Mycoplasma Genitalium Infection: An Emerging Sexually Transmitted Infection
Although the first reported association of Mycoplasma genitalium (M. genitalium) with inflammatory urogenital disease was over 35 years ago,1 we have just begun to appreciate the clinical significance of this pathogen as a sexually transmitted infection (STI). Recently, M. genitalium has been labeled as an “emerging” STI.2 As described by Le Roy and colleagues, M. genitalium was originally isolated from men with urethritis and linked to non-gonococcal urethritis (NGU). In women, M. genitalium infection has similar symptoms to infections caused by Chlamydia trachomatis and Neisseria gonorrhoeae such as cervicitis with pelvic inflammatory disease or tubal factor infertility, while perinatal complications are more limited.3-8
One of the driving forces behind the emergence of this infection has been the development of research-based nucleic acid amplification tests (NAATs), such as PCR, that have provided the means to detect M. genitalium in specimens collected from general and clinic-based populations. There is currently no commercially available FDA-cleared NAAT for M. genitalium detection, which has hindered the advancement of our knowledge on the natural history of the infection and its morbidity. Such knowledge is essential in the consideration of screening guidelines for M. genitalium. Furthermore, there are no current screening recommendations for M. genitalium in the U.S. Golden and colleagues present extensive European screening guidelines along with proposed Public Health Guidelines from Washington State as evidence of the urgent need to identify and quickly manage M. genitalium infection in the U.S.9 Contributing to this urgency is the rapid development of macrolide resistance among M. genitalium strains.3,10-12 Of greater concern is the emergence of fluoroquinolone resistance frequently associated with treatment failure in patients treated with moxifloxacin.12-15
Epidemiology and Burden of Disease with M. genitalium Infection
In 1981, Tully and colleagues reported cell culture isolation of a new mycoplasma from the urogenital tract of 2 of 13 men with NGU.1 In 1983, this new mycoplasma was named a new species, M. genitalium.16M. genitalium is highly fastidious in culture and can take weeks to months to grow. For this reason, there had been sparse clinical data on M. genitalium infection until over the last 20 years. With development of research-based (“in-house”) M. genitalium NAATs, studies began to emerge on the prevalence of the infection, risk factors, clinical manifestations, and natural history and treatment outcomes.
General Population Studies
Limited studies on the prevalence of M. genitalium infections in general populations suggest the infection is more prevalent than gonorrhea but less prevalent or similar to chlamydia prevalence.17-20 Manhart and colleagues evaluated the U.S. prevalence of M. genitalium infection in 18 to 27 year-olds by testing stored urine specimens using PCR; they found a prevalence of 1.1% in men and 0.8% in women, higher than the 0.4% prevalence of gonorrhea in the cohorts but lower than the prevalence of chlamydia (3.7% in men and 4.7% in women).17,18 Prevalence of M. genitalium infection was higher in African Americans and those reporting living with a sexual partner.17 Only 2.2% of participants reported painful urination and none reported urethral or vaginal discharge.17 A population-based study of M. genitalium prevalence in individuals 16 to 44 years of age in Britain that also tested urine by PCR found a prevalence of 1.2% in men and 1.3% in women, higher than prevalence of gonorrhea found in the cohort (<0.1% for both genders) but similar to chlamydia prevalence (1.1% in men and 1.5% in women).19,20 Prevalence was higher in African American men and both genders reporting select sexual risk behaviors.19 Most men (94%) and the majority of women (56%) did not report any symptoms consistent with an STI.19 Studies in clinic-based populations have revealed a much higher prevalence than seen in the general population and still higher than gonorrhea with similar or higher prevalence than chlamydia.11 Getman and colleagues tested urine and genital swab specimens from men (ages 18 to 78 years) and women (ages 14 to 70 years) who were seen at 7 geographically dispersed clinics in the U.S. using a research-use-only NAAT transcription-mediated amplification (TMA). They reported an M. genitalium prevalence of 17.2% in men (similar to chlamydia [17.8%] but higher than gonorrhea [4.2%]); and 16.3% in women (higher than chlamydia [9.3%] and gonorrhea [1.9%]).11 Predictors of higher M. genitalium infection prevalence were African American race and women having symptoms.11
While the majority of M. genitalium infections are asymptomatic, some can present with clinical syndromes that are also seen with chlamydia and gonorrhea. Therefore, specific testing for M. genitalium is required to confirm the bacteria as an etiology for the syndrome. Testing for other STIs is also necessary since co-infection of M. genitalium with other pathogens can occur (albeit infrequent)11 and different etiologies may require different treatments.
M. genitalium Infection in Men
In men, numerous studies have demonstrated a strong association of M. genitalium with symptomatic acute NGU, particularly nonchlamydial NGU (Figure 1).7 M. genitalium has been detected by PCR in 15% to 25% of symptomatic NGU cases and about 30% of cases of persistent or recurrent urethritis.2,21 There are sparse data that M. genitalium urethritis in men is complicated by epididymitis.2,7M. genitalium has also been detected in anorectal samples, usually in individuals without rectal symptoms.2,7 However, the bacteria has been reported as a cause of proctitis in men who have sex with men (MSM).21
M. genitalium Infection in Women
Numerous studies have shown an etiologic association between infection with M. genitalium and cervicitis (Figure 2).7 The bacteria has been detected in 15% to 30% of women presenting with clinical cervicitis as well as in women with persistent or recurrent cervicitis.2 There is evidence that M. genitalium infection can ascend to the upper genital tract in women resulting in pelvic inflammatory disease. A study by Baczynska and colleagues demonstrated that human fallopian tube cells can be infected with M. genitalium leading to inflammation and damaged cilia.22 Animal studies revealed that M. genitalium can infect and cause inflammation of the upper genital tract.23,24 Cohen and colleagues presented data that M. genitalium was detected in endometrium and fallopian tube tissue from women with salpingitis.25 Several other human studies strongly supported M. genitalium infection in the development of pelvic inflammatory disease.4M. genitalium has also been associated with an approximate 2-fold increased risk for spontaneous abortion, preterm birth and infertility. Although these associations are based on weaker evidence and with some studies having contradictory findings, awareness of the risks associated with M. genitalium infection continue to grow and have become more clinically concerning.4 In addition to the above clinical syndromes, M. genitalium has also been associated with over a 2-fold increased risk for HIV infection.26
Natural History of M. genitalium Infection
There are very limited data on the natural history of M. genitalium infection. Findings from a few studies suggest that the majority of M. genitalium infections in women naturally resolve (presumably through immune-mediated clearance) within 6 months of initial detection. One study of female sex workers in Kenya reported 83% of M. genitalium infections resolved after 3 months with 91% of infections resolving by 6 months from the time of initial testing.27 Similarly, a study of female sex workers in Uganda reported that 55% of M. genitalium infections resolved by 3 months after initial testing and 83% by 6 months. The time to resolution was longer in HIV-infected women with CD4 counts <350/mL.3,28 A study of adolescent females in the U.S., mostly African American, reported that 69% resolved M. genitalium infection by 8 weeks and 78% by 12 weeks after initial detection.29 The natural history of asymptomatic M. genitalium infection in men is poorly understood. Sparse data from 2 studies on the concordance of M. genitalium infection in couples have demonstrated low concordance rates from the perspective of the infected female patient. About 25% to 35% of male partners of infected female patients report becoming infected.29,30 While the low concordance rates of M. genitalium infection could reflect possible inefficient sexual transmission of bacteria from infected females to their male partners, it also could reflect the short duration of the infection.
Notwithstanding the limited data on the natural history of M. genitalium infection, the clinical risks associated with infection and the inherent propensity of M. genitalium to develop antibiotic resistance reflect that accurate diagnosis is necessary for rapid and appropriate treatment.
As described in depth by Gaydos in her 2017 Journal of Infectious Disease Supplement article,31 while there are no FDA-cleared M. genitalium assays currently available in the U. S., highly sensitive and specific research assays based NAATs have been in use since the early 1990s. These tests detect many infectious organisms including M. genitalium. The assay developed by Jensen and colleagues targets a conserved region of the 16S ribosomal RNA (rRNA) gene. This test continues to be used in research-based studies.
The FDA does allow companies to submit assay component test reagents for evaluation and possibly receive “analyte-specific reagent” (ASR) status so individual “kit” reagents can be sold separately for development of “in-house” tests for M. genitalium in the U.S. Only one company, Hologic (San Diego, CA), has achieved ASR status for its M. genitalium test reagents. This transcription mediated amplification (TMA) assay is now CE marked in Europe where it has been widely and effectively utilized in epidemiology studies, and may well have application in support of newly developed European Screening Guidelines for M. genitalium.11,32-37 It should be noted that the 2015 CDC STD Treatment Guidelines recommend considering M. genitalium testing in cases with persistent urethritis, cervicitis, and pelvic inflammatory disease in settings where a validated test is available to help guide treatment decisions.2
The three classes of antibiotics traditionally used to treat mycoplasmas are tetracyclines (e.g., doxycycline), macrolides (e.g., azithromycin), and quinolones (e.g., moxifloxacin). Doxycycline has been ineffective against M. genitalium NGU and cervicitis with median microbial cure rates under 50%.3 Limited doxycycline efficacy does not appear to be due to resistance.38 Azithromycin 1 g has been the first-line antibiotic treatment regimen for M. genitalium infections in the U.S. (often empirically used for urethritis and cervicitis treatment), but the microbial cure rates of azithromycin 1 g for urogenital M. genitalium infections have been declining since 2009. This has been demonstrated over the course of three randomized controlled NGU treatment trials (Figure 3)38 and in a meta-analysis of M. genitalium treatment consisting of mostly observational data (Figure 4).39
M. genitalium treatment failure with azithromycin 1 g is strongly associated with azithromycin-resistance. Resistance to M. genitalium strains often appears as being induced by treatment.3,10,15,40 A recent study showed that a longer course of azithromycin (1.5 g over 5 days) for M. genitalium urethritis did not cure more infections or lower the likelihood of azithromycin resistance development after treatment compared to single doses of azithromycin 1 g.41 Based on two recent U.S. studies, azithromycin-resistant M. genitalium strains occur in up to 42% to 80% of infections;11,12 high resistance rates are also being reported in countries outside the U.S.13,14
The fluoroquinolone moxifloxacin, given at 400 mg daily for 7-14 days, has been successful in curing urogenital M. genitalium infections that failed azithromycin and/or doxycycline.38 However, quinolone-resistant M. genitalium strains have emerged and cure rates with moxifloxacin have been declining based on studies published since 2013 (Figure 5).10,15,38 The 2015 CDC STD Treatment Guidelines recommend moxifloxacin for treatment of suspected or documented M. genitalium infections in the setting of persisting urethritis, cervicitis, or pelvic inflammatory disease (after azithromycin treatment).2 The only published U.S. study on quinolone resistance in M. genitalium infection reported that 26.7% of urogenital infections in HIV-infected MSM were due to quinolone-resistant strains.12
There is no guidance at this time on how to best manage M. genitalium infections in individuals in the U.S. who have failed azithromycin and moxifloxacin due to resistance. A recent study in Japan reported that 2 men with M. genitalium urethritis who failed moxifloxacin with strains that were quinolone- and macrolide-resistant were cured with minocycline 100 mg given twice a day for 14 days.42 While minocycline is available in the U.S., there is insufficient data on its efficacy for M. genitalium infections at this time to consider it a recommended treatment. With the propensity of M. genitalium for developing resistance, it is likely that a dual antibiotic treatment approach, as has been done for gonorrhea, will be recommended in the future. This is especially relevant as M. genitalium infection is responsible for more STIs than Neisseria gonorrhoeae and is the second-most prevalent STI next to Chlamydia trachomatis infection.43
M. genitalium infection is an emerging STI that is asymptomatic in the majority of infected individuals. The infection can cause clinical syndromes such as urethritis and cervicitis. There is limited evidence for an association with reproductive morbidity and prenatal or postnatal complications. NAAT is the preferred test for diagnosing M. genitalium infection. Presently, there is no FDA-cleared NAAT test for M. genitalium in the U.S. However, if a validated research-based M. genitalium NAAT assay is available or one becomes FDA-cleared, then its use may be considered in individuals with persisting urethritis, cervicitis, or pelvic inflammatory disease after azithromycin treatment. Azithromycin has been and is still considered the first-line treatment for M. genitalium infections in the U.S. However, with the emergence of azithromycin-resistant strains in close to half or more M. genitalium infections and their association with treatment failure, moxifloxacin is the recommended antibiotic for treating individuals with suspected or proven M. genitalium infection resistant to treatment with azithromycin. With the emergence of M. genitalium strains resistant to both macrolides and quinolones in the U.S., there are limited other M. genitalium treatment options. New drugs and treatment approaches are needed as is a vaccine to prevent M. genitalium infection.
- Tully JG, Taylor-Robinson D, Cole RM, Rose DL. A newly discovered mycoplasma in the human urogenital tract. Lancet. 1981;1:1288-1291.
- Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1-137.
- Manhart LE. Mycoplasma genitalium: An emergent sexually transmitted disease? Infect Dis Clin North Am. 2013;27:779-792.
- 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.
- LeRoy C, Pereyre S , Bebear C. Evaluation of two real-time PCR assays for detection of Mycoplasma genitalium in urogenital specimens. J Clin Microbiol. 2015;52:971-973.
- Manhart LE, Broad JM, Golden MR. Mycoplasma genitalium: should we treat and how? Clin Infect Dis. 2011;53:S129-S142.
- Taylor-Robinson D, Jensen JS. Mycoplasma genitalium: from Chrysalis to multicolored butterfly. Clin Microbiol Rev. 2011;24:498-514.
- Cazanave C, Manhart LE, Bébéar C. Mycoplasma genitalium, an emerging sexually transmitted pathogen. Med Mal Infect. 2012;42:381-392.
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- 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. 2015;60:1228-1236.
- 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.
- Dionne-Odom J, Geisler WM, Aaron KJ, et al. High prevalence of multidrug-resistant Mycoplasma genitalium in HIV-infected men who have sex with men in Alabama. Clin Infect Dis. 2017;66(5):796-798.
- Tagg KA, Jeoffreys NJ, Couldwell DL, Donald JA, Gilbert GL. Fluoroquinolone and macrolide resistance-associated mutations in Mycoplasma genitalium. J Clin Microbiol. 2013;51:2245-2249.
- Deguchi T, Kikuchi M, Yasuda M, et al. Multidrug-resistant Mycoplasma genitalium is increasing. Clin Infect Dis. 2016;62:405-406.
- 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.
- Tully JG, Taylor-Robinson D, Rose DL, Cole RM, Bove JM. Mycoplasma genitalium, a new species from the human urogenital tract. Int J Syst Bacteriol. 1983;33:387-396.
- Manhart LE, Holmes KK, Hughes JP, Houston LS, Totten PA. Mycoplasma genitalium among young adults in the United States: an emerging sexually transmitted infection. Am J Public Health. 2007;97:1118-1125.
- Miller WC, Ford CA, Morris M, et al. Prevalence of chlamydial and gonococcal infections among young adults in the United States. JAMA. 2004;291:2229-2236.
- Sonnenberg P, Ison CA, Clifton S, et al. Epidemiology of Mycoplasma genitalium in British men and women aged 16–44 years: evidence from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). Int J Epidemiol. 2015;44:1982-1994.
- Sonnenberg P, Clifton S, Beddows S, et al. Prevalence, risk factors, and uptake of interventions for sexually transmitted infections in Britain: findings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal). Lancet. 2013;382:1795-1806.
- Bissessor M, Tabrizi SN, Bradshaw CS, et al. The contribution of Mycoplasma genitalium to the aetiology of sexually acquired infectious proctitis in men who have sex with men. Clin Microbiol Infect. 201;22:260-265.
- Baczynska A, Funch P, Fedder J, et al. Morphology of human fallopian tubes after infection with Mycoplasma genitalium and Mycoplasma hominis--in vitro organ culture study. Hum Reprod. 2007;22:968-979.
- McGowin CL, Spagnuolo RA, Pyles RB. Mycoplasma genitalium rapidly disseminates to the upper reproductive tracts and knees of female mice following vaginal inoculation. Infect Immun. 2010;78:726-736.
- Møller BR, Taylor-Robinson D, Furr PM, Freundt EA. Acute upper genital-tract disease in female monkeys provoked experimentally by Mycoplasma genitalium. Br J Exp Pathol. 1985;66:417-426.
- Cohen CR, Mugo NR, Astete SG, et al. Detection of Mycoplasma genitalium in women with laparoscopically diagnosed acute salpingitis. Sex Transm Infect. 2005;81:463-466.
- Napierala Mavedzenge S and Weiss HA. Association of Mycoplasma genitalium and HIV infection: a systematic review and meta-analysis. AIDS. 2009;23:611-620.
- Cohen CR, Nosek M, Meier A, et al. Mycoplasma genitalium infection and persistence in a cohort of female sex workers in Nairobi, Kenya. Sex Transm Dis. 2007;34:274-279.
- Vandepitte J, Weiss HA, Kyakuwa N, et al. Natural history of Mycoplasma genitalium infection in a cohort of female sex workers in Kampala, Uganda. Sex Transm Dis. 2013;40:422-427.
- Tosh AK, Van Der Pol B, Fortenberry JD, et al. Mycoplasma genitalium among adolescent women and their partners. J Adolesc Health. 200;40:412-417.
- Thurman AR, Musatovova O, Perdue S, et al. Mycoplasma genitalium symptoms, concordance and treatment in high-risk sexual dyads. Int J STD AIDS. 2010;21:177-183.
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- Munson E, Bykowski H, Munson KL, et al. Clinical laboratory assessment of Mycoplasma genitalium transcription-mediated amplification using primary female urogenital specimens. J Clin Microbiol. 2016;54:432-438.
- Gaydos C, Maldeis NE, Hardick A, Hardick J, Quinn TC. Mycoplasma genitalium compared to chlamydia, gonorrhoea and trichomonas as an aetiological agent of urethritis in men attending STD clinics. Sex Transm Infect. 2009;85:438-440.
- Gaydos C, Maldeis NE, Hardick A, Hardick J, Quinn TC. Mycoplasma genitalium as a contributor to the multiple etiologies of cervicitis in women attending sexually transmitted disease clinics. Sex Transm Dis. 2009;36:598-606.
- 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.
- Seña AC, Lensing S, Rompalo A, et al. Chlamydia trachomatis, Mycoplasma genitalium, and Trichomonas vaginalis infections in men with nongonococcal urethritis: predictors and persistence after therapy. J Infect Dis. 2012;206:357-365.
- Aptima Mycoplasma genitalium assay [package insert]. CE marked, 20 January 2015. Document AW-14170-001, Rev002. San Diego, CA: Hologic, 2017.
- Manhart LE, Jensen JS, Bradshaw CS, Golden MR, Martin DH. Efficacy of antimicrobial therapy for Mycoplasma genitalium infections. Clin Infect Dis. 2015;61:S802-S817.
- Lau A, Bradshaw CS, Lewis D, et al. The efficacy of azithromycin for the treatment of genital Mycoplasma genitalium: a systematic review and meta-analysis. Clin Infect Dis. 2015;61:1389-1399.
- Jensen JS, Bradshaw CD, Tabrizi SN, Fairley CK, Hamasuna R. Azithromycin treatment failure in Mycoplasma genitalium-positive patients with nongonococcal urethritis is associated with induced macrolide resistance. Clin Infect Dis.2008;47:1546–1553.
- Read TR, Fairley CK, Tabrizi SN, et al. Azithromycin 1.5g over 5 days compared to 1g single dose in urethral Mycoplasma genitalium: impact on treatment outcome and resistance. Clin Infect Dis. 2017;64:250-256.
- Deguchi T, Ito S, Yasuda M, et al. Emergence of Mycoplasma genitalium with clinically significant fluoroquinolone resistance conferred by amino acid changes both in GyrA and ParC in Japan. J Infect Chemother. 2017;23:648-650.
- de Jong S, Rahamat-Langendoen JC, van Alphen P, et al., Large two-centre study into the prevalence of Mycoplasma genitalium and Trichomonas vaginalis in the Netherlands. International Journal of STD & AIDS. 2016;7(10):856-860.