International Journal of Antimicrobial Agents 21 (2003) 457 /462 www.ischemo.org Comparative analysis of azithromycin and ciprofloxacin in the treatment of chronic prostatitis caused by Chlamydia trachomatis Višnja Škerk a,*, Slavko Schönwald a, Ivan Krhen b, Arthur Banaszak c, Josip Begovac a, Jadranka Strugar c, Zvonimir Strapac c, Renata Vrsalovic a, Jacinta Vukovic c, Margita Tomas c a University Hospital for Infectious Diseases ‘Dr. Fran Mihaljevic’, Mirogojska 8, 10 000 Zagreb, Croatia b Clinical Hospital Centre Rebro, Zagreb, Croatia c PLIVA Pharmaceutical Company, Zagreb, Croatia Received 19 June 2002; accepted 10 September 2002 Abstract A total of 89 patients, ( /18 years), with symptoms of chronic prostatitis and inflammatory findings as well as the presence of Chlamydia trachomatis confirmed by DNA/RNA DIGENE hybridization method and/or by isolation, McCoy culture and Lugol stain in expressed prostatic secretion or in voided bladder urine collected immediately after prostatic massage, were examined. The patients were randomized to receive a total of 4.5 g of azithromycin for 3 weeks, given as a 3-day therapy of 1 /500 mg weekly or ciprofloxacin 500 mg b.i.d. for 20 days. Patients’ sexual partners were treated at the same time. Clinical and bacteriological efficacy were evaluated 4 /6 weeks after the end of therapy. Significantly higher eradication (36/45: 17/44; P/0.0002) and a significantly higher clinical cure (31/45: 15/44; P /0.0021) were achieved in the group of patients treated with azithromycin than in the ciprofloxacin group. # 2003 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Prostatitis; Chlamydia trachomatis ; Treatment; Azithromycin; Ciprofloxacin 1. Introduction Prostatitis is a disease entity that is diagnosed by symptoms, the microscopy of expressed prostatic secretion (EPS) and the culture of EPS and segmented urine samples . According to the duration of symptoms, prostatitis is described as either acute or, where symptoms are present for at least three months, chronic . What was previously denoted ‘prostatitis’ is today referred to as ‘prostatitis syndrome’ . Basic factors for the classification of prostatitis syndrome include clinical symptoms and signs as well as the presence of bacteria and leukocytes in both selectively collected urine samples and expressed pro- * Corresponding author. Tel.: /385-1-4603-222; fax: /385-1-4678235. E-mail address: [email protected] (V. Škerk). static secretion determined using Meares and Stamey localization technique . Classification of prostatitis according to Drach et al. differentiates between: (1) acute bacterial prostatitis; (2) chronic bacterial prostatitis; (3) chronic abacterial prostatitis; (4) prostatodynia . In 1995, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institute of Health recommended new classification of the prostatitis syndrome: (1) acute bacterial prostatitis; (2) chronic bacterial prostatitis; (3) chronic pelvic pain syndrome; (3A) inflammatory chronic pelvic pain syndrome; (3B) non-inflammatory chronic pelvic pain syndrome; (4) asymptomatic inflammatory prostatitis . The aim of this prospective, comparative, randomized study was to compare the efficacy and tolerability of azithromycin and ciprofloxacin in the treatment of chronic prostatitis caused by Chlamydia trachomatis . 0924-8579/03/$30 # 2003 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/S0924-8579(03)00056-6 458 V. Škerk et al. / International Journal of Antimicrobial Agents 21 (2003) 457 /462 2. Patients and methods Since the beginning of 1999, as part of two scientificresearch projects of the Ministry of Science and Technology of the Republic of Croatia, we have prospectively been investigating prostatitis syndrome and urogenital infections caused by C. trachomatis at the University Hospital for Infectious Diseases ‘Dr. Fran Mihaljevic’, Zagreb. In the period March 1, 1999/ February 28, 2002, we performed quantitative segmental bacteriological localization cultures and microscopy of EPS, as described by Meares and Stamey, on a total of 1352 males older than 18 years of age. The presence of C. trachomatis was looked for using a urethral swab and EPS specimens of all patients. C. trachomatis was confirmed by the DNA/RNA DIGENE hybridization method and/or by isolation, McCoy culture and Lugol stain. The majority of patients came to the Outpatient Department for Urogenital Infections and Sexually Transmitted Diseases because of symptoms of urogenital infection; only a few came because of symptoms and laboratory findings of their sexual partner, reactive arthritis or fear from having contracted a sexually transmitted disease. Of the 1352 patients, /10 WBC/ hpf in EPS was detected in 902 patients, and C. trachomatis in EPS of 324 patients. Some results from this study are currently in press . This prospective, comparative, randomized study, part two scientific-research project of the Croatian Ministry of Science and Technology, was conducted at the Outpatient Department for Urogenital Infections and Sexually Transmitted Diseases, University Hospital for Infectious Diseases ‘Dr. Fran Mihaljevic’, Zagreb, Croatia, between January 1, 2001 and December 31, 2001. The Ethics Committee of the University Hospital for Infectious Diseases ‘Dr. Fran Mihaljevic’, Zagreb, approved the study. 2.1. Patients We examined a total of 89 patients, older than 18 years of age, with inflammatory finding as well as the presence of C.trachomatis in expressed prostatic secretion (EPS) or in voided bladder urine collected immediately after prostatic massage (VB3). In all patients clinical symptoms were present for at least 3 months. There was no evidence of structural or functional abnormalities of genitourinary tract in these patients. 2.2. Diagnostic criteria The inclusion criteria for C. trachomatis prostatitis were the presence of ten or more WBC/hpf in EPS or VB3, presence of C. trachomatis in EPS or VB3, absence of C. trachomatis in urethral swabs and absence of other possible pathogens of chronic prostatitis in urethral swab specimens, VB1, VB2, EPS or VB3. Patients with hypersensitivity to macrolides or fluoroquinolones, severe renal or hepatic impairment (AST and/or ALT levels twice above the upper limit) as well as patients who had received any oral antibiotic 2 weeks prior to study enrolment and patients with chronic diarrhoeal diseases or other gastrointestinal conditions which could affect drug absorption, were excluded. 2.3. Methods The following data were obtained for each patient: medical history, clinical status including digitorectal prostatic examination, urethral swab specimens and selective samples of urine and EPS, according to the 4glass localization test. Urethral swab specimens were examined for C. trachomatis , Trichomonas vaginalis , Ureaplasma urealyticum and Mycoplasma hominis . In segmented samples of urine and EPS the number of leukocytes were determined and the number of Gram-positive and Gram-negative bacteria in 1 ml of sample. EPS and urine sample collected immediately after prostatic massage were examined for the presence of C. trachomatis , U. urealyticum , M. hominis and T. vaginalis . Quantitative segmented cultures and bacterial identification in three voided urine samples and EPS as well as bacteriological analysis of urethral swabs were performed at the Laboratory for Clinical Microbiology of the University Hospital for Infectious Diseases ‘Dr. Fran Mihaljevic, Zagreb, Croatia, using standard microbiological methods. Diagnosis of urogenital mycoplasma was confirmed by semi quantitative culturing and antimicrobial susceptibility test, Mycoplasma duo 62740, Sanofi, Diagnostic Pasteur. Diagnosis of T. vaginalis was confirmed by culture on Diamond modified medium. C. trachomatis was demonstrated in urethral swabs/EPS/VB3 using DNA/RNA hybridization method and/or by isolation, McCoy culture and Lugol stain. The isolation of C. trachomatis was performed at the Croatian Institute for Public Health, Zagreb, Croatia. 2.4. Antimicrobial treatment Patients were randomized according to a computerized randomization list to receive a total dose of 4.5 g of azithromycin given as a 3-day therapy of 1/500 mg weekly for 3 weeks or ciprofloxacin 500 mg b.i.d. for 20 days. Patients’ sexual partners were treated at the same time. Female partners with asymptomatic urogenital chlamydial infection and those with infection symptoms lasting longer than three weeks were treated with total dose of 3.0 g of azithromycin, while those with acute V. Škerk et al. / International Journal of Antimicrobial Agents 21 (2003) 457 /462 459 Table 1 Age of patients with chronic chlamydial prostatitis Age Patients treated with azithromycin Patients treated with ciprofloxacin Total 18 /19 20 /29 30 /39 40 /49 50 /59 60 /69 1 7 13 12 11 1 2 7 13 11 10 1 3 14 26 23 21 2 Total 45 44 89 Median9/S.D. 40.899/11.96 infection were given a single dose of 1.0 g of azithromycin. Clinical efficacy and tolerability of administered drug as well as possible adverse events were evaluated during, at the end and 4 /6 weeks after completion of therapy. Bacteriological efficacy of administered drug was evaluated 4 /6 weeks after completion of therapy, using methods identical to those used during study enrolment. 2.5. Statistics Statistical significance of observed differences between treatment groups was assessed by Yates corrected chi-square test or Fisher‘s exact test when appropriate. Differences in continuous variables were assessed by Student’s t -test. 3. Results A total of 89 patients with chronic prostatitis caused by C. trachomatis were available for this study. Treatment groups did not differ regarding age (Table 1, t/ 0.538717). Distribution of particular clinical symptoms (Table 2) was not statistically different between two therapeutic groups of patients (urethral P /0.9999, prostatic P / 0.6905, sexual P /0.9999, other P /0.9794). 39.489/12.75 Treatment groups did not differ according to digotorectal prostatic examination of the prostate gland (Table 3; P /0.9472). One patient treated with azithromycin had nausea as well as serum transaminases elevated on the level below three times of the upper limit immediately after completion of therapy. After two weeks serum transaminases were within normal range. Bacteriological evaluation of azithromycin and ciprofloxacin in the treatment of patients with chronic prostatitis caused by C. trachomatis is shown in Table 4. A significantly higher eradication was achieved in the group of patients treated with azithromycin (P / 0.0002). Clinical evaluation of azithromycin and ciprofloxacin efficacy in the treatment of chronic chlamydial prostatitis is shown in Table 5. A significantly higher clinical cure rate was achieved in the group of patients treated with azithromycin than in ciprofloxacin group (P /0.0021). 4. Discussion C. trachomatis is the most frequent cause of epididymitis in patients up to 35 years of age and according to recent literature data and results of our study of a total of 1352 patients, C. trachomatis is a common bacterial pathogen causing prostatitis [5,6]. Chlamydia tracho- Table 2 Incidence of clinical symptoms in patients with chronic chlamydial prostatitis Clinical symptoms Patients treated with azithromycin Patients treated with ciprofloxacin Total Urethral Prostatic Sexual 17 31 9 16 32 8 33 63 17 2 3 5 Other V. Škerk et al. / International Journal of Antimicrobial Agents 21 (2003) 457 /462 460 Table 3 Digitorectal examination of patients with chronic chlamydial prostatitis Prostate finding Patients treated with azithromycin Patients treated with ciprofloxacin Total Normal Soft and tender Hard 33 10 2 31 11 2 64 21 4 Total 45 44 89 matis is causally linked to acute and chronic prostatitis [7 /19]. Acute prostatitis is a disease entity where symptoms are present for less than 3 months, while symptoms in chronic prostatitis are present for at least 3 months . Other diagnostic criteria, the microscopy of EPS and the culture of EPS and segmented urine samples, are identical in both acute and chronic prostatitis with the exception of acute bacterial prostatitis when prostatic massage is contraindicated [1,2]. On the other hand, the European Association of Urology ‘Guidelines on urinary and male genital tract infections for 2002’, and many review articles about prostatitis syndrome, state that the role of C. trachomatis in chronic prostatitis is unclear and controversial [1,20/ 22]. We believe that the cause of these disagreements is the fact that EPS was not adequately analyzed for the presence of C. trachomatis . C. trachomatis is an intracellular Gram-negative bacteria with particular life cycle of development and growth which is complex and dimorphic . It is the most common bacterial pathogen of sexually transmitted diseases causing acute and chronic recurrent but also persistent infections . More than half of the infected persons have an aysmptomatic form of infection or a very mild clinical course  making it very difficult to determine when C. trachomatis infection started. For this reason, the classification of symptomatic Chlamydial infection of the prostate into acute and chronic is made on the basis of the duration of clinical symptoms present. Antimicrobial drugs used in the treatment of prostatitis caused by C. trachomatis must fulfill two main criteria: high susceptibility of C. trachomatis to these Table 4 Bacteriological evaluation of azithromycin and ciprofloxacin efficacy in the treatment of chronic chlamydial prostatitis drugs, and accumulation in prostatic tissue and secretion during chronic inflammation for 2 /4 weeks . C. trachomatis has good in vitro susceptibility to tetracycline, doxycycline, erythromycin, azithromycin, clarithromycin, rifampicin, ofloxacin and clindamycin . In vitro susceptibility testing of urogenital isolates of C. trachomatis demonstrated isolates simultaneously resistant to tetracycline, doxycycline, erythromycin, sulphamethoxazole and clindamycin, but sensitive to rifampicin, ciprofloxacin and ofloxacin . Azithromycin is a new member of macrolide group of antimicrobial drugs. It is well absorbed after oral use, quickly distributed throughout the body achieving high concentrations in tissues and slowly eliminated from them . The extensive tissue uptake of azithromycin has been attributed to cell uptake into lysosomes. MIC90 for C. trachomatis is 0.12 /0.25 mg/l . In clinical study as well as in clinical practice azithromycin has shown efficacy in the treatment of chlamydial prostatitis and other urogenital, sexually transmitted infections [29,30]. Ciprofloxacin is a highly active fluoroquinolone. Following oral dose it is rapidly absorbed and distributed throughout the body achieving concentrations in prostate tissues up to 2.3-fold higher than those in serum [31,32]. The MIC90 for C. trachomatis is 1 /1.3 mg/l . Ciprofloxacin is retained in cells for a short period of time, localized in the cytoplasma outside lysosomes and phagosomes . Ciprofloxacin administered in dose 2 /500 mg for 7 days achieved cure in 21.4 /61.5% of patients with chlamydial urethritis [33 /35]. Cure was recorded in 15 of 16 patients with pelvic inflammatory disease caused by C. trachomatis and receiving ciprofloxacin 2 /750 mg for 2 weeks . Ciprofloxacin is Table 5 Clinical efficacy of azithromycin and ciprofloxacin in the treatment of chronic chlamydial prostatitis Efficacy Efficacy Patients treated with azithromycin (n/45) Eradication 36 (80%) Persistence 9 (20%) Patients treated with ciprofloxacin (n/44) 17 (38.64) 27 (61.36) Patients treated with azithromycin (n /45) Cure 31 (68.9%) Improvement 4 (8.9%) Failure 10 (22.2%) Patients treated with ciprofloxacin (n/44) 15 (34.1%) 7 (15.9%) 22 (50%) V. Škerk et al. / International Journal of Antimicrobial Agents 21 (2003) 457 /462 the drug of choice for patients with inflammatory chronic pelvic pain syndrome (chronic abacterial prostatitis), meaning in patients in whom prostatitis pathogens cannot be detected in EPS by using standard microbiological methods [1,26]. It is possible that in some of these patients C. trachomtis is the pathogen causing prostatitis and that these are cases of chronic bacterial prostatitis caused by C. trachomatis . Our study has shown a correlation between results of in vitro study of the efficacy of ciprofloxacin against C. trachomatis and its efficacy in patients with chronic chlamydial prostatitis. Significantly higher eradication (36/45:17/44) and significantly higher clinical cure (31/ 45:15/44) were achieved in the group of patients treated with azithromycin compared with the the ciprofloxacin group. In patients with prostatitis caused by C. trachomatis , the drug of choice is azithromycin. 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