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Mycoplasma genitalium is increasingly appreciated as a common cause of sexually transmitted disease syndromes, including urethritis in men and cervicitis, endometritis, pelvic inflammatory disease, and possibly preterm birth, tubal factor infertility, and ectopic pregnancy in women. Despite these disease associations, which parallel those of Chlamydia trachomatis and Neisseria gonorrhoeae, the mechanisms by which this pathogen elicits inflammation, causes cellular damage, and persists in its only natural host (humans) are unique and are not fully understood. The purpose of this review is to briefly provide a historical background on the discovery, microbiology, and recognition of M. genitalium as a pathogen, and then summarize the recent advances in our understanding of the molecular biology and pathogenesis of this unique urogenital organism. Collectively, the basic scientific discussions herein should provide a framework for understanding the clinical and epidemiological outcomes described in the accompanying articles in this supplemental issue., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Mycoplasma genitalium is very difficult to grow in culture but has been more able to be studied for disease associations since the advent of research molecular amplification assays. Polymerase chain reaction (PCR) and other molecular assays have demonstrated an association with adverse disease outcomes, such as urethritis or nongonococcal urethritis in men and adverse reproductive sequelae in women-for example, cervicitis, endometritis, and pelvic inflammatory disease (PID), including an association with risk for human immunodeficiency virus. The lack of commercially available diagnostic assays has limited widespread routine testing. Increasing reports of high rates of resistance to azithromycin detected in research studies have heightened the need available commercial diagnostic assays as well as standardized methods for detecting resistance markers. This review covers available molecular methods for the diagnosis of M. genitalium and assays to predict the antibiotic susceptibility to azithromycin., Methods: A PubMed (US National Library of Medicine and National Institutes of Health) search was conducted for literature published between 2000 and 2016, using the search terms Mycoplasma genitalium, M. genitalium, diagnosis, and detection., Results: Early PCR diagnostic tests focused on the MPa adhesion gene and the 16S ribosomal RNA gene. Subsequently, a transcription-mediated amplification assay targeting ribosomes was developed and widely used to study the epidemiology of M. genitalium. Newer methods have proliferated and include quantitative PCR for organism load, AmpliSens PCR, PCR for the pdhD gene, a PCR-based microarray for multiple sexually transmitted infections, and multiplex PCRs. None yet are cleared by the Food and Drug Administration in the United States, although several assays are CE marked in Europe. As well, many research assays, including PCR, gene sequencing, and melt curve analysis, have been developed to detect the 23S ribosomal RNA gene mutations that confer resistance to azithromycin. One recently developed assay can test for both M. genitalium and azithromycin resistance mutations at the same time., Conclusions: It is recommended that more commercial assays to both diagnose this organism and guide treatment choices should be developed and made available through regulatory approval. Research is needed to establish the cost-effectiveness of routine M. genitalium testing in symptomatic patients and screening in all individuals at high risk of acquiring and transmitting sexually transmitted infections., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Variations in estimates of prevalence of trichomoniasis in men may reflect true differences in the burden of disease but are also affected by the performance of diagnostic methods and the type of specimen tested. In this study, men were evaluated at baseline and at follow-up, to evaluate syndromic management of urethritis and the effects of human immunodeficiency virus and trichomoniasis, in Lilongwe, Malawi. First-void urine specimens and urethral swabs were obtained at enrollment, for Trichomonas vaginalis culture; semen specimens were also obtained at follow-up. The sensitivities of testing methods using urine specimens and urethral swabs were equal; 67% of cases were identified by use of either specimen, and, in 47% of cases, both specimens tested positive. When semen specimens were included, all 3 specimens tested positive in only 19% of cases. Semen was the most sensitive single specimen, and, in 25.6% of cases, only semen specimens tested positive. Thus, prevalence of T. vaginalis infection in men is underestimated if only 1 specimen is tested.

Transmission of Chlamydia trachomatis and Neisseria gonorrhoeae among infected men and their female sex partners was examined using a design enhancing the likelihood that spread was directed from men to women. Chlamydia culture-negative specimens were examined using DNA amplification tests. Infection rates in women exposed to male sex partners with Chlamydia only were 65% (20/31) and with gonorrhea only were 73% (33/45). Infection of women by either agent was not influenced by the number of sexual exposures to or coinfection in men. There was a 98% (40/41) concordance of N. gonorrhoeae isolates among partners by auxotype and serovar. Chlamydia isolates were serotyped using ELISA and immunofluorescence testing and confirmed by nested polymerase chain reaction: 50% (6/12) of men and 57% (8/14) of women yielded mixed serovars. Sixty-four percent of pairs (9/14) were infected with identical serovars and an additional 28% shared at least one serovar. Multiple serovars of C. trachomatis, but not of N. gonorrhoeae, were common in sex partners and exchanged frequently.

CD4 cell counts and blood plasma and seminal plasma human immunodeficiency virus type 1 (HIV-1) concentrations were compared in HIV-1 RNA-seropositive men with urethritis and with or without genital ulcer disease (GUD). GUD was associated with lower CD4 cell counts (median, 258 vs. 348/microL) and increased blood plasma HIV-1 RNA (median, 240 x 10[3] vs. 79.4 x 10[3] copies/mL). Men with nongonococcal urethritis and GUD shed significantly greater quantities of HIV-1 in semen (median, 195 x 10[3] vs. 4.0 x 10[3] copies/mL) than men with nongonococcal urethritis without GUD. These levels decreased approximately 4-fold following antibiotic therapy. The results indicate an association between GUD and increased blood HIV-1 RNA levels. Increased HIV-1 in semen was demonstrated in some men with GUD; such an increase could lead to increased transmission, thus complicating interpretation of the role of the genital ulcer itself in the infectiousness of HIV. Reasons for increased HIV RNA in semen in men with GUD remain to be determined.

Control of Trichomonas vaginalis is assuming higher priority because recent studies have suggested that trichomoniasis enhances susceptibility to human immunodeficiency virus infection and the risk for delivery of low-birth weight infants. In a cross-sectional study, 50 cases were identified among 447 men attending a sexually transmitted disease clinic. As previously reported, trichomoniasis was associated with nonchlamydial nongonococcal urethritis. Other risk factors included sexual contact with an infected woman or prior treatment for trichomoniasis or nongonococcal urethritis. Urethral and first-void urine cultures were positive in 80% and 68% of positive cases, respectively. When combined, these two cultures diagnosed 49 (98%) of 50 cases. These data suggest that criteria for selection of men for culture should include presence of nonchlamydial nongonococcal urethritis, recent exposure to trichomoniasis, or a history of trichomoniasis or nongonococcal urethritis. In addition, combining urethral and urine sediment cultures may prove accurate for evaluating T. vaginalis infection.