Introduction

Prostatitis is a group of clinical syndromes which has been categorized by the United States National Institutes of Health (NIH) into several distinct entities as follows: acute bacterial prostatitis (ABP; category I), chronic bacterial prostatitis (CBP; category II), chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), inflammatory type (category IIIA) and noninflammatory type (category IIIB), and asymptomatic inflammatory prostatitis (category IV) [1]. CBP, the focus of this review, is characterized by chronic or recurrent urogenital symptoms with evidence of prostatic infections caused by the same organism lasting at least 3 months [2].

Clinical Presentation

CBP can occur in men of any age but is most common in those younger than age 50 [3]. Men with CBP may present with recurrent/intermittent irritative voiding symptoms (frequency, urgency, and nocturia), obstructive symptoms (hesitation, dribbling, slow stream, and retention), and/or dysuria. Some may experience pain or discomfort in the perineum, lower abdomen, testicles, penis, and occasionally sexual dysfunction (dysorgasmia and hematospermia). Systemic symptoms such as a low-grade fever may also be present. Prostatitis symptoms overlap with those of benign prostatic hyperplasia (BPH). A previous survey of office-based physicians found that dysuria distinguished chronic prostatitis from BPH (20% in visits for chronic prostatitis versus 2% in visits for BPH) [4]. Some men with CBP are asymptomatic at presentation but have a history of recurrent urinary tract infections (UTIs). The same organism is repeatedly isolated from the urine of men with CBP, sometimes even when the patients are not symptomatic.

The NIH Chronic Prostatitis Symptom Index (CPSI) from the Chronic Prostatitis Collaborative Research Network (CPCRN) is a validated questionnaire commonly used to assess symptom severity in men with chronic prostatitis (available at http://www.prostatitis.org/symptomindex.html). Although it is most commonly used for patients with CP/CPPS, the NIH CPSI has also been employed by research studies to measure patient response to therapies for CBP.

Epidemiology

The overall prevalence of prostatitis is approximately 8.2%, with estimates ranging from 2.2% to 9.7%, in population-based studies of males ranging from 20 to 79 years old [5]. Prostatitis accounts for about 5% of all ambulatory visits by men aged 18 years and older, including 8% of visits to urologists and 1% of visits to primary care physicians [6]. Prostatitis is diagnosed in an estimated two million visits in the USA annually and is the most common genitourinary diagnosis in men aged 18 to 50 years [6]. In men experiencing prostatitis symptoms, prostatic fluid cultures were positive for bacteria in only about 10% [7]. Among men with ABP, about 10% will develop CBP [8]. Overall, 4% to 14% of men presenting with prostatitis symptoms may have CBP [9, 10].

Risk Factors

CBP can develop after an episode of acute bacterial infection of the prostate. Risk factors for acquiring ABP include functional or anatomical anomalies that predispose to urogenital infections, chronic indwelling and intermittent bladder catheterization, and prostate biopsy [11,12,13]. Accordingly, periprocedural antimicrobial prophylaxis is indicated for all patients undergoing transrectal prostate biopsy (typically a fluoroquinolone given within 24 h) [14]. Antibiotic resistance is a significant risk factor for ABP after transrectal prostate biopsy despite antibiotic prophylaxis [12, 15]. Additionally, immunosuppression associated with HIV infection is a risk factor for bothersome lower urinary tract symptoms, including those caused by infections of the prostate [16].

Risk factors for CBP beyond those for ABP are not yet well established. In a retrospective study of 480 men with ABP, factors associated with progression from ABP to CBP were diabetes, prior manipulation (i.e., prostate biopsy, catheterization, urodynamic study, and transurethral resection of the prostate (TURP) within 4 weeks before the onset of ABP), not undergoing cystostomy to manage ABP, and urethral catheterization [8].

Microbiology

The most common etiologic agents of CBP are gram-negative bacilli. Escherichia coli causes about 75% to 80% of cases [17]. Other commonly reported pathogens include Enterococcus species, Enterobacteriaceae (e.g., Proteus mirabilis, Klebsiella species), and nonfermenting gram-negative bacilli (e.g. Pseudomonas aeruginosa) [8, 18, 19]. Certain organisms, including staphylococci, streptococci, Corynebacterium species, Chlamydia trachomatis, Ureaplasma urealyticum, Trichomonas vaginalis, Mycoplasma genitalium, Mycoplasma hominis, and Neisseria gonorrhoeae, have been associated with CBP, but whether they represent true pathogens or non-pathogens that are detected in urine samples due to presence in the urinary flora remains under debate [18, 20,21,22]. Among these organisms, staphylococci and streptococci have been more widely accepted as pathogens [18]. The potentially causative role of Chlamydia and gonorrhea species is supported by studies which found sexually transmitted infections caused by these species can infect the prostate of some men, causing elevations in prostate-specific antigen (PSA) levels [23, 24]. In individuals with underlying immunodeficiency such as those with HIV infection, chronic prostatitis may be caused by Mycobacterium tuberculosis, and Candida species, rarely Coccidioides immitis, Blastomyces dermatitidis, Histoplasma capsulatum, and Cryptococcus neoformans may be responsible, but these typically present indolently [20, 25].

Diagnosis

Initial evaluation of CBP should include history, a prostate examination, a urine voiding test, and urinalysis and urine culture. On prostate examination, prostatic hypertrophy, tenderness, bogginess, and/or nodularity may be noted in some patients. Semen analysis, PSA level, and transrectal ultrasonography–guided biopsy are not specifically indicated for the diagnosis of CBP [2]. Laboratory findings suggestive of infection and inflammation, such as elevated serum leukocytes and inflammatory markers, are not present in all patients.

Urine Voiding Test and Culture

The traditional voiding test described by many as the gold standard for the diagnosis of CBP is the Meares–Stamey four-glass test. This test involves collecting a sample of initially voided 5–10-mL urine in the first glass (VB1, urethral sample), a sample of midstream urine in the second glass (VB2, bladder sample), any expressed prostatic secretions after digital massage of the prostate in the third glass (EPS, prostatic sample), and a sample of subsequently voided urine in the fourth glass (VB3, prostatic sample). Bacterial prostatitis is diagnosed if pathogens are identified on cultures of prostatic samples (EPS and VB3) exclusively or at a level 10 times higher than in cultures of urethral and bladder samples (VB1 and VB2). Additionally, more than 10 leukocytes per high-power field in VB3 is suggestive of CBP [2].

However, a prior survey of urologists suggested that the four-glass test may not be frequently utilized in clinical practice, and even when performed, results of the test appear to have limited influence on the choice of antibiotic therapy [26]. Instead, men presenting with history and symptoms suggestive of CBP are often empirically treated with a course of oral antibiotic, and the presumed diagnosis of CBP is confirmed if there is a response to antibiotic therapy [7]. However, empiric treatment presents diagnostic challenges, since cultures are likely negative for someone while taking antibiotics, and further, it is not clear how long one should wait after cessation of antibiotics to obtain culture to confirm cure. A simpler, reasonable alternative to the four-glass test is a modified two-glass test, in which cultures of the post-massage urine sample (VB3) and the pre-massage bladder urine sample (VB2) are compared. This test is less cumbersome to perform and has a strong concordance with the 4-glass test [27].

Management

The cornerstone of treatment of CBP is oral antimicrobial therapy with an agent that has good tissue penetration in the prostate. Here we review the choice of antimicrobial agent and treatment duration, as well as other treatment options including local injections of antimicrobial agents, surgery, chronic antibiotic prophylaxis, and an emerging novel therapy utilizing bacteriophages.

Oral Antimicrobial Therapy

Antimicrobial Penetration into Prostatic Tissue

In the absence of known secretory or active transport mechanisms, only passive diffusion is presumably allowed across the barrier between the circulation and the prostate gland stroma [28]. Therefore, antimicrobials with high lipid solubility and no protein binding are permitted to achieve adequate penetration into the prostatic tissue and fluid. Furthermore, the degree of ionization as measured by a drug’s dissociation constant (pKa) and the pH gradient from the plasma to the prostatic fluid also influence drug entry and ion trapping once in the prostate. Given that the prostatic fluid is typically more acidic than the plasma, drugs with an alkaline pKa will ionize to a greater extent in the prostatic fluid than in the plasma. As a result, these drugs can achieve a high concentration in the prostate more readily than drugs with an acidic pKa [28, 29]. The prostatic fluid can however become relatively alkaline when the prostate is inflamed [18]. Overall, agents found to have good to excellent penetration into the prostatic fluid and tissue include fluoroquinolones, sulfonamides, tetracyclines, macrolides, tobramycin, netilmicin, and nitrofurantoin [28]. Prostatic tissue penetration achieved by drugs within the same class may vary to some extent [30]. In recent pharmacokinetic analysis, fosfomycin has been shown to achieve reasonable concentrations in uninflamed prostate [31]. Similarly, piperacillin-tazobactam has also been found to reach adequate intraprostatic concentrations [32].

Initial Treatment

Selection of an antimicrobial agent should be guided by susceptibility testing of the isolated pathogen and the agent’s ability to penetrate the prostate. Fluoroquinolones, given their excellent penetration into the prostate, are widely considered the first-line treatment, unless resistance is confirmed or strongly suspected [2, 18, 33]. Different oral fluoroquinolones are comparable with one another in terms of clinical and microbiological efficacy and safety, based on synthesized evidence from a systematic review of 18 randomized trials assessing antibiotic therapies for 2196 patients with CBP [34]. Fluoroquinolones compared in this review included ciprofloxacin, ofloxacin, levofloxacin (L-isomer of ofloxacin), lomefloxacin, and prulifloxacin. These agents, after given for 4 to 6 weeks, achieved a clinical success rate (defined as symptom cure or improvement) of about 70% to 90% at 6 months, and a pathogen eradication rate ranging from 67% to 81% [34]. Of note, in a nonblinded randomized trial included in this systematic review, adding a nutritional supplement (Serenoa repens (saw palmetto), Lactobacillus sporogenes (a probiotic), and arbutin) to an oral antibiotic therapy (prulifloxacin) was found to lead to improved symptoms than antibiotic therapy alone [35].

The optimal duration of oral antibiotic treatment is not yet clearly defined [17, 34]. Durations used in clinical trials evaluating efficacy of antibiotics for CBP typically range from four to 12 weeks [34]. The European Association of Urology (EAU) recommends a duration of 4 to 6 weeks [33]. A longer treatment duration, between six and 12 weeks, is often necessary to achieve pathogen eradication and prevent recurrence [2], whereas a treatment course shorter than 4 weeks has been associated with higher risks of relapse [36]. Careful monitoring of potential adverse effects from prolonged antibiotic therapy is necessary, such as Clostridioides difficile-associated diarrhea, tendinopathy (tendinitis and tendon rupture, especially in the elderly), and central nervous system toxicity for fluoroquinolones.

If the pathogen is resistant to fluoroquinolones or if the patient is intolerant of prolonged fluoroquinolone use or allergic, trimethoprim-sulfamethoxazole is a reasonable alternative. However, because of less efficient tissue penetration in the prostate than fluoroquinolones, trimethoprim-sulfamethoxazole may need to be administered for a longer course, usually 6 weeks or more, in order to be clinically effective [34]. Furthermore, there has been an increasing rate of resistance of Enterobacteriaceae to fluoroquinolones and trimethoprim-sulfamethoxazole [37,38,39]. In such scenarios, beta-lactams (e.g., cephalosporins) and tetracyclines (e.g., doxycycline) should be considered based on susceptibility testing.

However, the usefulness of these commonly used antibiotic agents is increasingly limited by the rising incidence of multidrug-resistant (MDR), extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae [2, 40, 41]. Fosfomycin is emerging as an option for treating CBP caused by MDR ESBL-producing pathogens. Data from both retrospective and prospective cohorts suggest that an oral regimen consisting of fosfomycin 3 g daily for 1 week followed by 3 g every 2 days for a treatment duration of 6–12 weeks can achieve a clinical cure rate of 50% to 77% and a pathogen eradication rate of > 50% for MDR pathogens [42, 43]. Cefoxitin is another consideration for CBP caused by difficult-to-treat ESBL-producing pathogens. In a recent prospective study of 23 patients with prostatitis (including 14 patients with CBP) caused by ESBL-producing Enterobacteriaceae resistant to fluoroquinolones and trimethoprim-sulfamethoxazole, cefoxitin-based antibiotic therapy reached a clinical cure rate of 77% (17 patients out of 22) and a pathogen eradication rate of 47% (9 patients out of 19) at 6 months [44]. However, cefoxitin use may be limited by its pharmacokinetics (every 6-h dosing) and propensity inducing the expression of beta lactamases. Further data on the efficacy and safety of fosfomycin, cefoxitin, and other agents are crucially needed to inform the treatment of CBP caused by MDR bacteria.

For intracellular and sexually transmitted organisms such as Chlamydia trachomatis and Mycoplasma genitalium, tetracyclines (e.g., doxycycline, minocycline), and macrolides (e.g., azithromycin, erythromycin, clarithromycin) are generally recommended given their effectiveness against these organisms and their ability to penetrate the prostate [33, 45]; other options include prulifloxacin, levofloxacin, and ofloxacin [34, 45]. Metronidazole is indicated for patients with Trichomonas vaginalis infections [33, 45].

Management of Recurrence

CBP recurs or relapses in 25% to 50% of patients after oral antimicrobial therapy [17, 46]. Recurrence may result from the development of antimicrobial resistance (due to bacterial virulence factors such as biofilm production [47]), functional or anatomical anomalies of the prostate, patient noncompliance with therapy, and drug interactions that lower the bioavailability of the oral antimicrobial agent. For example, fluoroquinolone resistance has been shown to occur more frequently in men with a large prostate size or an elevated post-void residual urine volume [48]. Prostatic calculi may also lower the efficacy of antimicrobial therapy and contribute to the development of antimicrobial resistance. In a prospective cohort of 101 patients, the presence of prostatic calculi was associated with a lower rate of microbiological eradication, a higher rate of relapse after antimicrobial therapy, and reduced symptom improvement [49]. Furthermore, it has long been suggested that bacteria causing CBP refractory to antibiotic therapy may survive in a milieu protected by biofilms [50,51,52]. Recently, studies have demonstrated that a large proportion of bacterial strains causing CBP are capable of producing biofilms, and prostatic calcifications are also related to calcified bacterial biofilms [53]. Biofilm-producing bacterial strains have also been associated with worse clinical response to therapy [47]. Additionally, bacterial sequestration in the seminal vesicles can also contribute to the persistence or recurrence of prostatic infections despite prolonged antibiotic treatment [54].

If recurrence occurs, repeat urine culture should be performed, and if positive, retreatment with the oral antimicrobial therapy previously effective for the patient is appropriate (e.g., repeating fluoroquinolone therapy) [17]. If the initial therapy was given for 4 weeks or less, a longer treatment duration (e.g., 6 weeks or more) may be needed to achieve clinical cure. However, if resistant pathogens are identified on urine culture, an alternative drug should be selected based on susceptibility testing. Aforementioned options such as fosfomycin and cefoxitin can be considered. Combination antibiotic therapy has also been proposed [48, 55, 56], but currently, there is limited evidence supporting this approach. Biofilm-producing bacterial strains may require long-term treatment regimens, and in particular, the use of antibiotics such as macrolides which are able to achieve high intracellular concentrations and inhibit biofilm production [30]. Lastly, imaging should be considered to evaluate for potential complications including prostatic calculi and abscess [49, 57].

Chronic Antibiotic Prophylaxis

In patients who appear to respond to antibiotic treatment but have persistent or recurrent symptoms and positive urine cultures when off antibiotic therapy, a chronic, low-dose daily prophylactic antibiotic can be used as suppressive therapy to prevent symptom flare-up [2, 18, 58, 59]. Intermittent antibiotic treatment during symptomatic episodes is an alternative strategy [17, 58]. Chronic oral antibiotic suppression for men with persistent or recurrent prostatic infections despite antibiotic treatment is frequently used in clinical practice, even though supporting data are presently lacking [2, 18]. This approach appears to be generally effective, so long as suppression can be maintained [17]. Suitable choices include nitrofurantoin, trimethoprim-sulfamethoxazole, methenamine, fluoroquinolones, cephalosporins, tetracyclines, or any agent previously effective for the isolated pathogen. Given the chronic nature of this therapy, selection of an agent with a favorable side effect profile is generally preferred [59]. In our experience, many patients who previously struggled with symptomatic recurrences have been well controlled with chronic low-dose prophylaxis with methenamine combined with a vitamin C supplement. However, the long-term utility of prophylaxis with methenamine therapy is not well documented in the existing literature [60].

Local Antimicrobial Injection

Direct injections of antimicrobial drugs into the prostate have been proposed by some groups. This approach may enhance intraprostatic drug concentrations compared with oral therapies and hence improve clinical and microbiological efficacy. Local injections also have the potential benefit of shortening treatment duration, thereby lowering risks of drug resistance and treatment side effects. Furthermore, antimicrobials that cannot penetrate the prostate when administered orally may be useful in this approach to target susceptible pathogens. In a randomized controlled trial of 50 patients with CBP, patients randomized to receive local injections had significantly improved symptom scores and rates of bacterial eradication than those who received intramuscular injections (cure rate of 33.3% versus 5%, respectively [p < 0.05]). [61]. In a retrospective cohort of 77 patients with possible CBP, local injections of antimicrobial agents were similarly associated with improved NIH CPSI scores [62]. We think that local injections of antimicrobial agents are a reasonable approach to consider in refractory cases where oral antimicrobial regimens fail. However, more data are needed to assess the efficacy and safety of local injections versus oral therapy in larger and broader patient samples, before wider adoption in clinical practice may be recommended.

Surgical Interventions

The role of surgery in the treatment of CBP remains limited. Generally, surgery is only indicated in refractory cases where oral antimicrobial therapies have failed, especially after complications such as prostatic abscess or calculi and systemic infections arise [17, 18, 46, 58, 59]. Transurethral removal of prostatic tissue, accomplished via TURP, radical TURP to remove the gland down to the true capsule, or transurethral vaporization of the prostate (TUVP), may resolve elevated post-void residual urine volumes, drain prostatic abscess, and remove prostatic calculi harboring bacterial infections [17, 18, 46, 59, 63]. However, TURP and radical TURP specifically carry the risk of injury to adjacent organs and posterior urethral stricture. In rare instances where recurrent septic episodes develop, radical prostatectomy may be required [46]. Radical prostatectomy includes removal of the seminal vesicles, which have been found to sequester bacteria to cause recurrence of prostatic infections despite prolonged antibiotic therapy [46, 54].

Currently, only limited data are available to inform the efficacy and safety of surgical treatment options for CBP. A recently conducted systematic review assessed the evidence base for surgical interventions for chronic prostatitis [64]. The review included 16 studies (12 case series and four review articles) and a total of 131 patients with both NIH category II and III prostatitis who received surgical interventions. Among these patients, 110 were treated with TURP by electrocautery, and 21 underwent radical prostatectomy including six via laparoscopic approach, four via robotic radical prostatectomy, and 11 via conventional open radical prostatectomy. Almost all patients underwent previous medical treatment before surgery, and five of the TURP patients and 12 of the radical prostatectomy patients also received a prior surgical intervention. Among the patients who underwent TURP, “cure” was reported in 78 patients (70%), improvement in 16 (15%), and unchanged in 16 (15%). Among the patients who underwent radical prostatectomy, 20 patients (95%) achieved a full resolution of prostatitis symptoms, and the remaining patient was initially symptom-free but after 4 months developed mild dysuria. No intraoperative or postoperative complications were reported by any of the included studies [64]. While these studies suggest that surgery may offer benefit to patients with CBP refractory to oral antimicrobial therapy, further evidence, especially evidence derived from randomized controlled trials and specific to the CBP population, is needed to inform clinical decision making.

Some authors have suggested that surgical removal of infected prostatic tissue, along with local injections of antimicrobial agents, should be second-line treatment options of men with CBP refractory to first-line oral antimicrobials, and chronic oral antibiotic suppression may be considered as a third-line option [59]. In the absence of definitive evidence, we recommend discussing the potential benefits and risks (e.g., tissue scarring for radical TURP) of each of these options in shared decision-making with individual patients.

Phage Therapy

Given the increasing antimicrobial resistance and frequent recurrence and relapse after oral antimicrobial therapy, there is a pressing need for novel therapies for patients with CBP. Phage therapy is emerging as a novel treatment option for CBP caused by antibiotic resistant organisms [65,66,67]. Phage therapy utilizes bacteriophages, which are viruses that can selectively infect and kill bacteria, including those that have grown resistant to antibiotics. Crucially, phages may penetrate biofilms produced by bacteria [67, 68]. As previously mentioned, biofilms can prevent penetration of antibiotics and contribute to the development of antibiotic resistance [47]. Recent data suggest that phages interact with cells of the immune system and these interactions lead to immunomodulatory effects, which are predominantly anti-inflammatory [69]. The phage-mediated immunomodulating effects could thus be beneficial in reducing inflammation in all forms of prostatitis [67]. Furthermore, it has been hypothesized that phages can cross the epithelial cells of the prostate, based on demonstrated phage transcytosis across epithelial cell layers in other solid organs [67, 70]. If this hypothesis is true, phages may play an important role in halting prostate inflammation and carcinogenesis. Bacterial infections can induce an inflammatory microenvironment in the prostate which in turn can disrupt the normal differentiation of prostate epithelial cells and lead to the development of putative precursor lesions to prostate cancer, such as proliferative inflammatory atrophy and prostatic intraepithelial neoplasia [71]. Phages may therefore contribute to the maintenance of immune homeostasis of the prostate and prevention of prostate cancer by exerting their immunomodulatory effects within the prostate [67].

Early data on phage therapy for the treatment of CBP are positive. In a cohort of 27 patients with CBP who previously failed antibiotic therapy and received phage therapy for an average of 47 days at the Phage Therapy Unit in Wrocław, 13 patients (48%) had no detectible pathogen in two consecutive bacterial cultures of EPS collected at least 2 weeks apart. Another six patients had no detectible pathogen in one EPS culture. Substantially reduced prostatitis symptoms, improved NIH CPSI scores, decreased EPS leukocyte counts, reduced prostate volume, and improved maximum urinary flow rate were also mentioned for an unspecified number of patients. No significant side effects were observed. Intrarectal phage administration was noted to lead to the best results [67, 72]. At the time of this writing, phage therapy is being evaluated in a randomized, placebo-controlled, double-blind clinical trial comparing phage therapy, antibiotic therapy, and placebo for 97 patients planned for TURP presenting with UTIs [73]. Evidence from this trial and further studies is required to inform adoption of phage therapy in the treatment of CBP and other types of UTIs.

Therapies for CP/CPPS

Since men with CBP and those with CP/CPPS often present with similar symptoms (with the latter being more prevalent), here we also briefly highlight common management options for CP/CPPS. CP/CPPS is mainly defined clinically by voiding symptoms and pelvic/perineal pain. In contrast to CBP, treatment options for CP/CPPS are less well-defined. Options include alpha-blockers (e.g., tamsulosin), antibiotics (e.g., fluoroquinolones), anti-inflammatory agents, finasteride, phytotherapy, and neuromodulatory agents, with a multimodal approach often employed [74, 75]. Nonpharmacologic options, including pelvic floor physical therapy, psychosocial counseling, acupuncture, and extracorporeal shock wave therapy, may also benefit some patients by decreasing prostatitis symptoms [74, 76, 77].

Conclusions

In conclusion, oral antimicrobial therapy remains the foundation of treatment of CBP. However, the usefulness of conventional antimicrobial agents, such as fluoroquinolones and trimethoprim-sulfamethoxazole, is increasingly limited by the rising rates of antimicrobial resistance. Our review highlights a clear need for further, more definitive evidence regarding the efficacy and safety of treatment options for CBP refractory to conventional oral antimicrobial agents, including the use of alternative agents such as fosfomycin, direct antimicrobial injections into the prostate, surgical interventions such as TURP, radical TURP, TUVP and radical prostatectomy, chronic oral antibiotic suppression, and phage therapy. Such evidence is urgently required to optimize clinical decisions in managing patients with difficult-to-treat CBP.