2016

European guideline on Mycoplasma genitalium infections

Jørgen Skov Jensen*1, Marco Cusini2, Mikhail Gomberg3
1
Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
2
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
3
Chief Researcher, Moscow Scientific and Practical Centre of Dermatovenereology and
Cosmetology.

*Corresponding author:

Jørgen Skov Jensen, Microbiology and Infection Control, Sexually Transmitted

Infections, Research and Development, Statens Serum Institut, Artillerivej 5, DK-2300
Copenhagen S, Denmark. Tel: +45 3268 3636, Fax: +45 3268 8129. E-mail: ([email protected])

Guideline editor:

Prof. Harald Moi, MD PhD, Section of STI, Department of infectious diseases,

dermatology and rheumatology, Oslo University Hospital, and Faculty of Medicine,
University of Oslo, Norway

Running title:

M. genitalium guideline

Abstract
M. genitalium infection contributes to 10-35% of non-chlamydial non-gonococcal
urethritis in men. In women, M. genitalium is associated with cervicitis and pelvic
inflammatory disease (PID). Transmission of M. genitalium occurs through direct
mucosal contact.
Clinical features and diagnostic tests
Asymptomatic infections are frequent. In women, symptoms are vaginal discharge and
dysuria, in men, urethritis, dysuria and discharge. Besides symptoms, indication for
laboratory test is a high-risk sexual behaviour. Diagnosis is achievable only through
nucleic acid amplification testing (NAAT). If available, NAAT diagnosis should be
followed with an assay for macrolide resistance.
Therapy
Therapy for M. genitalium is indicated in case of identification of M. genitalium in
clinical specimens or on an epidemiological basis.
Doxycycline has a poor efficacy (cure rates 30-40%), but does not increase resistance.
Azithromycin has a cure rate of 85-95% in macrolide susceptible infections. An
extended course appears to have a higher cure rate. A rapidly increasing prevalence of
macrolide resistance, most likely due to widespread use of azithromycin as a 1 g single
dose without test of cure, is drastically decreasing the overall cure rate. Moxifloxacin
can be used as second line therapy but resistance is increasing.
Recommended treatment for uncomplicated M. genitalium infection:
Azithromycin 500 mg on day one, then 250 mg on days 2-5 (oral) or
Josamycin 500 mg 3 times daily for 10 days (oral).
Recommended second line treatment and treatment for uncomplicated macrolide
resistant M. genitalium infection:
Moxifloxacin 400 mg od for 7 - 10 days (oral).
Recommended third line treatment for persistent M. genitalium infection after
azithromycin and moxifloxacin
Doxycycline 100 mg two times daily for 14 days can be tried and may cure 30%.
Pristinamycin 1 g four times daily for 10 days (oral).
Recommended treatment for complicated M. genitalium infection (PID, epididymitis)
Moxifloxacin 400 mg od for 14 days.

Introduction
Mycoplasmas are the smallest free-living micro-organisms.1 In the urogenital tract, the
relevant species are M. genitalium, Ureaplasma urealyticum, U. parvum, and M.
hominis. M. hominis and the ureaplasmas will not be dealt with in the present
guideline.
Mycoplasma genitalium was first isolated in 1980.2 M. genitalium infection is
unequivocally associated with male NGU3 and even stronger associated with non-
chlamydial non-gonococcal urethritis (NCNGU). The prevalence of M. genitalium in
men with NCNGU ranges from 10% to 35%3, thus contributing significantly to the
overall burden of disease. In comparison, M. genitalium is detected in only 1% to 3.3%
of men and women in the general population.4-6 In women, several studies have
demonstrated the association between M. genitalium and urethritis, cervicitis,
endometritis, and pelvic inflammatory disease (PID).7-11 In a recent meta-analysis,12
significant associations were found between M. genitalium and cervicitis (pooled odds
ratio (OR) 1.66), and pelvic inflammatory disease (pooled OR 2.14). M. genitalium has
been associated with preterm birth (pooled OR 1.89), and spontaneous abortion
(pooled OR 1.82), but the prevalence of M. genitalium in pregnant women in Europe is
low,13,14 and therefore, the relative importance of M. genitalium is probably small.
Studies have also shown an association with increased risk of tubal factor infertility
(pooled OR 2.43). In sub-analyses that accounted for co-infections, Lis et al found these
associations to be stronger.12
Persistence of M. genitalium after treatment is associated with recurrent or persistent
NGU, and up to 40% with this condition are M. genitalium positive.15 In a recent meta-
analysis, persistent M. genitalium was associated with a pooled odds ratio of 26 for
persistent urethritis.17 Thus, failure to eradicate M. genitalium leads to persistent or
recurrent disease in the vast majority of men with persistent infection and diagnosis
and optimal treatment is extremely important. The role of M. genitalium in facilitating
HIV transmission, in particular in Sub-Saharan Africa18-20 is another reason for concern
when eradication fails due to inappropriate treatment.

Transmission
Transmission is primarily by direct genital-genital mucosal contact. Genital-anorectal
transmission has been shown21 and may play a role as M. genitalium is commonly
found in the anal mucosa22,23 and the organism can be cultured from this site (Jensen,
unpublished). Oral-genital contact is less likely to contribute to any significant extent,
as carriage of M. genitalium in the oro-pharynx is low. Mother-to-child transmission at
birth has not been systematically studied, but M. genitalium has been detected in the
respiratory tract of newborn children.24 The risk of contracting M. genitalium per
sexual encounter has not been determined, but because M. genitalium is present in
lower concentration in genital tract specimens than C. trachomatis,25 it could be
considered slightly less contagious than chlamydia.
There are no estimates of the global burden of disease. In STI patients, the prevalence
is usually from 60 to 85% of that of C. trachomatis, but in the general population, the
ratio is generally significantly lower.4,6
Compared to C. trachomatis, the prevalence of M. genitalium infected patients appear
to peak approximately 5 years later for both men and women and to remain higher in
the older age-groups.26,27

Clinical features
Urogenital infections
Symptoms and signs in women:
• Among STD clinic attendees, 40 – 75% are asymptomatic.10,11
• Symptoms are related to cervical and urethral infection and include increased
or altered vaginal discharge (<50%), dysuria or urgency (30%) and, rarely, inter-
menstrual or post coital bleeding or menorrhagia.10,11,28
• Cervicitis.
• Rectal and pharyngeal infections are usually asymptomatic.
• Lower abdominal pain (<20%) should raise suspicion of pelvic inflammatory
disease (PID).

Complications in women:12
• PID (endometritis, salpingitis)
• Tubal factor infertility (probably)
• Sexually acquired reactive arthritis (SARA).29

Symptoms and signs in men3
 • 70% symptomatic.30
• Urethritis (acute, persistent, and recurrent)
• Dysuria
• Urethral discharge
• Balanoposthitis has been associated with M. genitalium infection in one
study.31


Complications in men:
• SARA.29
• Epididymitis

Ocular infections
Ocular infections can result in conjunctivitis in adults32 but is not systematically
studied. Neonatal conjunctivitis has not been systematically studied

Indications for laboratory testing [IV; C]
Symptoms
• Symptoms or signs of urethritis in men
• Mucopurulent cervicitis
• Cervical or vaginal discharge with risk factor for STI
• Intermenstrual or post-coital bleeding
• Acute pelvic pain and/or PID
• Acute epididymo-orchitis in a male aged <50 years
Risk factors
• Any of the above symptoms in a regular sexual partner
• Persons with high-risk sexual behaviour (age <40 years and >3 new sexual
contacts in the last year, more than 5 life-time partners and never tested)
• Sexual contact of persons with an STI or PID in particular contacts of M.
genitalium infected persons
• Before termination of pregnancy or other procedures, that breaks the cervical
barrier.
 • Regular testing of MSM, including anal sampling could be considered due to the
risk of increased HIV transmission

Laboratory diagnostics [III; B]
Recommended diagnostic assays:
Nucleic acid amplification tests (NAATs) identifying M. genitalium specific nucleic acid
(DNA or RNA) in clinical specimens are the only useful methods for diagnosis [III; B].
However, no commercially available NAAT assays have been evaluated up to the US
FDA approval standard, and the CE marked tests on the market suffer from limited
validation. Consequently, it is extremely important that diagnostic laboratories
carefully validate any commercial or in-house assays and participate in external quality
assurance assessment (EQA) schemes such as the EQUALIS EQA scheme
(http://www.equalis.se/sv/vaar-verksamhet/extern-
kvalitetssaekring/kvalitetssaekringsprogram/m-r/mycoplasma-genitalium-nukleinsyra-
288/). This EQA scheme has demonstrated substantial differences in the sensitivity of
participating laboratories.
With the widespread macrolide resistance in Europe, it is strongly recommended that
all positive tests be followed up with an assay capable of detecting macrolide
resistance mediating mutations. A variety of methods are available for this
purpose,27,33-37 and the main determinant for the selection of an assay is the practical
aspects from a laboratory point of view, and the sensitivity measured as the
proportion of screening positive tests capable of being resistance typed. The latter
aspect varies significantly between assays.
Determination of moxifloxacin resistance can also be carried out using molecular
methods although the correlate between mutations in parC and in vitro moxifloxacin
resistance is less clear. At present, detection of moxifloxacin resistance mediating
mutations is probably not indicated on a routine basis in Europe, as the level of
resistance is low (<5%)38 but it may be considered in the Asia-Pacific region where
moxifloxacin resistance is more common39-41 or in patients having acquired the
infection in this region.

Specimens
Due to the various assay formats, it is difficult to make firm conclusions regarding the
optimal sample type. First void urine (FVU) from men and women provide a good
diagnostic specimen which may be self-obtained.26 No data regarding the importance
of holding urine for a certain time are available, so procedures already in place for C.
trachomatis sampling can be followed. Vaginal swab (physician or self-collected) also
provide an appropriate sensitivity.42-44
No data is available regarding time after exposure to testing, but in analogy to C.
trachomatis, a two-week period is considered the minimal incubation time. Anal
samples are useful in MSM where as many as 70% of the infections will be missed if
this site is not sampled,45 but may also be relevant in women at risk.23 The association
between an anal infection and symptoms is uncertain, but the infection is likely to be
transmitted if not detected and treated.
In most settings it will be appropriate to use the same sampling procedure as for C.
trachomatis testing. However, some transport media such as the Aptima® transport
medium designed for C. trachomatis NAAT will lyse M. genitalium, and may provide a
poor sensitivity in an in-house assay. This should be careful evaluated for all in-house
assays and even for assays where a validated collection and nucleic acid purification kit
is not included [III B].

Management of patients
Information, explanation and advice for the patient
• Patients with M. genitalium infection should be advised to abstain from
unprotected sexual contact until they and their partners have completed
treatment, their symptoms have resolved, and their test of cure negative [IV;
C].
• Patients with M. genitalium infection (and their sexual contacts) should be
given information about the infection, including details about transmission,
prevention and complications. It is recommended that both verbal and written
information be provided. Patient information leaflets are available at the IUSTI
website [IV; C].
• Patients with anal infection including MSM should be informed about the risk
of transmission from this site and that the infection may be more difficult to
eradicate. Consequently, a test of cure is important.
 • Patients with M. genitalium infection should be screened for other STIs,
including C. trachomatis, N. gonorrhoeae, syphilis, HIV, and T. vaginalis where
appropriate [IV; C].

Pregnancy
• M. genitalium infections during pregnancy may be associated with a slight
increase in the risk of spontaneous abortion and preterm birth.12 In macrolide
susceptible infections, a five-day-course of azithromycin is generally
acceptable. The choice of drugs for macrolide resistant infections is difficult,
and risk associated with treatment with the available antibiotics may outweigh
the risk of adverse pregnancy outcome. Thus, treatment, especially in women
with infection with a macrolide resistant M. genitalium strain, may be
considered postponed until after delivery. Although little is known about
transmission during birth, the neonate should be observed for signs of
infection, primarily conjunctivitis and respiratory tract infection [IV; C].

Indications for therapy [IV; C]
• Identification of M. genitalium specific nucleic acid in a clinical specimen.
• On epidemiological grounds if a recent sexual contact has confirmed M.
genitalium infection (ideally specimens for M. genitalium NAAT should be
collected before treatment and treatment should await the result of testing).

Therapy
Treatment of individuals with M. genitalium urogenital infection prevents sexual
transmission and probably complications, including PID5 and tubal-factor infertility.12
Only few antimicrobial classes have activity against mycoplasmas including
tetracyclines, macrolides, and fluoroquinolones.
Doxycycline has a poor efficacy46-49 with microbiological cure rates between 30% and
40%, whereas azithromycin given as a 1 g single dose has a cure rate of approximately
85% in macrolide susceptible infections.46,47 A rapidly increasing prevalence of
macrolide resistance, most likely due to widespread use of azithromycin as a 1 g single
dose without test of cure, however, is drastically decreasing the overall cure rate.
Azithromycin given as an extended regimen with 500 mg day one followed by 250 mg
days 2-5 (1.5g total dose) is recommended as the primary choice for treatment of M.
genitalium infections. Using extended azithromycin or other macrolide antibiotics after
failure with the 1g single dose regimen will not eradicate M. genitalium.
Macrolide resistance rates varies significantly geographically, but where azithromycin
1g single dose is used for treatment of NGU, it is usually found in 30-45% of
samples.27,38,41,50
Josamycin is widely used in Russia with 500 mg three times a day for 10 days, but will
not eradicate macrolide resistant strains.
Moxifloxacin is the most commonly used second line antimicrobial. It is bactericidal
and has a cure rate approaching 100% in infections with susceptible strains.16,51-53
However, resistance has developed with treatment failures in up to 30%, primarily in
patients from the Asia-Pacific region. A significant proportion of the M. genitalium
strains had concurrent macrolide resistance mediating mutations leaving very few
available treatment options.40,54-56
Pristinamycin is the only antimicrobial with documented activity in patients failing both
azithromycin, moxifloxacin, and in many cases also extended dosage doxycycline (100
mg twice daily for 14 days).56 In Europe, it is registered only in France, but can be
acquired after special permit in most European countries. It should only be used in the
maximal recommended dose of 1g four times a day for 10 days (oral) as these patients
are facing their last known active antimicrobial therapy and dose reduction may lead
to failure.

Recommended treatment for uncomplicated M. genitalium infection in the absence
of macrolide resistance mediating mutations [IIb;B]
• Azithromycin 500 mg on day one, then 250 mg od days 2-5 (oral)
• Josamycin 500 mg 3 times daily for 10 days [IV.C]

Recommended treatment for uncomplicated macrolide resistant M. genitalium
infection [IIb;B]
• Moxifloxacin 400 mg od for 7 - 10 days (oral). The optimal duration of
treatment is uncertain and a few observational studies have found higher cure-
rate after longer treatment in cervicitis.54

Recommended second line treatment for uncomplicated persistent M. genitalium
infection [IIb;B]
• Moxifloxacin 400 mg od for 7 - 10 days (oral)

Recommended third line treatment for persistent M. genitalium infection after
azithromycin and moxifloxacin [III;B]
• Doxycycline 100 mg two times daily for 14 days can be tried and will eradicate
M. genitalium from approximately 30% of the patients, but the patient must be
informed about the poor eradication rate and accept to comply with advice
regarding sexual abstinence or condom use.
• Pristinamycin 1g four times daily for 10 days (oral). The patient should be
informed about the need to comply strictly with the dosage scheme.

Recommended treatment for complicated M. genitalium infection (PID, epididymitis)
[IV;C]
• Moxifloxacin 400 mg od for 14 days (oral).57

Partner notification
• Contact notification should be performed and documented by appropriately
trained professionals at the time of diagnosis to improve outcome [IV;C]
• Sexual contacts should be contacted and offered testing together with
counselling and treatment for M. genitalium infection (same antimicrobial as
index patient) and testing for other STIs [IV; C]
• All sexual contacts within the preceding 6 months of onset of symptoms or
diagnosis should ideally be evaluated, tested and treated [IV; C].
• If sexual contacts do not attend for evaluation and testing, epidemiological
treatment should be offered to a current partner with the same regimen as
given to the index patient [IV; C]


Follow-up and test of cure (TOC)
 • A TOC should be routinely performed in all patients due to the high prevalence
of macrolide resistance either present pre-treatment or developing during
treatment with azithromycin and in the absence of routine testing for
fluoroquinolone resistance [III; B]. This recommendation differs from the
BASHH and CDC guidelines58,59 where TOC for asymptomatic cases is not
recommended. However, it is a clinical experience that many patients enter a
stage of few or no symptoms after treatment, but with persistent carriage and
subsequent risk for spread of resistance in the community. Test of cure samples
should be collected no earlier than three weeks after start of treatment [III, B].
In patients responding to treatment, M. genitalium will be undetectable within
one week in most patients, but tests may become temporarily false negative in
patients failing treatment.60

Acknowledgements:

Paddy Horner, Keith Radcliffe, Henry de Vries, Anne Olsen, and Gilbert Donders are
thanked for comments to the guideline.

Proposed guideline review date: 2018

Composition of Editorial Board:

http://www.iusti.org/regions/Europe/pdf/2013/Editorial_Board.pdf

List of contributing organizations:

http://www.iusti.org/regions/Europe/euroguidelines.ht

Qualifying statement:
Decisions to follow these recommendations must be based on professional clinical
judgement, consideration of individual patient circumstances and available resources.
All possible care has been undertaken to ensure publication of the correct dosage of
medication and route of administration. However, it remains the responsibility of the
prescribing clinician to ensure the accuracy and appropriateness of the medication
they prescribe.

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APPENDICES
Search strategy
A Medline search was conducted in May 2015 using PubMed. The search heading was
kept broad (Mycoplasma genitalium) to include epidemiology, diagnosis, antimicrobial
resistance, drug therapy, clinical trials and prevention and control. Only publications
and abstracts in the English language were considered. The Cochrane library was
searched for all entries related to mycoplasma. Sexually transmitted diseases
guidelines produced by the US Centers for Disease Control (www.cdc.gov/std/) and the
British Association for Sexual Health and HIV (www.bashh.org) were also reviewed.

Appendix 1

Levels of evidence and Grading of recommendations

http://iusti.org/regions/Europe/pdf/2013/Levels_of_Evidence.pdf

Appendix 2

Declarations of interest

Jørgen Skov Jensen: None

Marco Cusini: None

Mikhail Gomberg: None

Harald Moi: None