Mycoplasma genitalium

M. genitalium causes symptomatic and asymptomatic urethritis among men and is the etiology of approximately 15%–20% of NGU, 20%–25% of nonchlamydial NGU, and 40% of persistent or recurrent urethritis (697,909,910). Infection with C. trachomatis is common in selected geographic areas (911–913), although M. genitalium is often the sole pathogen. Data are insufficient to implicate M. genitalium infection with chronic complications among men (e.g., epididymitis, prostatitis, or infertility). The consequences of asymptomatic infection with M. genitalium among men are unknown.

Among women, M. genitalium has been associated with cervicitis, PID, preterm delivery, spontaneous abortion, and infertility, with an approximately twofold increase in the risk for these outcomes among women infected with M. genitalium (766). M. genitalium infections among women are also frequently asymptomatic, and the consequences associated with asymptomatic M. genitalium infection are unknown.

M. genitalium can be detected among 10%–30% of women with clinical cervicitis (767,770,772,914–916). The existing evidence between M. genitalium and cervicitis is mostly supportive of a causal association. Elevated proinflammatory cytokines have been demonstrated among women with M. genitalium, with return to baseline levels after clearance of the pathogen (917).

M. genitalium is identified in the cervix or endometrium of women with PID more often than in women without PID (918–924). Prevalence of M. genitalium among women with PID ranges from 4% to 22% (925,926) and was reported as 60% in one study of women with postabortal PID (918). The association with PID is supported by early studies among nonhuman primates that determined that endosalpingitis develops after inoculation with M. genitalium (927). Recent studies evaluating the lower and upper genital tract using highly sensitive M. genitalium NAAT assays or the role of M. genitalium in histologically defined endometritis have reported significantly elevated risk for PID (928). However, most studies of M. genitalium and PID, even those that controlled extensively for other infections and behavioral and biologic risk, are cross-sectional. The few prospective studies that have evaluated the role of M. genitalium in establishing subsequent PID demonstrated increased PID risk; however, these were not statistically significant associations, often because of a lack of statistical power. No clinical trial data are available that demonstrate that treating M. genitalium cervical infection prevents development of PID or endometritis. Although data regarding the benefits of testing women with PID for M. genitalium and the importance of directing treatment against this organism are limited, the associations of M. genitalium with cervicitis and PID in cross-sectional studies using NAAT testing are consistent (928).

Data from case-control serologic studies (929–931) and a meta-analysis of clinical studies (766) indicate a potential role in causing infertility. However, seroassays are suboptimal and inconclusive. Similarly, evidence for a role for M. genitalium infection during pregnancy as a cause of perinatal complications, including preterm delivery, spontaneous abortion, or low birthweight, are conflicting because evidence is insufficient to attribute cause (766,932–934). Data are limited regarding ectopic pregnancy and neonatal M. genitalium infection (935,936).

Rectal infection with M. genitalium has been reported among 1%–26% of MSM (937–940) and among 3% of women (941). Rectal infections often are asymptomatic, although higher prevalence of M. genitalium has been reported among men with rectal symptoms. Similarly, although asymptomatic M. genitalium has been detected in the pharynx, no evidence exists of it causing oropharyngeal symptoms or systemic disease.

Urogenital M. genitalium infection is associated with HIV among both men and women (942–944); however, the data are from case-control and cross-sectional studies. Risk for HIV infection is increased among women with M. genitalium, and evidence indicates that HIV shedding occurs more often among persons with M. genitalium and HIV infection who are not taking ART than among persons without M. genitalium (942,944).

Antimicrobial Resistance

Resistance to azithromycin has been rapidly increasing and has been confirmed in multiple studies. Prevalence of molecular markers for macrolide resistance, which highly correlates with treatment failure, ranges from 44% to 90% in the United States, Canada, Western Europe, and Australia (697,702,945–953). Treatment with azithromycin alone has been reported to select for resistance (705,954,955), with treatment of macrolide-susceptible infections with a 1-g dose of azithromycin resulting in selection of resistant-strain populations in 10%–12% of cases. The prevalence of quinolone resistance markers is much lower (697,956–959). The first clinical treatment failures after moxifloxacin were associated specifically with the S83I mutation in the parC gene (954,960). Prevalence of the S83I mutation in the United States ranges from 0% to 15% (947); however, correlation with fluoroquinolone treatment failure is less consistent than that with mutations associated with macrolide resistance (953,961,962). Clinically relevant quinolone resistance often is associated with coexistent macrolide resistance (954).

Diagnostic Considerations

M. genitalium is an extremely slow-growing organism. Culture can take up to 6 months, and technical laboratory capacity is limited to research settings. NAAT for M. genitalium is FDA cleared for use with urine and urethral, penile meatal, endocervical, and vaginal swab samples (https://www.hologic.com/package-inserts/diagnostic-products/aptima-mycoplasma-genitalium-assay). Molecular tests for macrolide (i.e., azithromycin) or quinolone (i.e., moxifloxacin) resistance markers are not commercially available in the United States. However, molecular assays that incorporate detection of mutations associated with macrolide resistance are under evaluation.

Men with recurrent NGU should be tested for M. genitalium using an FDA-cleared NAAT. If resistance testing is available, it should be performed and the results used to guide therapy. Women with recurrent cervicitis should be tested for M. genitalium, and testing should be considered among women with PID. Testing should be accompanied with resistance testing, if available. Screening of asymptomatic M. genitalium infection among women and men or extragenital testing for M. genitalium is not recommended. In clinical practice, if testing is unavailable, M. genitalium should be suspected in cases of persistent or recurrent urethritis or cervicitis and considered for PID.

Treatment

M. genitalium lacks a cell wall, and thus antibiotics targeting cell-wall biosynthesis (e.g., ß-lactams including penicillins and cephalosporins) are ineffective against this organism. Because of the high rates of macrolide resistance with treatment failures (707) and efficient selection of additional resistance, a 1-g dose of azithromycin should not be used.

Two-stage therapy approaches, ideally using resistance-guided therapy, are recommended for treatment. Resistance-guided therapy has demonstrated cure rates of >90% and should be used whenever possible (759,963); however, it requires access to macrolide-resistance testing. As part of this approach, doxycycline is provided as initial empiric therapy, which reduces the organism load and facilitates organism clearance, followed by macrolide-sensitive M. genitalium infections treated with high-dose azithromycin; macrolide-resistant infections are treated with moxifloxacin (964,965).

Although the majority of M. genitalium strains are sensitive to moxifloxacin, resistance has been reported, and adverse side effects and cost should be considered with this regimen. In settings without access to resistance testing and when moxifloxacin cannot be used, an alternative regimen can be considered, based on limited data: doxycycline 100 mg orally 2 times/day for 7 days, followed by azithromycin (1 g orally on day 1 followed by 500 mg once daily for 3 days) and a test of cure 21 days after completion of therapy (963). Because of the high prevalence of macrolide resistance and high likelihood of treatment failure, this regimen should be used only when a test of cure is possible, and no other alternatives exist. If symptomatic treatment failure or a positive test of cure occurs after this regimen, expert consultation is recommended. Data are limited regarding use of minocycline in instances of treatment failure (966).

Recommended PID treatment regimens are not effective against M. genitalium. Initial empiric therapy for PID, which includes doxycycline 100 mg orally 2 times/day for 14 days, should be provided at the time of presentation for care. If M. genitalium is detected, a regimen of moxifloxacin 400 mg orally once daily for 14 days has been effective in eradicating the organism. Nevertheless, no data have been published that assess the benefits of testing women with PID for M. genitalium, and the importance of directing treatment against this organism is unknown.

Follow-Up

Test of cure is not recommended for asymptomatic persons who received treatment with a recommended regimen. In settings in which M. genitalium testing is available, persons with persistent urethritis, cervicitis, or PID accompanied by detection of M. genitalium should be treated with moxifloxacin.

Management of Sex Partners

Recent studies report a high concordance of M. genitalium among partners of males, females, and MSM; however, no studies have determined whether reinfection is reduced with partner treatment (940,967,968). Sex partners of patients with symptomatic M. genitalium infection can be tested, and those with a positive test can be treated to possibly reduce the risk for reinfection. If testing the partner is not possible, the antimicrobial regimen that was provided to the patient can be provided.

Special Considerations

HIV Infection

Persons who have M. genitalium and HIV infection should receive the same treatment regimen as those persons without HIV.

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