The bacterium Mycoplasma genitalium is difficult to study. The organism is fastidious and culture is difficult and, even when successful, it takes several weeks or even months for each isolate to grow. Serology in its more sophisticated forms may have a role in epidemiological studies but is not of value in diagnosis. Hence, nucleic acid amplification tests (NAATs) are the only available diagnostic tools, but no commercially available test has been released for diagnostic purposes.

THE EVIDENCE FOR M GENITALIUM AS A PATHOGEN USING ANIMAL AND TISSUE MODELS

Studies in non-human primates have clearly demonstrated the pathogenicity of M genitalium in both male and female animals. M genitalium can be isolated from an infected animal and can be transferred to an uninfected animal and cause disease fulfilling one of Koch’s postulates.¹

In vitro studies demonstrate the potential for M genitalium to attach to genital tract epithelial cells using a surface adhesin protein and then to enter the cells leading to the upregulation of cytokine genes with an associated inflammatory response.²M genitalium can also attach to spermatozoa giving a potential mechanism for spread to the female upper genital tract.³

EVIDENCE FOR M GENITALIUM AS A PATHOGEN IN MEN

Large numbers of papers on the role of M genitalium in male non-gonococcal urethritis (NGU) have been published since 1993 following the initial polymerase chain reaction based studies.^4–6 Although different criteria have been used to define patient and control groups, all the studies have uniformly shown a higher prevalence of M genitalium in the NGU groups (reviewed by Jensen⁷). Moreover, M genitalium appears to be detected with the highest prevalence in men with Chlamydia trachomatis negative NGU (NCNGU). Several studies have found that men with M genitalium positive NGU have symptoms as least as often as have those with chlamydial NGU.^8,9 When urethritis has been graded according to the number of polymorphonuclear leucocytes (PMNLs) in the urethral smear, men with M genitalium have had higher PMNL counts than men with M genitalium negative NCNGU, indicating a significant inflammatory potential. Systematic studies linking M genitalium to complications such as epididymitis and prostatitis are lacking although M genitalium DNA has been found both in the urethra of men with epididymitis,¹⁰ and in prostatic tissue of men with prostatitis.¹¹

EVIDENCE FOR M GENITALIUM AS A PATHOGEN IN WOMEN

In women, M genitalium can be detected in the genital tract and is found most commonly in those with genital tract symptoms or signs, or those who have an infected male partner. The presence of M genitalium is associated with cervicitis and urethritis in women,^12,13 and the inoculation of M genitalium in non-human primates leads to both lower genital tract disease and salpingitis.¹⁴M genitalium can be detected in the endometrium of women with pelvic inflammatory disease¹⁵ and, on a single occasion, has been found in the fallopian tube.¹⁶ In addition, serological studies suggest a strong association between past infection with M genitalium and tubal factor infertility.¹⁷

It therefore seems very likely that M genitalium is a sexually transmitted pathogen in women⁹ and responsible for at least some cases of urethritis, cervicitis, and pelvic inflammatory disease.

HOW TO DIAGNOSE M GENITALIUM: CURRENT AVAILABILITY OF TESTING AND FUTURE PROSPECTS

At present, NAATs are the only tools available for detection of M genitalium. Because of a very low load of mycoplasmas in some patients,¹⁸ tests with a very low limit of detection are needed in order to achieve sufficient assay sensitivity. No approved commercial assays have been made available although promising results with kits for research use have been presented.¹⁹ In the years to come, approved assays will most likely become available, but until then it is imperative that laboratories actively engage in external quality assurance programmes using real clinical specimens before they offer NAATs on a routine basis. The optimal specimen type may vary depending on the sample preparation method used in the laboratory. In one large study male first void urine was found to detect more infections with M genitalium, as well as with Chlamydia trachomatis, than urethral swabs although this might reflect the amount of specimen used in the sample preparation method. In women the use of more than one specimen may also improve diagnostic sensitivity—for example, supplementing a urine specimen with a cervical swab.²⁰

ANTIBIOTIC THERAPY FOR M GENITALIUM INFECTIONS

A number of different antibiotics have been used to treat M genitalium infections with varying degrees of success. Tetracyclines initially looked promising but more recent studies suggest that failure to fully eradicate the infection occurs in a high proportion of cases treated with these agents. Macrolides, in particular azithromycin, offer the best chance of cure with a 84% clearance in a recent randomised controlled trial performed in men with M genitalium urethritis.²¹ The newer quinolones, such as moxifloxacin, also have good activity against M genitalium in vitro (although ciprofloxacin and ofloxacin are less effective).²²

Because M genitalium grows very slowly a prolonged course of therapy may be required to eradicate it. In a preliminary open study from Scandinavia a trend towards improved outcome with longer duration of therapy was observed—azithromycin 1 g immediately eradicated 85% (11/13) of the M genitalium infections whereas a dose of 500 mg on day 1 followed by 250 mg daily for 4 days eradicated 95% (19/20) of infections.²³

Recommendations

With the current state of knowledge of M genitalium what interim recommendations can be given about screening, testing, and management?

Screening

It is premature to start population screening for M genitalium. To do so we need accurate information on the prevalence of infection and prospective data on the natural history of disease in infected individuals. Only with this information can the efficacy and cost effectiveness of screening be calculated for different populations. The proposed testing of urine samples for M genitalium from the NATSAL study²⁴ will provide essential prevalence information to help inform the role of screening in the future. The evidence linking M genitalium to pelvic inflammatory disease is strong but largely circumstantial and we still lack natural history studies which demonstrate a temporal relation between infection and disease. At least one such study is ongoing in the United States and another is planned for the United Kingdom, which will help to quantitate the risk of pelvic infection associated with M genitalium infection and define the role of screening.

Testing

Although a variety of “in-house” PCRs have been developed there is a clear and urgent need for an accurate, standardised, and quality assured test kit for M genitalium. Assuming a test is available who should be tested for M genitalium?

Testing men with symptomatic NGU is reasonable, in particular in those settings where empirical treatment with doxycycline is used. Two thirds of the M genitalium infected patients with urethritis will have persistent infection and often experience recurrent symptoms after doxycycline therapy. The same argument could also be used to justify testing patients presenting with complications such as epididymitis, prostatitis, and sexually acquired reactive arthritis.

Testing for M genitalium in women presenting with genital tract symptoms, such as genital discharge, intermenstrual bleeding, or pelvic pain is justified because of the association between M genitalium and cervicitis, endometritis, and clinical pelvic inflammatory disease. Further information on the natural history and prevalence of infection is needed before testing of asymptomatic women can be recommended.

Treatment

Specific treatment for M genitalium is appropriate in symptomatic patients in whom the organism has been detected and current evidence suggests that first line therapy with a 5 day course of azithromycin would be most appropriate. Single doses of azithromycin may be less effective in men with urethritis and occasionally macrolide resistance has been encountered. Patients with treatment failure after azithromycin have been successfully treated with moxifloxacin 400 mg daily for 10 days²⁵ but because of the risk of development of resistance this treatment should be considered second line.

The lack of prospective natural history data makes a firm recommendation to trace and treat all sexual contacts premature at present, but such an approach is reasonable for individual patients after appropriate discussion.

Summary

Based on the current evidence a recommendation to test patients with genital symptoms for M genitalium is justified and treatment of those found to be infected should be with azithromycin. The scope for testing will, however, be limited until validated and, preferably, commercially available tests become accessible.