Clinical Review

Sexually Transmitted Infections Caused by Mycoplasma genitalium and Neisseria gonorrhoeae: Diagnosis and Treatment

Journal of Clinical Outcomes Management. 2018 December;25(10):457-466

References

1. World Health Organization. Sexually transmitted infections (STIs). www.who.int/mediacentre/factsheets/fs110/en/. Fact Sheet #110. Updated August 2016. Accessed December 16, 2017.

2. World Health Organization. Growing antibiotic resistance forces updates to recommended treatment for sexually transmitted infections www.who.int/en/news-room/detail/30-08-2016-growing-antibiotic-resistance-forces-updates-to-recommended-treatment-for-sexually-transmitted-infections. Released August 30, 2016.

3. Centers for Disease Control and Prevention. Antibiotic/antimicrobial resistance biggest threats. www.cdc.gov/drugresistance/biggest_threats.html. Released February 27, 2018.

4. Taylor-Robinson D, Jensen JS. Mycoplasma genitalium: From chrysalis to multicolored butterfly. Clin Microbiol Rev. 2011;24:498-514.

5. Jensen JS. Mycoplasma genitalium: The aetiological agent of urethritis and other sexually transmitted diseases. J Eur Acad Dermatol Venereol. 2004;18:1-11.

6. Jaiyeoba O, Lazenby G, Soper DE. Recommendations and rationale for the treatment of pelvic inflammatory disease. Expert Rev Anti Infect Ther. 2011;9:61-70.

7. McGowin CL, Anderson-Smits C. Mycoplasma genitalium: An emerging cause of sexually transmitted disease in women. PLoS Pathog. 2011;7:e1001324.

8. Manhart LE, Broad JM, Golden MR. Mycoplasma genitalium: Should we treat and how? Clin Infect Dis. 2011;53 Suppl 3:S129-42.

9. Gaydos C, Maldeis NE, Hardick A, et al. Mycoplasma genitalium as a contributor to the multiple etiologies of cervicitis in women attending sexually transmitted disease clinics. Sex Transm Dis. 2009;36(1SE0):598-606.

10. Wiesenfeld HC, Hillier SL, Meyn L, et al. O04.6 Mycoplasma genitalium-Is it a pathogen in acute pelvic inflammatory disease (PID)? Sex Transm Infect. 2013 89:A34 http://sti.bmj.com/content/89/Suppl_1/A34.2. Accessed February 1, 2018.

11. Lis R, Rowhani-Rahbar A, Manhart LE. Mycoplasma genitalium infection and female reproductive tract disease: A meta-analysis. Clin Infect Dis. 2015;61:418-426.

12. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1-137.

13. Davies N. Mycoplasma genitalium: The need for testing and emerging diagnostic options. MLO Med Lab Obs. 2015;47:8,10-11.

14. Getman D, Jiang A, O’Donnell M, Cohen S. Mycoplasma genitalium prevalence, coinfection, and macrolide antibiotic resistance frequency in a multicenter clinical study cohort in the United States. J Clin Microbiol. 2016;54:2278-2283.

15. Tully JG, Taylor-Robinson D, Cole RM, Rose DL. A newly discovered mycoplasma in the human urogenital tract. Lancet. 1981;1(8233):1288-1291.

16. Taylor-Robinson D. The Harrison Lecture. The history and role of Mycoplasma genitalium in sexually transmitted diseases. Genitourin Med. 1995;71:1-8.

17. Horner P, Thomas B, Gilroy CB, Egger M, Taylor-Robinson D. Role of Mycoplasma genitalium and ureaplasma urealyticum in acute and chronic nongonococcal urethritis. Clin Infect Dis. 2001;32:995-1003.

18. Horner P, Blee K, O’Mahony C, et al. Clinical Effectiveness Group of the British Association of Sexual Health and HIV. 2015 UK National Guideline on the management of non-gonococcal urethritis. Int J STD AIDS. 2016;27:85-96.

19. Das K, De la Garza G, Siwak EB, et al. Mycoplasma genitalium promotes epithelial crossing and peripheral blood mononuclear cell infection by HIV-1. Int J Infect Dis. 2014;23:31-38.

20. McGowin CL, Annan RS, Quayle AJ, et al. Persistent Mycoplasma genitalium infection of human endocervical epithelial cells elicits chronic inflammatory cytokine secretion. Infect Immun. 2012;80:3842-3849.

21. Salado-Rasmussen K, Jensen JS. Mycoplasma genitalium testing pattern and macrolide resistance: A Danish nationwide retrospective survey. Clin Infect Dis. 2014;59:24-30.

22. Taylor-Robinson D, Bebear C. Antibiotic susceptibilities of mycoplasmas and treatment of mycoplasmal infections. J Antimicrob Chemother. 1997;40:622-630.

23. Taylor-Robinson D. Diagnosis and antimicrobial treatment of Mycoplasma genitalium infection: Sobering thoughts. Expert Rev Anti Infect Ther. 2014;12:715-722.

24. Ison CA. Biology of Neisseria gonorrhoeae and the clinical picture of infection. In: Gross G, Tyring SK, eds. Sexually Transmitted Infections and Sexually Transmitted Diseases.1st ed. Berlin, Heidelberg: Springer-Verlag; 2011:77-90.

25. Criss AK, Seifert HS. A bacterial siren song: Intimate interactions between neisseria and neutrophils. Nat Rev Microbiol. 2012;10:178-190.

26. Urban CF, Lourido S, Zychlinsky A. How do microbes evade neutrophil killing? Cell Microbiol. 2006;8:1687-1696.

27. World Health Organization, Dept. of Reproductive Health and Research. Global incidence and prevalence of selected curable sexually transmitted infections - 2008. www.who.int/reproductivehealth/publications/rtis/stisestimates/en/. Published 2012. Accessed February 6, 2018.

28. Centers for Disease Control and Prevention 2015 sexually transmitted diseases treatment guidelines. www.cdc.gov/std/tg2015/emerging.htm. Updated June 4, 2015.

29. Skerlev M, Culav-Koscak I. Gonorrhea: New challenges. Clin Dermatol. 2014;32:275-281.

30. Kirkcaldy RD, Ballard RC, Dowell D. Gonococcal resistance: Are cephalosporins next? Curr Infect Dis Rep. 2011;13:196-204.

31. Kidd S, Kirkcaldy R, Weinstock H, Bolan G. Tackling multidrug-resistant gonorrhea: How should we prepare for the untreatable? Expert Rev Anti Infect Ther. 2012;10:831-833.

32. Wang SA, Harvey AB, Conner SM, et al. Antimicrobial resistance for Neisseria gonorrhoeae in the United States, 1988 to 2003: The spread of fluoroquinolone resistance. Ann Intern Med. 2007;147:81-88.

33. Barbee LA, Kerani RP, Dombrowski JC, et al. A retrospective comparative study of 2-drug oral and intramuscular cephalosporin treatment regimens for pharyngeal gonorrhea. Clin Infect Dis. 2013;56:1539-434.

34. Sathia L, Ellis B, Phillip S, et al. Pharyngeal gonorrhoea - is dual therapy the way forward? Int J STD AIDS. 2007;18:647–8.

35. Tanaka M. Emergence of multidrug-resistant Neisseria gonorrhoeae strains circulating worldwide. Int J Urol. 2012;19:98-99.

36. Hamasuna R, Osada Y, Jensen JS. Isolation of Mycoplasma genitalium from first-void urine specimens by coculture with vero cells. J Clin Microbiol. 2007;45:847-850.

37. Razin S. Mycoplasma. In: Boricello SP, Murray PR, Funke G, eds. Topley & Wilson’s Microbiology and Microbial Infections. London, UK: Hodder Arnold; 2005:1957-2005.

38. Munson E, Bykowski H, Munson K, et al. Clinical laboratory assessment of Mycoplasma genitalium transcription-medicated ampliflication using primary female urogenital specimens. J Clin Microbiol. 2016;54:432-437.

39. Munson E, Wenten D, Jhansale S, et al. Expansion of comprehensive screening of male-sexually transmitted infection clinic attendees with Mycoplasma genitalium and Trichomonas vaginalis molecule assessment: a restrospective analysis. J Clin Microbiol. 2016;55:321-325.

40. Centers for Disease Control and Prevention. Recommendations for the laboratory-based detection of Chlamydia trachomatis and Neisseria gonorrhoeae--2014. MMWR Recomm Rep. 2014;63(RR-02):1-19.

41. Boyadzhyan B, Yashina T, Yatabe JH, et al. Comparison of the APTIMA CT and GC assays with the APTIMA combo 2 assay, the Abbott LCx assay, and direct fluorescent-antibody and culture assays for detection of Chlamydia trachomatis and Neisseria gonorrhoeae. J Clin Microbiol. 2004;42:3089-3093.

42. Graseck AS, Shih SL, Peipert JF. Home versus clinic-based specimen collection for Chlamydia trachomatis and Neisseria gonorrhoeae. Expert Rev Anti Infect Ther. 2011;9:183-194.

43. Sherrard J, Barlow D. Gonorrhoea in men: Clinical and diagnostic aspects. Genitourin Med. 1996;72:422-426.

44. Goh BT, Varia KB, Ayliffe PF, Lim FK Diagnosis of gonorrhea by gram-stained smears and cultures in men and women: role of the urethral smear. Sex Transm Dis. 1985;12:135-139.

45. World Health Organization. WHO Guidelines for the Treatment of Neisseria gonorrhoeae. www.who.int/reproductivehealth/publications/rtis/gonorrhoea-treatment-guidelines/en/. Published 2016. Accessed December 16, 2017.

46. Arbique JC, Forward KR, LeBlanc J. Evaluation of four commercial transport media for the survival of Neisseria gonorrhoeae. Diagn Microbiol Infect Dis. 2000;36:163-168.

47. Schink JC, Keith LG. Problems in the culture diagnosis of gonorrhea. J Reprod Med. 1985;30(3 Suppl):244-249.

48. Marrazzo JM, Apicella MA. Neisseria gonorrhoeae (gonorrhea). In: Bennett JE, Dolin R, Blaser MJ, eds. Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA: Elsevier; 2015:2446-2462.

49. Barry PM, Klausner JD. The use of cephalosporins for gonorrhea: The impending problem of resistance. Expert Opin Pharmacother. 2009;10:555-577.

50. Tabrizi SN, Unemo M, Limnios AE, et al. Evaluation of six commercial nucleic acid amplification tests for detection of Neisseria gonorrhoeae and other Neisseria species. J Clin Microbiol. 2011;49:3610-3615.

51. Goldenberg SD, Finn J, Sedudzi E, et al. Performance of the GeneXpert CT/NG assay compared to that of the Aptima AC2 assay for detection of rectal Chlamydia trachomatis and Neisseria gonorrhoeae by use of residual Aptima Samples. J Clin Microbiol. 2012;50:3867-3869.

52. Martin D. Mycoplasma genitalium, Mycoplasma hominis, and Ureaplasma species. In: Bennet J, Dolin R, Blaser M, eds. Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA: Elsevier Sauders; 2015:2190-2193.

53. Hannan PC. Comparative susceptibilities of various AIDS-associated and human urogenital tract mycoplasmas and strains of Mycoplasma pneumoniae to 10 classes of antimicrobial agent in vitro. J Med Microbiol. 1998;47:1115-1122.

54. Mena LA, Mroczkowski TF, Nsuami M, Martin DH. A randomized comparison of azithromycin and doxycycline for the treatment of Mycoplasma genitalium-positive urethritis in men. Clin Infect Dis. 2009;48:1649-1654.

55. Schwebke JR, Rompalo A, Taylor S, et al. Re-evaluating the treatment of nongonococcal urethritis: Emphasizing emerging pathogens--a randomized clinical trial. Clin Infect Dis. 2011;52:163-170.

56. Bjornelius E, Anagrius C, Bojs G, et al. Antibiotic treatment of symptomatic Mycoplasma genitalium infection in Scandinavia: A controlled clinical trial. Sex Transm Infect. 2008;84:72-76.

57. Nijhuis RH, Severs TT, Van der Vegt DS, et al. High levels of macrolide resistance-associated mutations in Mycoplasma genitalium warrant antibiotic susceptibility-guided treatment. J Antimicrob Chemother. 2015;70:2515-2518.

58. Pond MJ, Nori AV, Witney AA, et al. High prevalence of antibiotic-resistant Mycoplasma genitalium in nongonococcal urethritis: The need for routine testing and the inadequacy of current treatment options. Clin Infect Dis. 2014;58:631-637.

59. Touati A, Peuchant O, Jensen JS, et al. Direct detection of macrolide resistance in Mycoplasma genitalium isolates from clinical specimens from France by use of real-time PCR and melting curve analysis. J Clin Microbiol. 2014;52:1549-1555.

60. Bebear CM, de Barbeyrac B, Pereyre S, et al. Activity of moxifloxacin against the urogenital Mycoplasmas ureaplasma spp., Mycoplasma hominis and Mycoplasma genitalium and Chlamydia trachomatis. Clin Microbiol Infect. 2008;14:801-805.

61. Jernberg E, Moghaddam A, Moi H. Azithromycin and moxifloxacin for microbiological cure of Mycoplasma genitalium infection: An open study. Int J STD AIDS. 2008;19:676-679.

62. Tagg KA, Jeoffreys NJ, Couldwell DL, et al. Fluoroquinolone and macrolide resistance-associated mutations in Mycoplasma genitalium. J Clin Microbiol. 2013;51:2245-2249.

63. Couldwell DL, Tagg KA, Jeoffreys NJ, Gilbert GL. Failure of moxifloxacin treatment in Mycoplasma genitalium infections due to macrolide and fluoroquinolone resistance. Int J STD AIDS. 2013;24:822-828.

64. Shimada Y, Deguchi T, Nakane K, et al. Emergence of clinical strains of Mycoplasma genitalium harbouring alterations in ParC associated with fluoroquinolone resistance. Int J Antimicrob Agents. 2010;36:255-258.

65. Mobley V, Seña A. Mycoplasma genitalium infection in men and women. In: UpToDate. www.uptodate.com. Last updated March 8, 2017. Accessed February 13, 2018.

66. 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;19:941-945.

67. 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;18:414-418.

68. Bissessor M, Tabrizi SN, Twin J, et al. Macrolide resistance and azithromycin failure in a Mycoplasma genitalium-infected cohort, and response of azithromycin failures to alternative antibiotic regimens. Clin Infect Dis. 2014;60:1228-1236.

69. Jensen JS, Fernandes P, Unemo M. In vitro activity of the new fluoroketolide solithromycin (CEM-101) against macrolide-resistant and -susceptible Mycoplasma genitalium strains. Antimicrob Agents Chemother. 2014;58:3151-3156.

70. Centers for Disease Control and Prevention (CDC). Update to CDC’s sexually transmitted diseases treatment guidelines, 2006: Fluoroquinolones no longer recommended for treatment of gonococcal infections. MMWR Morb Mortal Wkly Rep. 2007;56:332-336.

71. Sexually transmitted diseases treatment guidelines, 2010. www.cdc.gov/std/treatment/default.htm. Published 2015. Accessed February13, 2016.

72. Centers for Disease Control and Prevention (CDC). Cephalosporin susceptibility among Neisseria gonorrhoeae isolates--United States, 2000-2010. MMWR Morb Mortal Wkly Rep. 2011;60:873-877.

73. Ohnishi M, Saika T, Hoshina S, et al. Ceftriaxone-resistant Neisseria gonorrhoeae, Japan. Emerg Infect Dis. 2011;17:148-149.

74. Centers for Disease Control and Prevention (CDC). Update to CDC’s sexually transmitted diseases treatment guidelines, 2010: Oral cephalosporins no longer a recommended treatment for gonococcal infections. MMWR Morb Mortal Wkly Rep. 2012;61:590-594.

75. Kirkcaldy RD, Weinstock HS, Moore PC, et al. The efficacy and safety of gentamicin plus azithromycin and gemifloxacin plus azithromycin as treatment of uncomplicated gonorrhea. Clin Infect Dis. 2014;59:1083-1091.

76. Seña AC, Taylor SN, Marrazzo J, et al. Microbiological cure rates and antimicrobial susceptibility of Neisseria gonorrhoeae to ETX0914 (AZD0914) in a phase II treatment trial for urogenital gonorrhea. (Poster 1308) Program and Abstract of ID Week 2016. New Orleans, LA, . October 25-30, 2016.

77. Taylor S, Marrazzo J, Batteiger B, et al. Single-dose zoliflodacin (ETX0914) for treatment of urogential gonorrhea. N Engl J Med. 2018;379:1835-1845.

78. Perry C, Dumont E, Raychaudhuri A. O05.3 A phase II, randomised, stdy in adults subjects evaluating the efficacy, safety, and tolerability of single doses of gepotidacin (GSK2140944) for treatment of uncomplicated urogenital gonorrhea. Sex Transm Infect. 2017;93(Suppl 2).

79. Bignell C, Unemo M, European STI Guidelines Editorial Board. 2012 European guideline on the diagnosis and treatment of gonorrhoea in adults. Int J STD AIDS. 2013;24:85-92.

80. O’Connor EA, Lin JS, Burda BU, et al. Behavioral sexual risk-reduction counseling in primary care to prevent sexually transmitted infections: A systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014;161:874-883.

The most common clinical presentations are urethritis in men and cervicitis in women.²⁹ While urethritis is most likely to be symptomatic, only 50% of women with acute gonorrhea are symptomatic.²⁹ In addition to lower urogenital tract infection, N. gonorrhoeae can also cause PID, ectopic pregnancy, infertility in women, and epididymitis in men.^29,30 Rare complications can develop from the spread of N. gonorrhoeae to other parts of the body including the joints, eyes, cardiovascular system, and skin.²⁹

N. gonorrhoeae can attach to the columnar epithelium and causes host innate immune-driven inflammation with neutrophil influx.²⁹It can avoid the immune response by varying its outer membrane protein expression. The organism is also able to acquire DNA from other Neisseria species³⁰ and genera, which results in reduced susceptibility to therapies.

The Gonococcal Isolate Surveillance Project (GISP), established in 1986, is a collaborative project involving the CDC and STI clinics in 26 cities in the United States along with 5 regional laboratories.³¹ The GISP monitors susceptibilities in N. gonorrhoeae isolates obtained from roughly 6000 symptomatic men each year.³¹ Data collected from the GISP allows clinicians to treat infections with the correct antibiotic. Just as they observed patterns of fluoroquinolone-resistant N. gonorrhoeae, there has been a geographic progression of decreasing susceptibility to cephalosporins in recent years.³¹

The ease with which N. gonorrhoeae can develop resistance is particularly alarming. Sulfonamide use began in the 1930s, but resistance developed within approximately 10 years.^30,32N. gonorrhoeae has acquired resistance to each therapeutic agent used for treatment over the course of its lifetime. One hypothesis is that use of single-dose therapy to rapidly treat the infection has led to treatment failure and allows for selective pressure where organisms with decreased antibiotic susceptibility are more likely to survive.³⁰ However, there is limited evidence to support monotherapy versus combination therapy in treating N. gonorrhoeae.^33,34 It is no exaggeration to say gonorrhea is now at risk of becoming an untreatable disease because of the rapid emergence of multidrug resistant N. gonorrhoeae strains worldwide.³⁵

Diagnosis

Whether the urethritis, cervicitis, or PID is caused by N. gonorrhoeae, M. genitalium, or other non-gonococcal microorganisms (eg, C. trachomatis), no symptoms are specific to any of the microorganisms. Therefore, clinicians rely on laboratory tests to diagnose STIs caused by N. gonorrhoeae or M. genitalium.

M. genitalium

Gram Stain. Because M. genitalium lacks a cell wall, it cannot be identified by routine Gram stain.

Culture. Culturing of this fastidious bacterium might offer the advantage of assessing antibiotic susceptibility;³⁶ however, the procedure is labor intensive and time consuming, and only a few labs in the world have the capability to perform this culture.¹² Thus, this testing method is primarily undertaken for research purposes.