Mycoplasma genitalium - Occurrence and antimicrobial resistance, 2003-2022
Mycoplasma genitalium
The Mycoplasma genitalium (MG) bacterium, which was only discovered in 1980, causes a sexually transmittable infection (STI) in men and women that may manifest as urethritis, cervicitis and pelvic infection. MG is also associated with infertility, particularly among women, but the causality remains undocumented. The symptoms cannot be distinguished from those of chlamydia and comprise vaginal discharge, pain on urination, contact bleeding and low-set abdominal pain, but a considerable share of the cases are symptom-free. Following chlamydia, MG is the most frequent STI with a 1-4% prevalence in the general population. However, the number is far higher (10-35%) among people with symptoms. The infection is detected by molecular methods (nucleic acid amplification tests, NAT) as culture takes months to complete and is very laborious.
In Denmark, more than 50% of MG infections are now caused by bacterial strains that have developed resistance to azithromycin (and other macrolides), which is the first-choice treatment, and an increasing share is also resistant to moxifloxacin (fluoroquinolone). ”European Guideline on the Management of Mycoplasma Genitalium Infections” clearly recommends obtaining macrolide resistance results before initiating treatment. A Danish report from 2018 by the Clinic for Sexually Transmitted Diseases, Bispebjerg Hospital, found a MG positive rate of 9%, and 57% of the infections contained bacteria with macrolide resistance-associated mutations (MRM). Overall, 3.8% had quinolone resistance-associated mutations (QRAM) and 2.6% were resistant to both classes of antimicrobials.
Data
The data used to prepare this report include all samples submitted to Statens Serum Institut (SSI) from Danish healthcare in the period from 1 January 2003 through 31 December 2022. Samples that were only submitted for macrolide and/or quinolone resistance determination from a microbiology department are not included in this report.
The report does not cover all of Denmark as MG diagnostics was implemented locally in some regions during the study period. It does, however, provide an overall estimation of the development in and the prevalence of MG in Denmark. The report therefore does not provide incidence estimates, but only number of cases and positive rates based on diagnostics performed at the SSI. In contrast to chlamydia, MG was not previously comprised by the laboratory notification system, but with the new executive order on notification of infectious diseases, MG achieves the same status as chlamydia.
A disease episode is defined by an interval exceeding 42 days between two positive test results, and all positive test results being confirmed by NAT. Negative episodes are defined using the same time interval. The data analysis is based on disease episodes and therefore does not depend on number of samples and test episodes per patient in the disease episode.
Data include demographic information such as age and sex, region of the submitting physician, positive and negative test results and detection of genetic markers of macrolide resistance.
Developments in MG occurrence and macrolide resistance are stated at four-year intervals, but annually for the COVID-19 period (2003, 2007, 2011, 2015, 2019-2021 and 2022). The report on quinolone resistance is based on episodes sampled from January 2018 to June 2022. A maximum of 200 annual samples were selected.
MG occurrence
In the period from 2003 to 2022, the SSI studied 77,785 episodes for MG. In 2022, 4,681 episodes were studied, compared with 1,356 in 2003, Table 1. In 2022, the number of studied episodes exceeded those of the preceding years, but the positive rate was lower (p < 0.001). In 2022, a total of 437 MG episodes were detected among 4,681 studied episodes (9.3%), distributed on 209 men (positive rate 13.7%) and 228 women (positive rate 7.2%).
Overall, the period from 2003 onwards has witnessed an increase in the MG positive rate from 4.1% to 9.3% with an average MG-positive rate of 8.5%.
MG cases, distribution by age and sex
Tables 2a and 2b present the age group distribution of MG cases by sex and number of persons tested. Most studies were received from the 20-24-year age group for both sexes. More women than men were tested in all age groups below 50 years of age.
Overall, an increase is seen in the positive rate for men and women alike in the period from 2003 to 2022, Table 2a and 2b. The period recorded a considerable increase in the share of positives, particularly among 15-24-year-olds, Figures 1a and 1b. For men and women alike, the highest share of positives was recorded in the 20-24-year age group. In 2022, the male positive rate was 19% and the female positive rate was 12.2%. In contrast, the highest positive rate for chlamydia was recorded in the 15-19-year age group.
Geographic distribution of MG-tested persons
As shown in Figure 2, the Capital of Region of Denmark contributed the greatest number of tested persons until 2011, after which the Capital Region of Denmark and the Central Denmark Region established diagnostic capacities locally. Data on the development of the positive rate are included only for the years and regions that have not started performing the analyses themselves. A low number of analyses was recorded for the two regions even after they started performing the analyses themselves, which is mainly due to analysis orders being placed by mistake. For the remaining regions, the number of persons tested followed a slightly increasing trend until 2022 when a considerable increase was observed in the number of persons tested from Region Zealand and the Region of Southern Denmark, Figure 2.
In 2022, the SSI tested 1,772 patients from Region Zealand and 1,539 patients from the Region of Southern Denmark, compared with 898 and 940, respectively, in 2021. No obvious explanation exists for the increase in the number of studies submitted from Region Zealand and the Region of Southern Denmark in 2022, but the increase is more pronounced for women tested with specialists in gynaecology, particularly tests from the municipalities of Roskilde, Næstved, Holbæk, Billund and Odense Some possible explanations are provided in EPI-NEWS 5/2024 . Additionally, the attention devoted to MG infection in the population is increasing why more people request being tested. However, as described in EPI-NEWS 5/2024, it is essential to limit MG testing to individuals with symptoms due to the high resistance level.
Among the regions that have not implemented testing locally, the highest positive rate in recent years was recorded in the North Denmark Region. The increased number of persons tested in Region Zealand and the Region of Southern Denmark did not produce a corresponding increase in the number of cases detected, which is reflected in the declining positive rate.
Treatment and development of antimicrobial resistance
The Danish treatment recommendations are based on the European guidelines by the International Union against Sexually Transmitted Infections (IUSTI) and supported by the WHO and the ECDC as shown in Table 3. The treatment may be complicated by the occurrence of antimicrobial resistance to macrolides and quinolones. The guidelines recommend that treatment of MG infections should always be preceded by determination of macrolide resistance. Quinolone resistance is not determined unless treatment with moxifloxacin has failed, and determination of quinolone resistance is currently only performed at the SSI.
Internationally, macrolide and quinolone resistance generally follow increasing trends, and reports from China have found up to 88% double resistance. Sweden had a lower percentage prevalence (13.9%) than Denmark, Norway, Great Britain, the US and Australia, Figure 3. The difference recorded is closely linked to the treatment strategies adopted by the countries; In Sweden, macrolide consumption has remained low as doxycycline has been used as first-choice treatment for chlamydia. In Denmark, azithromycin 1g administered as a single dose was previously the first-choice treatment for chlamydia treatment, but this was changed to doxycycline in 2018. The change was based on the increased macrolide resistance in MG and recent studies showing that doxycycline is significantly superior to azithromycin for treatment of rectal chlamydia. Furthermore, it was shown that rectal chlamydia is frequent in women even when anal sex is not reported, and untreated rectal chlamydia has been a suspected cause of frequent genital chlamydia relapses.
Since 2007, the SSI has used sequencing methods to further explore all positive tests. The methods used detect mutations in the 23S rRNA gene, which lead to azithromycin (macrolide) resistance.
Subsequently, methods have been established for detection of quinolone resistance-associated mutations (QRAM) in the parC gene, which, to a varying degree, give rise to moxifloxacin resistance.
Table 4 presents the development in macrolide resistance by sex. In 2022, a 71.3% resistance rate was observed, based on 311 of 436 tests. The resistance rate was 72.7% for women and 69.9% for men. Overall, a considerable percentage increase was observed for macrolide resistant episodes from 21.4% in 2007 to 71.3% in 2022. Throughout the period, the resistance rate has been largely comparable between the sexes.
From 2018 to 2022, QRAM was detected via random sampling of 514 MG-positive patients. Table 5 presents the development in quinolone and quinolone/macrolide resistance. Overall, the quinolone resistance rate remained largely constant in the period, whereas 2021 witnessed a high quinolone resistance rate of 9.8% (and a 7.3% double resistance rate), compared with the other years.
However, the difference from preceding and subsequent years is not statistically significant.
Conclusion
MG testing activity has followed an increasing trend over the years, but aggregate national figures are not available as part of the tests are made locally in some regions. In the same period, the positive rate has increased and is now nearly as high as that of chlamydia. Part of the positive rate increase may be explained by considerable tightening of the sampling indications why only symptomatic patients should undergo MG testing. The indications were tightened because well over half of the diagnosed patients will need moxifloxacin; an antibiotic that should only be used for serious infections and in cases when other antibiotics cannot be used. Thus, moxifloxacin and other fluoroquinolones should only be used to treat severe infections and infections that are not self-limiting. It is therefore very important that MG testing is not performed as part of screening for sexually transmittable infections in asymptomatic people. It cannot be excluded that the rising positive rate is real and reflects increased macrolide resistance. If a considerable share of MG infections were previously being treated with azithromycin given to persons with chlamydia and concurrent MG infection, the increasing share of macrolide resistant infections may keep driving transmission despite azithromycin treatment.
Thus, the occurrence of quinolone resistance currently remains low in Denmark, but as well over half of the diagnosed patients are already macrolide resistant, a large number of patients will receive treatment with moxifloxacin and treatment failure will occur. These patients cannot be treated with drugs authorised for treatment in Denmark and should therefore be referred to STI clinics that hold a single-issue permit for pristinamycine or another third-choice treatment.
Monitoring of MG infections is a relatively new area. We hope that the recent update to the Executive Order on Notification of Infectious Diseases will allow us to increase the degree of detail achieved by including data from all of Denmark.
This report is also described in EPI-NEWS 5/2024.