Efficacy of repeated cycles of combination therapy for the eradication of infecting organisms in chronic bacterial prostatitis

Abstract

A total of 137 patients with a diagnosis of chronic bacterial prostatitis (CBP) were subjected to combination pharmacological therapy with antibacterial agents (ciprofloxacin/azithromycin), alpha-blockers (alfuzosin) and Serenoa repens extracts. Of those, 88 patients (64.2%) showed microbiological eradication at the completion of a 6-week cycle of therapy. Of the remaining 49 patients showing persistence of the causative organism(s) or reinfection at the end of treatment, 36 completed a second cycle of combination therapy for 6 weeks: 27 patients (75%) showed eradication of the causative organism, whereas in nine cases persistence or reinfection was observed. The cumulative eradication rate of the present study – calculated on a total of 137 enrolled patients – is 83.9%.

Clinical examination showed a marked improvement of signs and symptoms linked to prostatitis. Remarkably, combination therapy could attenuate CBP symptoms prior to microbiological eradication, thus rapidly decreasing the impact of the disease on the quality of life of patients. Clinical remission was extended throughout a follow-up period of 30 months for 94% of patients, whereas seven patients showed relapse of the disease.

In summary, our results indicate that about 20% of patients enrolled in this study, who were refractory to a protocol of 6-week combination therapy, could be ‘rescued’ by a second cycle of treatment. Clinical follow-up data show that combination therapy could ensure extended relief from CBP symptoms, and a general improvement in quality of life.

Introduction

Chronic bacterial prostatitis (CBP) has been recently defined as a chronic or persistent infection of the prostate in which a pathogen can be demonstrated by a lower urinary tract segmented localisation test [1], but in which systemic symptoms are absent [2]. Infection is generally associated with a variety of urinary symptoms, often accompanied by pain in the pelvic region. The severity of these symptoms is usually scored by a worldwide-used index, the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), which is calculated on the basis of a questionnaire addressed to the patient [3]. Other clinical parameters may be necessary to complete the diagnosis of this complex condition, and additional analytical procedures (prostate sonography, urethral swab cultures, seminal fluid cultures, cytology, urine flow rate, urodynamic evaluation, etc.) are usually recommended [4].

CBP has been recently defined as ‘an evolving clinical enigma’ [5]. Indeed, widely accepted concepts and paradigms about classification, aetiology, diagnosis and treatment of this complex condition need to be frequently revised and updated, on the basis of new insights on the disease emerging from the results of clinical trials, or acquired in the setting of the daily clinical practice, in specialised centres treating large numbers of patients.

In particular, the knowledge of pathogenesis and treatment of CBP is continuously evolving. For more than a decade, an increasing number of experts have suggested that chronic prostatitis is a biofilm disease, as the growth of biofilm-encased microcolonies of sessile bacteria has been demonstrated in animal models of prostatitis, as well as in bacterial isolates and biopsies from patients with a history of CBP or other prostate conditions [6], [7], [8], [9]. More recently, it has been remarked that the unsatisfactory permanent cure rate of CBP may be due to the fact that bacteria can survive therapy by producing a biofilm [9]; in this context, delivery of higher doses of antibacterial agents was suggested as a possible approach for permanent eradication of infecting organisms [9]. An alternative approach could be based on the co-administration of first-line agents like fluoroquinolones [10] with drugs that have been shown to be adjuvant in the eradication of colonies of sessile pathogens by inhibiting the formation of biofilms, or by inducing the degradation/disruption of biofilm components. In recent years, 14/15-membered macrolide antibiotics like clarithromycin and azithromycin have been shown to display a significant anti-biofilm intrinsic activity [11]. Due to good penetration/bioavailability in the prostatic tissue fluids and to favourable pharmacodynamic characteristics [12], [13], macrolides are currently used in the treatment of Chlamydial prostatitis [14], [15], [16], [17] and have been indicated, together with fluoroquinolones, as preferred drugs for the treatment of prostatitis because of their activity on biofilms [18]. Indeed, combinations of macrolides with fluoroquinolones or beta-lactam antibiotics have been shown to be safe and effective in patients affected by complicated urinary tract biofilm infections [19], [20], and have been suggested to have high therapeutic potential in the treatment of CBP [21]. Thus, for treatment of CBP new combinations of antibacterial drugs are suggested and increasingly adopted, although still empirically. Combination therapy can also include other drugs, and antibiotics are increasingly associated with alpha-blockers and anti-inflammatories (usually referred to as ‘the three A-therapy’) [22]. In this context, combination of quinolone antibiotics and alpha-blockers, recommended for type II CBP by a recently published therapeutic algorithm [12], was shown to be effective in the treatment of bacterial prostatitis, and to reduce recurrences as defined by expressed prostatic secretion-positive segmental cultures [23]. Moreover, administration of quinolones, alpha-blockers and herbal extracts characterised by anti-inflammatory properties (quercetin and saw palmetto extracts) was shown to induce a significant improvement of symptoms, as scored by the NIH-CPSI [24]. Based on this and other evidence [22], combination therapy is increasingly adopted for treatment of patients affected by CBP [12], [18].

Although new therapeutic approaches have resulted in improved cure rates, relapses due to unsuccessful microbiological eradication continue in some cases to frustrate the efforts and the expectations of clinicians and patients. In this scenario, is believed that careful optimisation of therapeutic regimens can improve the effectiveness of available therapeutic agents, and enhance the cure rate of CBP. In this paper we report that in patients affected by CBP – showing persistence of infecting organisms after a first 6-week cycle of combination therapy – successful microbiological eradication can be achieved at the end of a second 6-week cycle of treatment.