Current Opinion in Infectious Diseases:
SEXUALLY TRANSMITTED DISEASES: Edited by Karen Rogstad
Time to manage Mycoplasma genitalium as an STI: but not with azithromycin 1 g!
Horner, Patricka,b; Blee, Karlab; Adams, Elisabetha,c
aSchool of Social and Community Medicine, University of Bristol, UK
bBristol Sexual Health Centre, University Hospitals Bristol NHS Foundation Trust, Tower Hill, Bristol
cAquarius Population Health, London, UK
Correspondence to Dr Patrick Horner, School of Social and Community Medicine, University of Bristol, 39 Whatley Rd, Bristol BS8 2PS, UK. Tel: +44 117 928 7387; e-mail: Paddy.Horner@bristol.ac.uk
Purpose of review: Mycoplasma genitalium is a sexually transmitted infection that causes significant morbidity in men and women and is a co-factor in HIV transmission. However, commercial diagnostic tests are not generally available for M. genitalium and sub-optimal treatment is often given. We review the literature on the burden of infection, how it may present in clinical practice and the effectiveness of current treatment regimens.
Recent findings: In-vivo and in-vitro data strongly suggest that M. genitalium is an important cause of urethritis, cervicitis, pelvic inflammatory disease and potentially asymptomatic proctitis. Studies now consistently demonstrate suboptimal eradication rates with the current treatment regimens recommended first line for the treatment of nongonococcal urethritis. Concurrently, there has been a rapid emergence of antibiotic resistance in M. genitalium, with macrolide resistance now appearing to be endemic in some centres, and quinolone resistance is beginning to emerge.
Summary: In the absence of specific M. genitalium diagnostic and antimicrobial resistance testing, azithromycin 1 g should not be used for the management of patients with symptomatic disease potentially caused by M. genitalium. This review offers an alternative evidence-based approach to managing such patients that should, theoretically, reduce the risk of the development of antimicrobial resistance.
Mycoplasma genitalium is an important sexually transmitted pathogen [1–3]. It is a common cause of nongonococcal urethritis (NGU) in men and cervicitis in women. It is associated with pelvic inflammatory disease (PID) and is probably causal, and potentially causes asymptomatic proctitis, although the latter is currently based only on biological plausibility (see below) [1–3,4▪▪,5▪▪]. Studies now consistently demonstrate suboptimal eradication rates with current treatment regimens of either azithromycin 1 g or doxycycline 100 mg twice daily for 7 days, with the concurrent apparently rapid emergence of antibiotic resistance in some centres (see below) [1–3,6▪▪–8▪▪,9,10,11▪▪,12,13▪▪,14,15▪]. As clinicians we remain blind to the problem, as the majority of the major commercial companies producing diagnostic bacterial sexually transmitted infection (STI) nucleic acid amplification tests (NAATs) do not currently have commercially available NAATs for M. genitalium. Two recently reported randomized controlled trials (RCTs), which began enrolling in 2006 and 2007, have demonstrated the inadequacy of current treatment regimens for M. genitalium. However, there are currently no registered RCTs to investigate the effectiveness of regimens that may be more effective (www.controlled-rials.com) [14,15▪]. Designing such trials to inform clinical practice will be complex as macrolide resistance appears to be increasing globally, with some centres having 20% or more prevalence, and quinolone resistance is beginning to emerge [1,8▪▪,9,10,11▪▪,12,13▪▪]. In addition, we have limited capability for routine diagnostic testing let alone routine antimicrobial resistance testing, which a number of experts now consider essential in order to inform local antimicrobial decision making [6▪▪,9,10,11▪▪,12,13▪▪,16]. By the time a new trial is conducted and reported, it may then be too late to implement the findings internationally given the apparent ability of M. genitalium to rapidly develop antimicrobial resistance. This happens probably as a result of the continued use of suboptimal regimens, which provide selective pressure for the emergence of resistant mutants [6▪▪,8▪▪,11▪▪,13▪▪,17,18]. In the last 2 years, various experts have called for commercially available M. genitalium NAATs, monitoring of M. genitalium antimicrobial resistance and for new antibiotic regimens, including RCTs, as they recognize the importance of antibiotic stewardship to monitor and limit the spread of infection [1–3,6▪▪,7▪▪,11▪▪,13▪▪]. In the absence of evidence from effective RCTs, we set out an alternative evidence-based approach to managing patients at increased risk for M. genitalium infection.
The epidemiology of M. genitalium has many of the features of a bacterial STI. It is more commonly detected in sexual partners of people with M. genitalium and tends to be associated with younger age groups [1,5▪▪,19–22]. People with multiple partners are at increased risk for testing M. genitalium-positive, and black ethnicity has also been associated with an increased risk, although in Europe this association is not as strong [19–24]. Community-based studies indicate that M. genitalium is present in about 2% (range 0.7–3.3%) of women in the general population under 30 years in developed nations and may be less common in men [5▪▪,19–22]. In men and women attending sexual health departments, the prevalence is between 3 and 13% [2,3,6▪▪,9,14,23,24]. Recent evidence suggests it may be more common in men who have sex with men (MSM), particularly if they are HIV-positive, than in heterosexual men with an overall prevalence rate of 2–11% [25,26,27▪,28,29▪▪]. This is probably because rectal infection with M. genitalium, which is probably sexually acquired, is detected more frequently than urethral infection in this group [25,26,27▪,28,30▪].
In asymptomatic individuals in the general population, about 2–5% of Chlamydia trachomatis-positive people are infected with M. genitalium[19–22]. Co-infection is more common in symptomatic disease [14,15▪,23,24].
PATHOGENESIS, REPLICATION AND DEVELOPMENT OF ANTIMICROBIAL RESISTANCE
A recent in-vitro study, using endocervical cell lines, demonstrated that M. gentialium can establish chronic infection [4▪▪]. At low loads, a cytopathic effect was not observed in the chronically infected cell lines but did result in the production of pro-inflammatory cytokines, which predominantly consisted of potent chemotactic and/or activating factors for phagocytes, including interleukin-8, monocyte chemotactic protein 1 and macrophage inflammatory protein 1. There was also evidence that these chronically infected cells may be more hyperresponsive to exogenous innate immune stimulation by other STIs and bacterial vaginosis. Infection is probably both intracellular and extracellular, and replication, although slow, eventually results after a number of weeks in a sufficient organism load to exert a cytopathic effect. This is consistent with clinical observations that higher loads are observed in men with symptomatic urethritis and that the incubation period before the development of disease may be longer than for C. trachomatis, which has a much shorter replication cycle of 48 h [1,24,31].
The M. genitalium adhesion genes have the ability to undergo reciprocal recombination with a family of repetitive DNA elements within the genome, which contributes to the heterogeneity of these proteins. The resulting antigenic variation probably contributes to immune evasion and the ability of M. genitalium to establish chronic infection in vivo. Mycoplasmas also have a high mutation rate that is likely to rapidly generate mutants [11▪▪,18]. High-level macrolide (azithromycin) resistance is mediated by an A-to-G substitution in A2059 and A2058 residues in region V 23S of the rRNA gene [1,6▪▪,11▪▪,13▪▪]. Single mutations in the GyrA and ParC of the DNA gyrase, which are critical target sites for the fluoroquinolones, confer antimicrobial resistance to fluoroquinolones [11▪▪].
Ison  expressed concern about the continual use of a single agent as a first-line therapy for an infection, as it provides selective pressure for the emergence of resistant mutants. M. genitalium, a slow replicating infection both intracellularly and extracellularly, with a high mutation rate, is likely to be at increased risk of this occurring when azithromycin is administered as a single dose, which has a much longer intracellular half-life than extracellular half-life [1,4▪▪,17,18,32]. There is emerging evidence, which needs to be confirmed, that development of resistance following use of azithromycin 1 g may be more likely in individuals with higher loads who are also more likely to be symptomatic [1,4▪▪,33].
M. GENITALIUM INFECTION IN FEMALES
The majority of women infected with M. genitalium are probably asymptomatic. Taylor-Robinson and Jensen , Manhart et al. and McGowin and Anderson-Smits  recently reviewed the association of M. genitalium with disease, concluding that it is associated with cervicitis particularly if diagnosed using a Gram-stained cervical smear, PID and probably urethritis and infertility. However, they were not unanimous in concluding that the association was causal and generally felt additional evidence was needed both in vivo and in vitro before one could conclude this [1–3]. Since then, further evidence has emerged both in vivo and in vitro[4▪▪,5▪▪,34]. A significant association with PID was observed by Bjartling et al. [5▪▪] in a case–control study, although only 4.9% of cases were infected. More recently Weisenfield et al. observed prevalence of 22% in women with acute PID. A possible explanation is that M. genitalium may cause PID with milder symptoms than C. trachomatis and is underrepresented in women with severe symptoms requiring laparoscopy [5▪▪,35]. This would be consistent with the recent in-vitro data as reviewed previously [4▪▪].
Thus, young women, at risk for an STI, with a vaginal discharge, post-coital bleeding and/or abdominal pain are potentially at increased risk for M. genitalium infection. Those with cervicitis and/or PID detected on examination have about a 4–25% chance of being infected [3,5▪▪,34].
M. GENITALIUM INFECTION IN MALES
The majority of men infected with M. genitalium are probably asymptomatic. Taylor-Robinson and Jensen  and Manhart et al.  recently reviewed the association of M. genitalium with disease, concluding that it causes acute and chronic NGU and that it is associated with balanoposthitis and possibly chronic prostatitis and epididymitis. There is no association between rectal symptoms and the presence or absence of M. genitalium and we are not aware of any studies investigating whether it can cause proctitis [1,25,26], although this would seem biologically highly likely given the recent observations of McGowin et al. [4▪▪].
Thus, male patients with symptoms of a urethral discharge and/or dysuria are at increased risk for having M. genitalium infection. This risk increases further (9–31%) if urethritis is detected on a Gram-stained urethral smear [1,2,36]. Although men with symptoms of balanoposthitis and epididymoorchitis are also probably at increased risk, this probably is dependent on the presence of urethritis [1,37].
There is good biological plausibility that M. genitalium can promote the acquisition and transmission of HIV [1,38,39▪▪]. The production of pro-inflammatory cytokines by infected cells will increase the presence and activation of HIV-susceptible cells, and HIV-infected women with high burden of M. genitalium infection are more likely to shed HIV DNA that those who are M. genitalium-negative [1,39▪▪]. Mavedzenge et al. [39▪▪] in a longitudinal study recently reported a two-fold increased risk of HIV-1 acquisition among Zimbabwean and Ugandan women who were infected with M. genitalium, and attributes approximately 9% of HIV-1 acquisitions to infection with this micro-organism. This is supported by previous studies demonstrating an association of M. genitalium with HIV infection [38,40]. Before a screening and treatment programme can be introduced as part of an HIV prevention strategy in sub-Saharan Africa, Manhart  suggested that there needs to be an accessible and accurate diagnostic test and an accessible and effective treatment regimen. Given the association of M. genitalium with rectal infection in MSM and the biological plausibility that this will cause proctitis (see above), it would seem highly likely that M. genitalium will be a co-factor for HIV transmission in MSM, although this has not been established using a longitudinal prospective cohort study [39▪▪].
Molecular diagnostic testing for M. genitalium using a NAAT that is approved for commercial use is not currently available from most of the major diagnostic companies. As a result, M. genitalium is not tested routinely in clinical practice. However, commercial tests with good performance are beginning to become available [41,42].
Asymptomatic infection is not diagnosed in the majority of cases, as it is not tested for and symptomatic infection can be caused by several different infections, one of which is M. genitalium. Patients with symptoms and signs of NGU and PID are managed syndromically, without waiting for the results of microbiological diagnostic test results for C. trachomatis and Neisseria gonorrhoeae. The current treatment regimens for these conditions continue to focus on effective treatment for C. trachomatis, and when clinically indicated N. gonorrhoeae; however, such regimens often have poor efficacy against M. genitalium[2,43,44]. The diagnosis of cervicitis is problematic, as there are a number of essentially subjective criteria including the presence of a mucopurulent discharge and/or contact bleeding on examination and ≥30 polymorphonuclear leucocytes per high-power field on Gram stain [1,2]. Consequently, although some clinicians will treat cervicitis without waiting for results of C. trachomatis and N. gonorrhoeae, most do not, and therefore without a readily available diagnostic test women will remain untreated for M. genitalium[43,45].
TREATMENT OF UNCOMPLICATED INFECTIONS
The commonly used treatment regimens are given in Table 1. Studies indicate that doxycycline 100 mg twice daily for 7 days is inferior to azithromycin 1 g as a single dose with microbiological failure rates of 55–83% compared with 12–33%, although more recently microbiological failure rates of single-dose azithromycin have been reported as high as 60% [1,2,6▪▪,9,15▪,46▪]. The increasing failure rate of azithromycin is the result of preexisting, probably endemic (13–100%), macrolide resistance in the population being treated [6▪▪–8▪▪,10,11▪▪,12,13▪▪]. A recent study by Twin et al.[13▪▪] suggests that ∼50% of those who fail treatment with azithromycin 1 g may develop macrolide resistance, which is sexually transmissible [1,13▪▪,30▪]. Although it remains unproven, there is concern that the frequent use of azithromycin 1 g is the cause of the rapid emergence of macrolide resistance over the past 10 years [6▪▪–8▪▪,11▪▪,13▪▪]. An extended regimen of azithromycin 500 mg then 250 mg on 4 days is more than 95% effective, unless macrolide resistance is present, which is believed to be the reason for the reduced treatment efficacy in the study by Jernberg et al.[6▪▪,47]. A 5-day regimen is biologically more sensible than a single dose, as M. genitalium is a slow growing intracellular and extracellular micro-organism. An added advantage of this regimen is that it does not appear to induce macrolide resistance [6▪▪]. There is currently no evidence that doxycycline treatment failure is associated with the development of tetracycline resistance .
Ofloxacin 200 mg twice daily for 10 days is suboptimal for treatment, with it being associated with more than 50% failure rate in one study, which is consistent with data from in-vitro antimicrobial susceptibility testing [1,47]. It is possible that some of those who fail develop quinolone resistance, as this is an emerging problem [9,10,11▪▪,16]. Moxifloxacin has high in-vitro activity against M. genitalium and has more than 95% effectiveness in treatment studies [1,2]. One recent study suggests that 400 mg for 14 days may be more effective than a 7-day course [48▪]. However, oral moxifloxacin should be used with caution and reserved for treatment failures because of rare but very serious adverse hepatic reactions [6▪▪].
TREATMENT OF COMPLICATED INFECTIONS
The recommended regimen for PID in the UK is doxycycline 100 mg twice daily for 14 days with a third-generation cephalosporin plus metronidazole to cover N. gonorrhoeae and anaerobes, respectively, or ofloxacin 400 mg twice daily for 14 days plus metronidazole if at low risk of N. gonorrhoeae. The doxycycline regimen is probably associated with more than 40% failure rate for M. genitalium-positive women, but no data are available for failure rate with ofloxacin . An alternative treatment regimen for PID is a third-generation cephalosporin followed by azithromycin 1 g/week for 2 weeks [43,44]. Given the pharmacokinetic and pharmacodynamic properties of azithromycin and the ability of M. genitalium to replicate extracellularly (see above), the possibility of treatment failure with the development of antimicrobial resistance is, in our opinion, a reasonable concern . Indeed in the original trial, of seven M. genitalium-positive patients, one failed therapy and she was in the azithromycin treatment arm . In the southwest of England, azithromycin 1 g then 500 mg once daily for 4 days can be substituted for doxycycline in women at risk for pregnancy (http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1194947353557). Although this regimen has not been formally evaluated in a clinical trial, experience in clinical practice has been positive and it should be effective against both Chlamydia and M. genitalium[6▪▪,31,50].
TREATMENT OF PARTNER(S)
There is a high concordance of M. genitalium infection between sexual partners indicating that partner notification and treatment are required to prevent reinfection and onward transmission [1,3]. Angarius et al.[6▪▪] observed that female M. genitalium-positive patients, often identified through partner notification, had more than 90% response to azithromycin 1 g, with a prolonged course of azithromycin eradicating M. genitalium in 100%. However, Twin et al.[13▪▪] observed that azithromycin 1 g in women was also associated with treatment failure and the development of macrolide resistance.
FUTURE TREATMENT AND MANAGEMENT STRATEGIES IN THE ABSENCE OF M. GENITALIUM NUCLEIC ACID AMPLIFICATION TESTS AND ANTIMICROBIAL RESISTANCE TESTS
Treatment of symptomatic, uncomplicated disease and epidemiological treatment of their partner(s) with azithromycin 1 g should be discontinued. Urgent consideration should be given to using doxycycline 100 mg twice daily for 7 days instead of single-dose azithromycin for the treatment of NGU in men and cervicitis in women, if opting to treat the latter. Available evidence from RCTs indicates that in men with NGU, clinical cure rates, in the same study, are similar with both regimens [14,15▪,43] and would be one strategy in attempting to halt the spread of M. genitalium macrolide-resistant isolates. For those who fail therapy with doxycycline, the extended regimen of azithromycin can then be used, and for those who fail this regimen moxifloxacin for 10–14 days . If azithromycin is to be used first line instead of doxycycline, then we would recommend restricting prescribing to a 5-day course. This could be pragmatically implemented by using an initial 1-g single dose (instead of 500 mg) followed by 250 mg once daily for 4 days, as this contains the currently recommended 1-gram stat dose to cover Chlamydia[14,15▪,43]. This may also lead to better outcomes in those with disease caused by C. trachomatis[14,15▪,31]. The use of an accurate point of care test for C. trachomatis and N. gonorrhoeae, which is now available commercially , offers an alternative strategy with doxycycline being prescribed for C. trachomatis-positive patients and extended azithroymcin regimen for those who are C. trachomatis-negative . Treatment of contacts should be with the same treatment regimen administered to the index case, and we would recommend that azithromycin 1 g should not be used [13▪▪].
The alternative treatment regimen for PID of a third-generation cephalosporin followed by azithromycin 1 g/week for 2 weeks should be used with caution (see above) [32,43,44,49]. For patients with persistent symptoms following treatment of complicated disease, an extended course of moxifloxacin or azithromycin should be considered.
FUTURE MANAGEMENT STRATEGIES WHEN M. GENITALIUM NUCLEIC ACID AMPLIFICATION TESTS AND ANTIMICROBIAL RESISTANCE TESTING ARE AVAILABLE
Where diagnostic testing for M. genitalium is available, we would recommend the aforementioned antimicrobial approach should still be used, but all patients with symptomatic disease should be tested for M. genitalium and retested 3–4 weeks post-treatment. Those found to be persistently infected after treatment with azithromycin and/or moxifloxacin should have antimicrobial resistance testing undertaken and consideration should be given to monitoring this at a national level [11▪▪]. The results of this can then be used to guide patient treatment, and also inform the most appropriate first-line and second-line therapy for the local population.
THE USE OF DUAL ANTIMICROBIAL THERAPY IN SYMPTOMATIC DISEASE
The use of dual antimicrobial treatment in patients with symptomatic M. genitalium infection merits urgent evaluation in vitro in order to inform decisions about the use of these and potentially other antimicrobials in combination in vivo. Although theoretically attractive, the two current first-line agents, azithromycin 1 g and doxycycline 100 mg twice daily for 7 days, are both sub-optimal in eradicating M. genitalium[6▪▪,12,14,15▪]. Although they may be synergistic, doxycycline is bacteriostatic and its effect in combination with azithromycin is to our knowledge unknown [1,12,17,53].
ASYMPTOMATIC SCREENING AND TREATMENT
Screening and treatment of asymptomatic individuals should not be undertaken unless it has been demonstrated to be cost-effective and it can be concluded that the adverse risk of treatment, primarily the generation of resistant mutants, does not outweigh the potential short-term benefits.
There is increasing evidence that M. genitalium is an important cause of symptomatic disease and that current first-line treatment regimens demonstrate suboptimal eradication rates for this micro-organism. Concurrently with increasing use of azithromycin 1 g, there has been a rapid emergence of macrolide antibiotic resistance in M. genitalium, which may now be endemic in some centres, and quinolone resistance is beginning to emerge. In the absence of specific M. genitalium diagnostic and antimicrobial resistance testing, we argue that azithromycin 1 g as a single dose should not be used for the management of patients with symptomatic disease potentially caused by M. genitalium.
Conflicts of interest
P.H. has received funding from HEFC, NHS, BASHH, the Bristol University, Imperial College London, the Crown Prosecution Service, Hologic, Cepheid and Rib-x for his salary, consultancy, lectures, patents, and providing evidence; E.A. has received funding from Cepheid, Bristol University, Atlas Genetics, Pharmaxis, Intermune, the NCSP, the Office for Sexual Health, Pathway Analytics, Gilead and Hologic for consultancy and lectures; K.B., none declared.
REFERENCES AND RECOMMENDED READING
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azithromycin; cervicitis; Mycoplasma genitalium; nongonococcal urethritis; pelvic inflammatory disease
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