Lesson 9. Mycoplasma genitalium

Mycoplasma genitalium has recently emerged as an important bacterial sexually transmitted infection (STI) (Figure 1). Recent data suggest the M. genitalium prevalence is as high or higher than the C. trachomatis prevalence in both males and females. The clinical presentation associated with M. genitalium infection is similar to that with Chlamydia trachomatis and infection with M. genitalium has been associated with the STI syndromes of urethritis, cervicitis, and pelvic inflammatory disease. In addition, M. genitalium may cause infertility and preterm delivery in pregnant people. It is frequently detected in the rectum, but whether it causes proctitis is unclear. Antimicrobial resistance in M. genitalium emerged around 2008 and has been rapidly expanding, making treatment of this infection challenging. Highly sensitive and specific diagnostic assays are available to detect it in clinical practice, and national guidelines outline recommendations for who should be tested and treated. In the following discussion, the terms “woman” or “women” are used to describe people who have a female sex assigned at birth (people with a cervix), including transgender men with a cervix and gender diverse people who have a cervix. Similarly, the terms “man” or “men” are used to describe people who have a male sex assigned at birth (people with a penis), including transgender women with a penis and gender diverse people who have a penis.

Surveillance Data

Mycoplasma genitalium is not a reportable infection in the United States and information on the prevalence of this infection is derived from three sources: (1) the 2017-2018 cycle of the National Health and Nutritional Examination Survey (NHANES), (2) a sentinel surveillance system in sexual health clinics, and (3) research studies. Among people of reproductive age (14–59 years of age) participating in NHANES, a population generally at low risk of STIs, M. genitalium prevalence was 1.7%, which is somewhat lower than C. trachomatis but higher than N. gonorrhoeae in a representative sample of young adults.[1,2,3,4] In contrast, the overall prevalence of M. genitalium among 1,743 attendees at 6 urban sexual health clinics in 2020 was 16.6%; among those participating in this surveillance study, 56% had genitourinary symptoms and 44% were asymptomatic (Figure 2).[5] In those sexual health clinic attendees, M. genitalium prevalence was significantly higher among males with symptoms than among males without symptoms, but there was no significant difference in prevalence between females with and without symptoms.[5]

• Sex: Whether M. genitalium prevalence differs by sex depends on the population surveyed. Among people at relatively low risk of STIs participating in the 2017-2018 cycle of NHANES, M. genitalium prevalence was similar in males and females (1.8% and 1.7% respectively).[2] The M. genitalium prevalence in the sexual health clinic surveillance study noted above was slightly higher in persons who identified as females (17.8%) than males (16.0%).[5]
• Age: Like other bacterial STIs, M. genitalium is most common among younger individuals. Among NHANES participants, M. genitalium prevalence was 3.9% in people 20–29 years of age, which was more than four times higher than prevalence in older adults 40–59 years of age (0.9%).[2] In the sexual health clinic surveillance study, the prevalence was higher for younger people and those younger than 19 years of age had a very high M. genitalium prevalence rate (30.4%) but this sample size was very small (23 people).[5] The higher prevalence in younger aged individuals may be due to higher levels of sexual activity in young people or possibly to the development of partial immunity after initial infections, although this latter hypothesis has not been rigorously explored.[6]
• Race/Ethnicity: M. genitalium infection is more common among people who report Black race and this is consistent in both community and sexual health clinic surveillance settings.[2,5] In 2020, M. genitalium prevalence was lowest among Hispanic and non-Hispanic White sexual health clinic attendees (11-12%), whereas it was 21% in people reporting non-Hispanic Black race/ethnicity.[5] The higher prevalence in these populations reflects health disparities in general rather than behavioral or biologic differences.
• Region and State: M. genitalium prevalence varies by geographic location. Among sexual health clinic patients in 2020, prevalence was lowest in the Pacific Northwest (9.9%) and highest in the South-Central United States (22-24%).[5]

Factors Associated with Acquisition of M. genitalium

The rate of new M. genitalium infections in women ranges from 0.9 per 100 person years among university students in Great Britain to 18.2 per 100 person years among women in the United States who engaged in transactional sex or were at high risk of STIs for other reasons.[7,8] Although relatively few studies have assessed factors associated with acquiring a new M. genitalium infection, bacterial vaginosis (BV) may play a role. Kenyan women engaging in transactional sex who had BV were more likely to subsequently acquire M. genitalium than women who did not have BV and health disparities amplify this.[7,9] Women in the United States with asymptomatic bacterial vaginosis, who reported Black race, were more likely to acquire a new M. genitalium infection than women reporting other races/ethnicities.[10] Other factors are likely associated with an increased risk of acquiring a new M. genitalium infection, but few longitudinal studies have been done to identify them. Incidence in males appears to be somewhat lower than in females, but potentially higher than the rate of other new bacterial STIs. Among men who have sex with women only (MSW) seeking sexual health care, the rate of new M. genitalium infections was 7 per 100 person-years, slightly higher than the rate of new chlamydia infections (6 per 100 person-years), and more than double the rate of new gonorrhea infections (3 per 100 person years).[11]

Impact

Between 2017-2018, there were an estimated 3 million people of reproductive age (14–59 years) in the United States with a prevalent M. genitalium urogenital infection.[2] To date, no monetary costs for M. genitalium infections have been calculated, but these infections have been associated with pelvic inflammatory disease (PID), infertility, and preterm delivery—all conditions associated with high costs.[12]

Organism and Classification

Mycoplasma genitalium is a member of the Mollicute Class of bacteria.[13] In 2018, a name change to Mycoplasmoides genitalium was proposed, but this has been disputed and most continue to refer to the organism as Mycoplasma genitalium.[13,14] Mycoplasmas are very small (0.5 and 1.5 μm in size) flask-shaped organisms; the protruding terminal (narrow) element contains an attachment organelle that drives gliding motility (Figure 3).[15] They are characterized by their absence of a rigid peptidoglycan cell wall, and fastidious nature. The latter makes culture challenging and few strains have been adapted to grow on agar. Tissue culture, requiring weeks to months, is typically used to isolate clinical strains of M. genitalium, but this has been accomplished by only a few laboratories globally.[16] Several other Mycoplasma species, including M. pneumoniae, M. hominis, M. fermentans, M. penetrans, Ureaplasma urealyticum, and U. parvum, are known to colonize humans, but only M. pneumoniae and M. genitalium are recognized human pathogens. Although M. penetrans has been associated with urethritis among men who have sex with men (MSM), to date, there is insufficient evidence linking M. hominis, U. urealyticum, U. parvum, and M. fermentans to disease syndromes.[17,18]

Transmission

The primary mode of transmission for M. genitalium is sexual. The organism is found infrequently in people who have not yet become sexually active, and approximately 30-50% of both members of a sexual partnership are concordantly infected.[19,20,21,22] However, the transmission probability from an infected to a susceptible partner has not been clearly defined. Limited evidence suggests that vertical transmission can occur in some instances. Mycoplasma genitalium has been detected in the trachea of an infant born to an infected birth parent and in conjunctival specimens from infants born to infected birth parents.[23,24] Auto-inoculation from the male urethra to the conjunctiva has also been documented.[25]

Natural History

The duration of M. genitalium infection varies substantially. Among women engaging in transactional sex, the median duration of infection ranged from 1 to 3 months, but up to 16% of women in one study had infection that persisted for at least 12 months.[19,26] In men treated with incompletely effective antibiotic regimens, the median duration of infection was 4.7 months, but the organism persisted after resolution of symptoms in some men for up to 11 months.[27] In another study, 30% of asymptomatic MSM with HIV who had M. genitalium cleared their infection spontaneously over an 18-month time period, with clearance possibly due to the production of M. genitalium-specific antibody that is present in urethral secretions.[28,29] Data on sequelae from asymptomatic infections are fairly limited, and the uncertainty over how often sequelae occur is a major factor in current testing and treatment guidelines.

Limited antimicrobials are available to treat M. genitalium infections. The lack of a rigid cell wall renders cell-wall mediated antibiotics ineffective and beta-lactam antibiotics, including penicillins, cephalosporins, and carbapenems, have no activity against M. genitalium. Culture is challenging and much of the available data on antimicrobial resistance are derived from pairing clinical treatment failure data with molecular detection of characteristic mutations. Minimum inhibitory concentrations (MICs) are not used in individual treatment decisions and are only performed in select research laboratories. Azithromycin, a macrolide antibiotic, and moxifloxacin, a fluoroquinolone antibiotic, have historically been the primary antimicrobials used to treat M. genitalium infections. Shortly after these two antibiotics began being used to treat M. genitalium infections (around 2008-2010), there was a rapid expansion of resistance to them. By 2016-2017, macrolide resistance had grown to greater than 50%, quinolone resistance to nearly 8%, and, globally, resistance to both antibiotic classes to approximately 3%.[30] As a result of these resistance trends, M. genitalium is one of three bacteria on the Watch List included in the United States Centers for Disease Control and Prevention (CDC) 2019 Report of Antibiotic Resistance Threats.[31] The following summarizes resistance data with antimicrobials that have been used to treat M. genitalium. Details regarding treatment recommendations are outlined below in the section on Treatment of Mycoplasma genitalium Infection. 

Azithromycin

During 2008-2013 M. genitalium azithromycin cure rates declined substantially, reflecting the emergence and spread of macrolide resistance.[32] Macrolide resistance to M. genitalium is due to single point mutations in the 23S rRNA gene, referred to as macrolide resistance mutations (MRMs).[33] The MRMs are similar to macrolide resistance in other microorganisms, but unlike antimicrobial resistance in Neisseria gonorrhoeae, there are no subtle gradations in susceptibility. Macrolide resistance in M. genitalium is bimodal, with either near-complete susceptibility (MICs ≤0.004 µg/mL) or total resistance (MICs ≥8 µg/mL) (Figure 4).[34] Macrolide resistance likely arose because of the widespread use of azithromycin. Mycoplasma genitalium has a high mutation rate and bacterial populations naturally include organisms with MRMs that survive and proliferate after azithromycin treatment.[35] Available data suggest that approximately 44-64% of M. genitalium isolates in the United States are resistant to azithromycin, with similar, if not higher, rates of resistance in other regions globally.[27,34,36,37] In addition, among baseline azithromycin-susceptible M. genitalium isolates, selection of resistant strains occurs in approximately 10% of those treated with azithromycin alone, but in less than 4% of people treated first with doxycycline followed by high dose azithromycin.[38,39]

Doxycycline

Despite relatively good susceptibility in the laboratory (MICs in United States strains range from less than 0.125 to 2.0 µg/mL), doxycycline has consistently low cure rates in clinical settings (Figure 5).[34] The low cure rate with doxycycline does not appear to be due to antimicrobial resistance. The tetM resistance determinant has not been identified in M. genitalium and, although numerous 16S rRNA mutations that are associated with tetracycline resistance in other organisms have been detected in M. genitalium, none have been linked to the efficacy of doxycycline treatment for M. genitalium.[40] Attempts to induce doxycycline resistance in the laboratory by passaging strains in sub-inhibitory concentrations have been unsuccessful.[41] 

Minocycline

Minocycline is an older and more potent tetracycline than doxycycline and has shown some efficacy when used for M. genitalium treatment failures. Among Australian patients in whom moxifloxacin had failed or was contraindicated, 68% experienced microbiologic cure after a 14-day regimen of minocycline.[42] No resistance mutations have been identified for minocycline. Older MICs range from 0.031-0.25 µg/mL, which is lower than doxycycline MICs.[43]

Moxifloxacin

Moxifloxacin has increasingly been used as a component of first-line M. genitalium therapy. Other fluoroquinolones, such as ciprofloxacin and levofloxacin, have limited efficacy against M. genitalium. Sitafloxacin, a more potent fluoroquinolone that is not available in the United States, is used for treatment failures in countries where it is available to clinicians. Prior to 2010, M. genitalium cure rates after moxifloxacin monotherapy treatment were uniformly 100%, but dropped to 89% after 2010 and have continued to decline.[44] Decreased cure rates after moxifloxacin are largely due to the emergence of quinolone resistance, mediated by ParC gene mutations. The ParC S83I has emerged as the mutation most strongly associated with treatment failure, and it was detected in 10% of specimens in the Americas tested between 2011-2017.[30,45,46] The presence or absence of the S83I mutation correlates strongly with fluoroquinolone treatment response. For example, in Australia, among people with M. genitalium who did not have the S83I mutation, the cure rate for a 7-day course of moxifloxacin monotherapy was 96.5%.[46] Concurrent mutations in the GyrA gene also increase the likelihood of resistance. When the GyrA mutation M95I was present in combination with the ParC S83I mutation, moxifloxacin treatment failure occurred in nearly 81% of Australian patients between 2019-2020, whereas only 43% failed when S83I alone was present in the absence of M95I.[46]

Pristinamycin

Pristinamycin is manufactured in France and available in some countries outside the United States. It is not approved by the US FDA and is not currently available in the United States. In other settings, it is an important treatment option for people in whom other antimicrobial treatments have failed with a cure rate of 75%, irrespective of whether it is used alone or in combination with doxycycline.[47] Little work has been done to determine resistance determinants for pristinamycin and only one potential mutation has been identified (A2062T in the 23S rRNA gene).[48]

Other Antibiotics

Omadacycline and tinidazole are US FDA-approved antibiotics with in vitro data suggesting they may be effective against M. genitalium. To date, neither has been tested in humans. Omadacycline is a newer tetracycline with MICs of 0.063-0.5 µg/ml, the same range as MICs for minocycline and somewhat lower than MICs for doxycycline (0.125-2 µg/mL) and tetracycline (0.5-16 µg/mL).[49] Tinidazole is a nitroimidazole antibiotic, with MICs ranging from 0.8-6.3 µg/mL, lower than MICs for two other nitroimidazoles used to treat bacterial vaginosis in women (metronidazole MIC range=6.3-12.5 µg/mL and secnidazole MIC range=3.1-12.5 µg/mL). Higher MICs for tinidazole may be due to a resistance mutation in the MG-342 gene, but no treatment outcome data are yet available to confirm this.[33]

Mycoplasma genitalium has a tropism for urogenital and rectal tissues. Infection with M. genitalium has been associated with a range of genitourinary manifestations, including urethritis, cervicitis, pelvic inflammatory disease (PID), and proctitis. In addition, M. genitalium may cause preterm delivery in pregnant people and female infertility. No definitive data link M. genitalium to epididymitis or male infertility, although studies on this are limited. Rare cases of conjunctivitis have been documented. Although M. genitalium has been identified in oropharyngeal specimens, pharyngitis has not been reported in people with M. genitalium in the oropharynx.

Urogenital Infections in Women

Urethritis

Mycoplasma genitalium has been detected in a small proportion of women with urethritis (4-9%) and has been linked to urethral inflammation and female urethritis.[50,51] Mycoplasma genitalium has also been detected in up to 22% of women reporting dysuria, a frequent complaint among women with urinary tract infections (UTI).[52] Notably, first-line therapies for female UTI, such as trimethoprim-sulfamethoxazole and nitrofurantoin, have poor efficacy against M. genitalium.

Vaginitis

In clinical settings, M. genitalium has been detected in 13-21% of women with vaginitis.[5,53] Although some studies have reported a significant association of M. genitalium and vaginitis, it is unclear whether the vaginitis results from M. genitalium infection of vaginal epithelial cells, M. genitalium infection of the cervix, or other causes.[53] Detection of M. genitalium in women with vaginitis may reflect synergy between M. genitalium and other bacteria that play a pathogenic role in bacterial vaginosis. The prevalence of M. genitalium in women with bacterial vaginosis is high, and some evidence suggests that bacterial vaginosis can enhance susceptibility to M. genitalium infection.[9,10]

Cervicitis

Mycoplasma genitalium has been detected in 10-29% of women with cervicitis (Figure 6).[54,55] Not all studies have shown a consistent association with M. genitalium and cervicitis, but those studies that accounted for other known causes of cervicitis (and/or define cervicitis as 30 polymorphonuclear cells or greater per high power field in cervical mucus) have shown that women with cervical M. genitalium infection are approximately two times more likely to have cervicitis than women without cervical M. genitalium.[12]

Pelvic Inflammatory Disease (PID)

Mycoplasma genitaliumhas been detected by NAAT in 4-18% of women with PID, and women with M. genitalium infection are approximately 2.0-2.5 times as likely to have PID as women without M. genitalium infection (Figure 7).[12,56,57] Some experts have debated the causal nature of this association, in part because few studies have followed women over time to observe the development of PID after a woman acquires M. genitalium. There are only two prospective studies that have addressed this issue, and when analyses are limited to these 2 studies, the relationship between M. genitalium and PID is less pronounced.[19] Larger and more rigorous longitudinal studies are needed to resolve the controversy. A strong relationship with post-abortal PID and perihepatitis (Fitz-Hugh Curtis syndrome) has also been reported.[58,59] Women with M. genitalium-associated PID have a similar clinical presentation as women with C. trachomatis-associated PID, with two exceptions: women with M. genitalium infection more frequently had abdominal tenderness on examination and were somewhat less likely to report post-coital bleeding.[60]

Infertility

Mycoplasma genitalium can ascend to the fallopian tubes and, in serologic studies that adjusted for prior chlamydial infection, women with antibodies to M. genitalium were 4–5 times more likely to have tubal factor infertility, suggesting that some women may suffer tubal occlusion after infection (Figure 8).[61,62,63] These data, however, are not consistent, and other studies have shown a more modest relationship with infertility.[12] Fecundability (probability of conception in a single menstrual cycle) may also be impaired during or after an M. genitalium infection.[64,65] For example, the per-menstrual cycle probability of pregnancy was 27% lower in Kenyan women with active M. genitalium infection and time to conception was 24% longer among women in the United States with serologic evidence of a prior M. genitalium infection.[65] Notably, delayed time to pregnancy may involve some synergy with M. genitalium and bacterial vaginosis. Fecundability among Kenyan women was nearly 50% lower when both M. genitalium infection and bacterial vaginosis were present, but there was only a marginal reduction in fecundability with either bacterial vaginosis or M. genitalium alone.[64]

Ectopic Pregnancy

There are limited data on M. genitalium and ectopic pregnancy, and the few studies that have been published are conflicting. One study demonstrated a modest and non-significant 60% increase in the odds of ectopic pregnancy among women with antibody to M. genitalium, but only among younger women (15-30 years of age). In contrast, M. genitalium was detected in Fallopian tube tissue among Saudi Arabian women with ectopic pregnancy more commonly than among women with total hysterectomies or tubal ligation (20.2% versus 3.9%).[66] To date, there is no consensus on whether M. genitalium infection can result in ectopic pregnancy.

Preterm Delivery

Pregnant people with M. genitalium may be at higher risk of preterm delivery. Two meta-analyses summarizing data published through 2021 demonstrated an approximately two-fold increase in the likelihood of delivery prior to 37 weeks.[12,67] Some evidence also suggests that pregnant people with M. genitalium may be at increased risk for spontaneous abortion, but relatively few studies have been conducted and data are conflicting.[12,67] Data are even more limited on whether M. genitalium is linked to lower birth weight.[68,69] Given these unclear consequences of asymptomatic infections in pregnancy and limited antimicrobial treatment options for pregnant people, screening asymptomatic pregnant people for M. genitalium is not currently recommended.[37]

Urogenital Infections in Men

Urethritis

Mycoplasma genitalium is responsible for 15-30% of nongonococcal urethritis (NGU) and is detected in more than 30% of men with non-chlamydial NGU.[70] Mycoplasma genitalium is also sometimes present in persons with gonococcal urethritis; among males from 6 United States cities with urethritis, 21.2% with M. genitalium also had Neisseria gonorrhoeae infection.[36] Symptoms associated with M. genitalium NGU are similar to those observed with C. trachomatis infection, although men with M. genitalium were more likely to report urethral discharge and to have cloudy or purulent discharge than men with other causes of NGU.[71] In clinical settings, M. genitalium has been a common cause of persistent and/or recurrent urethritis and may be present in up to 40% of people who have been treated with doxycycline or azithromycin without success.[70]

Epididymitis

It is unclear whether M. genitalium causes epididymitis. It has been detected in men with epididymitis, but this appears to occur rarely and there are no studies comparing detection of M. genitalium in men with and without epididymitis.[72,73]

Manifestations in Men or Women

Conjunctivitis

Although M. genitalium conjunctivitis has been documented, this is rare. Only one case of a man with M. genitalium-associated conjunctivitis has been reported.[25] The organism has also been detected in conjunctival specimens from infants born to infected birth parents, but this was not accompanied by information on whether the infants had conjunctivitis.[23]

Oropharyngeal Infection

Oropharyngeal infection with M. genitalium is rare. Using contemporary, highly sensitive NAAT assays, M. genitalium has been detected in the oropharynx in 1-5% of people, although it was found more frequently (12.3%) in one study of Italian MSM.[74,75,76] Mycoplasma genitalium-associated pharyngitis has not been reported.

Proctitis

Rectal M. genitalium prevalence in MSM ranges widely, from 1-30%, but was as high as 41.5% in young MSM and transgender women with HIV infection (Figure 9).[74,77] Among women, rectal M. genitalium has been detected in 2.6% of South African women and in as many as 22% of females attending sexual health clinics in the United States.[78,79] Although M. genitalium prevalence is often higher in people with than without rectal symptoms, data on whether it causes proctitis are conflicting. Some studies have identified an association and others have not.[80,81,82]

Reactive Arthritis

In rare circumstances, reactive arthritis may occur in people who have had an M. genitalium infection. There are case reports of M. genitalium (in the absence of chlamydia and gonorrhea) detected in the synovial fluid of a man with Reiter’s syndrome, in a man with seronegative rheumatoid arthritis, and in a man with sexually acquired reactive arthritis after M. genitalium urethritis.[83,84] However, there have been no systematic studies of the relationship of M. genitalium and Reiter’s syndrome.

Mycoplasma genitalium Diagnostic Testing

To diagnose M. genitalium infections, the preferred method is use of a Food and Drug Administration (FDA)-cleared nucleic acid amplification test (NAAT).[37] To date, there are no FDA-cleared point-of-care tests for the diagnosis of M. genitalium. Serologic assays and culture have been used in research settings but have no practical application in clinical care.

• Nucleic Acid Amplification Test: The FDA has cleared three NAATs to detect M. genitalium in clinical specimens. Most tests are approved for first-void urine and swab samples (urethral, vaginal, endocervical, penile-meatal), although there is some variability in approved sample type by manufacturer. Sensitivity of these assays is high, including 98% for urethral swabs (TMA only), 91-100% for male urine; 92-99% for vaginal swabs; 82-83% for endocervical swabs; and 78-86% for female urine specimens. Specificity is higher, ranging from 87-99%. Assays performed on self-obtained vaginal swab samples often have higher sensitivity than clinician-obtained vaginal swab samples, although this is not uniformly the case. Although none of these assays are FDA-cleared for use in extra-genital samples or for home testing, laboratories that have undergone a validation process and obtained CLIA certification for M. genitalium NAATs in oropharyngeal and/or rectal specimens may report results for clinical care.
• Serology: Although serology has been used in research efforts, it is not used in clinical practice to diagnose M. genitalium infections. Western Blot assays, which are labor-intensive and have an element of subjectivity in their interpretation, are the most common serologic assays and have only been implemented in a few laboratories.[62,63,65] ELISA assays have also been developed and used in studies of infertility, but are not sufficiently sensitive and specific to be used for diagnosis of M. genitalium infection.[85,86]
• Culture: Although it is possible to culture M. genitalium, it is a lengthy process that takes several weeks and typically requires tissue culture.[16] Few research laboratories have this capacity and culture is not used to diagnose M. genitalium infections in clinical settings.
  Check-on-Learning QuestionWhat is the preferred test for making a clinical diagnosis of Mycoplasma genitalium infection?Check
  -On-
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  Question

  What is the preferred test for making a clinical diagnosis of Mycoplasma genitalium infection?

  Blood for baseline and convalescent serology

  Culture of a clinical sample

  Nucleic acid amplification testing on a clinical sample

  Giemsa staining of urogenital fluid clinical sample
   

Resistance Testing

Mycoplasma genitalium resistance testing has been more widely available in Europe and Australia than in the United States. Macrolide resistance testing assays are commercially available in the United States through several laboratories, but at this time, assays that detect M. genitalium fluoroquinolone resistance are not commercially available.

• Macrolide Resistance Testing: Several commercially available NAAT assays incorporate the detection of genetic mutations linked to macrolide resistance. These assays detect both M. genitalium and any of five major macrolide resistance mutations (MRM) in the 23S rRNA gene that are associated with high rates of azithromycin treatment failure.[87] The MRM assays are a key component of resistance-guided therapy.[37] Although some of the assays that incorporate detection of MRM have lower sensitivity overall than the FDA-approved NAATs for detecting M. genitalium, their published sensitivity for detecting MRM ranges from 95-100%; specificity ranges from 95-97%.[88] First-generation versions of these assays do not have an internal control that confirms detection of wild type M. genitalium, making it impossible to differentiate between a truly negative (susceptible) result and a failure to amplify. In the United States, macrolide resistance testing is most often performed using a reflex process whereby samples positive for M. genitalium subsequently have resistance testing performed. Using this reflex process, the diagnostic test and resistance testing can usually be performed using the same clinical specimen. 
• Fluoroquinolone Resistance Testing: As quinolone resistance expands, additional assessment for quinolone resistance-associated mutations (QRAMs) may be needed, using a rule-out strategy. Detecting wild type sequences in the ParC gene effectively rules out the presence of quinolone resistance.[89] To date, in the United States, assays to detect QRAMs are not commercially available and clinical testing for fluoroquinolone resistance is not recommended. Although the concomitant detection of specific mutations in the GyrA gene more closely correlates with treatment failure, assays to detect these mutations are currently only available in research settings.[46]

When considering whether to test for M. genitalium, it is important to differentiate between screening and diagnostic testing. Screening is performed on asymptomatic people with the goal of identifying a pathogen that is not causing current clinical signs or symptoms, but may result in sequelae if not eradicated. Routine screening of asymptomatic persons for M. genitalium is not recommended.[37] Diagnostic testing is performed on symptomatic people with the goal of identifying the pathogen causing the clinical signs or symptoms and providing appropriate treatment. The 2021 STI Treatment Guidelines recommends diagnostic testing for M. genitalium in persons who have persistent and/or recurrent genitourinary symptoms, and that it be considered in all cases of PID.[37]

Diagnostic Testing

Guidelines on diagnostic testing for M. genitalium vary globally, ranging from recommendations in the European Guidelines to test any person with any STI syndrome for M. genitalium to recommendations in the 2021 STI Treatment Guidelines to test only men with persistent or recurrent urethritis, women with persistent or recurrent cervicitis, and to consider testing women with PID.[37,90] The 2021 STI Treatment Guidelines recommend using an FDA-clear NAAT for the testing process, but testing of extragenital sites for M. genitalium is not recommended.[37] If resistance testing with the capability to detect MRM is available, this should also be ordered to enable resistance-guided therapy. The following summarizes recommendations in the 2021 STI Treatment Guidelines for M. genitalium diagnostic testing for males with NGU, females with cervicitis and PID, persons with proctitis, and extragenital testing.[37]

• Males with NGU: For males with acute NGU, routine M. genitalium testing is not currently recommended.[37] Instead, testing and organism-directed therapy is only recommended for males with persistent or recurrent urethritis. This recommendation was established prior to documentation of a 60% reduction in the number of cases of persistent or recurrent urethritis after one sexual health clinic implemented routine M. genitalium testing and treatment with moxifloxacin for all men with NGU, suggesting benefit to routine testing for all males with acute NGU.[91]
• Female Cervicitis and PID: Given associations with cervicitis and PID, M. genitalium testing should be considered in females with cervicitis and/or PID; provider judgment should determine whether to test women with cervicitis and/or PID at the time of presentation.[37] For women with persistent or recurrent cervicitis, M. genitalium testing is recommended.[37]
• Proctitis: Although the prevalence of M. genitalium in the rectum can be high (up to 42% of MSM with HIV and up to 22% of women), the association with proctitis is inconsistent and most have asymptomatic infection.[77,79,80,81,82] For these reasons, routine testing of people with proctitis for M. genitalium is not recommended.[37] However, M. genitalium testing may be performed in people with persistent proctitis if N. gonorrhoeae and C. trachomatis have been ruled out.[37]
• Extragenital Testing: Testing for M. genitalium at extragenital sites, such as the pharynx, is not recommended, based primarily on the low overall prevalence of pharyngeal infection.[37]
  Check-on-Learning QuestionWhich one of the following best describes the recommendation in the 2021 STI Treatment Guidelines for when to perform Mycoplasma genitalium diagnostic testing?Check
  -On-
  Learning
  Question

  Which one of the following best describes the recommendation in the 2021 STI Treatment Guidelines for when to perform Mycoplasma genitalium diagnostic testing?

  It should be performed on persons who have persistent and/or recurrent genitourinary symptoms

  It should be performed in all persons who present with any new genitourinary symptom that is consistent with a sexually transmitted infection

  It should be performed in all persons who present with new symptoms consistent with urethritis or cervicitis

Screening

Asymptomatic people should not be screened for M. genitalium.[37] Unlike chlamydia and gonorrhea, screening for M. genitalium is not recommended for people with a cervix under the age of 25 years, nor is screening pregnant people at prenatal care visits recommended.[37] Mycoplasma genitalium is not included in the routine STI screening for bacterial STIs that is recommended for people taking HIV preexposure prophylaxis (PrEP).[92] The recommendation against screening is consistent across the globe, reflecting the uncertain consequences of asymptomatic M. genitalium infections and the mandate to avoid prescribing antibiotics when they may not be necessary.[93] In addition, screening for M. genitalium in pregnancy in asymptomatic persons is not recommended as the consequences of asymptomatic persons in pregnancy remain unknown and there are limited antimicrobials available for treatment of M. genitalium in pregnant people.[37] Nevertheless, if future evidence demonstrates causal relationships with infertility, adverse pregnancy outcomes, or increased transmission or acquisition of HIV, screening may be warranted.

Reporting Requirements

Mycoplasma genitalium is not a reportable infection. Therefore, there are no reporting requirements.

Approach to Treatment

It is important to conceptually understand that M. genitalium does not have a peptidoglycan cell wall and thus antibiotics that work by targeting cell wall synthesis (e.g., penicillins and cephalosporins) do not have activity against M. genitalium.[37] Earlier attempts to treat M. genitalium used monotherapy with either azithromycin or doxycycline. These antibiotics, when used alone, have relatively low cure rates and the cure rates have declined over time with increasing resistance, especially with macrolide resistance (Figure 10).[94,95,96] Due to high rates of resistance to azithromycin and low efficacy of doxycycline monotherapy, these antimicrobials are now only used as a component of sequential therapy for M. genitalium.[37] Moxifloxacin, a fluoroquinolone antibiotic, has also become a key antimicrobial used to treat M. genitalium infections. Ideally, the recommended approach for treating M. genitalium is to (1) use sequential therapy with two antibiotics and (2) use macrolide resistance testing (with assays that can detect MRM) to guide the specific regimen used. The rationale for using a sequential therapy with doxycycline followed by a second antibiotic is to reduce the overall M. genitalium organism burden prior to the course of moxifloxacin or azithromycin; this approach enhances cure rates and reduces antimicrobial resistance. The detection of MRM correlates highly with azithromycin treatment failure, but macrolide resistance testing is not often available in the United States. Accordingly, the following discussion will include2021 STI Treatment Guidelines recommendations for when resistance testing is available and when it is not available.[37]

Recommended Treatment if Resistance Testing is Available

Resistance-guided therapy using MRM detection was developed to enhance treatment efficiency and efficacy for persons diagnosed with M. genitalium. Since detection of MRM correlates highly with azithromycin treatment failure, the absence of MRM indicates a macrolide susceptible infection where azithromycin can be prescribed. The use of azithromycin for macrolide-susceptible infection reduces the empiric use of moxifloxacin, which has more significant side effects than azithromycin and should only be used when there are no other safer alternatives. Using a resistance-guided approach, patients diagnosed with M. genitalium infection start treatment with a 7-day course of doxycycline (100 mg orally twice daily for 7 days), with the second component of the regimen determined by the results of the resistance testing.[37] Patients with macrolide sensitive infections follow the initial doxycycline regimen with high-dose azithromycin (1g orally on day one followed by 500 mg orally once daily for three additional days, for a total of 2.5g). Patients with macrolide-resistant infections follow the doxycycline 7-day course with a 7-day course of oral moxifloxacin 400 mg daily.[37] The sequential approach yielded cure rates of 95% for doxycycline followed by high dose azithromycin and 92% for doxycycline followed by moxifloxacin when first implemented.[39] When moxifloxacin is contraindicated, CDC guidelines recommend sequential therapy with 7 days of doxycycline followed by the high-dose azithromycin course, but with a test of cure added at 21 days after completion of the high-dose azithromycin.[37] Minocycline (100 mg orally twice daily for 14 days) may also be an option for patients who cannot take moxifloxacin.

Recommended Treatment if Resistance Testing is Not Available

In most clinical settings in the United States, M. genitalium macrolide resistance testing is not available and therefore not incorporated into clinic protocols. Thus, most clinicians treat M. genitalium infection without information about macrolide resistance.[37] The empiric approach utilizes a two-stage treatment regimen with the first stage using 7 days of oral doxycycline, followed by a second stage consisting of oral moxifloxacin 400 mg for 7 days, which is exactly the same regimen outlined above when macrolide resistance is identified.[37] The rationale for using this two stage approach is that doxycycline up front can reduce the overall M. genitalium organism burden prior to the course of moxifloxacin, which has the effect of improving clinical cure rates and may reduce the likelihood of moxifloxacin resistance developing.

Treating M. genitalium in Women with PID

Non-pregnant women who present with PID and are managed as an out-patient should receive the recommended empiric treatment PID regimen that consists of ceftriaxone 500 mg in a single intramuscular dose plus doxycycline 100 mg orally twice daily for 14 days plus metronidazole 500 mg orally twice daily for 14 days.[97] Women with PID and a positive test for M. genitalium should first receive the standard PID treatment, followed by moxifloxacin 400 mg orally twice daily for 14 days, with the addition of the moxifloxacin to specifically target M. genitalium.[37] Although the standard PID regimen is not effective against M. genitalium, the doxycycline will reduce the M. genitalium organism load prior to treatment with moxifloxacin.[98] In addition, the metronidazole in the PID treatment regimen may have some activity against M. genitalium; women in a randomized trial who received a metronidazole-containing PID regimen were significantly less likely to have a persistent cervical M. genitalium infection than women who did not receive metronidazole.[57]

Treatment in Pregnancy

Mycoplasma genitalium infection in pregnancy has emerged as a major challenge. Azithromycin is the only antibiotic available in the United States that can be used in the M. genitalium treatment regimens during pregnancy. Although use of empiric azithromycin alone has a significant chance for treatment failure due to the high rates of macrolide resistance, tetracyclines (including doxycycline and minocycline) and fluoroquinolones (including moxifloxacin) are generally contraindicated during pregnancy. Although there are no controlled human studies of doxycycline during pregnancy, it is generally not prescribed given concerns over staining of primary teeth in infants and associations with congenital anomalies, although the latter are weak associations.[99,100] Similar concerns apply to minocycline. All fluoroquinolones, including moxifloxacin, are considered class C drugs in pregnancy and should not be used unless there is no other safer alternative.[101,102] Pristinamycin is considered safe in pregnancy, but is not available in the United States. In this setting, the treatment risks should be weighed against the potential sequelae of M. genitalium infection during pregnancy and discussed with the patient. Given these challenges, expert consultation is generally recommended.

Treatment of Neonates and Children

Mycoplasma genitalium has rarely been detected in neonates and children and there are no specific recommendations for treatment in non-adults.[37] If treatment of M. genitalium is required, age- and weight-specific recommendations and safety considerations for each of the recommended antibiotics (doxycycline, azithromycin, moxifloxacin) should be followed. In general, given the potential adverse effects of doxycycline and moxifloxacin in young children, expert consultation is advised. 

Post-Treatment Follow-Up and Tests of Cure

The 2021 STI Treatment Guidelines do not recommend tests of cure in people whose symptoms have resolved.[37] The rationale for this is twofold. First, the benefit of identifying and treating asymptomatic infections in the absence of definitive evidence that asymptomatic M. genitalium infections cause sequelae is unclear. Second, the continued expansion of antimicrobial resistance in M. genitalium increases the risk of untreatable infections and highlights the importance of using antibiotics only when there is a clear benefit. The exception to the CDC recommendation against tests of cure is when high dose azithromycin must be used instead of moxifloxacin in the absence of macrolide resistance data. Because of uncertain cure with azithromycin, a test of cure is recommended, but should be done no sooner than 21 days after the treatment regimen has been completed to allow sufficient time for residual nucleic acids to clear.

Management of Sex Partners

Given the high concordance of infection between sex partners (30-50%), the 2021 STI Treatment Guidelines note that sex partners of people with M. genitalium can be tested, and if positive, treated.[19,22,37] Ideally, this approach would focus on people in ongoing partnerships, with the goal of using concomitant treatment to prevent reinfection. If testing of the sex partner is not an option, the partner can be treated empirically with the same antibiotic regimen as used to treat the person diagnosed with M. genitalium.[37] Expedited partner therapy should not be used for sex partners of people with M. genitalium infections. Its efficacy has not been evaluated for M. genitalium, and it may contribute to ongoing development and spread of resistance.

Counseling and education for patients in whom M. genitalium is detected should be consistent with that provided to patients with other bacterial STI. The following summarizes key counseling messages for persons diagnosed with M. genitalium infection.

• Resuming Sexual Activity: When treated for M. genitalium infection, people should be told to abstain from sexual activity until they have completed both antibiotics in their sequential therapy, their symptoms have resolved and any ongoing sex partners have either been tested or completed their own antibiotic treatment.
• Partner Notification: People with whom a person has an ongoing sexual relationship should be notified and encouraged to get an M. genitalium test (and treatment if positive) to reduce the risk of re-infection. People with whom the patient does not intend to have sex with again do not need to be notified.
• Follow-up Testing: Follow-up testing for M. genitalium should only be done in people with persistent or recurrent symptoms. People who are asymptomatic after completing their antibiotic treatment should not be tested again, with one exception. Persistent, ongoing infection despite symptom resolution after azithromycin has been observed. Therefore, when macrolide resistance testing is not available and azithromycin is prescribed instead of moxifloxacin, a test of cure 21 days after the antibiotics have been completed is recommended.
• STI Prevention: At the time a person is receiving treatment for an STI, it is appropriate to provide counseling messages on how to prevent STIs in the future (e.g., limiting the number of sex partners and consistently using condoms).

• Mycoplasma genitalium is not a reportable infection and the estimated number of people infected is based on survey data. Between 2017-2018, there were an estimated 3 million people of reproductive age in the United States with an M. genitalium infection.
• Mycoplasma genitalium is most common among females younger than 25 years of age
• Asymptomatic M. genitalium infection occurs frequently; M. genitalium can also cause urethritis in males and is associated with cervicitis, pelvic inflammatory disease, infertility, and preterm delivery in females. It infects the rectum and may cause proctitis but evidence is inconsistent.
• Screening asymptomatic people for M. genitalium is not recommended. Diagnostic testing is recommended for people with persistent or recurrent symptoms.
• FDA-cleared NAATs are the preferred method of detecting M. genitalium. Validated specimen types include male and female urine and clinician- and self-collected urethral, vaginal, and endocervical swab specimens. Rectal specimens can be tested in laboratories that have validated this procedure. Culture is challenging and is not used in clinical care.
• Treatment of M. genitalium is limited to a few antibiotics. Due to the lack of a rigid cell wall, neither beta-lactams, cephalosporins, nor carbapenems have activity against M. genitalium. Doxycycline has low cure rates and antibiotic resistance in M. genitalium has emerged rapidly, reaching nearly 60% for azithromycin and up to 10% for moxifloxacin.
• Resistance-guided therapy leverages assays that detect macrolide resistance; it can increase cure rates and reduce selection for resistance. People with macrolide-sensitive infections should receive sequential treatment with doxycycline (100 mg bid for 7 days) followed by high-dose azithromycin (1 g on day 1 followed by 500 mg on days 2-4). Non-pregnant people with macrolide-resistant infections should receive sequential treatment with 7 days of doxycycline followed by 7 days of moxifloxacin (400 mg daily).
• If resistance-guided therapy is not available or not utilized, treatment for non-pregnant people should consist of sequential treatment with doxycycline (100 mg bid for 7 days) followed by 7 days of moxifloxacin (400 mg daily).
• Treatment of M. genitalium during pregnancy is challenging, primarily due to potential toxicity to the fetus with doxycycline and moxifloxacin. If treatment is required, the best option is high-dose azithromycin (1 g on day 1 followed by 500 mg on days 2-4), followed by a test of cure 21 days after completing treatment.
• Except for people who must be treated with high dose azithromycin in the absence of resistance testing, tests of cure in asymptomatic people are not recommended.
• Clinicians should seek expert consultation for the treatment of pregnant people, treatment of young children, and in cases of treatment failure after moxifloxacin.
• Ongoing sex partners of people diagnosed with M. genitalium infection should be tested and treated with the same regimen their partner received. Presumptive treatment should only be provided when testing is not possible.