To the best of our knowledge, this study is the most comprehensive survey of M. genitalium and U. urealyticum in Norway. The prevalence of C. trachomatis has been well mapped and provides information on the population being tested. This forms a basis for evaluating and discussing the prevalence of the other sexually transmitted microbes.
M. genitalium was relatively common in this study population, with a prevalence of 3.6 % compared to 11.9 % for C. trachomatis. A study from Molde in 2010 showed a significantly lower prevalence of M. genitalium (2 %, n = 950, p = 0.01) (20). This may be due to methodological differences or to differences in the two populations studied.
Our observations are consistent with figures published from Central Norway from 2012, where M. genitalium was detected in 3.9 % of women and 3.2 % of men in a sample of 1 114 persons (21). In both studies the prevalence was highest in women aged 20 – 24 years: 5.1 % in Vestfold/Telemark and 6.5 % in Central Norway. However, prevalence may be affected by testing patterns for C. trachomatis. For example, figures from the Norwegian Institute of Public Health indicate that women are more likely to undergo routine testing for C. trachomatis, whereas men are more often tested as part of contact tracing or on the basis of symptoms (22).
Several factors suggest that this study has probably underestimated the prevalence of M. genitalium. There is debate regarding the type of sample most suitable for detecting M. genitalium in women. In a few studies where both urine samples and swabs from the vagina/cervix were tested from the same patients, the positivity rate was higher for the swabs (12, 23). Prevalence may thus have been underestimated in our population, in which only urine samples were examined
M. genitalium is more difficult to detect than C. trachomatis as the bacterial load of the former is often low. The method used to extract bacterial DNA is therefore critical (24, 25). The importance of choosing an appropriate method is illustrated by a study that compared three different methods for extraction of C. trachomatis DNA and found that the proportion of positive findings ranged from 4.3 % to 7.7 % (26). No association has been observed between bacterial load and disease. Indeed, a small number of bacteria can also cause disease, and detection of weak positive samples is therefore important (24). Emphasising this issue has resulted in methodological improvements in our laboratory.
The fact that only 10 % of tests in this study were ordered primarily for M. genitalium and U. urealyticum may indicate that there is little emphasis on this issue by those ordering the tests. This is underlined by the fact that in 89 % of the samples positive for M. genitalium, analysis of this microbe had not been requested; the results were therefore not reported back to those who ordered the tests.
Undiscovered infections lead to increased risk of transmission of infections within the population. As with C. trachomatis, studies have shown that M. genitalium can lead to significant sequelae for some patients. In a large study from the USA, Haggerty and colleagues showed that 15 % of women with clinically suspected pelvic inflammatory disease were infected with M. genitalium, and a causal link was established between the microbe and endometritis (27). A Swedish study from 2012 showed a strong association between M. genitalium infection and pelvic inflammatory disease, as did a recent meta-analysis of mycoplasma infection and female reproductive system diseases (28, 29).
Untreated pelvic inflammatory disease can have consequences such as ectopic pregnancy, chronic pelvic pain, recurrent pelvic inflammatory disease and infertility (14). M. genitalium has also been observed attaching to sperm in vitro; if large numbers of microbes act in this way, sperm motility may be reduced. Whether this affects male fertility is uncertain (1).
The course of untreated M. genitalium infection is little documented, and is difficult to study for ethical reasons as the microbe is regarded as pathogenic. Studies of patients with urethritis who were treated empirically with doxycycline show that persistent mycoplasma infections do occur (30). Some of the mechanisms behind the bacterium’s ability to cause persistent infection were revealed in an in vitro study of endocervical cells (31).
Since the treatment of chlamydia infection is different from that of mycoplasma, diagnostics for M. genitalium will be essential (4, 6). The current study shows that co-infections do occur (Fig. 1) and that proven chlamydia infection does not rule out infection with M. genitalium. Treatment of mycoplasma infection is more complex than that of chlamydia as the former microbe has a high mutation rate and rapidly adapts to its surroundings (1). It thus has an extensive ability to develop antibiotic resistance, and the number of treatment options is decreasing. Today a 5-day course of azithromycin is recommended for treatment of M. genitalium infection (4).
Genital infections such as urethritis and pelvic inflammatory disease are treated empirically with doxycycline, but this cures only 22 – 45 % of mycoplasma infections (6). M. genitalium was detected in 41 % of men with urethritis who returned after experiencing therapeutic failure with doxycycline (30). Check-ups revealed that these patients subsequently tested negative for M. genitalium after treatment with azithromycin and 90 % were by then symptom free. There were similar findings of M. genitalium infection (44 %) in women with pelvic inflammatory disease who returned after therapeutic failure (27).
In a recent Norwegian study, macrolide resistance was demonstrated in 48 % of M. genitalium infections (32). This means that azithromycin does not cure all cases of mycoplasma infection either. Moxifloxacin is at present the only treatment option in cases of macrolide resistance. This antibiotic may have unpleasant side effects and is unlicensed in Norway (33). The rapid development of antimicrobial resistance could lead to a situation where it is difficult to provide adequate treatment. However, we can prevent the development and spread of resistant strains by checking therapeutic efficacy after 3 – 4 weeks and by including resistance testing as part of the diagnostic process (6, 34).
Of the microbes examined in this study, U. urealyticum was the most prevalent (17.6 %) and was most common in those aged 15 – 24 years. A study of students in Northern Norway yielded results similar to ours, although prevalence there was generally lower. C. trachomatis was found in 3.5 % of those tested, M. genitalium in 0.9 % and U. urealyticum in 8.7 % (15).
In clinical trials, the high prevalence of U. urealyticum in control groups can make results difficult to interpret (16). Nevertheless, a causal link between U. urealyticum and urethritis has been shown in young patients and those with few lifetime sexual partners. This may suggest that repeated exposure to the bacterium can lead to tolerance and asymptomatic infection without inflammation (2, 3). Conditions in the host and variable virulence thus appear to play a part in the microbe’s pathogenicity. This forms a basis for testing patients with symptomatic urethritis for U. urealyticum if no other agents are detected.
In contrast to chlamydia, genital mycoplasma infections are not defined as infectious diseases of danger to public health in the Infectious Disease Control Act. M. genitalium does not cause merely a harmless «itch»; it can give rise to infections with serious consequences (1, 13, 29). Nevertheless, it is difficult to estimate how often the microbe migrates to the upper genital tract. The majority of cases of pelvic inflammatory disease appear to be asymptomatic and few patients seek treatment (13, 14, 35). In addition, samples are rarely taken from the upper genital tract due to its limited accessibility (12, 13), and study populations are therefore often small. Studies of pelvic inflammatory disease often rely on detection of pathogens in the cervix. Although detected indirectly, it is likely that these microbes can also cause pelvic inflammatory disease, in common with C. trachomatis (14, 29). From prospective studies, it is estimated that approximately 15 % of cases of untreated chlamydia develop into pelvic inflammatory disease, whereas the risk seems to be somewhat lower with mycoplasma infection (35).
The symptoms of mycoplasma and chlamydia infection cannot be distinguished, but M. genitalium seems to produce symptoms more often (7). We believe that M. genitalium should be included as a standard test when there are symptoms of urethritis and cervicitis, and in pelvic inflammatory disease in women (10, 13, 36). There may also be an indication for testing women prior to surgical abortion (35). Several studies show that M. genitalium is transferred to the partner in 55 – 70 % of cases (7, 9, 30), and partner therapy and possibly contact tracing should be considered.
Guidelines on antibiotic use in the primary healthcare service recommend the testing of patients with symptoms (4). Testing of asymptomatic individuals is, however, more difficult. In 40 – 60 % of cases, patients with M. genitalium do not have symptoms (10, 11, 25). Asymptomatic carriage is an epidemiological problem and without opportunistic screening, prevalence will increase. Laboratories in Norway unofficially report increasing numbers of positive samples. In a national retrospective study from Denmark (n = 31 600), a significant increase in M. genitalium was seen from 2006 (2.4 %) to 2010 (3.8 %). The increase is considered real, although part of it may be due to methodological improvements (37).
The spread of infection can be reduced by testing individuals upon change of sexual partner, where the individual in question has multiple sexual partners or a partner with a proven infection. Testing for M. genitalium in common with C. trachomatis may be a natural approach to this preventative work. Before initiating comprehensive screening, the potential consequences – both for society and for the individual – should be examined more closely. Any changes in testing strategy must take into account the increasing antimicrobial resistance and declining therapeutic options.
In Sweden, where doxycycline is conventionally used to treat chlamydia, studies show similar prevalence of M. genitalium and C. trachomatis (5, 28). When we see an increase both in Sweden and in Denmark, we can expect similar developments in Norway. Surveillance should therefore be established, and clearer guidelines for the testing and treatment of M. genitalium are required. Greater knowledge of the prevalence, pathogenesis and treatment of M. genitalium and U. urealyticum will be important going forward, and more studies should be initiated (38).