Chlamydial urethritis

Authors

Yoshiki Hiyama (Department of Urology, Sapporo Medical University, School of Medicine, Sapporo, Japan)

Satoshi Takahashi (Department of Infection Control and Laboratory Medicine Sapporo Medical University, School of Medicine, Sapporo, Japan)

Mitsuru Yasuda (Center for Nutrition Support and Infection Control, Gifu University Hospital, Gifu, Japan)

Naoya Masumori (Department of Urology, Sapporo Medical University, School of Medicine, Sapporo, Japan)

Executive summary

According to the WHO, the estimated numbers of patients with chlamydial infection were 131 million and 127 million worldwide in 2012 and 2016, respectively. Chlamydia trachomatis (C. trachomatis) generally infects through sexual intercourse. Genital chlamydial infection mainly causes slight specific subjective symptoms or lacks them. Therefore, the chance to visit clinics is easily lost, and genital chlamydial infection keep untreated and the source of infection.

In men, C. trachomatis generally account for about half of causative pathogen of non-gonococcal urethritis. In 20 to 30% of total cases with gonococcal urethritis, C. trachomatis also infect simultaneously.

In women, C. trachomatis has been the predominant pathogen of sexually transmitted infections worldwide. Genital chlamydial infection in women often causes the obstetric issue including infertility and miscarriage. Therefore, women with genital chlamydial infection are possible to be exposed to the threat of reproductive health.

Microbiological diagnosis was done by using specimen of first void urine in men and cervical swab in women. Nucleic acid amplification tests (NAATs) . The downsides of NAATs are time and cost.

Enzyme immunoassay (EIA) test can be useful for the country impossible to put NAATs to practical use. EIA test is less sensitive to detect C. trachomatis than NAATs, however, EIA test is able to detect C. trachomatis if adequate elementary bodies exist in first void urine.

Due to the previous systematic review, azithromycin and doxycycline are appropriate as recommended treatment regimen. The other antimicrobial agents, clarithromycin, levofloxacin, tosufloxacin, sitafloxacin and minocycline are commonly appropriate as alternative treatment regimen. Fortunately, there have been a few drug-resistant C. trachomatis strains reported from Europe and USA. To take possible resistant strains into consideration may be insignificant in clinical and practical situations.

Test of cure to detect therapeutic failure is considered 3-4 weeks after completing therapy. The post treatment infections do not result only from treatment failure but also from reinfection.

Introduction

Urogenital chlamydial infection is the most common sexually transmitted infection. Chlamydia trachomatis (C. trachomatis) causes urethritis, uterus cervicitis, pharyngeal infection and proctitis. Many cases of chlamydial infection are reported worldwide every year. Genital chlamydial infection in women can also cause obstetric issues, including infertility and miscarriage. It is thus very important to reduce the number of patients with chlamydial infection. For that purpose, appropriate care should be conducted with the latest knowledge.

Method

We searched the literature regarding chlamydial urethritis available in PubMed and also considered other relevant publications up to October 2019. We used the terms Chlamydia trachomatis and urethritis combined with the terms diagnosis, evaluation, management and treatment, for the search strategy. For the purpose of this review a total of 59 eligible publications screened by title and abstract were included in the analysis.

Epidemiology

According to the WHO, the estimated numbers of patients with chlamydial infection were 131 million and 127 million worldwide in 2012 and 2016, respectively1-4) (LE: 3). The estimated pooled global prevalence of chlamydia in 15–49-year-old men was 2.7% (95% CI: 1.9–3.7), with regional values ranging from 1.2 to 4.0%3) (LE: 3).

According to the CDC, the rates of reported cases of chlamydial infection were highest among adolescents and young adults aged 15–24 years during the period from 2014 through 20185)6) (LE: 3). In 2017, the rate among 15–19-year-old men was 924.5 cases per 100,000 and the rate among those aged 20–24 years was 1705.4 cases per 100,000. In 2018, the rate among 15–19-year-old males was 959.4 cases per 100,000 and for those aged 20–24 years it was 1784.5 cases per 100,000.

Pathogen

Chlamydial urogenital infection is commonly caused by the urogenital biovar (serovars D-K) of C. trachomatis. C. trachomatis is a strict intracellular pathogen7). In chlamydial infection, elementary bodies (EB) infect target cells. After entering the host cell, they transform into reticulate bodies (RB) to grow and divide within a membrane-bound, host-derived parasitophorous vacuole called an inclusion. Once a critical number of bacteria has been reached, the RB transform back into EB. These are released and can then infect other target cells. Chlamydial appropriation and exploitation of the host cell machinery during invasion, inclusion formation and development are fundamental to success. However, these processes and intermediates trigger proinflammatory signaling pathways that drive innate cell influx of cytokines and chemokines such as IL-17, IK-12, IFN-ϒ, and iNOS, and activin release8-11) (LE: 3).

Clinical presentation

C. trachomatis causes trachoma, severe follicular conjunctivitis12)13) (LE: 3), and can also infect columnar epithelial cells of the urethra, uterus cervix, pharynx14-16) and rectum17)18) (LE: 3) as well. Genital chlamydial infections include urethritis and acute epididymitis19)20) in men, and cervicitis and pelvic inflammatory disease21)22) in women. In addition, pharyngeal infection and proctitis can also occur as extragenital chlamydial infections.

C. trachomatis generally infects through sexual intercourse. Genital chlamydial infection mainly causes mild subjective symptoms or lacks them. Genital infections due to C. trachomatis are asymptomatic in about 50% of men23)24) (LE: 3). The rate of positive results was 4 to 5% in a screening test of C. trachomatis for asymptomatic men in their 20s25) (LE: 3). Therefore, the chance to visit clinics is easily missed, and genital chlamydial infection remains an untreated source of infection. The incubation period is variable but is typically 1 to 3 weeks19)24) (LE: 3). However, given the relatively slow replication cycle of the organism, symptoms may not appear until several weeks after exposure in those persons who develop symptoms. When men have symptoms, they may present with a mucoid or watery urethral discharge, and complain of dysuria. Their discharge may be scanty, clear or only observed after milking the urethra.

In men, C. trachomatis generally accounts for about half of the causative pathogens of non-gonococcal urethritis. In 20 to 30% of the cases with gonococcal urethritis, C. trachomatis also infects simultaneously26)27) (LE: 3). There is no strong evidence that C. trachomatis causes infertility in men. However, it has been associated with male subfertility and infertility28-30) due to damage in the epithelia cells involved in spermatogenesis or apoptosis of spermatozoa caused by chamydial lipopolysaccharide. (LE: 3).

In women, C. trachomatis is the predominant pathogen of sexually transmitted infections worldwide. Genital chlamydial infection in women often causes pelvic inflammatory disease followed by obstetric issues, including infertility and miscarriage21)22)31) (LE: 3). Therefore, women with genital chlamydial infection are exposed to a possible threat to reproductive health.

Diagnosis

Microbiological diagnosis was done using specimens of first void urine for men and cervical swabs for women. Nucleic acid amplification tests (NAATs) (GR: B), including real-time polymerase chain reaction (real-time PCR)32-37) (LE: 2b), transcription-mediated amplification (TMA)38) (LE: 2b), strand displacement amplification (SDA)38) (LE: 2b), quenching probe polymerase chain reaction (QProbe PCR)39) (LE: 3), PCR and hybridization40) (LE: 3), transcription reverse-transcription concerted reaction (TRC)41) (LE: 3) are currently the most suitable examinations because of their high sensitivity and specificity to detect C. trachomatis.

The downsides of NAATs are time and cost. Although NAAT-based diagnostics often requires a second visit of patients, the QProbe PCR of Toyobo and XpertTM assay of Cepheid are commercially available rapid NAATs that can provide point-of-care testing of individual samples in approximately 90 min39)42) (LE: 3) (GR: C).

Enzyme immunoassay (EIA) can be useful for countries in which it is impossible to put NAATs to practical use43)44) (LE: 3) (GR: C). EIA is less sensitive to detect C. trachomatis than NAATs but can detect C. trachomatis if adequate elementary bodies exist in first void urine. In addition, there is a useful EIA that detects C. trachomatis within 30 minutes for rapid diagnosis.

Treatment

Some macrolides45)46) (LE: 2a), fluoroquinolones47-50) (LE: 2a) and tetracyclines50)51) (LE: 2a) have anti-chlamydial activities, and can be chosen for standard treatment regimens. Penicillin, cephalosporin and aminoglycoside have less anti-chlamydial activity than the standard treatment regimen. Therefore, they should not be used for treatment.

According to previous systematic reviews52)53) (LE: 1a), azithromycin and doxycycline are appropriate for treatment (GR: A). Other antimicrobial agents (clarithromycin, levofloxacin, tosufloxacin, sitafloxacin and minocycline) are appropriate as alternative treatments54)55) (GR: B).

Fortunately, there have been few drug-resistant C. trachomatis strains reported from Europe and United States56) (LE: 3). Taking possible resistant strains into consideration may be unnecessary in most clinical and practical situations.

Cure testing to detect therapeutic failure is considered 3–4 weeks after completing therapy57) (LE: 2) (GR: B). It was reported that of the 35 subjects with C. trachomatis strains genotyped at enrollment and follow-up, 7 (20%) had the same ompA sequence at both visits, whereas 28 (80%) had discordant sequences58). Posttreatment infections do not result only from treatment failure but also from reinfection (LE: 3) (GR: C).

Management of asymptomatic men whose female sexual partner diagnosed as genital chlamydial infection

If asymptomatic men have pyuria, C. trachomatis is detected by NAATs in most men. If they do not have pyuria, C. trachomatis is detected in 20 to 30% of men59) (LE: 2). In principal, treatment should be done for men who are positive for C. trachomatis; however, treatment for all men visiting the clinic must be conducted if the couple has a problem about violent and/or psychological discord.

Summary

Treatment regimen

・Recommended treatment regimen (GR: A)

1.Azithromycin 1g once a day

2.Doxycycline 100mg twice a day for 7 days

・Alternative treatment regimen (GR: B)

1.Clarithromycin 200mg twice a day for 7 days

2.Ofloxacin 200mg thrice a day for 7 days

3.Levofloxacin 500mg once a day for 7 days

4.Tosufloxacin 150mg twice a day for 7 days

5.Sitafloxacin 100mg twice a day for 7 days

6.Minocycline 100mg twice a day for 7 days

Diagnostic method ・Nucleic acid amplification test (GR: A) 1.Transcription mediated amplification (Hologic) 2.Strand displacement amplification (Becton Dickinson) 3.Polymerase chain reaction and hybridization (Greiner Bio-One) 4.Real time polymerase chain reaction (Roche, Abbott, Seegene, Cepheid, Bio-Rad) 5.Quenching probe polymerase chain reaction (Toyobo) 6.transcription reverse-transcription concerted reaction (Tosoh)

Enzyme immunoassay (GR: C)

References

1)Newman L, Rowley J, Vander Hoorn S et al. Global Estimates of the Prevalence and Incidence of Four Curable Sexually Transmitted Infections in 2012 Based on Systematic Review and Global Reporting. PLoS One. 2015, 10: e0143304.

2)Report on global sexually transmitted infection surveillance 2015. Available at: https://www.who.int/reproductivehealth/publications/rtis/stis-surveillance-2015/en/

3)Rowley J, Vander Hoorn S, Korenromp E et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016. Bull World Health Organ. 2019, 97: 548-562P.

4)Report on global sexually transmitted infection surveillance, 2018. Geneva: World Health Organization; 2018. Available at: https://www.who.int/reproductivehealth/publications/stis-surveillance-2018/en/

5)Sexually Transmitted Disease Surveillance 2018. Available at: https://www.cdc.gov/std/stats18/default.htm

6)Sexually Transmitted Disease Surveillance 2017. Available at: https://www.cdc.gov/std/stats17/default.htm

7)Moulder JW. Interaction of chlamydiae and host cells in vitro. Microbiol Rev. 1991, 55: 143-90.

8)Hafner LM. Pathogenesis of fallopian tube damage caused by Chlamydia trachomatis infections. Contraception. 2015, 92: 108-15.

9)Schoborg RV. Chlamydia persistence -- a tool to dissect chlamydia--host interactions. Microbes Infect. 2011, 13: 649-62.

10)Reddy BS, Rastogi S, Das B et al. Cytokine expression pattern in the genital tract of Chlamydia trachomatis positive infertile women - implication for T-cell responses. Clin Exp Immunol. 2004, 137: 552-8.

11)Refaat B, Al-Azemi M, Geary I et al. Role of activins and inducible nitric oxide in the pathogenesis of ectopic pregnancy in patients with or without Chlamydia trachomatis infection. Clin Vaccine Immunol. 2009, 16: 1493-503.

12)Hu VH, Harding-Esch EM, Burton MJ et al. Epidemiology and control of trachoma: systematic review. Trop Med Int Health. 2010, 15: 673-91.

13)Hammerschlag MR. Chlamydial infections. J Pediatr. 1989, 114: 727-34.

14)van Rooijen MS, van der Loeff MF, Morré SA et al. Spontaneous pharyngeal Chlamydia trachomatis RNA clearance. A cross-sectional study followed by a cohort study of untreated STI clinic patients in Amsterdam, The Netherlands. Sex Transm Infect. 2015, 91: 157-64.

15)Park J, Marcus JL, Pandori M et al. Sentinel surveillance for pharyngeal chlamydia and gonorrhea among men who have sex with men--San Francisco, 2010. Sex Transm Dis. 2012, 39: 482-4.

16)Hamasuna R, Takahashi S, Uehara S et al. Should urologists care for the pharyngeal infection of Neisseria gonorrhoeae or Chlamydia trachomatis when we treat male urethritis? J Infect Chemother. 2012, 18: 410-3.

17)Marcus JL, Bernstein KT, Stephens SC et al. Sentinel surveillance of rectal chlamydia and gonorrhea among males--San Francisco, 2005-2008. Sex Transm Dis. 2010, 37: 59-61.

18)Quinn TC, Goodell SE, Mkrtichian E. Chlamydia trachomatis proctitis. N Engl J Med. 1981, 305: 195-200.

19)O'Connell CM, Ferone ME et al. Chlamydia trachomatis Genital Infections. Microb Cell. 2016, 3: 390-403.

20)McConaghy JR, Panchal B et al. Epididymitis: An Overview. Am Fam Physician. 2016 , 94: 723-726.

21)Rekart ML, Gilbert M, Meza R et al. Chlamydia public health programs and the epidemiology of pelvic inflammatory disease and ectopic pregnancy. J Infect Dis. 2013, 207: 30-8.

22)Bender N, Herrmann B, Andersen B et al. Chlamydia infection, pelvic inflammatory disease, ectopic pregnancy and infertility: cross-national study. Sex Transm Infect. 2011, 87: 601-8.

23)Kent CK, Chaw JK, Wong W et al. Prevalence of rectal, urethral, and pharyngeal chlamydia and gonorrhea detected in 2 clinical settings among men who have sex with men: San Francisco, California, 2003. Clin Infect Dis. 2005, 41: 67-74.

24)Lanjouw E, Ouburg S, de Vries HJ et al. 2015 European guideline on the management of Chlamydia trachomatis infections. Int J STD AIDS. 2016, 27: 333-48.

25)Takahashi S, Takeyama K, Miyamoto S et al. Incidence of sexually transmitted infections in asymptomatic healthy young Japanese men. J Infect Chemother. 2005, 11: 270-3.

26)Ito S, Hanaoka N, Shimuta K et al. Male non-gonococcal urethritis: From microbiological etiologies to demographic and clinical features. Int J Urol. 2016, 23: 325-31.

27)Workowski KA, Bolan GA：Sexually transmitted diseases treatment guidelines, 2015. MMWR. 2015, 64：1-137.

28)Bezold G, Politch JA, Kiviat NB et al. Prevalence of sexually transmissible pathogens in semen from asymptomatic male infertility patients with and without leukocytospermia. Fertil Steril. 2007, 87: 1087-97.

29)Greendale GA, Haas ST, Holbrook K et al. The relationship of Chlamydia trachomatis infection and male infertility. Am J Public Health. 1993, 83: 996-1001.

30)Joki-Korpela P, Sahrakorpi N, Halttunen M et al. The role of Chlamydia trachomatis infection in male infertility. Fertil Steril. 2009, 91(4 Suppl): 1448-50.

31)Trent M, Bass D, Ness RB et al. Recurrent PID, subsequent STI, and reproductive health outcomes: findings from the PID evaluation and clinical health (PEACH) study. Sex Transm Dis. 2011, 38: 879-81.

32)Choe HS, Lee DS, Lee SJ et al. Performance of Anyplex™ II multiplex real-time PCR for the diagnosis of seven sexually transmitted infections: comparison with currently available methods. Int J Infect Dis. 2013, 17: e1134-40.

33)Ursi D, Crucitti T, Smet H et al. Evaluation of the Bio-Rad Dx CT/NG/MG® assay for simultaneous detection of Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium in urine. Eur J Clin Microbiol Infect Dis. 2016, 35: 1159-63.

34)Taylor SN, Liesenfeld O, Lillis RA et al. Evaluation of the Roche cobas® CT/NG test for detection of Chlamydia trachomatis and Neisseria gonorrhoeae in male urine. Sex Transm Dis. 2012, 39: 543-9.

35)Gaydos CA, Van Der Pol B, Jett-Goheen M et al. Performance of the Cepheid CT/NG Xpert Rapid PCR Test for Detection of Chlamydia trachomatis and Neisseria gonorrhoeae. J Clin Microbiol. 2013, 51: 1666-72.

36)Nye MB, Osiecki J, Lewinski M et al. Detection of Chlamydia trachomatis and Neisseria gonorrhoeae with the cobas CT/NG v2.0 test: performance compared with the BD ProbeTec CT Qx and GC Qx amplified DNA and Aptima AC2 assays. Sex Transm Infect. 2019, 95: 87-93.

37)Gaydos CA, Cartwright CP, Colaninno P et al. Performance of the Abbott RealTime CT/NG for detection of Chlamydia trachomatis and Neisseria gonorrhoeae. J Clin Microbiol. 2010, 48: 3236-43.

38)Kumamoto Y, Matsumoto T, Fujisawa M et al. Detection of Chlamydia trachomatis and Neisseria gonorrhoeae in urogenital and oral specimens using the cobas® 4800, APTIMA Combo 2® TMA, and ProbeTec™ ET SDA assays. Eur J Microbiol Immunol (Bp). 2012, 2: 121-7.

39)Miyazaki N, Yamagishi Y, Izumi K et al. Evaluation of rapid measurement of Chlamydia trachomatis and Neisseria gonorrhoeae by using automatic gene analyzer "GENECUBE". Jpn J Antibiot. 2016, 69: 291-298.

40)Meyer T, Klos C, Kofler R et al. Performance evaluation of the PelvoCheck CT/NG test kit for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae. BMJ Open. 2016, 6: e009894.

41)Ishiguro T, Saitoh J, Horie R et al. Intercalation activating fluorescence DNA probe and its application to homogeneous quantification of a target sequence by isothermal sequence amplification in a closed vessel. Anal Biochem. 2003, 314: 77-86.

42)Gaydos CA. Review of use of a new rapid real-time PCR, the Cepheid GeneXpert® (Xpert) CT/NG assay, for Chlamydia trachomatis and Neisseria gonorrhoeae: results for patients while in a clinical setting. Expert Rev Mol Diagn. 2014, 14: 135-7.

43)Mahilum-Tapay L1, Laitila V, Wawrzyniak JJ et al. New point of care Chlamydia Rapid Test--bridging the gap between diagnosis and treatment: performance evaluation study. BMJ. 2007, 335: 1190-4.

44)Nadala EC, Goh BT, Magbanua JP et al. Performance evaluation of a new rapid urine test for chlamydia in men: prospective cohort study. BMJ. 2009, 339: b2655.

45)Takahashi S, Matsukawa M, Kurimura Y et al. Clinical efficacy of azithromycin for male nongonococcal urethritis. J Infect Chemother. 2008, 14：409-12.

46)Takahashi S, Kiyota H, Ito S et al. Clinical Efficacy of a Single Two Gram Dose of Azithromycin Extended Release for Male Patients with Urethritis. Antibiotics. 2014, 3：109-20.

47)Takahashi S, Ichihara K, Hashimoto J et al. Clinical efficacy of levofloxacin 500 mg once daily for 7 days for patients with non-gonococcal urethritis. J Infect Chemother. 2011, 17：392-6.

48)Takahashi S, Hamasuna R, Yasuda M et al. Clinical efficacy of sitafloxacin 100 mg twice daily for 7 days for patients with non-gonococcal urethritis. J Infect Chemother. 2013, 19：941-5.

49)Ito S, Yasuda M, Seike K et al. Clinical and microbiological outcomes in treatment of men with non-gonococcal urethritis with a 100-mg twice-daily dose regimen of sitafloxacin. J Infect Chemother. 2012, 18：414-8.

50)Takahashi S, Hamasuna R, Yasuda M, Ishikawa K, Hayami H, Uehara S, et al.：Nationwide surveillance of the antimicrobial susceptibility of Chlamydia trachomatis from male urethritis in Japan. J Infect Chemother. 2016. 22：581-6.

51)Romanowski B, Talbot H, Stadnyk M et al. Minocycline compared with doxycycline in the treatment of nongonococcal urethritis and mucopurulent cervicitis. Ann Intern Med. 1993. 119: 16-22.

52)Kong FY, Tabrizi SN, Law M, Vodstrcil LA, Chen M, Fairley CK, et al.：Azithromycin versus doxycycline for the treatment of genital chlamydia infection：a meta-analysis of randomized controlled trials. Clin Infect Dis. 2014. 59：193-205.

53)Páez-Canro C1, Alzate JP, González LM et al. Antibiotics for treating urogenital Chlamydia trachomatis infection in men and non-pregnant women. Cochrane Database Syst Rev. 2019. 25; 1: CD010871.

54)Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2015. Available at: https://www.cdc.gov/std/tg2015/tg-2015-print.pdf

55)WHO guidelines for the treatment of Chlamydia trachomatis. Available at: https://apps.who.int/iris/bitstream/handle/10665/246165/9789241549714-eng.pdf;jsessionid=85E146CE8D841C084418469E73714CF6?sequence=1

56)Borel N, Leonard C, Slade J et al. Chlamydial Antibiotic Resistance and Treatment Failure in Veterinary and Human Medicine. Curr Clin Microbiol Rep. 2016. 3: 10-18.

57)Renault CA, Israelski DM, Levy V et al. Time to clearance of Chlamydia trachomatis ribosomal RNA in women treated for chlamydial infection. Sex Health. 2011. 8: 69-73.

58)Kapil R, Press CG, Hwang ML et al. Investigating the epidemiology of repeat Chlamydia trachomatis detection after treatment by using C. trachomatis OmpA genotyping. J Clin Microbiol. 2015. 53: 546-9.

59)Takahashi S, Kurimura Y, Hashimoto J et al. Management for males whose female partners are diagnosed with genital chlamydial infection. J Infect Chemother. 2011. 17: 76-9.