemic delivery of antibacterial drugs is not recommended (GoR D).

1 Introduction

Approximately 10% of men with symptoms of chronic prostatitis have bacteriuria with pathogens that can be proven to originate from infection of the prostate using the Meares and Stamey four-glass or the pre and post-prostate massage two-glass test. These patients meet the criteria for NIH category II chronic bacterial prostatitis (CBP) and represent the focus of this chapter. Most cases of chronic bacterial prostatitis are caused by Gram-negative uropathogens, mainly belonging to the Enterobacteriaceae family, though infection by Pseudomonas spp. is occasionally diagnosed. Gram-positive pathogens include Enterococcus as the most frequently detected genus. The role of certain Gram-positive or sexually-transmitted bacteria is still debated. The purpose of this guideline is to evaluate the evidence supporting current treatment options for patients with chronic bacterial prostatitis, including treatment-refractory cases.

1.1 Prostatitis syndromes

Prostatitis syndromes are among the most common conditions encountered in urologic practice. Classification of prostatitis syndromes is based on the clinical presentation of the patient, the presence or absence of pathogenic bacteria and/or white blood cells in expressed prostatic secretions (EPS) or post-massage urine [1]. Prostatitis is described as chronic when symptoms are present for at least three months. Symptoms mainly include (i) pain, localized at the perineum, scrotum, testes, penis, lower back, groin, pubic area, (ii) voiding symptoms, both irritative (frequency, urgency, etc.) and obstructive (hesitancy, intermittency, weak stream, incomplete emptying), and in some cases (iii) sexual dysfunction (erectile, ejaculatory, etc.).

1.2 Classification

The internationally-accepted classification of prostatitis syndromes follows the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/National Institutes of Health (NIH) recommendations (Table 1) [2], and recognizes four main categories of prostatitis.

Table 1: National Institutes of Health Prostatitis Syndrome Classification [2]

I	Acute Bacterial prostatitis
II	Chronic Bacterial Prostatitis
III	Chronic Prostatitis/Chronic Pelvic Pain Syndrome
	a)	Inflammatory
	b)	Non-Inflammatory
IV	Asymptomatic Inflammatory Prostatitis

Acute bacterial prostatitis (NIH category I) is defined as an acute bacterial infection of the prostate, associated with severe prostatitis symptoms, signs and symptoms of systemic infection like fever, chills and malaise, and acute bacterial urinary tract infection [3].

Chronic bacterial prostatitis (NIH category II) is defined as a chronic (>3 months) bacterial infection of the prostate demonstrated by adequate microbiological tests, with documented relapsing bacteriuria caused by the same bacterial strain. Only about 10% of men with chronic prostatitis symptoms have chronic bacterial infection of the prostate that can be demonstrated by the four-glass test [4].

Other categories of prostatitis include chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) (NIH category III), which is diagnosed in patients with chronic prostatitis symptoms, but is not associated with prostatic infection proven by standard microbiological methods.

Prostatitis diagnosed in the absence of symptoms the disease is termed asymptomatic inflammatory prostatitis (NIH category IV).

1.3 Epidemiology

The incidence of bacterial prostatitis may be higher than previously reported. A study performed in year 2005 evaluated new physician-diagnosed prostatitis cases in a managed care population over a two-year interval [5]. The incidence of acute or chronic bacterial prostatitis was 1.26 cases per 1,000 men per year.

2 Methods

We defined one major research question: “What is the optimal treatment for patients with chronic bacterial prostatitis?” This main question was then divided into five issues:

1. What is the first-choice antimicrobial drug category and which drugs have the best evidence for clinical efficacy?
2. Which agents can be administered to treat pain and voiding symptoms in patients with CBP?
3. What is the optimal duration of therapy?
4. What is the desired length of follow-up?
5. What is the major outstanding issue for treatment?

2.1 Review of the literature

We searched the major databases covering the years 1999–2016 (e.g., PubMed/Medline, Embase, Cochrane Library, Biosis, Science Citation Index) using the search term bacterial prostatitis in binary combinations with the terms: chronic, treatment, outcome, complications, antibiotic, antibacterial, antimicrobial. Similar searches were also conducted using the search term bacterial prostatitis in binary combinations with the terms: trimethoprim, refractory, antibiotic resistance, surgery, TURP, prostatectomy. To identify papers not yet indexed in the major databases, we reviewed the tables of contents of the most recent issues of the major journals of urology, andrology, or other relevant journals. Papers published in non-peer-reviewed journal supplements were not included. The microbiological rationale supporting restriction of the literature search to the years 1999–2016, is based on the fact that in most countries a minimal inhibitory concentration (MIC) shift has taken place in the late ‘90s in the pathogens causing chronic bacterial prostatitis. Single case reports were excluded, while case series were included in the review process.

The studies were rated according to the levels of evidence (LoE) and the grades of recommendation (GoR) defined by the International Consultation on Urological Diseases (ICUD) standards [6].

2.1.1 Results

These searches identified a total of 2,067 articles, including 1,425 articles published from 1999–2016. Review of the titles and abstracts of the 1,425 identified articles, identified a total of 111 articles that met the criteria for detailed analysis and rating. These 111 articles were reviewed in detail for design, quality and conduct of the study, using a standard checklist adopted from the CONSORT statement (available at www.consort-statement.org).

2.2 Rating of the literature

Of the 111 articles reviewed in detail, in total 82 papers met the criteria for rating (Table 2).

Table 2: Results of literature database search, main characteristics of included articles and studies and consensual rating of evidence

Study type	First author, year, reference	Number of evaluated subjects or involved specimens	Design aspects	Critical findings	Rating of evidence
Systematic reviews and meta-analyses
	Perletti, 2013 [7]	2,196 randomized patients (18 studies)	ciprofloxacin, levofloxacin, lome- floxacin, ofloxacin and prulifloxacin were compared.	Four out of five studies comparing two different fluoroquinolones indicate equivalence between levofloxacin and ciprofloxacin, prulifloxacin and levofloxacin, lomefloxacin and ofloxacin, and lomefloxacin and ciprofloxacin. Equivalence was shown both at the microbiological and clinical levels. The rates of adverse effects of therapy also appeared to be equivalent in the compared treatment arms. Meta-analysis of lomefloxacin versus comparator fluoroquinolones confirmed such equivalence.	Level 1a
				In contrast to the Bundrick trial [9], the study by Zhang [14] indicated increased microbiological and clinical cure in the levofloxacin arm, compared to ciprofloxacin. When pooled studies were analyzed by a random-effects model, the difference between levofloxacin and ciprofloxacin was not significant (microbiological efficacy: risk-ratio 1.18, 95% CI 0.81 to 1.71; clinical efficacy at the end of therapy: risk-ratio 1.16, 95% CI 0.93 to 1.46).
Randomized clinical trials
	Naber, 2002 [8]	182	Multicenter, comparing lomefloxacin 400 mg once daily vs. ciprofloxacin 500 mg twice daily for 4 weeks.	At 5–9 days, 4–6 weeks, 3 and 6 months after therapy eradication rates were 80, 72, 74, and 63% in the lomefloxacin group and 84, 81, 82, and 72% in the ciprofloxacin group.	Level 1b
	Bundrick, 2003 [9]	377	Multi-center, comparing oral levofloxacin 500 mg once daily vs. oral ciprofloxacin 500 mg twice daily for 28 days.	Microbiologic eradication rates were 75% for levofloxacin and 76.8% for ciprofloxacin; 6-month relapse rates were similar.	Level 1b
	Giannarini, 2007 [10]	96	Randomized, double-blind, comparing a 4-week oral course of either prulifloxacin 600 mg or levofloxacin 500 mg once daily.	6 months after therapy, the microbiological cure rate was 72.73% for prulifloxacin and 71.11% for levofloxacin (p=0.86).	Level 1b
	Cai, 2009 [11]	143	Randomized, open-label trial, comparing oral 600 mg plurifloxacin once-daily for 14 days, with (group A) or without (group B) Serenoa repens (160 mg), Urtica dioica (120 mg) and quercetin (100 mg) and curcumin (200 mg), once-daily, oral, for 14 days. Patients were diagnosed with CBP caused by traditional uropathogens. Six months follow-up.	At the end of therapy 90% and 27% patients from groups A and B were symptom-free, respectively (P<0.0001). At the end of follow-up, 91% and 22% patients from groups A and B were recurrence and symptom-free, respectively (P<0.0001).	Level 1b
	Paglia, 2010 [12]	180	Multicenter, double-blind trial, enrolling patients with CBP (microbiological diagnosis of ongoing CBP episode not required), randomized to 750 mg oral levofloxacin once-daily for 14 days, 750 mg oral levofloxacin once-daily for 21 days, or 500 mg oral levofloxacin once-daily for 28 days.	Clinical success rates for high-dose subjects (750 mg for 21 days [64.9%]) were noninferior to 500 mg for 28 days (69.3%). At 3 and 6 months post-therapy, clinical success rates were higher for the 500 mg, 4-week treatment group. Longer durations of treatment with lower doses of levofloxacin appear to prolong the relapse-free intervals.	Level 1b
	Cai, 2010 [13]	211	Randomized, open-label study comparing oral prulifloxacin (600 mg once-daily) for 14 days with oral doxycycline (100 mg twice-daily) for 21 days, in patients with Chlamydial prostatitis, assessed with mucosal IgA and PCR.	30 days after the end of therapy, prulifloxacin showed equivalent clinical success rates, compared to doxycycline (prulifloxacin: 82.5% doxycycline: 79.9%; P=0.08). Prulifloxacin decreased more efficiently mucosal IgA and IL-8 levels.	Level 1b
	Zhang, 2012 [14]	408	Randomized, open-label trial, comparing oral levofloxacin (500 mg, once-daily for 4weeks) with ciprofloxacin (500 mg twice-daily for 4 weeks). The follow-up period was 6 months.	Microbiologic eradication rates were 86% for levofloxacin and 60% for ciprofloxacin (P<0.05); clinical success rates were 93% for levofloxacin and 72% for ciprofloxacin  (P<0.05). Microbiological recurrence rates were 4% for levofloxacin and 19% for ciprofloxacin  (P<0.05).	Level 1b
	Stamatiou, 2014 [15]	144	Randomized, open label study, comparing antibacterial agents (various drugs, according to sensitivity tests: prulifloxacin, ciprofloxacin, levofloxacin, co-trimoxazole, tetracycline, azithromycin; aminoglycosides; doses unknown), administered for 15 days with (group 1) or without (group 2) various phytotherapeutic agents (saw palemtto 320 mg/day, or Pygeum africanum, 200 mg/day).	61% of patients in group 1 and 68% of patients in group 2 were asymptomatic and microbiologically eradicated (not significantly different). Phytotherapy does not seem to add benefits to antibacterial treatment.	Level 1b
	Busetto 2014 [16]	153	Randomized, open-label trial, comparing oral 600 mg plurifloxacin once-daily for 21 days, with (group A) or without (group B) a single formulation of Serenoa repens (320 mg), Lactobacillus sporogens (200 mg) and arbutin (100 mg), once-daily, for 30 days. 6 months follow-up.	Microbiological recurrence at 2 months was observed in 27.6% patients in group A, and in 7.8% patients in group B. NIH-CPSI scores were: Group A 12.00±4.34, Group B 5.23±2.76 at 2 months; Group A 10.48±4.14, Group B 4.11±2.32 at 4 months; Group A 13.26 ± 4.88, Group B 3.67 ± 1.98 at 6 months. Combined therapy appears to achieve better control and fewer recurrences.	Level 1b
Non-randomized cohort studies
	Naber, 2000 [17]	65	Multi-center study of ciprofloxacin 500 mg twice-daily for 28 days.	Eradication rates were 32/39 (82.1%) after 3 months, 26/34 (76. 4%) after 6 months and 13/22 (59.1%) after 9 months.	Level 2a
	Kunishima, 2008 [31]	10	Multi-center study investigating administration of  200 mg gatifloxacin twice daily for 4–8 weeks.	58.1% symptomatic response rate 4 weeks after treatment.	Level 3
	Naber, 2008 [18]	117	Multi-center open-label study investigating levofloxacin 500 mg once daily, oral, for 28 days. Patients were followed for 6 months.	Microbiological eradication rate was 82/98 (83.7%) at 1 month and the continued eradication rate was 52/57 (91.2%) at 6 months post treatment.	Level 2a
	Panagopoulos, 2009 [19]	39	Single-cohort, open-label study, assessing the effect of oral antibacterial treatment (ciprofloxacin 500 mg twice-daily, levofloxacin 500 mg once-daily, ofloxacin 200 mg twice-daily) administered for 6 weeks to CBP patients, followed by a 12-month follow-up.	Microbiological success and clinical remission was achieved in 64.7% of patients. 35.3% of patients relapsed within an average of 4.75 months. “The microscopy and culture of EPS and segmented samples according to Meares and Stamey are the cornerstones of diagnosis of chronic bacterial prostatitis” [19].	Level 2b
	Skerk, 2009 [20]	169	Single-cohort study, assessing the efficacy of “Croatian standard” antibacterial treatment on patients with prostatic infection caused by various organisms (Chlamydia trachomatis 20%, Trichomonas vaginalis 18%, Enterococci 19%, Escherichia coli 18%, and others).	Comparison of NIH-CPSI symptom scores showed that the most severe clinical presentation of disease was recorded in patients with infection caused by E. coli and Enterococcus. Clinical success was paralleled by bacteriological eradication in chronic bacterial prostatitis caused by C. trachomatis, Enterococcus and E. coli (kappa >0.2 <0.5), but not by T. vaginalis.	Level 2b
	Magri, 2010 [21]	55	Cohort open-label study in patients with Chlamydial infection. Oral levofloxacin 500 mg once-daily plus azithromycin 500 mg thrice-weekly (three consecutive days).	Microbiological eradication rate was 94%; symptom remission, assessed with the NIH-CPSI questionnaire was significant and sustained for a 18-month follow-up period.	Level 2b
	Kolumbić Lakos, 2011 [22]	30	Cohort open label study in patients with severe, relapsing CBP. Switch therapy: intravenous azithromycin (500 mg/day) and ciprofloxacin (800 mg/day) for 3 days, followed by oral ciprofloxacin (1000 mg/day) for 25 days.	Microbiological eradication was 90% 4–6 weeks after the end of therapy and 80% at follow-up visit (6 months off-therapy). Clinical symptoms assessed with the NIH-CPSI test were severe (17–31 points) in all cases (100%) at enrollment, and were mild or absent in 83% of cases 4–6 weeks off-therapy.	Level 2b
	Magri, 2011 [23]	267	Nonrandomized, single-center study, comparing oral, once-daily 500 mg ciprofloxacin plus azithromycin 500 mg thrice-weekly (three consecutive days) for 6 weeks, versus oral, once-daily 750 mg ciprofloxacin plus azithromycin 500 mg thrice-weekly (three consecutive days) for 4 weeks. All patients were on continuous alpha-blocker and Serenoa repens therapy.	Daily dosage of the fluoroquinolone is more crucial than the duration of therapy, as administration of the cumulative dose of 21 g of ciprofloxacin at the rate of 750 mg/day for 4 weeks, rather than 500 mg/day for 6 weeks, increased eradication rates from 62.35% to 77.32% and the total bacteriological success from 71.76% to 85.57%. In particular, increased eradication of Enterococci was observed in the Cipro- 750 cohort. Symptoms, flowmetry parameters and sexual function were significantly improved after pathogen eradication.	Level 2b
	Zhao, 2012 [24]	101	Cohort, open label study, comparing patients with vs. without prostatic calculi. Therapy (levofloxacin 500 mg daily; ciprofloxacin 250 mg twice daily; co-trimoxazole (80/400 mg) two tablets twice daily; and roxithromycin 150 mg twice daily), was designed on the basis of pathogen sensitivity.	Prostatic calculi influence the outcome of antimicrobial therapy in CBP patients. Eradication rates at the end of the study were 43.6% in patients with calculi, and 72.6% in patients without calculi. A decrease ≥50% of the total NIH-CPSI score was assessed in 38.5% and 58.1% of these patients, respectively (P,0.05).	Level 2b
	El Meliegy, 2015 [25]	151	Cohort open-label study. Levofloxacin 500 mg once-daily for 28 days.	Symptom cure rate was 58.9% (per-protocol). Microbiological eradication: 53.45% patients had pathogen loads in VB3 or EPS >103 at day 28 (eradication rate 46.55%?).	Level 2b
	Magri, 2016 [26]		Single cohort study, investigating the effect of administration of aminoglycisode antibiotics (netilmicin, 4.5 mg/kg, once-daily, intramuscular) in CBP cases with contraindication to fluoroquinolone treatment, or fluoroquinolone-resistant pathogens.	Fifty-five out of 70 patients (78.6%) showed eradication of the causative pathogen, and a significant decrease of the NIH-Chronic Prostatitis Symptom Index (NIH-CPSI) total score from a baseline median value of 21 to 14 at the end of therapy, and to 9 and 8 at 6-month and 12-month follow-up assessments, respectively. Additional clinical parameters like the urinary peak flow rate, the percent voided bladder, the serum PSA, the International Prostate Symptom Score and the prostate volume decreased significantly in the group of eradicated patients only.	Level 2b
Case-control studies
	Hu, 2002 [32]	50	Study investigating amikacin 400 mg daily for 10 days via submucosal anal (30 cases) or intramuscular injection (20 cases).	“Cure rate” 33.3% for anal submucosal injection vs. 5% for IM injection (P<0.05).	Level 3
	Nickel, 2008 [33]	146	Multi-center study comparing levofloxacin vs. ciprofloxacin for 4 weeks with 6 months of follow-up.	Bacterial eradication rate was 74.0%, not different from men with no localization of pathogenic bacteria.	Level 3
Case-series
	Weidner, 1999 [27]	40	E. coli chronic bacterial prostatitis treated with 4 weeks of ciprofloxacin 500 mg bid with 12–24 months follow-up.	Microbiological eradication was 92% at 3 months and 70–80% 12–24 months after treatment.	Level 2b
	Nickel, 2001 [34]	14	Various regimens.	57% “moderate to marked improvement”, similar to response in patients with category III.	Level 3
	Gutierrez, 2004 [35]	105	Various regimens.	Symptoms either disappeared or diminished, irrespective of whether positive cultures remained.	Level 3
	Guercini, 2005 [36]	320	Antibiotic cocktails (based on cultures) with betamethasone by prostate infiltration, weekly for 3 doses.	68% of patients were “cured clinically”.	Level 3
	Chen, 2006 [37]	7	Combination of ciprofloxacin, doxazosin, allopurinol and biofeedback perineal massage.	Bacterial eradication rate was 71% after ciprofloxacin treatment during a follow-up of 6 months.	Level 3
	Magri, 2007 [28]	137	Combination therapy with ciprofloxacin, azithromycin, alfuzosin and a S. repens extract for 6 weeks.	64.2% microbiological response at the end of Rx. Of 49 patients showing persistence or reinfection at the end of treatment, 36 completed a second combination therapy cycle: 27 patients (75%) showed eradication. The cumulative eradication rate was 83.9%.	Level 2b
	Magri, 2007 [29]	104	Combination therapy with ciprofloxacin, azithromycin, alfuzosin and a S. repens extract for 6 weeks.	Eradication rates parallels symptom remission in CBP patients affected by prostatitis caused by uncommon pathogens.	Level 2b
	Los-Arcos, 2015 [30]	15	Fosfomycin-trometamine, oral, 3 grams every 48–72 hours, for 6 weeks.	Eight patients out of 15 (53%, among which 4/5 (80%) with MDR isolates) showed persistent microbiological eradication, 7/15 patients (47%) patients showed clinical response.	Level 2b
Expert opinion
	Naber, 1999 [62]	//	Review of guidelines	For chronic bacterial prostatitis, a category of its own is proposed rather than using the general category of complicated UTI.	Level 4
	Lipsky, 1999 [63]	//	Review	Trimethoprim-sulfamethoxazole or, preferably, a fluoroquinolone for 6 to 12 weeks.	Level 4
	Stevermer, 2000 [64]	//	Review	Antibiotics are continued for at least 3 to 4 weeks, although some men require treatment for several months.	Level 4
	Shoskes, 2001 [65]	//	Review	Ciprofloxacin has been shown to be effective. Newer quinolones may be more effective against gram-positive pathogens and anaerobes.	Level 4
	Naber, 2001 [38]	//	Review		Level 3
	Iakovlev, 2002 [66]	//	Review		Level 4
	Fowler, 2002 [67]	//	Review (minimal data)	Fluoroquinolone antibiotics given for 2 to 4 weeks will cure about 70%.	Level 4
	Wagenlehner, 2003 [39], 2003 [40], 2004 [41], 2005 [42], 2005 [43], 2006 [44], 2007 [45]	//	Reviews of pharmacokinetics and pharmacodynamics	Fluoroquinolones are first-choice agents.	Level 3
	Croom, 2003 [46]	//	Review	28 days of oral levofloxacin 500 mg daily achieved similar clinical and bacteriological response rates to oral ciprofloxacin 500 mg twice daily.	Level 3
	Fish, 2003 [47]	//	Review focusing on antimicrobial penetration into prostate tissue and seminal fluid	Fluoroquinolone concentrations at the site of infection should be sufficient for treatment of susceptible pathogens.	Level 3
	Charalabopoulos, 2003 [48]	//	Review focusing on antimicrobial penetration into prostate tissue and secretions	Beta-lactam agents penetrate poorly. Good to excellent penetration into prostatic fluid and tissue has been demonstrated with many antimicrobial agents, including tobramycin, netilmicin, tetracyclines, macrolides, quinolones, sulfonamides and nitrofurantoin. Pharmacokinetic studies of antimicrobials use heterogenous methodology. Antibiotic concentrations in prostatic fluid suitable for treatment of infections are only achieved with fluoroquinolones, macrolides, lincosamides and trimethoprim.	Level 3
	Zvara,2004 [68]	//	Review	Minimally invasive therapies (intraprostatic injections) are not a standard of care in the treatment of chronic prostatitis.	Level 4
	Skerk, 2004 [69]	//	Croatian guidelines	Ciprofloxacin is the drug of choice.	Level 4
	Nickel, 2005 [49]	//	Review		Level 3
	Liu, 2005 [70]	//	Review	Recommends fluoroquinolones, especially levofloxacin and gatifloxacin.	Level 4
	David, 2005 [71]	//	Review	Only trimethoprim and the fluoroquinolones possess both the appropriate bactericidal activity and the ability to diffuse into the prostate. Levofloxacin shows particularly good penetration.	Level 4
	Wagenlehner, 2008 [50]	//	Review	Follow up of at least 6 months is necessary. Most fluoroquinolones with this indication should be sufficient for susceptible pathogens.	Level 3
	Naber, 2008 [51]	//	Review	The fluoroquinolones (2–4 weeks) are the first choice, in particular levofloxacin is as effective as ciprofloxacin but shows a better prostatic penetration and is given once daily.	Level 3
	Wagenlehner, 2009 [52]	//	Review	The 4-glass and 2-glass diagnostic tests are clinically equivalent. A comprehensive algorithm with three-level treatment is proposed. Fluoroquinolones (level 1) should be administered for 4 weeks. In case of failure or resistance, re-treatment or co-trimoxazole therapy for 3 months is recommended (level 2). In case of recurrence, repeated courses of treatment or long-term treatment (6 months) could be considered (level 3). Transurethral resection regarded as last resort or as therapy for concomitant obstruction.	Level 3
	Lipsky, 2010 [53]	//	Review	Questions the definition of CBP, as less than 50% of patients with chronic prostate infection has a UTI relapse history. Culture of prostatic tissue from biopsy is not advised. A comprehensive list showing concentrations of antibacterials in prostatic tissue or fluid is provided. Illustrates pros and cons of therapy with Fluoroquinolones, trimethoprim, tetracyclines and macrolides. Fluoroquinolones should be administered for 4–6 weeks; longer in case of infected prostate stones or other types of genitourinary pathology. Evidence is lacking to support long-term suppressive antibacterial therapy.	Level 3
	Magri, 2010 [54]	//	Review – consensus panel	Diagnostic workup of CBP analyzed in detail. Questions classification of CBP as solely occurring in men showing a history of repeated UTIs.  Provides a tentative list of first, second and third-line antibacterial agents. Considers combination therapy with alpha-adrenoceptor blockers, NSAIDS or other agents.	Level 3
	Perletti, 2011 [72]	//	Review	Reviews the pharmacokinetics, prostate distribution and antibacterial activity of azithromycin and macrolides. Examines a number of important non-antibiotic effects of macrolides (inhibition of bacterial quorum-sensing, accumulaiton on phagocytic cells, stimulation of bacterial killing by neutrophils and subsequent negative modulation of immune response and inflammation).	Level 4
	Dickson, 2013 [73]	//	Review	Recommends 400 mg oral norfloxacin, twice-daily, for 4 weeks, or 300 mg oral trimethoprim daily for 4 weeks. If Chlamydia or ureaplasma are diagnosed as causative agents, recommends 100 mg oral doxycycline, twice-daily, for 2–4 weeks.	Level 4
	Wagenlehner, 2013 [55]	//	Review	Optimal fluoroquinolone treatment duration for CBP is 20 days. When Pseudomonas aeruginosa and enterococci often fail to respond a three-month course of co-trimoxazole can be administered. In patients resistant to both fluoroquinolones and co-trimoxazole, no evidence-based recommendaiton can be given, and antibiotic choice must be guided by microbiological advice and local protocols.	Level 3
	Bowen, 2015 [56]	//	Review of controlled trials	Evidence-based statements: (1) We don't know whether levofloxacin and ciprofloxacin differ in effectiveness at improving clinical success rates or whether levofloxacin and prulifloxacin differ in effectiveness at improving symptoms at 6 months in men with chronic bacterial prostatitis; (2) We don't know whether levofloxacin and other fluoroquinolones (ciprofloxacin and prulifloxacin combined in analysis) differ in effectiveness at improving microbiological eradication rates in men with chronic bacterial prostatitis; (3) We don't know whether local injections of antimicrobial drugs improve symptoms compared with no treatment as we found no direct information from RCTs; (4) We found no direct information from RCTs about transurethral resection of the prostate in the treatment of men with chronic bacterial prostatitis.	Level 3
	Rees, 2015 [57]	//	Review - consensus panel	A treatment algorithm suggests Recommendations: (1) Consider offering uroselective alpha-adrenergic antagonists (4–6 weeks) as first line treatment in CBP and CP/CPPS patients presenting voiding LUTS. (2) Antimicrobial treatment should be an initial treatment of CBP and CP/CPPS.For early-stage CBP a quinolone should be offered for 4–6 weeks. (3) NSAIDS should be offered for short-term treatment of pain to patients with early-stage CBP. (4) Phytotherapy has a modest beneficial effect on symptom improvement in CBP. (5) Psychosocial symptoms should be assessed in both early and late stages of CBP and CP/CPPS. (6) In case of partial response to antibiotics one course of antibacterials at sufficient dosage and durations should be considered.	Level 3
Cost- effectiveness Studies		//	Review
	Kurzer, 2002 [58]	Hypothetical cohort of 100 men	Model comparing 90 days of trimethoprim-sulfamethoxazole and 14, 28 and 60 days of ciprofloxacin.	Ciprofloxacin 500 mg twice daily for 28 days appears to be the most cost effective treatment.	Level 3
	Sanchez Navarro, 2002 [74]	50	Analysis of pharmacy and chart records		Level 4
Pharmacokinetic, in vitro, laboratory, or animal model studies
	Drusano, 2000 [59]	Population pharmacokinetic analysis of prostate penetration by levofloxacin 33 subjects	Monte Carlo simulation of Levofloxacin concentrations in plasma and prostate tissue after repeated administration of 500 mg levofloxacin orally.	Mean prostate tissue/plasma concentration ratio was 4.14. 70% of the population had a penetration ratio in excess of 1.0.	Level 3
	Rippere-Lampe, 2001 [75]	Rat model		Cytotoxic necrotizing factor type 1-positive uropathogenic E. coli caused more inflammation-mediated and histological damage than isogenic CNF1-negative mutants despite similar bacterial counts.	Level 4
	Velasco, 2001 [76]	83 patients with FQ resistant E. coli isolates	Comparison of quinolone resistant E. coli isolates of invasive urinary tract infection and prostatitis cases versus cystitis cases.	Quinolone resistance of invasive cases was 8% versus 20% in cystitis cases. Quinolone resistant E. coli is less likely to produce invasive disease than susceptible E. coli.	Level 4
	Naber, 2001 [77]	10 normal volunteers	Gatifloxacin concentrations in plasma, urine, ejaculate, prostatic and seminal fluid, and sperm cells.	Good penetration into prostatic and seminal fluid suggest that gatifloxacin may be a good alternative.	Level 4
	Giannopoulos, 2001 [78]	50	Pefloxacin concentrations in serum and prostate tissue after 800 mg intravenuous pefloxacin were determined in BPH tissue using a microbiological plate assay.	Tissue levels of pefloxacin were well above MICs of common bacteria causing bacterial prostatitis. Pefloxacin could be a satisfactory alternative for surgical prophylaxis and treatment of bacterial prostatitis.	Level 4
	Scelzi, 2001 [79]	12 TURP patients	Lomefloxacin concentrations in serum and prostate tissue after 400 mg oral administration.	Tissue/serum ratio was >2 in prostatic capsule and >1.6 in adenomatous tissue. Lomefloxacin could be an efficacious therapeutic option for treatment of chronic prostatitis.	Level 4
	Horcajada, 2002 [80]	23 E. coli isolates	Emergence of quinolone-resistance in faeces of patients with prostatitis treated with ciprofloxacin for 1 month.	11 of 23 patients, developed quinolone-resistant strains, during and just after therapy. 2 months after treatment, these were completely displaced by quinolone-susceptible E. coli.	Level 4
	Lee, 2005 [81]	Rat model	Experimental administration of catechin, an extract of green tea.		Level 4
	Johnson, 2005 [82]	17 E. coli prostatitis isolates	Molecular analysis	Prostatitis isolates exhibited more virulence factors than cystitis isolates (n=23).	Level 4
	Wagenlehner, 2006 [60], 2008 [61]	12 healthy volunteers and 39 TURP patients	Concentrations of moxifloxacin in plasma, urine, prostatic fluid, prostate tissue.	Moxifloxacin might be a good alternative for the prostatitis treatment.	Level 3
	Cattoir, 2006 [83]	1	Quinolone resistance mechanisms in an E. coli clinical isolate (Ar2)		Level 4
	Wang, 2006 ]84], 2008 [85]	Rat model	Vancomycin and amikacin evaluated.	Higher antibiotic concentration in the prostate tissues than in sera.	Level 4
	Soto, 2007 [86]	32 E. coli prostatitis isolates		Strains causing prostatitis produced biofilm in vitro more frequently than those causing other urinary tract infections and had a higher frequency of hemolysin (p=0.03 and 0.0002, respectively).	Level 4
	Han, 2008 [87]	Rat model		Lycopene may have a synergistic effect with ciprofloxacin in prostatitis treatment.	Level 4
	Miri, 2016 [88]	Rat model of E.coli prostatitis	Nine groups of animals treated with various combinations of ciprofloxacin (150 mg/kg once daily), ginseng (15 mg/kg once-daily), vehicle (saline) or no treatment.	Compares to ciprofloxacin alone, the combination ciprofloxacin-ginseng protects the prostatic tissue from apoptosis and damage caused by inflammatory cell infiltration, interstitial fibrosis and acinar changes.	Level 4

According to the hierarchy of study types these papers included: one systematic review and meta-analysis, 9 randomized clinical trials, 11 non-randomized cohort studies, 2 case-control studies, 8 case series, 32 articles incorporating expert opinion, 2 cost-effectiveness studies, and 17 in vitro, laboratory or animal model studies (Table 2).

2.2.1 Search results

Results of database search, and a general outline of included articles and trials are shown in table 2.

One level 1 (LoE 1a) Cochrane systematic review and meta-analysis including total 2,196 patients was identified [7].

Nine level 1 randomized clinical studies (LoE 1b) were identified [8], [9], [10], [11], [12], [13], [14], [15], [16]. These studies included a total of 1,894 participants (Table 2).

The committee identified 14 Level 2 items (2 studies with LoE 2a, 12 studies with LoE 2b): 10 non-randomized cohort studies [17], [18], [19], [20], [21], [22], [23], [24], [25], [26] and 4 case series [27], [28], [29], [30]. These studies included a total of 1,290 participants (Table 2).

The committee identified 31 level three items including: one non-randomized cohort study [31], two case-control studies [32], [33], four case series [34], [35], [36], [37], 20 expert opinion reviews [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], one cost-effectiveness study [58] and and 3 in vitro, laboratory, or animal model studies [59], [60], [61]. These studies included a total of 652 patients with chronic prostatitis, 12 healthy volunteers and 39 TURP patients (Table 2).

The committee identified 27 Level 4 studies including: 12 articles based on expert opinion [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], one cost-effectiveness study [74], and 14 in vitro, laboratory, animal model, or pharmacokinetic studies [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88] (Table 2).

3 Clinical presentation and recommended evaluation of patients with chronic bacterial prostatitis

3.1 Diagnosis

Chronic bacterial prostatitis is characteristically associated with recurrent urinary tract infections caused by the same bacterial strain. It represents the most frequent cause of recurrent urinary tract infections in young and middle aged men. If not treated adequately from its early onset, CBP can be a devastating disease, characterized by relapsing episodes that may occasionally involve systemic symptoms, like fever and malaise. Potential complications of this condition include: prostatic abscess, urosepsis, and acute urinary retention.

Accurate diagnosis of chronic bacterial prostatitis (NIH category II) is based on quantitative cultures and microscopy of specimens obtained from lower urinary tract segmented tests. The four-glass procedure, first described by Meares and Stamey, allows culture and pathogen detection in first-void, midstream, post-massage urine and expressed prostatic secretions (EPS) [89]. This test is considered the gold standard for diagnosis of CBP, though no modern controlled study has yet been performed to support this recommendation. Nickel et al validated a simpler test to assess inflammation/infection as a screening test in primary care patient populations [90]. This “two-glass” test, based on the culture of pre- and post-massage urine samples, is a reasonable alternative when EPS cannot be obtained or when direct microbiological assistance is not available, as EPS should be examined immediately after sampling.

3.2 Microbiology

A bacterial strain is considered to be the causative pathogen of a specific case of CBP if its colony forming unit (CFU) value in EPS or post-massage voided urine is at least 10 times higher than the load found in midstream or first-voided urine. When a specific pathogen is detected by non-culture techniques (PCR, etc.), such ratio is impossible to assess. Hence, the diagnosis of CBP becomes more cumbersome, and should be based on different and multiple parameters to achieve good specificity.

The bacterial spectrum of chronic bacterial prostatitis has been investigated in patients from tertiary care institutions in 1989 [4], [91]. Similar to the experience with acute prostatitis, these series reported that facultative Gram-negative bacilli (especially E. coli) were responsible for the great majority of cases. Though one study questions the consistency of cultures of Gram-positive bacteria in chronic prostatitis patients [92], recent reports have shown a preponderance of Gram-positive cocci in clinical trials or case series [9], [23], [93]. The continuous evolution of pathogen populations worldwide and nationwide makes it impossible to draw a conclusive picture on the spectrum of pathogens in CBP. It can be stated, though, that most trial reports indicate that the bacterial spectrum of CBP causative agents resembles that of complicated urinary tract infections, with a preponderance of Enterobacteriaceae like E. coli, Proteus spp., Klebsiella spp., and others. P. aeruginosa and Enterococci are also isolated, but are more difficult to treat. Concerning the pathogenic role of Gram-positive bacteria, Naber and coworkers have demonstrated that the concordance between microbiological eradication and clinical symptom remission is high when stringent criteria (10,000 CFU/mL in VB3 or EPS specimens, compared to 1,000 CFU/mL for Enterobacteriaceae) are applied in the diagnosis of Gram-positive prostatitis [18].

3.3 Other issues related to clinical assessment

3.3.1 Semen culture

A comprehensive study of 40 men with E. coli chronic bacterial prostatitis evaluated the role of semen analysis and cultures. Bacteriospermia (>10³ CFU/ml) was documented in 21 (53%) of the 40 men prior to treatment [27]. Therefore, semen culture alone is not sufficient to diagnose chronic bacterial prostatitis [14]. A retrospective analysis of a cohort of 696 patients showed that addition of cultures of total ejaculates collected after emission of the post-massage urine (in the frame of a 4-glass test) may increase the rate of pathogen detection [94]. Randomized controlled studies are warranted to draw any conclusion in this regard.

3.3.2 Imaging studies and urodynamics

The role of transrectal prostate ultrasound and urodynamic investigations was evaluated in a prospective study of 164 men. This study showed that these procedures cannot differentiate between chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome [95]. Nevertheless, ultrasound and urodynamic evaluations, together with uroflowmetry, are pivotal to assess the severity of prostatitis syndromes.

A recent study report shows that prostatitis can be differentiated from prostate cancer using Prostate Imaging-Reporting and Data System (PI-RADS) [96]. This study enrolled 68 patients with cancer suspicious lesions. T2w imaging, diffusion weighted imaging, dynamic contrast enhancement, and MR-Spectroscopy were acquired. Furthermore, T2-morphology, ADC-value, perfusion type, citrate/choline-level, and lesion localization were evaluated. Although differentiation between prostatitis and cancer was possible, significant overlap between prostatitis and other benign findings was evidenced. The authors concluded that PI-RADS is only suitable to a limited extent for the primary assessment of prostatitis [96].

In another study, tecnetium-99m scintigraphy imaging was performed in 19 patients with chronic bacterial prostatitis, compared to controls and patients with CP/CPPS [97]. Hot uptake was found in 68% of chronic bacterial prostatitis patients and 70% of patients with chronic pelvic pain syndrome. Based on the results of these studies it is not possible to draw a final conclusion concerning the benefit of imaging procedures in diagnosing chronic bacterial prostatitis with high specificity.

3.3.3 National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI)

The NIH-CPSI provides a standardized assessment of chronic prostatitis symptoms [98]. The NIH-CPSI was designed as a tool for monitoring treatment response in clinical trials of chronic prostatitis/chronic pelvic pain syndrome rather than as a diagnostic tool. Though – due to the overlapping symptoms between CBP and CPPS – the CPSI test has been used for symptom evaluation in some CBP clinical studies, validation of this instrument in assessing the clinical response to therapy and symptom severity in patients with category II chronic bacterial prostatitis has not yet been conducted.

4 Principles of therapy

4.1 Antimicrobial treatment

Appropriate antimicrobial therapy represents the cornerstone of successful treatment of patients with bacterial prostatitis. For effective antimicrobial therapy the pathogens at the site of infection must be exposed to a drug concentration sufficient to kill the bacteria or inhibit their growth, ultimately eradicating the causative pathogens from that site. Evidence suggests that bacteria in prostatic tissue may survive in a milieu protected by biofilms, and that patients affected by biofilm disease may show more severe prostatitis symptoms [99], [100], [101]. Although the efficacy of antimicrobial agents against biofilm-associated bacteria is markedly decreased, fluoroquinolones and macrolides are more active against biofilms than other drugs, e.g. beta-lactams or aminoglycosides [72], [102], [103].

The available evidence derived from pharmacokinetic studies of antimicrobial agents and their penetration into the prostate has been comprehensively reviewed by Charalabopoulos et al. [48] and by Goto et al. [104].

Antibacterial agents achieving concentrations sufficiently high to treat chronic infections in the prostate are fluoroquinolones, macrolides, trimethoprim and aminoglycosides. Other agents whose concentrations have been tested in prostatic tissues include imipenem, aztreonam, clindamycin, and few cephalosporins (reviewed in [48], [53], [104]).

Because of their excellent pharmacokinetic and pharmacodynamic characteristics, fluoroquinolones are considered the drugs of choice for antimicrobial treatment of chronic bacterial prostatitis. The fluoroquinolones ciprofloxacin, levofloxacin, ofloxacin, lomefloxacin and prulifloxacin have been tested in the frame of randomized-controlled trials [8], [9], [10], [11], [13], [14].

Since clinical experience suggests that relapse and reinfection are commonly observed in patients with chronic bacterial prostatitis, only the results of clinical studies with a follow-up of at least six months are characterized by higher levels of evidence [105]. Overall, it appears that 60–80% of patients with E. coli and other Enterobacteriaceae can be cured with a four-week course of fluoroquinolone therapy (Table 2). However, clinical experience suggests that prostatitis due to P. aeruginosa or Enterococcus is more difficult to eradicate. Ciprofloxacin remains one of the best antipseudomonal fluoroquinolones for prostatic infections. In some cases, fluoroquinolones like levofloxacin or off-label moxifloxacin, showing improved activity against Gram-positive pathogens, might be a better option in case of enterococcal infections.

Levofloxacin was investigated in three recent clinical studies. The studies by Bundrick et al. [9] and Zhang et al. [14] were randomized double-blind multicenter trials comparing levofloxacin 500 mg once daily to ciprofloxacin 500 mg twice daily and found that levofloxacin was equivalent [9] or superior [14] to ciprofloxacin, respectively. In the Bundrick study, the microbiological eradication rate by patient at four weeks was 75% in the levofloxacin group and 77% in the ciprofloxacin group. In the Zhang study, 86% and 60% were the eradication rates os levofloxacin and ciprofloxacin, respectively. One study by Naber et al. was a nonrandomized patient cohort study investigating levofloxacin 500 mg once daily [18]. The study also used different classification schemes for the diagnosis of chronic bacterial prostatitis. The total eradication rate at four weeks was 79%, and at six months 92%. The specific eradication rates of E. faecalis and of P. aeruginosa, assessed in a classification scheme comparable to the Bundrick study [9] were 56% (10/18) and 100% (3/3), respectively. Other studies have been published, confirming the efficacy of levofloxacin in the treatment of CBP (e.g. [25]).

In general, metanalysis of data from randomized studies showed no differences in efficacy between different fluoroquinolones [7]. In particular, pooled analysis of two RCTs comparing ciprofloxacin vs. levofloxacin [9], [14] showed that pathogen eradication was higher for levofloxacin, when data were analyzed using a fixed effect model (risk-ratio for eradication for levofloxacin vs. ciprofloxacin: 1.22; 95% CI: 1.11 to 1.34, P<0.001). However, significance was lost if a random-effects model was applied (risk-ratio: 1.18; 95% CI: 0.81 to 1.71, P=0.38). This meta-analysis was characterized by considerable heterogeneity (94%).

When CBP is caused by atypical/intracellular bacteria (Chlamydia spp., Mycoplasmata, etc.), a number of therapeutic options are available. Fluoroquinolones, tetracyclines and macrolides have been tested in the frame of controlled trials [13], [106], [107], [108], [109]. In general, azithromycin and doxycycline are potent and equally active against chlamydial infections [108], and azithromycin achieves higher rates of eradication, compared to ciprofloxacin [109].

4.2 Duration of antibiotic treatment and clinical follow-up

We identified a single randomized clinical study comparing different durations of fluoroquinolone treatment. Paglia and coworkers compared administration of levofloxacin 750 mg daily for 21 days with 500 mg daily for 28 days. Clinical success rates for high-dose subjects (64.9%) were noninferior to the group taking 500 mg for 28 days (69.3%) [12]. However, at 3 and 6 months post-therapy clinical success rates were higher for the 500 mg group, suggesting that longer durations of treatment may prolong the relapse-free intervals, even with lower doses of levofloxacin.

Almost all examined studies used a four week treatment regimen (e.g. [8], [9], [10], [17], [18]). In one noncomparative study, treatment with gatifloxacin was four to eight weeks [31]. A cost-effectiveness study comparing different antibiotics and duration concluded that ciprofloxacin 500 mg twice daily for 28 days was the most cost-effective treatment [58]. Based upon these results, we conclude that an oral fluoroquinolone should be given for at least four weeks after the initial diagnosis of chronic bacterial prostatitis.

The off-therapy follow up in most clinical studies was at least 6 months (e.g. [8], [9], [10], [17], [18]); such period or longer is also desirable in the clinical routine.

4.3 Various procedures

One study investigated amikacin 400 mg daily administered for 10 days via submucosal injection [32]. This study reported inferior results, compared with known oral eradication rates. Thus, non-systemic delivery of antibiotics cannot be recommended (GoR D).

No published study in the last 17 years evaluated the effect of prostate surgery on chronic bacterial prostatitis. Expert opinion only recommends interventions in patients with chronic bacterial prostatitis who have proven severe bladder outflow obstruction, often worsening a concomitant benign hyperplasia. Such recommendation has not been validated by clinical studies.

4.4 Refractory disease

There are limited data available on treatment outcomes for patients who fail initial therapy for chronic bacterial prostatitis. One study investigated 36 patients with refractory chronic bacterial prostatitis and documented susceptibility of the same persisting pathogen to fluoroquinolones and macrolides [28]. Of these 36 patients, 27 (75%) were cured by a second cycle of combination pharmacological therapy with the same antibacterial agents used in the first cycle (ciprofloxacin, azithromycin). No other study evaluated patients with recurrent disease. As more studies of this important issue are warranted, currently no recommendation can be given for refractory patients.

4.5 Resistant disease

In case of fluoroquinolone resistance ascertained at diagnosis, or in case of resistance acquired during a first course fluoroquinolone therapy, the therapeutic options are limited and usually not based on robust evidence.

In general, when fluoroquinolones can’t be administered because of chemoresistance of causative pathogens, but also when intolerance issues complicate or impede fluoroquinolone therapy (e.g., a history of tendonitis), antibacterial therapy may be attempted with antibacterial agents against which the causative pathogens are susceptible, based on careful analysis of the antibiogram. Intuitively, the choice of the therapeutic agent should be directed towards drugs that have shown some activity in specific CBP cases, as documented by cohort studies, case-control studies, or case series (see paragraph 4.1, above) (GoR C). Among these agents, macrolides, aminoglycosides, fosfomycin, and aminoglycosides may be considered.

Trimethoprim, alone combined with sulphamethoxazole, has been used for decades for treatment of CBP, being the best available treatment option in the pre-fluoroquinolone era. With this agent pathogen eradication is achieved in approximately 30–60% of cases (reviewed in [110]).

Orally administered trimethoprim distributes efficiently to prostatic fluids (3.3 mcg/ml), achieving a twofold concentration compared to plasma [111]. Limited evidence from randomized studies is available supporting the use of co-trimoxazole or trimethoprim in CBP. In 1979, Smith and colleagues reported the results of a double-blind study performed on 27 per-protocol patients, randomized to receive twice-daily oral co-trimoxazole (880–400 mg) for 10 days or 12 weeks [112]. Pathogen eradication (Enterobacteriaceae in all cases) was assessed in 20% of the former group and 60% of the latter group. In general, eradication rates with co-trimoxazole are lower, compared to fluoroquinolones. Co-trimoxazole may be considered a second-choice agent, used in the frame of a long-term therapy (at least three months).

In recent years, a growing number of studies focused on the natural antibiotic fosfomycin [30], [113], [114], [115]. The interest has been fostered by the fact that the resistance rates of uropathogens against fosfomycin remains relatively low in the era of multidrug resistance. For the moment only case series or small cohort studies have been published. Though the studies published so far appear to be moderately biased, the results seem to be promising, as satisfactory eradication rates (55%) upon exposure to relatively low doses of the drug (3 grams every 48–72 hours) have been achieved [30].

A recent nonrandomized, single-cohort study has shown that aminoglycosides show eradication rates of 78% (ranging between 56% [Enterococcus faecalis] and 85% [Escherichia coli]) [26]. Additional randomized-controlled trials are warranted to further validate these data.

4.6 Management of pain and voiding symptoms

Chronic bacterial prostatitis is characterized by pain and voiding disturbances, but published literature on the treatment of these symptoms is scarce, and so far no randomized controlled trial has addressed these issues. Nevertheless, in the daily practice symptomatic therapy is administered to CBP patients, also on the basis of evidence demonstrating the efficacy of analgesics or alpha-blockers in attenuating the symptoms of CP/CPPS.

In 2015 the Prostatitis Expert Reference Group (PERG), an ad hoc panel of experts from UK, generated a series of recommendations concerning pain and voiding symptom management in patients with CBP and CP/CPPS [57]. The bases for these recommendations included the NICE guidelines on the pharmacological management of neuropathic pain and various other guidelines and sources. According to a Delphi panel approach-generated consensus within the PERG, (i) in patients with early-stage disease who present with pain symptoms, regular paracetamol may be offered; (ii) NSAIDS should be offered only for short-term treatment (4–6 weeks) of pain to patients with early-stage CBP whose symptoms are suspected to be due to an inflammatory process; (iii) in patients with early-stage CBP use of opioids for pain management should be avoided; and (iv) if pain is considered to be neuropathic, treatment with a gabapentinoid, a tricyclic antidepressant or a selective serotonin reuptake inhibitor is suggested [57], [116].

Concerning voiding symptoms, a Delphi panel process generated several consensus-based recommendations. For CBP, (i) treatment with alpha-adrenergic antagonists should be considered in patients who present with significant voiding LUTS, but (ii) if no relief from LUTS or other CBP symptom is reached within 4–6 weeks, treatment should be stopped and different pharmacological therapies should be considered. Moreover, (iii) preference may be given to uroselective alpha-blockers llike alfuzosin, tamsulosin and silodosin [57].

4.7 Alternative and complementary medicine approaches

Two animal studies investigated catechin, a green tea extract, and ginseng, in combination with ciprofloxacin in the treatment of chronic bacterial prostatitis [81], [88]. These experiments point to statistically significant decreases in bacterial growth and improvements in prostatic inflammation compared with ciprofloxacin only groups.

A randomized clinical trial showed that Serenoa repens plus Urtica dioica, curcumin and quercitin extracts, associated with prulifloxacin are able to improve symptoms and quality of life of CBP patients, compared to fluoroquinolone monotherapy [11]. Additional studies are necessary to confirm the microbiological efficacy of these approaches.

5 Discussion and conclusions

Antimicrobial resistance to fluoroquinolones is increasing world-wide. The impact of fluoroquinolone resistance on the treatment of chronic bacterial prostatitis has not been evaluated systematically. However, an increasing number of countries no longer recommend common first-line agents for treatment of chronic bacterial prostatitis [117]. From a pharmacological viewpoint, treatment failure with increasing pathogen MICs has been observed anecdotally in our patients with chronic bacterial prostatitis, as we have seen in the case of upper and lower urinary tract infections and other urogenital infections, such as gonorrhea (for which fluoroquinolones are no longer recommended in the USA).

In patients with pathogens still susceptible to trimethoprim-sulfamethoxazole and resistant to fluoroquinolones, expert opinion recommends a three-month course of treatment with trimethoprim-sulfamethoxazole. In patients with pathogens resistant to fluoroquinolones and trimethoprim-sulfamethoxazole, currently no high-graded recommendation can be given, though off-label administration of agents that were shown to be effective in case series or observational cohort studies may be attempted, if “salvage” antibacterial therapy is deemed necessary in severe and complicated clinical cases.

6 Future research

The microbiological success of treatment of chronic bacterial prostatitis mainly depends upon the pharmacological properties of antimicrobial agents in the prostate and the susceptibility of the pathogens to such agents.

The mounting worldwide resistance rates against fluoroquinolones require swift responses, and clinical trials with new antibiotics, or studies assessing the efficacy of old antibacterial agents in CBP are urgently needed. As drugs like aminoglycosides, carbapenems, tigecycline, fosfomycin, and others have been recovered in prostatic tissues (surgical specimens in most cases) or have been tested in single patients or healthy volunteers [115], [117], [118], [119], new studies are warranted to confirm the distribution of these agents to prostatic ducts, their concentrations in prostatic secretions, and, ultimately, their efficacy against chronic bacterial prostatitis in a randomized setting.

Future research should also be directed to the activity of agents active in biofilms, to evaluate possible synergism for the treatment of chronic bacterial prostatitis.

Studies validating the effect of alpha-blocker, analgesic and anti-inflammatory therapies in CBP patients are also urgently needed.

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