Has the Time Come to Systematically Test for Mycoplasma genitalium?

Mycoplasma genitalium has gained attention in the general scientific community as the smallest known free-living organism and the first to be chemically synthesized.1 Clinically, M. genitalium was first identified among 2 men with nongonococcal urethritis (NGU),2 has been consistently associated with NGU in men,3 and is clearly sexually transmitted between heterosexual partners.4 Nevertheless, the majority of epidemiologic investigations have focused on men, and less evidence exists linking M. genitalium infection in women to reproductive tract disease. In this issue of the journal, Gaydos et al present data linking M. genitalium to cervicitis among a predominantly young, African American group of women attending a sexually transmitted diseases clinic,5 adding further supporting evidence to the hypothesis that M. genitalium is also pathogenic in women. Gaydos et al sought to determine the prevalence of various organisms among women attending an inner city STD clinic and assess their relationship with cervicitis using rigorous laboratory assessments employing multiple nucleic acid amplification tests with different targets. Despite testing for Neisseria gonorrhoeae, Chlaymdia trachomatis, and Trichomonas vaginalis, after adjusting for other reproductive tract pathogens only M. genitalium was significantly associated with cervicitis. Although it was somewhat surprising that cervicitis was not associated with either N. gonorrhoeae or C. trachomatis, this may be partially due to a broad definition of cervicitis (cervical discharge or easily induced cervical bleeding or clinician-noted diagnosis of cervicitis). Despite the clear association between M. genitalium and cervicitis observed in this study, not all studies have been consistent. In fact, 5 of the now 13 (38%) published studies presenting data on cervicitis failed to observe a significant association with M. genitalium,6–10 and at least 2 other analyses in 2 separate populations have also failed to report strong associations (Manhart, unpublished data). Thus, while the study conducted by Gaydos et al adds to the evidence supporting an association between M. genitalium and cervicitis,11–17 the published data on this are far from consistent. Many of these studies used different definitions of cervicitis, which almost certainly contributes to the differences in results. Furthermore, virtually all of these studies assessed prevalent cervicitis and prevalent M. genitalium infection at the same point in time. This makes it impossible to draw conclusions about either temporal sequence and/or causality. Longitudinal studies that evaluate both the acquisition of M. genitalium and the development of cervicitis will be essential to definitively determine to what extent this emerging sexually transmitted organism is causally associated with cervicitis. Although cervicitis was the focus of the Gaydos investigation, the more important concern with cervical pathogens is whether they are able to ascend from the cervix into the upper reproductive tract and cause serious sequelae such as pelvic inflammatory disease, ectopic pregnancy, and infertility. The limited number of studies conducted on upper reproductive tract infection are mostly consistent and suggest that M. genitalium can result in pelvic inflammatory disease18 and infertility.19 While further studies are necessary to confirm these observations, this suggests that, irrespective of its role in cervicitis, infection with M. genitalium is something clinicians should pay attention to. The prevalence of M. genitalium in Gaydos’ population was remarkably high (19.2%) and higher in fact than C. trachomatis (11.1%), N. gonorrhoeae (4.6%), or T. vaginalis (15.3%). In other STD clinic populations, prevalence of M. genitalium in women has ranged between 4% to 6%10–14; prevalences as high as that observed by Gaydos et al have previously only been reported in African populations,15 or adolescents.8 If M. genitalium is truly pathogenic, this high prevalence suggests that it may be cause a disproportionate number of cases of cervicitis and/or upper tract disease relative to our usual suspects (N. gonorrhoeae and C. trachomatis). This has important implications for treatment. The standard therapies for cervicitis are either doxycycline (100 mg bid × 7 days) or azithromycin (1 g single dose).20 Although there are no studies explicitly designed to evaluate treatment of M. genitalium infection in women, doxycycline was clearly inferior to azithromycin among men with NGU in a recent randomized comparison study,21 and the standard therapies for pelvic inflammatory disease (cefoxitin and doxycycline) were similarly ineffective for women with M. genitalium.22 Only moxifloxacin has not been associated with treatment failures. At first glance, this may suggest that azithromycin should be the preferred therapy for cervicitis in areas of high M. genitalium prevalence. However, there are 2 challenges to such an approach. First, azithromycin resistance has begun to emerge,23 and this may be a particular problem in areas where the first-line therapy for NGU and cervicitis is azithromycin, which is popular among both clinicians and patients for its single dose nature and traditionally high efficacy. But perhaps a greater barrier is that there is currently no commercially available diagnostic test for M. genitalium. Testing for this organism is only available in research settings using either labor-intensive in-house polymerase chain reaction assays or a research use only transcription mediated amplification assay developed by Gen-Probe (Gen-Probe, Inc., San Diego, CA). Without the widespread ability to test for M. genitalium, the prevalence of M. genitalium is unknown in most settings and clinicians in STD and reproductive health clinics are left to guess whether a woman has an M. genitalium infection. Unfortunately, the clinical spectrum of M. genitalium infections is not substantially different from either gonococcal or chlamydial infections, leaving much to chance. And we seem to be caught in a catch-22–diagnostic test manufacturers are waiting for definitive evidence that M. genitalium causes upper reproductive tract sequelae and the inclusion of M. genitalium in the CDC STD treatment guidelines before bringing a test to market. Clinical decision-makers are waiting for the availability of a commercial diagnostic test before calling for widespread testing for M. genitalium. Systematic testing of symptomatic women for established sexually transmitted infection pathogens such as C. trachomatis and N. gonorrhoeae is a mainstay of STD care. M. genitalium has been consistently more prevalent than N. gonorrhoeae in virtually every study that has measured both organisms, and is often more prevalent than C. trachomatis. It is definitively associated with NGU in men, and Gaydos et al have just provided further evidence of an association with cervicitis in women.5 Yet we find ourselves unable to test women for this organism, likely missing a substantial number of infections. Although further confirmatory evidence of an association between M. genitalium and upper reproductive tract disease is necessary before implementing screening programs, perhaps the time has come for a commercially available assay and systematic testing of symptomatic women. This would facilitate the more definitive longitudinal studies necessary to determine the causal association of M. genitalium in female reproductive tract disease, and allow for the identification of infected women for appropriate treatment.