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Contents included in this summary

 

1. Microbiology

Mycoplasma genitalium belongs to the Mollicutes class, and with a genome of only 580 kilobases in size, is the smallest known self-replicating bacterium. It lacks a cell wall, and hence is not visible by Gram stain. The organism is fastidious and typically requires weeks or months to culture.

M. genitalium has been detected from genito-urinary, rectal and respiratory tract specimens, but carriage in the throat seems to be rare. The specialised tip-like structure of M. genitalium enables it to adhere to and invade epithelial cells.

2. Epidemiology

2.1 Prevalence in general population and risk factors for infection

Prevalence estimates for M. genitalium infection in men and women in the general population range from 1–2%, being slightly higher in women. Amongst STI clinic attendees, prevalence ranges are higher, from 4–38%.

2.2 Sexual transmission

Transmission is primarily by genital-genital contact, but M. genitalium has also been detected in the ano-rectal compartment and transmission by penile-anal contact has been established. As carriage in the oro-pharynx is uncommon, the relative contribution of oral sex is likely to be very small.

2.3 Co-infection with other STIs

M. genitalium is associated with the detection of other bacterial STIs, C. trachomatis being the most frequently isolated co-organism. An association between M. genitalium and HIV transmission and acquisition is biologically plausible and supported by some studies in sub-Saharan Africa.

2.4 Clinical associations

2.4.1 Non-gonococcal urethritis (NGU)

M. genitalium infection is unequivocally and strongly associated with NGU. M. genitalium is also associated with persistent and recurrent urethritis. M. genitalium is also associated with persistent and recurrent urethritis, where up to 40% of patients may have M. genitalium detected

2.4.2 M. genitalium in the female reproductive tract

Several studies support an association of M. genitalium infection in cisgender women with post coital bleeding and cervicitis, endometritis and pelvic inflammatory disease (PID).

2.4.3 Asymptomatic infection

The evidence suggests that the majority of people infected with M. genitalium in the genital tract do not develop disease. There is no evidence that screening asymptomatic individuals will be of benefit, and indeed is likely to do harm at a population level. Current asymptomatic partners (including non-regular partners where there is likely to be further sexual contact and risk of reinfection) of individuals with disease caused by M. genitalium infection should be tested and/or offered epidemiological treatment (using the same antimicrobial regimen as used in the index patient). This is to reduce the risk of re-infection in the index case.

3. Clinical features

3.1 Signs and symptoms in males:

  • None – the majority are asymptomatic
  • Urethral discharge
  • Dysuria
  • Penile irritation
  • Urethral discomfort
  • Urethritis (acute, persistent, recurrent)
  • Balanoposthitis (in one study)

3.2 Complications in males:

  • Sexually acquired reactive arthritis
  • Epididymitis

The clinical presentation of M. genitalium urethritis is similar to other causes and thus clinical features of acute symptomatic NGU cannot be used to determine the infective aetiology. Although the proportion of infected men that develop symptoms is unknown this is likely to be <10%.

Urethral discharge may be present spontaneously or on expression, and urethritis is confirmed by demonstrating five or more polymorphonuclear leucocytes (PMNLs) per high power (x1000) microscopic field (averaged over five fields with the greatest concentration of PMNLs) on a smear obtained from the anterior urethra.

It is possible that sexually acquired reactive arthritis may occur as a result of M. genitalium infection. An association with epididymitis is possible, but current data are lacking to support an association with prostatitis. M. genitalium has been demonstrated at high prevalence in rectal samples from men who have sex with men (MSM) (particularly HIV-positive MSM).

3.3 Signs and symptoms in females

  • None – the majority are asymptomatic
  • Dysuria
  • Post-coital bleeding
  • Painful inter-menstrual bleeding
  • Cervicitis
  • Lower abdominal pain (see Complications: PID)

3.4 Complications in females

  • Pelvic inflammatory disease
  • Tubal factor infertility (uncertain association)
  • Sexually acquired reactive arthritis
  • Pre-term delivery

Individuals with cervicitis due to M. genitalium frequently have no symptoms at all. If present, symptoms are nonspecific, with the most common symptom being post-coital bleeding. Although the proportion of infected women that develop symptoms is unknown this is likely to be <5%.

Examination is frequently normal, but on speculum examination the presence of mucopurulent cervical discharge, cervical friability and elevated numbers of PMNLs on cervical sample Gram staining are suggestive of infection.

Clinical signs and symptoms of M. genitalium -associated PID are similar to, and indistinguishable from, PID due to C. trachomatis.

4. Recommendations for testing

4.1 Based on symptoms

  • BASHH recommend testing for M. genitalium infection in people with non-gonococcal urethritis 
  • BASHH recommend testing for M. genitalium infection in people with signs and symptoms suggestive of pelvic inflammatory disease 
  • Consider testing for M. genitalium infection in people with signs or symptoms of mucopurulent cervicitis, particularly post-coital bleeding 
  • Consider testing for M. genitalium infection in people with epididymitis 
  • Consider testing for M. genitalium infection in people with sexually-acquired proctitis 

4.2 Based on risk factors

  • BASHH recommend testing current sexual partners of persons infected with M. genitalium

Asymptomatic individuals with confirmed chlamydia and/or gonorrhoea infection should not be routinely tested for M. genitalium.

5. Diagnosis

It is recommended that all M. genitalium positive specimens should be tested for macrolide resistance mediating mutations. In the absence of local resistance testing, the Public Health England (PHE) Reference laboratory offers a molecular macrolide and fluoroquinolone susceptibility genotyping assay for specimens positive for M. genitalium.

5.1 Specimen collection

5.1.1 Men

First void urine (FVU) is the most sensitive specimen type (sensitivity 98-100%). FVU has been shown to be more sensitive than urethral swabs.

5.1.2 Women

Most studies suggest that in women, vulvovaginal swabs are the most sensitive specimen, followed by endocervical swabs. Using both vaginal and endocervical swabs increases the sensitivity further.

5.1.3 Considerations for people following gender reassignment surgery (GRS)

There are a paucity of data concerning M. genitalium infection in individuals following GRS. It is therefore difficult to recommend an optimal specimen type but this should be guided by sexual history and symptoms. For more detail, clinicians should refer to the forthcoming BASHH standards for trans and non-binary people document.

5.2 Recommendations:

  • BASHH recommend first void urine as the specimen of choice in cisgender men
  • BASHH recommend vaginal swabs (clinician- or self-taken) as the specimen of choice in cisgender women
  • BASHH recommend that where possible, all M. genitalium -positive specimens should be tested for macrolide resistance mediating mutations

5.3 Window period:

There are no data on the incubation period for M. genitalium, or on the likely window period before a laboratory test becomes reliably positive. However, it is likely that sensitive tests will detect early infection.

6. Management

6.1 General advice

Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health of themselves and their partner(s). This should be reinforced with clear and accurate written information. A patient information leaflet for M. genitalium can be found on the guidelines page of the BASHH website. 

Patients should be advised to abstain from sexual intercourse until 14 days after the start of treatment, and until symptoms have resolved. Where azithromycin has been used this is especially important because of its long half-life, and is likely to reduce the risk of selecting/inducing macrolide resistance if the patient is re-exposed to M. genitalium. We recommend a test of cure (TOC) should be performed in all patients.

6.2 Treatment of uncomplicated urogenital infection (urethritis, cervicitis)

See Fig. 1 for suggested treatment pathway for men presenting with NGU who subsequently test positive for M. genitalium.

Fig 1. Suggested treatment pathway for men presenting with non-gonococcal urethritis who subsequently test positive for M. genitalium

Fig 1. Suggested treatment pathway for men presenting with non-gonococcal urethritis who subsequently test positive for M. genitalium

  • Doxycycline 100mg bd for seven days followed by azithromycin 1g orally as a single dose then 500mg orally once daily for 2 days[A] where organism is known to be macrolide-sensitive or where resistance status is unknown
  • Moxifloxacin 400mg orally once daily for 10 days if organism known to be macrolide-resistant or where treatment with azithromycin has failed[B]

[A] Given that most individuals will have had doxycycline as first-line treatment for uncomplicated infection, a repeat course is unnecessary once the M. genitalium positive result is known. Azithromycin should be given immediately after doxycycline, and ideally within 2 weeks of completing doxycycline. If this is not possible, the course of doxycycline should be repeated prior to giving azithromycin.

[B] Treatment failure is defined as persistent symptoms following treatment, or a positive test of cure taken five weeks post-treatment.

6.3 Treatment of complicated urogenital infection (PID, epididymo-orchitis)

6.3.1 There are few studies examining the efficacy of extended azithromycin regimens in the treatment of PID and epididymo-orchitis caused by M. genitalium. Data from a recent PID RCT showed high rates of macrolide resistance mutations in specimens positive for M. genitalium. Given the need for prompt and effective treatment in complex STI syndromes, patients with confirmed M. genitalium infection, or who have a partner who has tested positive for M. genitalium should be given moxifloxacin as a 14-day regimen.

  • Moxifloxacin 400mg orally once daily for 14 days

6.4 Partner notification (PN)

Only current partner(s) (including non-regular partners where there is likely to be further sexual contact) should be tested and treated if positive. This is to reduce the risk of re-infection to the index patient. Partners should be given the same antibiotic as the index patient unless there is available resistance information to suggest otherwise.

6.5 Alternative regimens

Very little evidence exists for the effectiveness of the following regimens but they may be considered:

  • Doxycycline 100mg bd for seven days[C] then pristinamycin 1g orally four times daily for 10 days
  • Pristinamycin 1g orally four times daily for 10 days
  • Doxycycline 100mg orally twice daily for 14 days
  • Minocycline 100mg orally twice daily for 14 days

[C] Prior treatment with doxycycline will reduce M. genitalium load and has been demonstrated to be of benefit if administered prior to extended azithromycin and also pristinamycin treatment which is only 75% effective as mono-therapy.

6.6 Rectal infection

This should be managed in the same way as urogenital infection. For severe proctitis, a longer course of moxifloxacin (14 days) may be considered.

6.7 Sourcing of unlicensed products

Pristinamycin is not currently available in the UK and must be imported against a prescription. The cost of importing medicines can be high and availability is inconsistent. An MHRA register of licensed wholesalers who can import medicines without a UK Marketing Authorisation is available at: https://www.gov.uk/government/publications/human-and-vetinary-medicines-register-of-licensed-wholesale-distribution-sites-december-2014. At the time of writing, pristinamycin was available from several wholesalers with a lead time of two to three weeks.

6.8 Pregnancy and breastfeeding

6.8.1 Pregnancy

Data on M. genitalium and its association with adverse pregnancy outcomes are limited, however it has been associated with a small increased risk of preterm delivery and spontaneous abortion. Azithromycin use during pregnancy is unlikely to increase the risk of birth defects or adverse pregnancy outcomes. A three-day course of azithromycin can be used for uncomplicated M. genitalium infection detected in pregnancy. The use of moxifloxacin in pregnancy is contra-indicated. In women with likely macrolide resistance, or with upper genital tract infection in pregnancy, options are limited. Although doxycycline is considered safe for use in the first trimester by the FDA, the BNF advises against its use in all trimesters. There are no data regarding the use of pristinamycin in pregnancy. An informed discussion should be had with the pregnant woman around the risks associated with the use of these medicines in pregnancy and the risks of adverse outcomes associated with M. genitalium infection, and where possible treatment should be delayed until after pregnancy.

6.8.2 Breastfeeding

Very low levels of azithromycin are detected in breast milk, and systemic exposure in infants does not exceed that observed when azithromycin is administered for treatment, therefore risk is considered to be low. Infants should be monitored for possible side effects due to effects on the gastrointestinal flora including diarrhoea and candidiasis.

Doxycycline is excreted into breast milk and is contraindicated in nursing mothers due to the risk of tooth discolouration and effects on bone growth. Use of moxifloxacin is contraindicated during breastfeeding. Pristinamycin is contraindicated during breastfeeding due to its side effect profile.

6.9 Adverse events

Azithromycin, doxycycline, moxifloxacin and pristinamycin can all cause gastro-intestinal problems including nausea but symptoms are most frequently reported with doxycycline and azithromycin doses over 1g. Caution should be taken when prescribing azithromycin or moxifloxacin to patients already on medications which may prolong the QT interval. The European Medicines Agency committee has recommended that the use of fluoroquinolone antibiotics should be restricted following a review of their disabling and potentially long-lasting side effects. Healthcare professionals should advise patients to stop treatment with a fluoroquinolone antibiotic at the first sign of side effects involving muscles, tendons, bones or the nervous system. The only absolute contra-indication to moxifloxacin is known hypersensitivity to this class of drugs. Hepatotoxicity has been reported but is very rare (<1/10 000).

6.10 HIV

Treatment of M. genitalium in HIV-positive individuals is the same as that for HIV-negative individuals.

6.11 Test of Cure and follow up

TOC is vital in ensuring microbiological clearance of infection and is recommended for all patients with confirmed M. genitalium, even if the infection was initially sensitive to macrolides, to detect resistance which may have emerged following treatment. Persistence of M. genitalium has been demonstrated in the absence of symptoms in men treated for NGU. This occurs in about 10-20% of men treated with doxycycline, but is not associated with development of AMR. Persistence of M. genitalium following treatment with azithromycin and moxifloxacin is strongly associated with antimicrobial resistance.

  • BASHH recommend all patients should attend for a TOC five weeks (and no sooner than three weeks in order to avoid false negative results) after the start of treatment to ensure microbiological cure and to help identify emerging resistance 

Treatment failures should be reported to PHE at: https://hivstiwebportal.phe.org.uk

7. Auditable Outcome Measures

New cases of M. genitalium should have SHHAPT (Sexual Health and HIV Activity Property Type) code “C16” submitted to GUMCAD (performance standard 97%)

Individuals treated for M. genitalium should have a TOC at least 5 weeks after the start of treatment (performance standard 97%)

Cases of confirmed treatment failure by positive TOC should be reported to PHE at: https://hivstiwebportal.phe.org.uk

Individuals should be provided with written information about their diagnosis and management (performance standard 97%)

PN should be performed and documented according to the BASHH statement on PN for sexually transmissible infections (performance standard 97%)

full guideline available from…

www.bashh.org/guidelines

British Association for Sexual Health and HIV. British Association for Sexual Health and HIV national guideline for the management of infection with Mycoplasma genitalium (2018). 

First included: September 2019.