We detected M genitalium
at a high prevalence (15%) among an urban US population of women with non-gonococcal, non-chlamydial PID, similar to that found in prior PID studies among Kenyan (16%)16
and UK women (13%).15
In the PEACH study, about 14% of women were infected with C trachomatis
, 15% were infected with N gonorrhoeae
and 5% were co-infected with these two pathogens.7
Thus, M genitalium
was as prevalent as C trachomatis
or N gonorrhoeae
among this population of women with PID.
Women with endometrial M genitalium
were over three times more likely to have histologically confirmed endometritis compared to women without M genitalium
identified at this site. Our study suggests that the relationship between M genitalium
and endometritis is independent and causal, since among women without concurrent N gonorrhoeae
and/or C trachomatis
, endometrial M genitalium
was associated with over a 13-fold risk of incident endometritis at the 30 day follow up visit. Our results are consistent with previous cross-sectional studies associating M genitalium
with PID.14 16
Further, we found that although pelvic pain was similar between women testing positive and negative for M genitalium
, women who tested positive for M genitalium
alone reported significantly less pelvic pain than women who tested positive for N gonorrhoeae
alone. Pelvic pain scores were lower and similar among women who tested positive for M genitalium
alone and C trachomatis
alone, suggesting that, like C trachomatis
, M genitalium
may also play a role in asymptomatic or “silent” PID.
To our knowledge, ours is the first study to investigate treatment failure among PID patients with M genitalium
identified in the endometrium. Persistence of M genitalium
following treatment with a standard Centers for Disease Control and Prevention recommended PID treatment regimen was very high: 44% of women with baseline endometrial positive specimens tested positive again 30 days following treatment. In contrast, only 2–4% of women in the PEACH study had persistent or recurrent gonococcal or chlamydial cervicitis when retested at 30 days.7
Women with M genitalium
identified in the endometrium at baseline were four times as likely to experience persistent endometritis and approximately 4.5 times as likely to experience treatment failure—defined as the presence of both endometritis and pelvic pain 30 days following treatment for PID.
Several attributes of M genitalium
indicate that it is resistant to cefoxitin and doxycycline. First, mycoplasmal bacteria lack a cell wall and are thus resistant to cell wall inhibiting antibiotics. Second, an M genitalium
strain with increased tetracycline resistance has been isolated21
and M genitalium
is associated with persistent non-gonococcal urethritis among men treated with tetracyclines.22
Most women with PID are treated with antibiotics directed toward N gonorrhoeae
and/or C trachomatis
, despite the fact that these pathogens account for only a third to a half of PID cases. Indeed, in the PEACH study approximately 60% of women had non-gonococcal, non-chlamydial PID.7
Over a third of the women had persistent endometritis post treatment,7
identifying a sizeable portion as having ongoing upper genital tract inflammation and demonstrating that antibiotics used to treat this critically important upper tract syndrome are suboptimal. M genitalium
has demonstrated variable resistance to fluoroquinolones23
and susceptibility to macrolides, although azithromycin resistant strains have recently been identified.24
A newer quinolone, moxifloxacin, has recently been shown to exhibit a high degree of activity against M genitalium
Randomised clinical trials assessing these alternative regimens for the treatment of M genitalium
and PID are needed.
It is possible that other organisms resistant to doxycycline or cefoxitin may have confounded the relationship between M genitalium
and persistent endometritis. However, M genitalium
was not associated with endometrial M hominis
or U urealyticum
—organisms that express tetracycline resistance25
and contain tet
M genes that encode tetracycline resistance.26
Further, adjustment for these pathogens only slightly attenuated the relationship between M genitalium
and persistent endometritis. Additionally, we recognise that PID may recur among women who engage in risky sexual behaviour during treatment, and this may also confound treatment failure comparisons. However, in models adjusted for self reported partner treatment and intercourse, M genitalium
was significantly predictive of treatment failure, supporting the idea that M genitalium
antibiotic resistence may lead to persistent PID.
Although a positive M genitalium
test was not significantly predictive of reproductive morbidity in our study, results were in the hypothesised direction. Infertility, chronic pelvic pain and recurrent PID were more common among women testing positive for endometrial M genitalium
, and women who tested positive were less likely to become pregnant or have a live birth. Certainly, these reproductive outcomes are more subject to misclassification and bias than shorter term outcomes due to loss of follow up and reliance on self reported data. Such misclassification may have biased our results towards the null. Additionally, it is possible that women may have had prior M genitalium
infection that resulted in tubal damage preceding the baseline PEACH study PID episode. As such prior infection would not be identified using PCR, which identifies acute infection, this may have biased our results towards the null. Indeed, in a study of 308 women undergoing in vitro fertilisation treatment, women determined to have tubal factor infertility were over three times as likely to be seropositive for M genitalium
Moreover, among a study of 212 couples attending infertility clinics, although M genitalium
was not detected by PCR in any cervical swab specimens, M genitalium
seropositivity was strongly associated with tubal factor infertility.28
This supports the idea that previous M genitalium
infection may result in permanent damage and occlusion of fallopian tubes. Lastly, although we found M genitalium
to be associated with treatment failure, we have previously reported that short-term markers, including pelvic tenderness at 5 and 30 days, are not predictive of reproductive morbidity in the PEACH study population.29
As over two-thirds of women in the PEACH study presented for treatment with 3 or more days of pelvic pain,7
and since delayed care for PID is associated with almost a threefold increased risk for infertility,30
all women in the PEACH study may have been at increased risk for reproductive sequelae regardless of short-term treatment response. Indeed, women in the PEACH study experienced distressingly high rates of morbidity regardless of microbial aetiology of PID (infertility 17%,7
recurrent PID 14%7
and chronic pelvic pain 37%31
). Certainly, women with M genitalium
identified in either the cervix or endometrium had high rates of infertility (18%), recurrent PID (28%) and chronic pelvic pain (44%). These infertility rates are approximately 2.5 times higher than that reported from a study utilising 2002 National Survey of Family Growth data,32
suggesting that preservation of fertility may be suboptimal for many women treated for PID.
Recommended PID treatment regimens are based on clinical trial data demonstrating overall high rates of clinical cure. PID is well recognised though as having a polymicrobial aetiology, and not all microbial infections may respond equally well to the same antimicrobial. In our study of women with clinically suspected PID, we found M genitalium to be associated with endometritis and short-term PID treatment failure, as evidenced by persistent endometritis and continued pelvic pain. We conclude that cefoxitin and doxycycline, a Center for Disease Control recommended PID treatment regimen, is ineffective for the treatment of M genitalium upper genital tract infection.
- Mycoplasma genitalium is frequently detected from the cervix and endometrium of women with clinically suspected pelvic inflammatory disease (PID).
- M genitalium is associated with endometritis and short-term PID treatment failure, as evidenced by persistent endometritis and continued pelvic pain.
- Cefoxitin and doxycycline, a Center for Disease Control recommended PID treatment regimen, is ineffective for the treatment of M genitalium upper genital tract infection.