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Table 1.Detection rates of Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Ureaplasma urealyticum, Haemophilus influenzae and adenovirus from male urethritis in Urethritis No. of patients N. gonorrhoeae C. trachomatis M. genitalium U. urealyticum H. influenzae adenovirus All cases 424 127 (30.0) 177 (41.7) 45 (10.6) 57 (13.4) 22 (5.2) 28 (6.6) GU 127 127 (100) 34 (26.8) 3 (2.4) 12 (10.2) 0 3 (2.4) NGU 297 0 143 (48.1) 42 (14.1) 44 (14.8) 22 (7.4) 25 (8.4) CU 143 0 143 (100) 7 (4.9) 14 (9.8) 0 0 NCNGU 154 0 0 35 (22.7) 30 (19.5) 22 (14.3) 25 (16.2) Table was modified from Ito s report in 8). GU: gonococcal urethritis, NGU: non-gonococcal urethritis, CU: chlamydial urethritis, NCNGU: non-chlamydial NGU 174
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Table 2. Clinical trials for NGU including C. trachomatis or M. genitalium infection Author Country Gambini 19) Italy Maeda 37) Falk 20) Sweden Wikstrom 21) Sweden Takahashi 65) Bradshaw 25) Anagrius 22) Sweden Jernberg 30) Norwey Stamm 31) USA Björnelius 23) Sweden Hagiwara 32) Twin 36) Couldwell 33) Gundevia 34) Bissessor 35) Mena 24) USA Study period Study Design Regimens for treatment Microbiological efficacies (%) C. trachomatis M. genitalium 1998 1999 Open labeled DOXY 200 mg/day, 7 days 33/35 (94.3) AZM 1 g single dose 14/17 (82.4) 1999 2000 Open labeled, LVFX 100 mg 3/day, 7 days 21/22 (95.5) 4/12 (33.3) 2000 Open labeled DOXY 200 mg stat 100 mg/day, 8 days 6/18 (37.5) Lymecycline 300 mg 2/day, 10 days AZM 500 mg stat 250 mg/day, 4 days 8/8 (100) Treatment failure cases by tetracycline AZM 500 mg stat 250 mg/day, 4 days 8/8 (100) 2002 2004 Open labeled DOXY 200 mg stat 100 mg/day 8 days 1/7 (14.3) EM 500 mg 2/day, 10 days 2/11 (18.2) AZM 1 g stat or 500 mg stat 250 mg/day, 4 days 100% (6/6) Treatment failure cases by DOXY or EM AZM 1 g stat or 500 mg stat 250 mg/day, 4 days 14/14 (100) 2004 Open labelled, AZM 1 g single dose 12/15 (80) 3/3 (100) 2004 2005 Open labeled AZM 1 g single dose 23/32 (71.9) Treatment failure cases by AZM MFLX 400 mg 1/day, 10 days 9/9 (100) 1998 2005 Retrospective, DOXY 200 mg stat 100 mg/day 8 days 35/91 (38.5) cross-over AZM 1 g single dose 57/65 (87.7) AZM 500 mg stat 250 mg/day, 4 days 13/14 (92.9) 2005 2006 Retrospective AZM 1 g single dose 144/183 (78.6) AZM 1 g stat additional AZM 1 g 28/28 (73.7) AZM 500 mg stat 250 mg/day, 4 days 78/98 (80.0) OFLX 200 mg twice/day 10 days 4/9 (44.4) MFLX 400 mg/day 7 days 3/3 (100) 2003 2004 Double blind Rifalazil 2.5 mg stat 0/5 (0) 2002 2004 Multicenter controlled Open labeled, cross-over Rifalazil 12.5 mg stat 0/7 (0) Rifalazil 25 mg stat 0/5 (0) AZM 1 g stat 6/7 (85.7) DOXY 200 mg stat 100 mg/day, 8 days 13/76 (17.1) AZM 1 g single dose 33/39 (84.6) Treatment failure cases by DOXY AZM 500 mg stat 250 mg/day, 4 days 47/63 (74.6) Treatment failure cases by AZM 1 g AZM 500 mg stat 250 mg/day, 4 days 3/3 (100) AZM 1 g single dose 25/30 (83.3) 2004 2007 Open labeled, 2007 2009 Open labeled AZM 1 g single dose 77/111 (69.4) 2008 2011 Open labeled AZM 1 g single dose or AZM 500 mg stat 250 mg/day, 4 days 12/26 (46.2) Treatment failure cases by AZM MFLX 400 mg/day 10 days 4/13 (30.8) 2009 Open labeled AZM 1 g single dose 64/87 (73.6) AZM stat 250 mg/day, 4 days 10/15 (66.7) DOXY 200 mg/day 7 days 2/5 (40) MFLX 400 mg/day 10 days 5/6 (83.3) 2012 2013 Open labeled AZM 1 g single dose 95/155 (61.3) Treatment failure cases by AZM MFLX 400 mg/day 10 days 53/60 (88.3) Treatment failure cases by AZM and MFLX Pristinamycin 4 g/day 10 days 6/7 (85.7) 2002 2004 RCT DOXY 200 mg/day, 7 days 14/31 (45.2) AZM 1 g stat 20/23 (87.0) (Continued) 176
Author Country Schwebke 16) USA Manhart 17) USA Takahashi 38) Hamasuna 9) Ito 39) Takahashi 10) Study period Study Design Table 2. (Continued) Regimens for treatment Microbiological efficacies (%) C. trachomatis M. genitalium 2006 2009 RCT DOXY 200 mg/day, 7 days (with or without tinidazole) 55/58 (94.8) 12/38 (30.8) AZM 1 g single dose (with or without tinidazole) 41/53 (77.4) 30/45 (66.7) 2007 2011 RCT DOXY 200 mg/day, 7 days 63/68 (92.7) 15/35 (42.9) AZM 1 g single dose 67/76 (90.5) 20/45 (44.4) 2011 Open labeled, LVFX 500 mg/day 7days 18/19 (94.7) 3/5 (60) 2011 Open labeled, GFLX 200 mg 2/day, 7 days 72/72 (100) 15/18 (83.3) 2012 Open labeled, STFX 200 mg/day, 7 days 33/33 (100) 11/11 (100) 2010 2012 Open labeled, STFX 200 mg/day, 7 days 45/47 (95.7) 15/16 (93.8) The data from clinical trials involving more than 10 patients are shown in the table. DOXY: doxycycline, AZM: azithromycin, LVFX: levofloxacin, MFLX: moxifloxacin, OFLX: ofloxacin, STFX: sitafloxacin RCT: randomized controlled trial Agents Table 3. MIC distribution of 48 C. trachomatis strains isolated in mg/l 0.002 0.004 0.008 0.016 0.03 0.06 0.125 0.25 0.5 1 2 4 8 MIC50 MIC90 DOXY 16 40 2 0.125 0.125 CPFX 29 27 2 0.5 1 LVFX 36 22 0.25 0.5 STFX 44 14 0.03 0.06 AZM 32 23 3 0.03 0.06 The table was modified from Takahashi s report 43). DOXY: doxycycline, CPFX: ciprofloxacin, LVFX: levofloxacin, STFX: sitafloxacin, AZM: azithromycin 177
Agents Table 4. MIC distribution of 39 M. genitalium strains isolated worldwide mg/l 0.002 0.004 0.008 0.016 0.03 0.06 0.125 0.25 0.5 1 2 4 8 MIC50 MIC90 DOXY 2 6 14 10 6 1 0.25 1 CPFX 4 8 7 7 13 4 8 MFLX 3 4 18 7 1 1 1 4 0.125 8 AZM 4 15 8 1 1 14 0.008 8 The table was modified from Jensen s report 29). The number of strains in this table was 39 and data from 1 strain in Jensen s report was excluded because of insufficient data. 178
Table 5.The worldwide prevalence of M. genitalium genomes which have macrolide-resistance or fluoroquinolone-resistance related mutations Author Country Chrisment 47) France Shimada 52) Shimada 55) Couldwell 33) Twin 36) Tagg 40) Yew 48) New Zealand Pond 49) UK Kikuchi 53) Salado-Rasmussen 46) Denmark Murray 56) Deguchi 54) Getman 11) USA Gosse 51) Norway Unemo 50) Sweden, Denmark, Norway Study period Macrolide-resistance Mutations Prevalence (%) Fluoroquinolone-resistance Mutations on ParC with amino-acid change Prevalence (%) 2003 2010 A2059G, A2059C, A2059C, A2058G, A2062T, C2038T 13/98 (13.2) NT NT 2006 2010 A2058G, T2185G 4/25 (16) NT NT 2006 2008 NT NT Ser83 Asn, Asp87 Tyr, Asp87 Val, Lys97 Arg 4/58 (6.9) 2008 2011 A2058G, A2058T, 15/32 (42.8) Ser83 Ile, Asp87 Asn, Asp87 Gly, 6/32 (18.8) A2059G Met95 Ile 2007 2009 A2058G, A2059G, 16/82 (19.5) NT NT A2059C 2008 2011 A2058G, A2058G, 62/143 (43.3) Gly81 Cys, Asp82 Asn, Ser83 Ile, 22/143 (15.4) Aso58T, 2019G Ser83 Arg, Asp97 Asn, Asp87 His, Asp87 Tyr, Asp87 Gly, Val103 Ile 2009 A2059G 4/9 (44.4) NT NT 2011 A2058G, A2059G 9/22 (40.9) Ser83 Ile 1/22 (4.5) 2011 2013 A2058G, A2059G 5/68 (7.4) Ser83 Ile, Ser83 Asn, Asp87 Asn, Ala119 Glu 18/51 (35.3) 2006 2010 A2058G, A2058T, 385/1,085 (35.5) NT NT A2059G 2012 2013 NT NT Pro62 Ser, Ser83 Ile, Ser83 Arg, 19/140 (13.6) Asp87 Asn, Ile90 Asn 2013 2014 A2058 any, 19/57 (33.3) Ser83 any, Asp87 any 29/57 (50.9) A2059 any 2013 2014 A2058 any, 86/178 (48.3) NT NT A2059 any 2015 A2058G, A2058T, 35/87 (40.2) NT NT A2059G, A2059C 2016 2017 A2058G, A2058T, 170/290 (41.4) Ser83 Ile, Ser83 Asn, 18/274 (6.6) A2059G, A2059C Ser83 Arg, Asp87 Asn, Asp87 His 179
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