Etiology and treatment of chronic bacterial prostatitis the Croatian experience Višnja Škerk University Hospital for Infectious Diseases "Dr. Fran Mihaljevic" Zagreb Croatia Milano, Malpensa, 14 Nov 2008
The aim of our study was to investigate the etiology and treatment of chronic bacterial prostatitis, especially the significance of Chlamydia trachomatis and Ureaplasma urealyticum in prostatitis syndrome and the possibilities for treatment.
This research is a part of several scientific research projects of the Ministry of Science, Education and Sports of the Republic of Croatia: Urogenital infections caused by C. trachomatis (no. 0143004) Etiology and treatment of chronic prostatitis (no. 0108149) Clinical significance of urogenital mycoplasma (no. 0143003) Diagnosis and treatment of patients with prostatitis syndrome (no. 143-1080002-0050)
The study was conducted at the Outpatient Department for Urogenital Infections, University Hospital for Infectious Diseases Dr Fran Mihaljevic Zagreb, Croatia, between March 1, 1999 and June 30, 2008. The Ethics Committee of the Hospital approved the study. An informed consent was signed by all the patients.
PATIENTS In the 9 year study, we examined a total of 3029 patients over 18 years of age with symptoms of chronic prostatitis and no evidence of structural or functional lower genitourinary tract abnormalities.
The inclusion criteria for chronic prostatitis was the duration of symptoms for at least 3 months. The patients complained of one or more of the following symptoms: urethral symptoms (voiding dysfunction, urinary urgency, frequency, nocturia, dysuria) prostatic symptoms (pain and discomfort in the low back and in the perineal, suprapubic, penile, scrotal, or groin areas) sexual symptoms (pain during or after ejaculation or erectile dysfunction)
METHODS The following data were obtained for each patient: - medical history - clinical status - digitorectal prostatic examination - urethral swab specimens - selective samples of urine and EPS (Meares and Stamey 4-glass localization technique) - the severity of chronic prostatitis symptoms scored by the Croatian translation of the NIH-CPSI questionnaire was performed in only a small number of patients
METHODS Urethral swab specimens were examined for the presence of Chlamydia trachomatis, Ureaplasma urealyticum and Mycoplasma hominis.
METHODS Quantitative segmented cultures and bacterial identification as well as the number of leukocytes were determined in three voided urine samples (first voided- VB 1, midstream - VB 2, and urine bladder sample collected immediatelly after prostatic massage - VB 3 ) and expressed prostatic secretion (EPS). (Standard microbiological methods, Clinical Microbiology Laboratory of the Hospital)
METHODS EPS or VB 3 were examined for the presence of Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis and Trichomonas vaginalis.
METHODS Urogenital mycoplasma Trichomonas vaginalis Chlamydia trachomatis semiquantitative culturing antimicrobial susceptibility test Mycoplasma duo and S.I.R. Mycoplasma test (Clinical Microbiology Laboratory of the Hospital) culturing on DIAMOND modified medium (Clinical Microbiology Laboratory of the Hospital) isolation on McCoy cells Lugol stain (01.03.1999. - 31.12.2002.) immunofluorescent typing with monoclonal antibodies (01.01.2003.- onging); (Croatian Institute for Public Health, Zagreb, Croatia) DNA/RNA Digene hybridization method (Clinical Microbiology Laboratory of the Hospital)
The diagnostic criteria for chronic bacterial prostatitis were as follows: - presence of clinical symptoms, - presence of 10 WBC s /hpf in EPS or VB 3 - a bacterial count of 10 3 cfu/ml or more, - if only Gram-positive cocci are found in EPS, a bacterial count of 10 4 cfu/ml or more is required, - finding of ten or many times greater number of bacteria in EPS or VB 3, than VB 1 or VB 2.
The diagnostic criteria for chronic prostatitis caused by C. trachomatis were: -presence of clinical symptoms, -presence of 10 WBCs /hpf in EPS or VB 3 -presence of C. trachomatis in EPS or VB 3 -absence of C. trachomatis in urethral swabs -absence of other possible pathogens of chronic prostatitis in urethral swabs, EPS or VB 3.
The diagnostic criteria for chronic prostatitis caused by U.urealyticum or M.hominis were: -presence of clinical symptoms, -presence of 10 WBCs /hpf in EPS or VB 3, -presence of U. urealyticum or M. hominis in EPS or VB 3, -absence of U. urealyticum or M. hominis in urethral swabs, -absence of other possible pathogens of chronic prostatitis in urethral swabs, EPS or VB 3
The diagnostic criteria for nonbacterial prostatitis or inflammatory chronic pelvic pain syndrom were: - presence of clinical symptoms, - presence of 10 WBCs /hpf in EPS or VB 3, - absence of possible bacterial pathogens of chronic prostatitis in EPS or VB 3, - presence of Trichomonas vaginalis in EPS or VB 3
The diagnostic criteria for non-inflammatory chronic pelvic pain syndrome were: - presence of clinical symptoms, - no white cells in EPS or VB 3 - absence of possible pathogens of chronic prostatitis in EPS or VB 3
RESULTS The etiology of chronic prostatitis syndrome in patients treated at the University Hospital for Infectious Diseases Dr Fran Mihaljevic from 1999 to 2008 Microorganism confirmed Patients in EPS or VB 3 > 10 WBCs/hpf in EPS < 10 WBCs/hpf in EPS Total no. no. (%) no. (%) no. (%) Chlamydia trachomatis 302 (15,46) 465 (43,26) 767 (25,16) Trichomonas vaginalis 211 (10,80) 101 (9,40) 312 (10,30) Ureaplasma urealyticum 158 (8,09) 63 (5,86) 221 (7,30) Escherichia coli 213 (10,90) 20 (1,86) 233 (7,69) Enterococcus 173 (8,85) 29 (2,70) 202 (6,67) Proteus mirabilis 73 (3,74) 7 (0,65) 80 (2,64) Klebsiella pneumoniae 34 (1,74) 4 (0,37) 38 (1,25) Streptococcus agalactiae 37 (1,89) 12 (1,12) 49 (1,62) Pseudomonas aeruginosa 5 (0,26) 2 (0,19) 7 (0,23) Mycoplasma hominis 15 (0,77) 12 (1,12) 27 (0,89) Staphylococcus aureus 2 (0,10) 2 (0,19) 4 (0,13) Mixed infection 74 (3,79) 31 (2,88) 105 (3,47) None 657 (33,62) 327 (30,42) 984 (32,49) Total 1954 1075 3029
A high incidence of etiologically confirmed chronic prostatitis syndrome cases, especially high percentage of sexually transmitted pathogens, can be explained through: - selective population referred to our outpatient department due to a suspected urogenital or sexually transmitted infection - regular analysis in these patients for the presence of Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis and Trichomonas vaginalis with the most sophisticated microbiological methods
In the period from 1999 until 2006, a total of 389 patients with chronic bacterial prostatitis were treated with azithromycin: - 307 patients with chronic prostatitis caused by Chlamydia trachomatis - 82 patients with chronic prostatitis caused by Ureaplasma urealyticum
Azitromycin total dose 4.0 g 4.5 g 6.0 g Comparative drugs Ciprofloxacin Clarithromycin Doxycycline Antimicrobial treatment in 389 patients
Clinical efficacy and tolerability of administered drug as well as possible adverse events were evaluated during, at the end, and at 4-6 weeks of therapy completion. Clinical response definitions: Cure complete resolution of urethral, prostatic and sexual symptoms Improvement incomplete resolution of urethral, prostatic or sexual symptoms, but no need for additional therapy; and Failure no apparent response or progression of urethral, prostatic or sexual symptoms, or additional antibiotic therapy needed.
Bacteriologic efficacy of the administered drug was evaluated at 4-6 weeks of therapy completion using methods identical to those used on study enrolment. Bacteriologic response definitions: Eradication eradication of Chlamydia trachomatis or Ureaplasma urealyticum at post-treatment visit; and Persistence persistence of Chlamydia trachomatis or Ureaplasma urealyticum at post-treatment visit
Published papers Škerk V, Schönwald S, Krhen I, et al. Azithroymcin in the treatment of chronic prostatitis caused by Chlamydia trachomatis. J Chemother 2001;13:664-5. Škerk V, Schönwald S, Krhen I, et al. Comparative analysis of azithromycin and clarithromycin efficacy and tolerability in the treatment of chronic prostatitis caused by Chlamydia trachomatis. J Chemother 2001;14:384-9. Škerk V, Schönwald S, Krhen I, et al. Comparative analysis of azithromycin and ciprofloxacin in the treatment of chronic prostatitis caused by Chlamydia trachomatis. Int J Antimicrob Agents 2003;21:457-62. Škerk V, Krhen I, Lisić M, et al. Azithromycin: 4.5 or 6.0 gram dose in the treatment of patients with chronic prostatitis caused by Chlamydia trachomatis a randomized study. J Chemother 2004;16:408-10. Škerk V, Krhen I, Lisić M, et al. Comparative randomized pilot study of azithromycin and doxycycline efficacy in the treatment of prostate infection caused by Chlamydia trachomatis. Int J Antimicrob Agents 2004;24:188-91.
Published papers 6. Škerk V, Čajić V, Markovinović L, et al. Azithromycin in the treatment of prostatitis caused by U.urealyticum. Medicus 2006;15:183-5. 7. Škerk V, Mareković I, Markovinović L, et al. Comparative randomized pilot study of azithromycin and doxycycline efficacy and tolerability in the treatment of prostate infection cuased by Ureaplasma urealyticum. Chemotherapy 2005;52:9-11. 8. Škerk V, Markovinović L, Zekan S, et al. The significance of Chlamydia trachomatis in urethritis and prostatitis differences in therapeutic approach Croatian experience. J Chemotherapy Feb 2009 in press 9. Škerk V, Roglić S, Čajić V, et al. Comparison of clinical symptoms scored by the National Institutes of Health Chronic Prostatitis Symptoms Index (NIH-CPSI) and laboratory results for the assessment of clinical and bacteriological efficacy of antimicrobial treatment in patients with chronic prostatitis syndrome. J Chemotherapy Apr 2009 in press
Škerk V, Schönwald S, Krhen I i sur. Comparative analysis of azithromycin and clarithromycin efficacy and tolerability in the treatment of chronic prostatitis caused by Chlamydia trachomatis. J Chemother 2002;14:384-9. Bacteriological evaluation of azithromycin and clarithromycin efficacy in the treatment of patients with chronic prostatitis caused by Chlamydia trachomatis Bacteriological evaluation Antimicrobial treatment AZITHROMYCIN CLARITHROMYCIN 4.5 g / 3 weeks 2 x 500 mg / 15 days n (%) n %) Eradication 37 (80.43) 36 (80.00) Persistence 9 (19.57) 9 (20.00) T O T A L 46 45 P=0,83
Škerk V, Schönwald S, Krhen I i sur. Comparative analysis of azithromycin and clarithromycin efficacy and tolerability in the treatment of chronic prostatitis caused by Chlamydia trachomatis. J Chemother 2002;14:384-9. Clinical evaluation of azithromycin and clarithromycin efficacy in the treatment of patients with chronic prostatitis caused by Chlamydia trachomatis Clinical evaluation Cure Failure Antimicrobial treatment AZITHROMYCIN CLARITHROMYCIN 4.5g / 3 weeks 2 x 500 mg / 15 days n (%) n (%) 32 (69.57) 14 (30.43) 32 (71.11) 13 (28.89) T O T A L 46 45 P=0,946
Škerk V, Schönwald S, Krhen I i sur. Comparative analysis of azithromycin and ciprofloxacin in the treatment of chronic prostatitis caused by Chlamydia trachomatis. Int J Antimicrob Agents 2003;21:457-62. Bacteriological evaluation of azithromycin and ciprofloxacin efficacy in the treatment of chronic chlamydial prostatitis Efficacy P=0,0002 Patients treated with azithromycin (n=45) 36 (80%) 9 (20%) Patients treated with ciprofloxacin (n=44) 17 (38,64) 27 (61,36) Eradication Persistence TOTAL 45 44
Škerk V, Schönwald S, Krhen I i sur. Comparative analysis of azithromycin and ciprofloxacin in the treatment of chronic prostatitis caused by Chlamydia trachomatis. Int J Antimicrob Agents 2003;21:457-62. Clinical efficacy of azithromycin and ciprofloxacin in the treatment of chronic chlamydial prostatitis Efficacy Cure Improvement Failure P=0,0021 Patients treated with azithromycin (n=45) 31 (68, 89%) 4 (8,89%) 10 (22,22%) Patients treated with ciprofloxacin (n=44) 15 (34,09%) 7 (15,91%) 22 (50%) TOTAL 45 44
Škerk V, Krhen I, Lisić M i sur. Comparative randomized pilot study of azithromycin and doxycycline efficacy in the treatment of prostate infection caused by Chlamydia trachomatis. Int J Antimicrob Agents 2004;24:188-91. Bacteriological evaluation of azithromycin and doxycycline efficacy in the treatment of prostate infection caused by C. trachomatis Efficacy Patients treated with azithromycin (n=82) Patients treated with doxycycline (n=43) Eradication 65 (79,27%) 33 (76,74%) Persistence 17 (20,73%) 10 (23,26%) TOTAL 82 43 P=0,82
Škerk V, Krhen I, Lisić M i sur. Comparative randomized pilot study of azithromycin and doxycycline efficacy in the treatment of prostate infection caused by Chlamydia trachomatis. Int J Antimicrob Agents 2004;24:188-91. Clinical efficacy of azithromycin and doxycycline in the treatment of prostate infection caused by C. trachomatis Efficacy Patients treated with azithromycin (n=82) Patients treated with doxycycline (n=43) Cure 56 (68,29%) 30 (69,77%) Improvement 3 (3,66%) 2 (4,65%) Failure 23 (28,05%) 11 (25,58%) TOTAL 82 43 P=0,94
Comparison of the efficacy of different doses of azithromycin in the treatment of 307 patients with chronic chlamydial prostatitis EFFICACY AZITHROMYCIN n=82 4,0 g total 1x1g po. per week 4 weeks ANTIMICROBIAL THERAPY AZITHROMYCIN n=182 4,5 g total 1x500 mg po. 3 days per week 3 weeks AZITHROMYCIN n=43 6,0 g total 1x1g po per week 6 weeks BACTERIOLOGICAL ERADICAT ION 65 (79%) 151 (83%) 35 (81%) PERSISTENCE 17 31 8 CLINICAL CURED 56 (68%) 124 (68%) 31 (72%) NOT CURED 26 58 12
Efficacy of azithromycin and doxycycline in the treatment of chronic prostatitis caused by U.urealyticum ANTIMICROBIAL THERAPY EFFICACY BACTERIOLOGICAL ERADICATION PERSISTENCE CLINICAL CURED NOT CURED AZITHROMYCIN n=32 4,5g total 1x500mg po. 3 days per week 3 weeks 25 7 22 10 DOXYCYCLINE n=31 2x100mg po. 21 days 23 8 21 10 P=0,77 P=1,0
CONCLUSION Azithromycin is an efficient and safe antimicrobial drug for the treatment of chronic prostatitis caused by C.trachomatis. It is recommended: In a total dose of 4.5 g po. during 3 weeks, administered for 3 days in doses 1x500mg per day OR In a total dose of 4.0 g po. during 4 weeks, administered in a single dose of 1x1.0 g per week
CONCLUSION Azithromycin is efficient and safe antimicrobial drug for the treatment of chronic prostatitis caused by U.urealyticum. It is recommended In a total dose of 4.5g po. during 3 weeks, administered for 3 days in dose 1x500mg per day