Update on Sexually Transmitted Infections

September 17-20, 2007; Chicago, Illinois

David N. Fisman, MD, MPH, FRCP(C)

Disclosures

February 28, 2008

In This Article

Mycoplasma genitalium: Pathogen or Passenger?

The next speaker, Dr. Jorgen Jensen of the Statens Serum Institut, presented arguments in favor of classifying the presence of Mycoplasma genitalium in the genital tract as a true "STI." M genitalium is a small (< 1 micron), flask-shaped bacterium that lacks a cell wall. In contrast to viruses, mycoplasmas are able to grow on cell-free media, although they also appear to be able to survive intracellularly. The human genital tract is a microbiologically rich environment, so that the presence of an individual species of bacterium in the genital tract does not identify that microorganism as a pathogen per se. However, M genitalium is known to produce experimental urethritis in nonhuman primates, and can be reisolated and transmitted to other primates, partially fulfilling Koch's postulates for causation by a microorganism.[10]M genitalium causes experimental salpingitis in marmoset monkeys, although it has been difficult to isolate this microorganism from experimental lesions -- perhaps suggesting a postinfectious or reactive inflammatory process initiated by initial infection).[17] Dr. Jensen reviewed additional clinical data suggesting that this microorganism is indeed a sexually transmitted pathogen, and the implications that "STI status" for M genitalium has for management of individuals with nongonococcal urethritis (NGU) and other common STI syndromes.

The basic clinical pillars for reclassification of M genitalium infection as an STI include:

  • The strong association between the presence of this microorganism in the genital tract and STI syndromes in men and women;

  • Evidence that directed treatment aimed at eradicating this microorganism results in elimination of STI symptoms, and conversely, that absence of effective therapy is associated with persistent symptoms; and

  • Evidence favoring sexual transmission of the microorganism.

However, acceptance of the role of M genitalium as a pathogen has been slow for a variety of reasons, and perhaps principal among these is the difficulty of identifying clinical infection with this microorganism. Culture is insensitive, and serologic diagnosis is both insensitive and nonspecific, due to cross-reactivity with Mycoplasma pneumoniae serology. In the research setting, PCR targeting 16S rRNA or the microorganism's adhesion gene appears to be a sensitive tool for diagnosis, but is technically demanding, due both to the genetics of the microorganism (eg, hypervariable regions in the adhesin gene) and the relatively small number of microorganisms present in some infections.

Association Between M genitalium and STI Syndromes

Evidence in men. The original impetus to classify M genitalium infection as an STI related to the implication of this microorganism as a possible cause of NGU. Acknowledged etiologies of NGU include C trachomatis infection, infection with Ureaplasma urealyticum, trichomoniasis, and viral infections -- including herpes simplex viruses types I and II and infection with adenovirus. However, up to half of all cases of NGU are of unknown etiology. Dr. Jensen asked rhetorically whether it is reasonable to believe that M genitalium accounts for 15% to 25% of all NGU.

There are several lines of evidence to suggest that this may, indeed, be the case. Many patients with NGU respond to treatment with tetracyclines or macrolides, although this is also consistent with Ureaplasma and Chlamydia as etiologic agents of NGU. The association of M genitalium with NGU dates from 1981, when this microorganism was identified in 2 of 13 men with unexplained NGU.[11] Epidemiologic evidence suggests that M genitalium is indeed more commonly present in individuals with NGU than in asymptomatic individuals. For example, Dr. Jensen described a study that he and his colleagues published in 1993. The study was a case-control study in which 52 men with NGU were compared with 47 asymptomatic male controls. The odds of identification of C trachomatis or M genitalium were approximately 4-fold higher in individuals with NGU than in the controls. Of interest, the controls were more likely to have Ureaplasma than the individuals with NGU.[12] Several similar studies, with similar results, have been published subsequently. (Dr. Jensen had a beautiful forest plot from a meta-analysis, showing a summary odds ratio [OR] of 7 for NGU in the presence of M genitalium, but I haven't been able to find this.)

NGU is not the only STI syndrome to have been reported in association with M genitalium in men. Individuals with chronic prostatitis have had a high prevalence of M genitalium in semen specimens relative to control men.[13] A single case report suggested that, like gonococcus and C trachomatis, M genitalium may be a cause of sexually transmitted conjunctivitis; Bjornelius and colleagues[14] reported a 22-year-old man with coexistent M genitalium urethritis and conjunctivitis.

Evidence in women. Although M genitalium has been associated with otherwise unexplained cervicitis in women, the magnitude of this association has been smaller than that seen for NGU in men.[14,15] (Again, Dr. Jensen had a great forest plot that doesn't seem to be published.) M genitalium has also been implicated as an agent that plays a role in disease of the female upper genital tract; Cohen and colleagues[17] were able to identify the pathogen by PCR in 9 of 48 women with endometritis and 1 of 57 women without endometritis in a study conducted in Kenya, an OR of nearly 13.[17] In the multicenter PEACH study, M genitalium was identified in 8% of endometrial specimens from women with histologically confirmed endometritis.[18]

Other investigators have also identified associations between the presence of M genitalium in the female genital tract and risk for pelvic inflammatory disease in women,[19,20] as well as chronic sequelae of pelvic inflammatory disease, such as tubal factor infertility. A case-control study by Svenstrup and colleagues[21] found an OR of 4.5 (95% confidence interval [CI] 1.2-16) for tubal factor infertility in women with serologic evidence of past infection with M genitalium. Of interest, the OR for past infection with C trachomatis, a pathogen widely accepted as an etiologic agent of tubal factor infertility, was only 1.9 (0.7-5.2).[21]

M genitalium and Persistence of STI Syndromes in the Absence of Specific Therapy

A second line of epidemiologic evidence favoring the classification of M genitalium infection as an STI relates to the persistence of NGU in individuals who do not receive therapy that eradicates M genitalium. Dr. Jensen described a study that evaluated 78 men with persistent posttreatment urethritis; 41% of these men had persistent M genitalium identified by PCR. Men who had been treated with azithromycin were less likely to be M genitalium-positive than those treated with erythromycin or doxycycline.[22]

A case-control study by Yokoi and colleagues[23] compared individuals with "postgonococcal urethritis" (PGU) (signs and symptoms of gonorrhea persisting after eradication of Neisseria gonorrhea infection) with individuals with resolution of symptoms. The OR for PGU among individuals with baseline M genitalium infection was 8.4; after removing individuals with predictable PGU due to coinfection with C trachomatis, this OR increased to 14.5.[23]

In data derived from the PEACH study, mentioned above, and presented at the 2007 meeting of the International Society for Sexually Transmitted Diseases Research (ISSTDR), the identification of M genitalium in clinical specimens was a strong predictor of histologic endometritis (OR 3.4, 95% CI 1.6-8.7), but also predicted persistent endometritis following treatment with cefoxitin and doxycycline (OR for persistence 3.7 [1.6-6.9]), as well as recurrent pelvic inflammatory disease.[24]

Concordance of Infection Within Sexual Partnerships and Clusters

A third important line of epidemiologic evidence suggesting that M genitalium is a sexually transmitted pathogen is the concordance of infection status in sexual partners of infected individuals. A number of studies have found that the prevalence of M genitalium carriage in the genital tracts of sex partners of individuals with apparent M genitalium infection is higher than would be expected, on the basis of the prevalence of carriage in the general population.[15,22] Furthermore, molecular epidemiologic data, which is based on typing of the mgpB gene, have shown that strains are identical within a sexual partnership, but distinct from strains in other, unrelated partnerships.[25]

Specific Therapy for M genitalium Infection and Emergence of Antimicrobial Resistance

An important reason for determining whether M genitalium represents a true sexually transmitted pathogen is the differential effectiveness of antimicrobials used for empirical treatment of NGU for eradication of M genitalium. For example, tetracyclines are highly effective for the treatment of genital tract infection with C trachomatis. However, tetracyclines eradicated M genitalium in only 10 of 30 men and women with urethritis or cervicitis treated at a Swedish STI clinic.[26] In the same study, azithromycin (1.5 g over 5 days) eradicated infection in all 36 individuals treated with that drug. Single-dose azithromycin (1 g) appears less effective than 1.5 g in divided doses, but is still more effective than doxycycline.

Similar results were obtained in a multicenter, nonrandomized trial, comparing therapy with doxycycline with single-dose azithromycin. M genitalium was eradicated in only 17% of men and 37% of women with doxycycline (200 mg orally day 1, then 100 mg once daily for 8 days), whereas single-dose azithromycin eradicated M genitalium in ≥ 85% of individuals of both sexes. Almost all individuals with treatment failure received 1.5 g of azithromycin over 5 days; the azithromycin salvage regimen eradicated > 95% of persistent infections.[27]

In individuals who fail treatment with azithromycin, moxifloxacin (400 mg once daily x 10 days) appears to be a highly effective treatment alternative. Bradshaw and colleagues[28] reported 9 individuals seeking STI-related care at a clinic in Melbourne, Australia, who experienced apparent treatment failure with azithromycin. All had signs and symptoms of urethritis eradicated after moxifloxacin 400 mg once daily for 10 days.[28] Bacterial isolates from individuals with treatment failure had markedly reduced susceptibility to macrolide antibiotics, including erythromycin and azithromycin.

Unfortunately, antimicrobial resistance has been identified as an important issue in the treatment of genital tract infection with M genitalium. Mutations in domain V of bacterial 23S rRNA confer resistance to macrolides; the nature and mechanism of resistance are similar to those that have been described in M pneumoniae strains with diminished susceptibility to macrolides. Dr. Jensen's lab has developed a pyrosequencing assay for rapid characterization of 23 S rDNA in M genitalium. Using this assay, he found that few infected individuals have resistance mutations pretreatment, but these mutations were commonly identified in individuals with relapsed infection following azithromycin therapy in studies conducted in Sweden and Denmark. In addition to macrolide resistance, Dr. Jensen described individual cases of apparent resistance to fluoroquinolone antibiotics, such as moxifloxacin, in Sweden. An individual case described by Dr. Jensen has been infected with M genitalium for approximately 18 months, and remains infectious notwithstanding multiple, prolonged courses of several antimicrobial agents.

Summary and Questions

In conclusion, the weight of the available evidence, including laboratory-based animal studies, and epidemiologic evidence that links M genitalium to STI syndromes, indicating that genital tract transmission occurs in the context of sexual partnerships, suggests that M genitalium infection should, indeed, be classified as an STI. The importance of identifying M genitalium as a distinct and common STI pathogen relates to the differential susceptibility of this microorganism to tetracyclines, macrolide agents, and fluoroquinolones: Treatment failures in individuals treated for urethritis with tetracycline or doxycycline appear common. The emergence of macrolide resistance in this pathogen highlights the importance of better understanding of the role that M genitalium plays in STI syndromes, and the need for studying alternative antimicrobial regimens for treatment of M genitalium infections.

Several audience members asked questions following Dr. Jensen's presentation. Dr. Angelika Stary of Vienna asked whether M genitalium is seen in association with bacterial vaginosis because another Mycoplasma species (Mycoplasmahominis) has been strongly associated with this condition. Dr. Jensen answered that M genitalium carriage may actually be less common in the vagina in the presence of bacterial vaginosis.[29]

Dr. Lindsay Nicolle, of the University of Manitoba in Winnipeg, Manitoba, Canada, asked whether perinatal transmission of infection to neonates is seen with M genitalium, as is recognized with genital tract pathogens, such as C trachomatis. Dr. Jensen responded that he was aware of a single instance of perinatally acquired infection in a premature infant. He noted that the prevalence of infection with M genitalium in pregnant women appears low.[30]

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