Mycoplasma genitalium infection in males and females

INTRODUCTION — Mycoplasma genitalium is a bacterium that is a common cause of nongonococcal urethritis in males and cervicitis in females. It also may be a cause of pelvic inflammatory disease (PID) in females. It is uncertain whether M. genitalium causes proctitis in men who have sex with men (MSM).

M. genitalium infection is discussed here. Other causes of urethritis, cervicitis, and PID, are discussed elsewhere. (See "Urethritis in adult males" and "Acute cervicitis" and "Pelvic inflammatory disease: Clinical manifestations and diagnosis".)

Infections caused by other Mycoplasma species are also discussed in detail elsewhere. (See "Mycoplasma pneumoniae infection in adults" and "Mycoplasma pneumoniae infection in children" and "Mycoplasma hominis and Ureaplasma infections".)

MICROBIOLOGY — M. genitalium was first described in 1981 after being isolated from the urethral specimens of two men diagnosed with nongonococcal urethritis [1]. It is a member of the Mycoplasmataceae family and Mollicutes class of bacteria [2]. It lacks a cell wall and is thus not visible following Gram staining. With a genome of only 580 kilobases in size, M. genitalium is the smallest known self-replicating bacterium. Its genomic structure is similar to the larger and more well-known pathogen Mycoplasma pneumoniae, a cause of atypical bacterial pneumonia [3]. It appears that M. genitalium evolved from M. pneumoniae by reductive evolution [4]. (See "Mycoplasma pneumoniae infection in adults".)

Culture of M. genitalium is extremely difficult, as the organism is fastidious and may require one to two months to grow. In vitro growth is enhanced by cocultivation with mammalian cells, but even under the best circumstances, only about 50 percent of samples from infected patients yield positive cultures [5]. Culture is thus unlikely to ever be used for the diagnosis of M. genitalium infections.

PATHOGENESIS — There is no solid evidence that M. genitalium causes clinical disease outside the genitourinary tract [6-8]. Studies in both male and female nonhuman primates, in which genital infection developed following urogenital inoculation of M. genitalium, demonstrate its pathogenicity [9]. A specialized terminal tip-like structure allows M. genitalium to attach to, adhere to the surface of, and enter cells. [10]. Upon entry into the epithelial cell, M. genitalium evades the host immune response through modulation of the immune system, including suppression and stimulation of lymphocytes and upregulation of cytokine expression [11]. The tissue destruction caused by M. genitalium is partially due to the secretion of mycoplasmal toxins and harmful metabolites like hydrogen peroxide. However, most of the clinical disease manifestations associated with M. genitalium infection are thought to be due to the host's immune response to cell invasion [8]. Most M. genitalium infections in females are cleared within six months, but some may persist for approximately one year [12,13].

EPIDEMIOLOGY

Prevalence — Globally, the prevalence estimates of M. genitalium range between 1 and 4 percent among males and 1 and 6.4 percent among females [14-16]. In studies from the United States, the prevalence of M. genitalium is approximately 1 percent among young adults in the general population, placing it between that of Neisseria gonorrhoeae (0.4 percent) and Chlamydia trachomatis (2.3 percent) [17]. Higher M. genitalium prevalence rates, ranging from 4 to 38 percent, have been reported among sexually transmitted infection (STI) clinic attendees and cohorts with multiple STI risk factors [18-21]. As an example, one study found a prevalence of M. genitalium of 7.7 percent in females attending a Seattle STI clinic, compared with a prevalence of 5.8 percent for C. trachomatis and 2.4 percent for N. gonorrhoeae [22].

Risk factors for infection — Risk factors associated with M. genitalium infection appear to be similar to those associated with C. trachomatis infection. In studies from the United States and Europe, these include young age (eg, <20 to 22 years old), smoking, recent sexual intercourse, and an increasing number of sexual partners [17,22-28].

In one study, having had ≥2 sexual partners over the previous year and bacterial vaginosis were independently associated with M. genitalium colonization [29]. In a study of female sex workers in Uganda, the prevalence of M. genitalium was higher in HIV-positive women than in HIV-negative women [30]. (See 'Coinfection with other sexually transmitted infections' below.)

Evidence of sexual transmissibility — Sexual transmissibility of M. genitalium is supported by both clinical and molecular epidemiologic evidence. As above, M. genitalium is detected more frequently among sexually experienced than sexually naive adolescents, and infection is associated with an increasing number of sexual partners [17,23,26,27,29]. Additionally, the organism is more likely to be detected in the sexual partners of M. genitalium-positive compared with -negative individuals [26,31-34]. In one meta-analysis of 10 studies evaluating infections among sexual partners, 39 to 50 percent of male partners of infected females and 40 to 50 percent of female partners of infected males were also infected [35].

Furthermore, in DNA-typing studies, sexual partners who were concurrently infected with M. genitalium often harbored genomically identical bacterial strains [36-38]. In one study comparing the M. genitalium genotype profiles of 31 concurrently infected couples and 74 unrelated pairs of individuals, a concordance rate of 87.1 percent was observed for the couples compared with only 5.4 percent for the unrelated pairs of individuals [38].

Coinfection with other sexually transmitted infections

Bacterial sexually transmitted infections — Coinfections with M. genitalium and other bacterial sexually transmitted infections (STIs) frequently have been reported among high-risk males and females [25,26,30,39-42]. As an example, in a study of men with urethritis, 35 percent of those with C. trachomatis, 14 percent of those with N. gonorrhoeae, and 19 percent with both infections were also infected with M. genitalium [41]. C. trachomatis is the most commonly reported coinfecting organism in patients with M. genitalium infection. The high frequency of STI coinfections in M. genitalium-positive individuals is not surprising given the shared epidemiologic characteristics among these organisms. It has also created challenges in discerning the independent role of M. genitalium in the pathogenesis of urogenital disease.

HIV — Numerous observational studies have suggested an association between M. genitalium and HIV infection [30,43-49]. In a nested case-control study of high-risk women in Kampala, Uganda, there was an association between HIV acquisition and M. genitalium detection three months prior to the HIV-positive result [50]. Similarly, in another study, M. genitalium was detected more frequently in the 183 females who subsequently became infected with HIV compared with the 337 matched controls (14.8 versus 6.5 percent) [48]. The presence of M. genitalium was independently associated with genital HIV RNA detection in a longitudinal cohort study of 131 Zimbabwean women with recent HIV seroconversion [51].

These findings are supported by in vitro studies, in which M. genitalium reduced the integrity of the endocervical epithelial barrier and activated HIV target cells, thus providing a possible mechanism whereby this organism enhances HIV transmissibility [52].

ASSOCIATED CLINICAL SYNDROMES — Epidemiologic studies have suggested a strong etiologic link between M. genitalium infection and urethritis in males and a moderate etiologic link with cervicitis. It may be a cause of pelvic inflammatory disease (PID) in females. Although rectal M. genitalium infection rates are high among men who have sex with men (MSM), it is uncertain whether M. genitalium causes proctitis. Because of the difficulties with isolating this pathogen in culture, knowledge about the clinical manifestations of M. genitalium infection is based on nucleic acid amplification tests (NAATs).

Nongonococcal urethritis in men — Infection with M. genitalium has been strongly associated with acute nongonococcal urethritis (NGU). When present, the typical symptoms of urethritis caused by M. genitalium are similar to those reported in urethritis from other causes and include dysuria, urethral pruritus, and purulent or mucopurulent urethral discharge [53]. NGU cases are frequently asymptomatic [28,31,54,55]. However, NGU due to M. genitalium infection appears to be symptomatic more often than with C. trachomatis infection. In one study, 70 percent of M. genitalium-infected males reported symptoms compared with only 40 percent of C. trachomatis-infected males [31]. On examination, urethral discharge is often present. However, as with chlamydial urethral infections, the discharge may not be grossly evident, and urethral stripping, or milking, may be necessary for detection [41]. M. genitalium infection also may be associated with balanitis (ie, inflammation of the glans penis) and posthitis (ie, inflammation of the foreskin) [56]. (See "Urethritis in adult males", section on 'Clinical manifestations'.)

In a meta-analysis of 19 observational studies that evaluated M. genitalium infection using polymerase chain reaction (PCR) assays, 436 of 2069 patients with NGU (21.1 percent) had M. genitalium detected compared with 121 of 1810 controls (6.7 percent, pooled odds ratio [OR] 3.8, 95% CI 3.0-4.9) [8,57]. Subsequent systematic reviews of additional observational studies have supported this association, which is particularly strong in cases of nonchlamydial NGU (NCNGU) [10,58].

M. genitalium infection is estimated to account for 15 to 20 percent of NGU cases reported per year among males in the United States [53]. Among males with NCNGU, M. genitalium has been detected in 18 to 46 percent of cases [59]. Similarly, M. genitalium detection was frequent in males with persistent or recurrent urethritis following empiric therapy, particularly when doxycycline was used initially for treatment instead of azithromycin [10,58,60]. (See 'Treatment' below.)

M. genitalium may also be associated with urethritis in females, although data are too limited to draw clear conclusions [10,58].

Cervicitis — M. genitalium is a recognized sexually transmitted infection (STI) in females. Overall, cumulative evidence suggests an association between M. genitalium and cervicitis, although some results are conflicting [12,46,61,62]. Females with cervicitis due to M. genitalium frequently have no symptoms at all, similar to those with cervicitis due to C. trachomatis [25,26,32,55]. When present, symptoms associated with M. genitalium infection are usually nonspecific, with the most commonly reported symptom being vaginal discharge [26,63,64]. Other symptoms include vaginal itching, dysuria, and pelvic discomfort [25]. Clinical findings associated with M. genitalium cervicitis include the purulent or mucopurulent cervical discharge and cervical friability. If specifically sought, elevated numbers of polymorphonuclear leukocyte cells on vaginal wet smear or cervical fluid Gram stain may be found [32,55,65-67]. (See "Acute cervicitis", section on 'Clinical presentation'.)

In a meta-analysis of 20 studies, most of which employed in-house PCR testing to identify M. genitalium, detection of the organism was associated with cervicitis (OR 1.66, 95% CI 1.35-2.04) [68]. In one study from the meta-analysis that included 719 females who had cervical specimens obtained at an STI clinic, those with M. genitalium detected by PCR were more likely to have mucopurulent cervicitis (defined by the presence of either visible purulent discharge or ≥30 polymorphonuclear cells [PMNs] per high power field on Gram stain of cervical smear) compared with those without detectable M. genitalium (48 versus 28.6 percent) [23]. After controlling for infections with other STIs that cause cervicitis, the study observed a threefold increased risk of mucopurulent cervicitis in females infected with M. genitalium.

In contrast, other studies of high-risk female populations have failed to demonstrate an association between M. genitalium detection and cervicitis, despite high M. genitalium detection rates [25,39]. As an example, in a study of 331 adolescent females presenting with genitourinary symptoms or STI risk factors to an urban health center in the United States, M. genitalium was detected in 22.4 percent but was not associated with vaginal symptoms or signs (purulent cervical discharge or cervical friability) of cervicitis [25].

Inconsistent associations between M. genitalium and cervicitis are likely due to the lack of a standard definition of cervicitis. Most, but not all, studies that defined cervicitis as ≥30 PMNs per high power field in the cervical smear observed higher rates of M. genitalium in females with cervicitis than in those without [58].

Pelvic inflammatory disease — M. genitalium can ascend from the lower to upper genital tract after sexual transmission [11], and several studies have reported associations between detection of the organism and clinical signs or symptoms of pelvic inflammatory disease (PID) [29,61,69-72]. Clinical manifestations of M. genitalium-associated PID include mild to severe pelvic pain, abdominal pain, abnormal vaginal discharge, and/or bleeding, similar to PID due to C. trachomatis. In a study of females with clinically suspected PID, females with M. genitalium-associated PID were less likely to have elevated systemic inflammatory markers or elevated leukocyte count and were less likely to present with mucopurulent cervicitis or report high pain scores when compared with females with N. gonorrhoeae infection [73]. Females with PID due to M. genitalium and C. trachomatis reported similar symptoms. (See "Pelvic inflammatory disease: Clinical manifestations and diagnosis", section on 'Clinical features'.)

Overall, the data suggest a possible association and causative role between M. genitalium and PID, although the risk of PID with M. genitalium infection does not appear as high as that with C. trachomatis. In a meta-analysis of 10 studies, the pooled OR for PID among females with M. genitalium infection was 2.14 (95% CI 1.31-3.49) [68]. The following studies illustrate the range of findings:

●In a study of 50 females with nongonococcal, nonchlamydial PID, M. genitalium was present in 14 percent of endometrial biopsies [69]. Similarly, in a study of females presenting to a Kenyan STI clinic with pelvic pain, M. genitalium was detected from cervical and/or endometrial samples more frequently in the 58 females with histologically diagnosed endometritis than in the 57 without (16 versus 2 percent) [70].

●In a prospective study of 2246 sexually active English female college students, the baseline prevalence of M. genitalium in self-collected vaginal specimens was low (3.3 percent), and there was a nonsignificant increase in incidence of PID over a 12-month period among females with detectable M. genitalium compared with those in whom it was not detected (risk ratio 2.35, 95% CI 0.74-7.46) [29]. Subsequent analysis suggested that an estimated 4.9 percent of females with M. genitalium infection developed PID compared with 14.4 percent of those with C. trachomatis infection [74]. Based on the risk of PID suggested by these data, it would be difficult to determine if screening asymptomatic females for M. genitalium could prevent PID.

●In a smaller prospective study of females undergoing termination of pregnancy in Sweden, the incidence of postprocedure PID was higher among the 49 females who tested positive for M. genitalium at baseline than among the 168 STI-negative controls matched for age and procedure (12.2 versus 2.4 percent) [71].

Although PID in general is associated with infertility, it is unclear whether M. genitalium leads to tubal factor infertility, with different studies showing conflicting results [10]. A meta-analysis of observational studies suggested that M. genitalium is also associated with adverse pregnancy outcomes, such as preterm birth and spontaneous abortion [68].

Proctitis in men who have sex with men — It is uncertain whether M. genitalium is a cause of proctitis in men who have sex with men (MSM). In one study of 166 MSM with proctitis in Australia, M. genitalium was identified in 17 percent as a single pathogen and in 22 percent as a copathogen [75]. However, in another study of over 1000 MSM in Australia, M. genitalium was isolated from the rectum at comparable rates among asymptomatic men and those with symptomatic proctitis [76].

The clinical features of proctitis are discussed in detail elsewhere. (See "Evaluation of anorectal symptoms in men who have sex with men", section on 'Proctitis'.)

DIFFERENTIAL DIAGNOSIS — Other sexually transmitted pathogens, especially C. trachomatis and N. gonorrhoeae, can cause similar disease presentations. Additionally, nonsexually transmitted infections and noninfectious conditions can occasionally cause signs and symptoms comparable to those seen in sexually transmitted infectious syndromes.

The differential diagnoses of the specific syndromes associated with M. genitalium infection are discussed in detail elsewhere:

●(See "Urethritis in adult males", section on 'Nongonococcal urethritis' and "Urethritis in adult males", section on 'Differential diagnosis'.)

●(See "Acute cervicitis", section on 'Epidemiology and etiology'.)

●(See "Pelvic inflammatory disease: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

●(See "Evaluation of anorectal symptoms in men who have sex with men", section on 'Proctitis'.)

DIAGNOSIS — The diagnosis of M. genitalium infection can be made through detection of the organism using polymerase chain reaction (PCR) or other, more recently developed nucleic acid amplification tests (NAATs), if available. The preferred specimens are a first-void urine sample in males and a vaginal swab in females [24,39,77-81].

The diagnoses of the clinical syndromes associated with M. genitalium are discussed elsewhere. (See "Urethritis in adult males", section on 'Diagnosis' and "Pelvic inflammatory disease: Clinical manifestations and diagnosis", section on 'Evaluation' and "Acute cervicitis", section on 'Diagnosis'.)

Whom to test — The optimal role for M. genitalium testing is uncertain.

●Our approach – We favor testing for M. genitalium in the following individuals:

•Symptomatic patients with urethritis, cervicitis, and pelvic inflammatory disease (PID), including those with persistent symptoms after empiric treatment.

•Sex partners of the above patients, if they are seen before laboratory results for the index case are available; if the index case laboratory results are available when the partner is seen, we test only partners of those who have tested positive for M. genitalium.

Support for this approach comes from a large study from a single center that transitioned its approach to nongonococcal urethritis from testing only for C. trachomatis and N. gonorrhoeae and empirically treating with azithromycin to testing also for M. genitalium and empirically treating with doxycycline (followed by moxifloxacin if positive for M. genitalium) [82]. The latter approach was associated with a lower rate of visits for persistent urethritis (3 versus 8 percent); following the transition, M. genitalium was detected at 18 percent of visits.

●Guideline recommendations – This approach is consistent with guidelines from the United Kingdom [83], Europe [84], and Australia [85], although in some of those guidelines, the strength of the recommendation is lower for testing females with cervicitis. (See 'Cervicitis' above.)

Guidelines from the United States Centers for Disease Control and Prevention (CDC) recommend testing for M. genitalium only in patients with persistent symptoms of urethritis and cervicitis following completion of standard syndromic treatment [53]. These guidelines also state that M. genitalium testing should be considered in the initial evaluation of cervicitis and among females with PID.

●No role for routine screening – Routine screening for M. genitalium in asymptomatic individuals is not recommended. Detection and treatment of infections due to M. genitalium in high-risk asymptomatic persons have not yet been demonstrated to prevent PID, infertility, adverse pregnancy outcomes, and/or HIV transmission in either males or females [86]. Research needed to address these important questions may be performed in the near future.

Microbiologic testing — The tests of choice for detection of M. genitalium in clinical specimens are NAATs. In the United States, two NAATs have been cleared by the US Food and Drug Administration (FDA) for this purpose [87]. Other assays are available in other parts of the world [88,89]. If NAAT-based assays for simultaneous detection of M. genitalium and macrolide-resistance genes are available, as in some countries (eg, Europe, Asia, and Australia, but not the United States), these should be used. (See 'Antimicrobial susceptibility' below.)

Specimens that can be tested with these assays include the following:

●For males: Urethral swab, urethral meatus swab (either clinician- or self-collected), and urine; these are equally sensitive.

●For females: Vaginal swab (either clinician- or self-collected), endocervical swab, and urine; the vaginal swab is the optimal specimen because it has higher sensitivity compared with other specimen types.

The same specimen can be used to test for C. trachomatis and N. gonorrhoeae.

Urine specimens should be a first-void urine (ie, the first 10 mL of the initial stream of urine collected without precleaning of the genital areas). Ideally, the patient should not have voided in the two hours prior to specimen collection.

The sensitivity of the M. genitalium assays that are FDA cleared for use in the United States ranges from 78 to 100 percent; the specificity ranges from 96 to 99 percent [90].

Traditional microbiologic methods of bacterial diagnosis are not clinically useful in the diagnosis of M. genitalium infections. The lack of a cell wall prevents M. genitalium identification by routine Gram staining, and its fastidious growth requirements make in vitro cultivation for diagnosis nearly impossible [6,91,92]. Additionally, there are no standardized serologic tests for M. genitalium [93]. (See 'Microbiology' above.)

TREATMENT

Antimicrobial susceptibility — M. genitalium has relatively limited susceptibility to antibiotic agents. The main active agents are azithromycin and certain fluoroquinolones, although resistance is an issue for each to varying degrees, as discussed below. As a class, mycoplasmas are largely susceptible to tetracyclines, but M. genitalium is an exception to this generalization [10]. Although the organism appears susceptible to the tetracyclines in vitro, microbiologic treatment failures range from 60 to 70 percent [58]. The lack of a cell wall renders mycoplasmas, including M. genitalium, resistant to classes of antibiotics that target cell wall synthesis, such as penicillins and other beta-lactams. It is important to recognize that the in vitro susceptibility studies with this organism are extremely limited, as relatively few cultivated strains are available for study.

●Azithromycin – M. genitalium is inherently susceptible to azithromycin, but resistance has been increasing globally. A systematic review of 57 studies evaluating the frequency of macrolide-resistance-associated mutations in M. genitalium isolates estimated that the prevalence increased from 10 percent in 2010 to 51 percent in 2016 to 2017 [94]. Resistance was greater in the Western Pacific and Americas compared with Europe. Macrolide resistance is mediated by mutations in the 23S ribosomal RNA gene that develop following antibiotic exposure, suggesting antibiotic-induced resistance. Almost all strains tested following azithromycin treatment failure have macrolide-resistance mutations [95,96]. In small studies, the proportion of isolates harboring these mutations has ranged from 14 to 80 percent, and this appears to be increasing [97-101].

●Fluoroquinolones – Among the fluoroquinolones, moxifloxacin has been used most commonly for M. genitalium and has been reported in most series to be ≥90 percent effective [102]. Sitafloxacin appears to be equally effective and is available outside the United States. However, reports of mutations in M. genitalium genes parC and gyrA, which are associated with fluoroquinolone resistance, have emerged [99,103,104]. In a systematic review of 25 studies, fluoroquinolone-resistance-associated mutations were reported in 7.7 percent of M. genitalium isolates globally [94]. The presence of such mutations has been associated with fluoroquinolone treatment failure [103,105]. There is some evidence that fluoroquinolone treatment failures may be increasing, but given the use of different drugs worldwide, the extent of this problem is unclear [102].

In the United States, there are no commercially available antibiotic resistance tests for M. genitalium. Nucleic acid amplification tests (NAATs) that are able to detect the organism and macrolide resistance mutations at the same time are available in many parts of the world and will be available in the future in the United States [106].

Impact of empiric syndromic therapy on M. genitalium — The clinical syndromes with which M. genitalium is associated, nongonococcal urethritis, cervicitis, and pelvic inflammatory disease (PID), are typically treated empirically, prior to knowledge of the specific causative pathogen. Empiric treatment of these syndromes includes coverage of C. trachomatis, generally with multi-dose doxycycline or, as an alternative, azithromycin (usually as a single 1 g dose). Details of the empiric treatment regimens are discussed elsewhere. (See "Urethritis in adult males", section on 'Initial therapy' and "Acute cervicitis", section on 'No identifiable pathogen' and "Pelvic inflammatory disease: Treatment in adults and adolescents", section on 'Antibiotic selection'.)

Although these regimens are effective for C. trachomatis, they are associated with suboptimal microbiologic cure rates for M. genitalium. A seven-day course of doxycycline substantially reduces organism load in most cases of M. genitalium urethritis, but it results in microbiologic cure in only 30 to 40 percent [58,107]. Similarly, because of emerging resistance to azithromycin, pooled microbiologic cure rates with a single 1 g dose of azithromycin were lower in studies published after 2009 compared with those published earlier (67 versus 85 percent) [108]; the single 1 g dose additionally contributes to the emergence of azithromycin-resistant variants.

Thus, it is important to recognize that M. genitalium is an important cause of clinical treatment failures following initial empiric treatment of sexually transmitted infection (STI) syndromes (especially for nongonococcal urethritis and probably cervicitis), as discussed further below [109].

Empiric M. genitalium therapy in select clinical treatment failure cases — The possibility of M. genitalium should be considered in all patients with persistent urethritis, cervicitis, or PID following initial empiric therapy. Many patients who present with persistent symptoms may not have been tested for M. genitalium at initial presentation. We favor testing for M. genitalium in such patients and using directed therapy in those who test positive, as detailed below. (See 'Directed therapy of documented infection' below.)

However, if such testing is not available or if testing is pending and the patient has severe symptoms, it is reasonable to treat empirically for M. genitalium in patients with persistent urethritis or cervicitis. Whether M. genitalium contributes to persistent PID is uncertain, and we only treat for M. genitalium in patients with persistent PID if they test positive for the pathogen.

The approach to empiric treatment for M. genitalium in patients with persistent urethritis or cervicitis depends on their original treatment regimen:

●Patients originally treated with doxycycline – For those who have persistent and severe symptoms following treatment with a regimen that included doxycycline, we suggest high-dose azithromycin (1 g on day 1 followed by 500 mg on days 2 through 4) [107,110]. This regimen can result in high microbiologic cure rates in individuals with macrolide-susceptible M. genitalium, and the high dose minimizes the emergence of macrolide resistance with azithromycin therapy [101,107]. Lower azithromycin doses have been associated with emergent azithromycin resistance in approximately 10 percent of cases. Microbiologic treatment failures can be high when this regimen is used for macrolide-resistant isolates (which may be the majority of cases of M. genitalium infections); nevertheless, azithromycin-based regimens can be associated with clinical cure rates of 65 to 75 percent, even in the setting of macrolide resistance [111]. Although moxifloxacin has high microbiologic cure rates, we favor azithromycin in this setting and reserve moxifloxacin for patients with documented M. genitalium infection, given its cost and potential toxicity.

●Patients originally treated with azithromycin – For those who have persistent symptoms following treatment with a regimen that included azithromycin, we favor deferring therapy unless the patient tests positive for M. genitalium, in which case the approach is discussed elsewhere (see 'Directed therapy of documented infection' below). Treatment failure following azithromycin regimens are associated with macrolide-resistance mutations, for which microbiologic cure rates are low with azithromycin-based regimens. As an example, in a study that included 23 males and females with persistent M. genitalium following initial therapy with single-dose azithromycin, only 8 (34 percent) were cured with a subsequent five-day course of azithromycin [112]. Although moxifloxacin is associated with high microbiologic cure rates, given its cost and potential toxicity, we prefer to reserve it only for patients with documented M. genitalium infection. However, if M. genitalium testing is not possible, and other causes of persistent urethritis or cervicitis (eg, Trichomonas vaginalis, reinfection or persistence of C. trachomatis and N. gonorrhoeae, and for cervicitis, bacterial vaginosis) have been ruled out, it is reasonable to cautiously use moxifloxacin, as indicated for directed therapy.

Directed therapy of documented infection — For individuals who have documented M. genitalium infection (whether they were tested at the initial presentation or because of persistent symptoms following empiric treatment), we suggest moxifloxacin 400 mg once daily for seven days to maximize both clinical and microbiologic cure. In some countries outside the United States, sitafloxacin, another fluoroquinolone, is used as the primary fluoroquinolone for treating M. genitalium infections [101]. If a fluoroquinolone is not possible because of cost or contraindication, high-dose azithromycin (1 g on day 1 followed by 500 mg on days 2 through 4) is an alternative for those who were not previously treated with azithromycin, but it is associated with a higher rate of microbiologic failure [101,107,111].

For patients who are tested only at the time of persistent or recurrent symptoms following syndromic treatment, the United States Centers for Disease Control and Prevention (CDC) recommends giving a second course of doxycycline 100 mg twice daily for seven days immediately followed by moxifloxacin [53]. Although doxycycline usually does not result in microbiologic cure of M. genitalium, it reduces bacterial load in most patients. Lowering the level of organism with doxycycline pretreatment is theorized to prevent the emergence of fluoroquinolone resistance and increase microbiologic cure with subsequent fluoroquinolone treatment. However, clinical evidence suggesting that this approach is better than moxifloxacin alone is lacking.

If tests that simultaneously detect M. genitalium and macrolide antibiotic-resistance genes are used, those results can inform antibiotic selection. Specifically, if an isolate does not have detected macrolide resistance, the high-dose azithromycin regimen can be used, and if not, a moxifloxacin-based regimen can be used (the CDC suggests a course of doxycycline prior to either azithromycin or moxifloxacin in this approach). This resistance-guided strategy has been associated with overall microbiologic success rates greater than 90 percent while minimizing toxicity of fluoroquinolones [107,110]. However, such tests are not widely available (and are not available in the United States).

Most of the evidence supporting moxifloxacin treatment is from observational studies [58,96,102,112]. A meta-analysis of 17 observational studies evaluating moxifloxacin for M. genitalium infections reported a pooled microbiologic cure rate of 96 percent (95% CI 90 to 99 percent) [102]. As an example, in one of those studies, 32 males and females with persistent M. genitalium after initial therapy with azithromycin were treated with moxifloxacin (400 mg orally for seven days), and all of the 23 patients who returned for follow-up had microbiologic cure [112]. Nevertheless, reports of mutations in M. genitalium associated with fluoroquinolone resistance and treatment failure have also emerged. In an Australian study of 60 individuals with documented M. genitalium who failed initial treatment with azithromycin, 53 (88 percent) were cured with moxifloxacin, and all those who failed moxifloxacin had baseline fluoroquinolone-resistance mutations in pretreatment samples [96]. Furthermore, use of fluoroquinolones may be limited by a number of uncommon but severe associated adverse events, including Achilles tendinitis and rupture, peripheral neuropathy, central nervous system disease, and in older patients and those with vascular disease, aortic aneurysm rupture. (See 'Antimicrobial susceptibility' above and "Fluoroquinolones", section on 'Adverse effects'.)

The complexity of M. genitalium therapeutic decision-making will be resolved in the near future once tests for the simultaneous detection of the organism and macrolide antibiotic-resistance genes become more generally available. Overall, initial treatment success rates higher than 90 percent can be expected when azithromycin is prescribed only to patients infected with strains that do not have macrolide-resistance gene mutations, and all others are treated with a quinolone antibiotic. This strategy minimizes antibiotic toxicity as well [107,110].

Management of moxifloxacin treatment failure — Although uncommon, microbiologic or clinical failure following moxifloxacin poses a management challenge. The appropriate approach is unknown, and clinical trials are needed, especially in males. Patients with persistent infection despite moxifloxacin therapy should be managed in consultation with an expert in sexually transmitted infections.

Several approaches appear promising:

●Pristinamycin 1 g four times daily for 10 days (available mainly in European countries and in Australia). In small observational studies, this has been associated with microbiologic cure rates of 75 to 100 percent [84,96,113,114].

●Minocycline 100 mg twice daily for 14 days – In a series of 35 patients, this was associated with a microbiologic cure rate of 71 percent [113].

●Nitroimidazoles – In a randomized trial evaluating the value of treating anaerobics in patients with pelvic inflammatory disease, M. genitalium detection was unexpectedly less frequent among those who received metronidazole (4 versus 14 percent among those who did not) [115]. Subsequently, an in vitro study showed that the nitroimidazoles were active against M. genitalium [116]. Tinidazole was the most potent of the nitroimidazoles tested.

PARTNER MANAGEMENT — Most management guidelines recommend that sexual partners of laboratory-confirmed cases of M. genitalium should be tested for M. genitalium and treated, if positive. Although the incubation period of this pathogen remains undefined, case finding should target sexual partners in the past 60 days. If testing of sexual partners of index patients with confirmed M. genitalium is not possible, we favor empirically treating for M. genitalium, given the evidence of sexual transmission of this organism. (See 'Microbiologic testing' above.)

Treatment for partners of patients with confirmed M. genitalium infection is the same as for patients. (See 'Directed therapy of documented infection' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sexually transmitted infections".)

SUMMARY AND RECOMMENDATIONS

●Microbiology – Mycoplasma genitalium is a member of the Mycoplasmataceae family of bacteria. It is not visible on Gram stain because it lacks a cell wall, and culture of the organism is very difficult. (See 'Microbiology' above.)

●Prevalence and risk factors – The prevalence of M. genitalium is approximately 1 percent in the general population but considerably higher among individuals at high risk for sexually transmitted infections (STIs). Risk factors for M. genitalium infection are similar to those associated with Chlamydia trachomatis infection and include young age and more than one recent sexual partner. (See 'Epidemiology' above.)

●Clinical syndromes – M. genitalium is an important cause of nongonococcal urethritis in males, cervicitis in females, and possibly pelvic inflammatory disease (PID) in females. It is uncertain whether it causes proctitis in men who have sex with men (MSM). There is no clear evidence that M. genitalium is associated with any human diseases outside the anogenital tract. (See 'Associated clinical syndromes' above.)

The clinical manifestations of M. genitalium urogenital infection are similar to those caused by C. trachomatis infection in both males and females. M. genitalium urethritis is typically symptomatic, whereas females with cervicitis associated with M. genitalium are more frequently asymptomatic. (See 'Associated clinical syndromes' above and "Clinical manifestations and diagnosis of Chlamydia trachomatis infections".)

●Diagnosis – M. genitalium infection is diagnosed by detection of the organism using nucleic acid amplification tests (NAATs) on urogenital specimens, such as first-void urine in males and a vaginal or cervical swab in females. We suggest testing symptomatic patients with urethritis, cervicitis, and PID for M. genitalium. We also suggest testing patients who have persistent symptoms following empiric syndromic therapy. (See 'Diagnosis' above.)

●Approach to persistent symptoms after initial syndromic therapy – Empiric treatment of urethritis, cervicitis, and PID includes coverage of C. trachomatis, generally with multi-dose doxycycline or single-dose azithromycin. While these regimens are active to varying degrees against M. genitalium, they are not optimal, and clinical treatment failure is commonly associated with M. genitalium infection. For patients with persistent symptoms who were not tested for M. genitalium at initial presentation, we suggest testing for M. genitalium rather than empirically treating for the organism. If testing is unavailable, the approach to empiric therapy of M. genitalium depends on the regimen initially used. (See 'Impact of empiric syndromic therapy on M. genitalium' above and 'Empiric M. genitalium therapy in select clinical treatment failure cases' above.)

●Directed therapy of M. genitalium – For treatment of patients with proven M. genitalium infection, we suggest moxifloxacin (Grade 2C). The dose is 400 mg orally for seven days. If there are concerns about moxifloxacin, high-dose azithromycin is a reasonable alternative as long as the patient had not previously received it for the current infection. When azithromycin is used for therapy of M. genitalium, we suggest a dose of 1 g once followed by 500 mg daily for the next three days (Grade 2C). (See 'Directed therapy of documented infection' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate would like to acknowledge Victoria Mobley, MD, MPH, and Arlene C Seña, MD, MPH, who contributed to an earlier version of this topic review.