Leading article. Chronic prostatitis an infectious disease? Giessen, Germany

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1 Journal of Antimicrobial Chemotherapy (2000) 46, JAC Leading article Chronic prostatitis an infectious disease? Kurt G. Naber a * and Wolfgang Weidner b a Urologic Clinic, Hospital St Elisabeth, Straubing; b Department of Urology, University of Giessen, Giessen, Germany It has been estimated that up to half of all men suffer from symptoms of prostatitis at some time in their lives. 1 In the early 1990s, prostatitis resulted in 2 million office visits per year in the USA, 2 rivalling the number of visits for benign prostatic hypertrophy (BPH) at the time. It is the most frequent urological diagnosis in men less than 50 years of age and the third most common urological diagnosis in men greater than 50 years of age. 2 It has been clearly demonstrated that chronic prostatitis has an impact on a patient s quality of life similar to a myocardial infarction, angina or Crohn s disease. 3 Prostatitis is a major health care issue, as important as the other two major prostatic diseases, BPH and carcinoma. 4 Even so, our knowledge of prostatitis is still somewhat limited. Acute bacterial prostatitis The term prostatitis, suggests that this disease is of an inflammatory nature, possibly caused by an infective agent. This obviously holds true for patients with acute bacterial prostatitis. These patients often present with a flu-like illness with systemic symptoms, indicating tissue invasion, in addition to local symptoms of bacteriuria, such as urinary urgency, dysuria, frequency, etc. On physical examination the prostate can feel tense and be exquisitely tender. There are leucocytes in the prostatic fluid and midstream urine: culture of either usually reveals Escherichia coli, or less commonly, other bacteria such as Klebsiella, Pseudomonas, Enterococcus spp., etc. Prostatic massage, however, should not be performed in these patients because this could induce septicaemia. The majority of these patients get better when treated with appropriate antibiotics. Occasionally, patients develop complications such as urinary retention, septicaemia, prostatic abscess and, in rare cases, metastatic infections such as pyogenic vertebral osteomyelitis. 5 How often such an acute infection becomes a chronic infection is unclear. Chronic prostatitis syndrome In contrast, the term chronic prostatitis is applied to a mixture of different entities that cannot be clearly separated with our present knowledge. Therefore, this complex is best described as a syndrome of various types of chronic pelvic pain, voiding disturbances and sexual dysfunction, of which the pelvic pain is the most prominent symptom (as compared with patients with BPH and those with erectile dysfunction). 6 Stress and psychological problems, particularly depression, are very commonly found in these patients, but it is not yet clear whether, a priori, psychological dysfunctions cause this syndrome, or if this syndrome itself causes the psychological dysfunction. Classification of prostatitis syndrome Various classification systems have been used to define which patients with this syndrome have an infection, which have an inflammatory process of other aetiology and which have other problems, e.g. neuromuscular, psychogenic disorders, etc. In the past, the classification of Drach et al. 7 was most frequently used. It is based on the bacteriological localization patterns obtained by the four glass test. 8 In this classification the chronic prostatitis syndrome is divided into: (i) chronic bacterial prostatitis; (ii) non-bacterial prostatitis; and (iii) prostatodynia depending on whether the prostatic secretion contains: (a) bacteria and leucocytes; (b) leucocytes only; or (c) neither. Chronic bacterial prostatitis is also diagnosed when the number of bacteria cultured in prostatic fluid or in urine obtained after prostatic massage (specimen VB3 in the four glass test) is at least 10 times greater than in the first voided (VB1) and midstream urine (VB2) specimens. An inflammatory process is assumed if the number of leucocytes exceeds 10 per high *Corresponding author. Professor and Head of Urologic Clinic, St Elisabeth Hospital, St Elisabeth Strasse 23, D Straubing, Germany. Tel: ; Fax: ; NaberK@klinikum-straubing.de 2000 The British Society for Antimicrobial Chemotherapy 157

2 power field ( 400) or 1000 per L in prostatic fluid or VB3, without pyuria in VB2. 8 Because of the lack of knowledge concerning the epidemiology, pathophysiology, diagnosis and treatment of prostatitis, the National Institutes of Health (NIH) of the USA started an international initiative. A new classification system, 9 which provides uniform definitions of the various types of prostatitis, was proposed in order to facilitate collaborative research. The NIH and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) proposed this new classification system in and this was reaffirmed in 1998 (Table I). Which pathogens cause chronic prostatitis? There is a continuing debate about which bacteria can be considered as pathogens. In the most conservative approach only those bacteria that can be localized to the expressed prostatic secretions and that cause documented recurrent urinary tract infections (UTIs) are included. 11 By this definition, few bacteria other than E. coli, other Enterobacteriaceae, such as Klebsiella, Enterobacter, Proteus and Serratia spp, and Pseudomonas aeruginosa are considered to be pathogens. Enterococci and staphylococci would not be included even though these pathogens can often be localized to the prostate and may be associated with the chronic prostatitis syndrome Furthermore, in several clinical studies, Gram-positive cocci have been cultured from prostatic secretions in numbers meeting the criteria of Meares & Stamey 8 and these patients responded to antibiotic therapy. A number of other microorganisms have been reported as likely causes of this syndrome: Trichomonas vaginalis, Chlamydia trachomatis, genital mycoplasmas, difficult-toculture coryneforms, genital viruses and, rarely, mycobacteria, gonococci, parasites and fungi have all been implicated in prostatitis. 20 Evidence of the misclassification of at least some cases of non-bacterial prostatitis is also accumulating. 4 Immunological evidence, such as the existence of antibodies to uropathogenic bacteria in patients with negative cultures 21,22 suggests a bacterial presence. This is supported by evidence of both bacterial DNA 23 and cultured Table I. NIH/NIDDK Classification of Prostatitis 10 Category I II III IIIA IIIB IV Classification acute bacterial prostatitis chronic bacterial prostatitis chronic pelvic pain syndrome (CPPS) CPPS: inflammatory CPPS: non-inflammatory asymptomatic inflammatory prostatitis cryptic bacteria 20 detected in prostate biopsies and prostatic fluid of patients with sterile cultures. As many as 50% of transperineal prostatic biopsies in patients with chronic inflammatory prostatitis grow bacteria. 24,25 Thus, the full impact of infection remains unresolved in chronic inflammatory prostatitis. The role of antimicrobial therapy in chronic prostatitis Despite reports that fewer than 10% of prostatitis cases are bacterial, 26 a much higher proportion of men diagnosed with prostatitis receive antimicrobials. Antibiotic therapy is recommended for acute bacterial prostatitis and chronic bacterial prostatitis; it is of debatable benefit in patients with inflammatory chronic pelvic pain syndrome. 27 The therapeutic problems with antimicrobials are, on one hand, the different biological status of the pathogens (which are often in a biofilm infection) and, on the other hand, the penetration barrier for many agents. Only a few antibiotics are able to penetrate sufficiently well into prostatic secretions. Penetration depends mainly on the degree of ionization of the compound in plasma. In the acidic prostatic secretions, a weak base such as trimethoprim (with a pka of 7.4) can be expected to be concentrated about four- or five-fold compared with plasma. 28 Clinical studies have shown, however, that the ph of prostatic fluid in patients with chronic prostatitis is often neutral or alkaline. 29 In this case no concentration of trimethroprim could be expected. This may explain why the results obtained with trimethoprim or co-trimoxazole generally did not produce cure rates of 50%. Because of their favourable pharmacokinetic properties, the fluoroquinolones may be better options. The quinolones are zwitterions with a different pk a in an acidic and an alkaline milieu. 28 For example, the isoelectric point of ciprofloxacin is at ph 7.4, which corresponds to the ph of plasma. At this ph only 10% of ciprofloxacin is ionized and thus it can penetrate through biological barriers. We determined the concentrations of several quinolones (ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, norfloxacin and ofloxacin) in the prostatic fluid of volunteers. 30 We obtained prostatic fluid by prostatic massage and took care to ensure that the prostatic fluid was not contaminated by urethral urine with a high antibiotic content: the volunteers were not allowed to void between drug intake and prostatic massage. We also administered an iv renal contrast medium at the same time as the quinolones, enabling us to detect urinary contamination at levels of 1%. The quinolones penetrated into prostatic fluid to variable degrees. It was lowest for norfloxacin (c. 10%) and highest for lomefloxacin (c. 50%), but none of the concentrations within prostatic fluid exceeded the corresponding plasma concentrations. In contrast, all quinolones were concentrated within seminal fluid: concentration of 158

3 lomefloxacin exceeded plasma concentrations by c % and those of ciprofloxacin being seven- to nine-fold higher than the plasma concentration. 30 For gatifloxacin, a new fluoroquinolone with activity against Gram-negative and Gram-positive uropathogens, as well as against gonococci, chlamydia, ureaplasma, mycoplasma and anaeobes, the concentrations in prostatic and seminal fluids were about the same as in plasma. 31 The concentrations of quinolones in prostatic tissue obtained from patients undergoing transurethral resection of the prostate also, in general, exceeded the corresponding plasma concentration, the ratio being lowest for ofloxacin (c. 1), and highest for ciprofloxacin and enoxacin (c. 2). 30 Several clinical studies of quinolone therapy for prostatitis have been published. 32 The results are difficult to compare, however, because not all workers used the Meares & Stamey technique 8 for diagnosis. The duration of treatment, which should be for a minimum of 2 4 weeks, and the follow-up period also differed tremendously. Only a few studies had a follow-up period of 4 weeks or more. Since, in chronic prostatitis, relapse is the main problem, the followup period must be sufficiently long in order to confirm that the patient is cured. Results of studies of quinolones with a follow-up period of at least 6 months are shown in Table II. Initial clinical results with fluoroquinolones are promising, at least in patients with chronic bacterial prostatitis due to E. coli and other Enterobacteriaceae. The therapeutic role of these drugs, however, needs to be defined by controlled studies with utilization of an internationally accepted protocol. Such a protocol was proposed at the 3rd International Symposium on Clinical Evaluation of Drug Efficacy in UTI. 33 Other causes of the chronic prostatitis syndrome Other pathogenic mechanisms of the chronic prostatitis syndrome have been suggested. Barbalias et al. 34,35 proposed that there was a sympathetically mediated urethral spasm synchronous with voiding and thus used the term painful male urethral syndrome instead. In the majority of, but not all, patients urinary flow rate (both maximum and mean) was, indeed, decreased. The video study of micturition showed a distal narrowing of the prostatic urethra with a high maximum urethral closure, and in several patients there was also a proximal urethral stenosis (incomplete funnelling). The authors also found increased urethral pressures at rest, i.e. without voiding, in an area corresponding to the distal urethra and/or the membranous urethral segment. This condition may be a form of detrusor internal sphincter dysynergia. The increased urethral pressure may push bacteria retrogradely into the prostatic ducts and cause discomfort or pain: later this may result in inflammation. McNeal 36 found that inflammation in the peripheral zone of the prostate occurred more frequently than in the central zone. Furthermore, all of the ducts from the peripheral zone drain into the distal part of the prostatic urethra, beyond the verumontanum. This urethral segment corresponds to the site of the distal urethral narrowing seen in the video studies. However, the authors did not find any statistically significant difference in the urodynamic parameters in patients with or without inflammatory findings (leucocytes) in prostatic secretion. This region of the prostate is known to be rich in -adrenergic receptors. Therefore, treatment with -blockers, especially the newer selective -1-blockers, may relieve symptoms. In a large clinical study, Barbalias et al. 37 treated patients with either non-bacterial prostatitis or prostatodynia with demonstrable high maximal urethral closure pressure with -blockers: 50% of a group with documented chronic bacterial prostatitis were also given -blockers. Ciprofloxacin was given to all patients with positive cultures of expressed prostatic secretions, and to 50% of those with non-bacterial prostatitis. The recurrence rate of bacterial prostatitis was significantly reduced by -blockade and symptom relief was achieved for many months. For non-bacterial prostatitis a lower rate of symptom recurrence was found in Table II. Eradication of pathogens (bacteriological cure) in patients with chronic bacterial prostatitis treated with fluoroquinolones Quinolone Dosage q12h Duration of No. of evaluable Bacteriological Duration of (mg) therapy (days) patients cure (%) follow up (months) Reference Norfloxacin Norfloxacin Ofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin , 46 Ciprofloxacin Only studies are listed in which the diagnosis was derived from application of the Meares & Stamey 8 technique and a follow up of at least 6 months was available. 159

4 patients receiving only -blockers compared with those treated with a combination of -blockers and antibiotics. About 90% of patients with prostatodynia responded to -blockade given for up to 6 months. 37 Urinary reflux into the prostatic ducts owing to functional urethral obstruction 35 may also lead to a chemical inflammatory reaction. 38 Patients with non-bacterial prostatitis were treated with allopurinol for 240 days in a placebo-controlled study in order to determine the effects of a reduction in the urate concentration. 38 Patients showed relief of symptoms. It was postulated that prostatic inflammation in non-bacterial prostatitis is due to increased levels of purine- and pyrimidine-containing metabolites in prostatic ducts, a novel concept that deserves further examination. 39 Conclusion In contrast to acute bacterial prostatitis the chronic prostatitis syndrome is caused by infection and needs antimicrobial therapy in only a minority of patients. 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5 28. Naber, K. G. & Madsen, P. O. (1999). Antibiotics: basic concepts. In Textbook of Prostatitis. (Nickel J. C., Ed.) pp Isis Medical Media, Cambridge. 29. Pfau, A., Perleberg, S. & Shapiro, A. (1978). The ph of the prostatic fluid in health and disease: implications of treatment in chronic bacterial prostatitis. Journal of Urology 119, Naber, K. G. (1993). Role of quinolones in treatment of chronic bacterial prostatitis. In Quinolone Antimicrobial Agents, (Hooper, D. C. & Wolfson, J. S., Eds), pp American Society for Microbiology, Washington, DC. 31. Naber, C. K., Steghafner, M., Kinzig-Schippers, M., Sörgel, F., Stahlberg, H. J., Hajos, A. K. & Naber, K. G. (1999). Gatifloxacin: plasma and urine concentrations and penetration into prostatic and seminal fluid after single oral dose of 400 mg in volunteers. (Abstract P447) Journal of Antimicrobial Chemotherapy 44, Suppl. A, Naber, K. G. & Weidner, W. (1999). Prostatitis, epididymitis and orchitis. In Infectious Diseases, (Armstrong, D. & Cohen, J. Eds), pp Mosby, London. 33. Naber, K. G. & Giamarellou, H. (1994). Proposed study design in prostatitis. Infection 22, Suppl 1. S59 S Barbalias, G. A., Maeres, E. M. & Sant, G. R. (1983). Prostatodynia: clinical and urodynamic characteristics. Journal of Urology 130, Barbalias, G. A. (1990). Prostatodynia or painful male urethral syndrome? Urology 36, McNeal, J. E. (1983). The prostate gland morphology and pathobiology. Monographs in Urology 4, Barbalias, G. A., Nikiforidis, G. & Liatsikos, E. N. (1998). Alphablockers for the treatment of chronic prostatitis in combination with antibiotics. Journal of Urology 159, Persson, B. E., Ronquist, G. & Ekblom, M. (1996). Ameliorative effect of allopurinol on nonbacterial prostatitis: a parallel doubleblind controlled study. Journal of Urology 155, Nickel, J. C., Siemens, D. R. & Lundie, M. J. (1997). Ameliorative effect of allopurinol on nonbacterial prostatitis: a parallel doubleblind controlled study. Journal of Urology 157, Schaeffer, A. J. & Darras, F. S. (1990). The efficacy of norfloxacin in the treatment of chronic bacterial prostatitis refractory to trimethoprim-sulfamethoxazole and/or carbenicillin. Journal of Urology 144, Petrikkos, G., Peppas, T., Giamarellou, H., Poulios, K., Zouboulis, P. & Sfikakis, P. (1991). Four year experience with norfloxacin in the treatment of chronic bacterial prostatitis, Seventeenth International Congress of Chemotherapy, Berlin, FRG, June 23 28, 1991, Abstract Futuramed, Munich. 42. Pust, R. A., Achenheil-Koppe, Gilbert P. & Weidner, W. (1989). Clinical efficacy of ofloxacin (Tarivid ) in patients with chronic bacterial prostatitis: preliminary results. Journal of Chemotherapy 1, Suppl. 4, Weidner, W., Schiefer, H. G. & Brähler, E. (1991). Refractory chronic bacterial prostatitis: a re-evaluation of ciprofloxacin treatment after a median follow up of 30 months. Journal of Urology 146, Weidner, W. & Schiefer, H. G. (1991). Chronic bacterial prostatitis: therapeutic experience with ciprofloxacin. Infection 19, Suppl. 3, S Pfau, A. (1987). Therapie der unteren Harnwegsinfektionen beim Mann unter besonderer Berücksichtigung der chronischen bakteriellen Prostatitis. Aktuelle Urologie 18, Pfau, A. (1991). The treatment of chronic bacterial prostatitis. Infection 19, Suppl. 3, S Naber, K. G., Busch, W., Focht, J. & the German Prostatitis Study Group (1999). Ciprofloxacin in the treatment of chronic prostatitis: a prospective, non-comparative multicentre clinical trial with long term follow-up. International Journal of Antimicrobial Agents 14,

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