Japanese guidelines for the treatment of UTIs & STDs; for making up KAUTI guidelines

1. 9th International Catholic Urology Symposium 9th. June. 2007 Catholic Research Institute oｆ Medical Science, Seoul, Korea Japanese guidelines for the treatment of UTIs & STDs; for making up KAUTI guidelines Tetsuro Matsumoto, MD, PhD Professor and Chairman, Department of Urology, University of Occupational and Environmental Health, Kitakyushu, Japan UOEHurology

2. I met him in 1998. Our history started at that time!! UOEHurology

3. Sister relationship between Department of Urology, Catholic University and UOEH Dec. 2000, Seoul UOEHurology

4. Sister relationship between Department of Urology, Catholic University and UOEH March, 2001, Kitakyushu UOEHurology

5. Asian Association of UTI/STD (AAUS) Established in 2003 President; Tetsuro Matsumoto (Japan), Vice president; Yong-Hyun Cho (Korea), Organizing Committee; Paul A. Tambyah (Singapore), Min Eui Kim (Korea), Hiromi Kumon (Japan), Prasit Tharabichitkul (Thailand), Bill Wong (Hong Kong), Xiang Shen Chen (China), Yodor Lim (Philippines),,Iwan Asmara Achmad (Indonesia), Stephen Yang (Taiwan), Roman Kozlof (Russia), Chul Sung Kim (Korea) Secretary; Tetsuro Muratani (Japan), Sang Don Lee (Korea), Vladimir Rafalski (Russia) International Advisory Committee; Kurt Naber (Germany), Jean Claude Pechere (Switzerland), John Krieger (USA) Honorary Members; Joichi Kumazawa (Japan), Yoshiaki Kumamoto (Japan), Sadao Kamidono (Japan),Chong Wook Lee (Korea), Nicolay Lapatkin (Russia) 3rd Board Meeting in Seoul 15, May, 2005 (Photo by K. Naber) UOEHurology

6. Guidelines for the treatment of urinary tract infection (UTI) UOEHurology

7. IDSA Guidelines for the treatment of UTIs Clin. Infect. Dis. 29:745-758,1999. Excellent evidence-based guidelines, however……. UOEHurology

8. Guidelines for the treatment of UTIs Eur. Urol. 40:576-588,2001. Made by Urologists, however….. UOEHurology

9. Need our own guidelines? These guidelines are quite excellent and helpful for us. However, our own guidelines are necessary, because there are many difference in the region or areas in many points of view such as antimicrobial susceptibility pattern, patients characteristics, drug use tendency, government’s policies, insurance systems etc. UOEHurology

10. Japanese guidelines for antimicrobial use Japanese Society of Infectious Diseases & Japanese Society of Chemotherapy, 2005 Part of UTI and STD were described by urologists, and guidelines were tried fit to other guidelines which were made by the other societies. UOEHurology

11. Uncomplicated UTI Acute uncomplicated cystitis Acute uncomplicated pyelonephritis UOEHurology

12. Isolation frequency of bacteria in urinary tract infection Complicated UTI Uncomplicated UTI Citrobacter & Enterobacter Citrobacter & Enterobacter GPC Fungi CNS S. epidermidis Streptococci E.coli CNS E. faecalis S. epidermidis Klebsiella spp. MSSA Klebsiella spp. MRSA Proteus spp. Enterococcus spp. E.coli Serratia marcescens E. faecalis P. aeruginosa NFGNR UOEHurology

13. Acute uncomplicated cystitis in women A, I ST 3d, OFLX 3d A,II NFLX 3d, CPFX 3d, FLRX 3d, Trimeth 3d B, I Nitrofran 7d, FOM SDT E, Ib-lactam 3d UOEHurology

14. Antibiotics selection for AUC in Japan ・Penicillins; Resistant bacteria(>30% in E. coli) ・Penicillin + BLI; Resistance rate in arround 14% ・Cephems; Immediate recurrence after 3 days regimen ・New oral cephems; Resistance rate in 2 to 13%. Duration of treatment remains unknown. ・Fluoroquinolones; Good for 3 days regimen (resistance rate in around 10%) ・Sulfo/Trim; Standard drug for AUC in US and Europe, not in Japan UOEHurology

15. Resistance rate in isolates from uncomplicated UTI Ampicillin /sulbactam Amoxicillin /clavulanate Faropenem Cefaclor Cefuroxime Cefotiam Cefteram Cefpodoxime Cefditoren Cefcapene Ciprofloxacin Levofloxacin Fosfomycin Co-trimoxazole Nitrofurantoin Resistant ratio (%) NIT CCL CTM /SBT CDTR FOM /CVA CPFX CPDX E. coli 87、P. mirabilis 3, M. morganii, S. marcescens, K. pneumoniae, Gram-positive bacteria 14 UOEHurology

16. Initial treatment of acute uncomplicated cystitis DrugsTreatment duration OralFluoroquinolones3 days New oral cephalosporins7 days Penicillins + BLI 7 days Pregnant womenNew oral cephalosporins3 days Elderly women Fluroquinolones3 to 7 days （Japanese guideline,2005） UOEHurology

17. Acute uncomplicated pyelonephritis in women A, I14d therapy A,II mild case：oral NQ, severe case：parenteral NQ B, I mild or moderate case-7d therapy B,II mild case-ST B,III GPC-AMPC, AMPC/CVA UOEHurology

18. Initial treatment of acute uncomplicated pyelonephritis DrugsTreatment duration OralFluoroquinolones 7 to 14 days New oral cephalosporins 14 days Parenteral1st to2nd gen. cephalosporins Penicillins + BLI + Aminoglucosides Parenteral fluoroquinolones Switch to oral fluoroquinolones 14 days or cephalosporins （Japanese guideline,2005） UOEHurology

19. Complicated UTI Chronic complicated cystitis Chronic complicated pyelonephritis UOEHurology

20. Complicated UTI ・Predisposing factors in the urinary tract or whole body ・Should be controlled predisposing factors ・Should not be treated only by antimicrobials ・Various causative bacteria ・Antimicrobial-resistant bacteria ・Proper use of antimicrobials to prevent increase of antimicrobial-resistant bacteria UOEHurology

21. EAU guideline for complicated UTI 1.UTI with complicating factors or Nosocomial UTI Initial therapy;NQ,Penicillins/BLI, II~III Cephems, Aminoglycosiges Duration of therapy;3-5 daysafter defevescence or control/ elimination of complicating factors 2. In case of failure of initial therapy or severe case NQif not used initially, Penicillin/BLI, III Cephems, Carbapenems + Aminoglycosides 3. In case of candida Fluconazole, Amphotericin B ( Naber et al, Eur Urol,2001) UOEHurology

22. Isolation frequency of bacteria in urinary tract infection Complicated UTI Uncomplicated UTI Citrobacter & Enterobacter Citrobacter & Enterobacter GPC Fungi CNS S. epidermidis Streptococci E.coli CNS E. faecalis S. epidermidis Klebsiella spp. MSSA Klebsiella spp. MRSA Proteus spp. Enterococcus spp. E.coli Serratia marcescens E. faecalis P. aeruginosa NFGNR UOEHurology

23. Enterococcus faecalis (n=192) Range 1-16 1-8 2-32 0.5-16 0.5->128 8->128 0.5-8 2-64 4->512 32-256 0.25-128 0.5-128 0.125->32 0.125-32 0.06-32 0.06->128 0.16-8 BP 8 8 16 2 8 8 4 4 512* 16 1 2 2 2 4 2 2 S-ratio 97.4 100 99.0 73.4 7.6 0.6 98.4 10.3 73.4 0 55.1 63.0 67.6 68.8 27.6 35.9 92.2 Range 0.016->16 0.125-32 0.06-16 0.125-4 0.03->16 8->128 BP 2 4 8 2 1 4 S-ratio 85.4 100 100 99.0 1.1 0 PCG ABPC PIPC FRPM CPR CZOP IPM MEPM GM AMK CPFX LVFX TFLX GFLX MINO CAM TEL ST VCM TEIC LZD QPR/DPR ABK UOEHurology

24. Escherichia coli (n=283) Range 0.25->128 0.125->128 0.5->128 0.03-128 0.06-16 0.004->128 0.008->128 0.016-64 0.008-16 0.06-2 0.004-0.125 0.25-128 0.25->128 0.06->128 Range 0.008-128 0.008->128 0.008-128 0.25-128 0.5->128 0.5->128 BP 8 16 8 8 8 8 8 8 8 4 4 16 8 2 S-ratio 61.1 84.8 92.6 96.8 98.6 97.2 97.9 98.2 97.6 100 100 99.7 90.5 90.1 BP 1 2 2 4 16 16 S-ratio 80.2 79.2 80.2 87.6 99.7 99.5 ABPC PIPC CEZ CTM CAZ CTRX CTX CPR AZT* IPM MEPM CMZ CCL CPDX CPFX LVFX GFLX MINO AMK ISP* UOEHurology

25. Pseudomonas aeruginosa (n=242) Range 0.25->256 0.25->256 0.5->128 0.5->128 0.5->256 0.5->128 1->128 0.5->128 1->128 0.25-128 0.03->128 Range 0.25->128 1->128 1->128 0.25->125 0.03->128 0.125->128 0.03->32 0.03-64 0.06->128 4->128 0.25->16 0.5-16 BP* 64 64 16 16 8 8 8 8 8 4 4 S-ratio** 87.2 93.0 73.1 74.4 78.9 70.7 66.9 77.3 67.4 74.4 78.5 BP 4 16 16 4 1 2 1 4 1 4 2 S-ratio 85.5 92.6 91.7 88.0 76.9 70.7 77.3 80.6 78.5 3.7 4.6 PIPC PIP/TAZ CPZ CPZ/SBT CAZ CFS CPR CZOP AZT IPM MEPM GM AMK ISP TOB CPFX LVFX TFLX PZFX PUFX MINO ST PL-B MIC90 = 4 *Breakpoint MIC, **Susceptible ratio UOEHurology

26. Treatment drugs for the complicated cystitis （Oral） Fluoroquinolones Cephalosporins Penicillins + BLI Duration; 7 to 14 days （Japanese guideline, 2005） UOEHurology

27. Treatment of complicated pyelonephritis • Select drugs among • 2nd to 3rd gen chapalosporins, penicillins + BLI, Aminoglycosides and carbapenems • according to patient’s characteristics and • suspected pathogens • 2.Switch to oral drugs 3 to 5 days after • defevescence in patients with high fever (38C) • Duration of treatment; 2 weeks, • 3 to 4 weeks for • opportunistic pathogens (Japanese guideline, 2005) UOEHurology

28. Treatment guidelines for STDs UOEHurology

29. Guidelines for the treatment of STDs Sexually Transmitted Diseases Treatment Guidelines, 2006; Workowski KA, Berman SM, MMWR 55(RR11):1-94,2006. UOEHurology

30. Japanese guidelines for STDs Guidelines for the diagnosis and treatment of STDs 2006; Japanese Society for Sexually Transmitted Diseases UOEHurology

31. Genital Chlamydial infection UOEHurology

32. Genital chlamydial infection 48-72hr 0hr EB Host cell 6-8hr RB 20-24hr inclusion UOEHurology

33. Azithromycin 1g orally single dose Doxycycline 100mg orally twice a day 7days Erythromycin base 500mg four times a day 7 days Erythromycin ethylsuccinate 800mg orally four times a day 7 days Ofloxacin 300mg orally twice a day 7days Levofloxacin 500mg orally once a day 7 days UOEHurology

34. Trends of genital Chlamydial infection in Japan • Genital chlamydial infection is the most common STDs in both sex. • Half of male urethritis was caused by C. trachomatis. • Both of gonococcus and chlamydia were detected concomitantly in 20-30% male urethritis. • C. trachomatis was concomitantly detected in the pharynx in 10-20% of female genital chlamydial infection. • Asymptomatic chlamydial infection has been increasing in high school students, especially in girls. • PCR is the most popular detection methods. • Newer detection kits such as BD probe-Tech and • Aptima-Combo 2 are now available. • While PCR negative mutant strains were detected in high rate • in Sweden and other European countries, no such strains was • identified in Japan. UOEHurology

35. Japanese guideline for the treatment of genital chlamydial infection （2006） Oral drug 1）Azithromycin 1,000mg x 1Single dose 2) Clarithromycin200mg x 27 days 3）Minocycline100mg x 27 days 4）Doxycycline100mg x 27 days 5）Levofloxacin100mg x 37 days 6）Tosufloxacin150mg x 27 days 7) Gatifloxacin 200mg x 2 7 days 3）〜7）;should not use for pregnant women Parenteral drug (Severe case) Minocycline100mg x 2div3〜5 days followed by oral drug UOEHurology

36. Gonococcal infection UOEHurology

37. Uncomplicated gonococcal infections of the cervix, Urethra, and Rectum Ceftriaxone 125mg IM single dose Cefixime 400mg orally single dose Ciprofloxacin 500mg orally single dose Ofloxacin 400mg orally single dose Levofloxacin 259mg orally single dose + Treatment for Chlamydia if not ruled out UOEHurology

38. Trends of gonococcal infection in Japan • Gonococcus has been changing in infecting sites, and the pharynx has been the most important infection site. • PCR is not suitable detection method for the pharyngeal infection. • Susceptibility of N. gonorrhoeae to antimicrobial such as fluoroquinolones, penicillins, tetracyclines, macrolides and oral cephalosporins has been quite low. Therefore, no oral drugs were not able to use in the treatment. • Parenteral drugs such as ceftriaxone, cefodizime and • spectinomycin are effective for the treatment of gonococcal • urethritis and cervicitis. • Ceftriaxone is the most suitable drug for the treatment of • gonococcal infections including pharyngitis. UOEHurology

39. Prevalence of drug resistant strain of N. gonorrhoeae in 5 areas (2005) Resistant ratio (%) （STD reseach group in Kitakyushu & KAUTI) Penicillin Oral cephems Quinolones Tetracycline ■: Kitakyushu(n=238),■: Yamaguchi(n=80), ■: Tokyo(n=88),■: Nagoya(n=93),■: Korea(n=29) UOEHurology

40. Japanese guideline for the treatment of gonococcal infection （2006） Ceftriaxone 1.0g Single dose; Urethritis, Cervicitis, Pharyngitis etc Cefodizime 1.0g Single dose; Urethritis & Cervicitis Multiple doses are necessary for pharyngitis Spectinomycin 2.0g Single dose; Urethritis & Cervicitis単回投与 UOEHurology

41. Summary • We need our own guidelines based on the our own evidences and the local antimicrobial susceptibility. • It also should match to insurance system. • It should be revised every 2 or 3 years. Thank you very much for your attention Manneken pis in my home UOEHurology