International http://std.sagepub.com/ Journal of STD & AIDS Mycoplasma genitalium: a review GM Daley, DB Russell, SN Tabrizi and J McBride Int J STD AIDS published online 11 February 2014 DOI: 10.1177/0956462413515196 The online version of this article can be found at: http://std.sagepub.com/content/early/2013/12/16/0956462413515196 Published by: http://www.sagepublications.com Additional services and information for International Journal of STD & AIDS can be found at: Email Alerts: http://std.sagepub.com/cgi/alerts Subscriptions: http://std.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav >> OnlineFirst Version of Record - Feb 11, 2014 What is This? Downloaded from std.sagepub.com at Pres Ospedaliero S Anna PARENT on March 21, 2014 Int J STD AIDS OnlineFirst, published on February 11, 2014 as doi:10.1177/0956462413515196 Review article Mycoplasma genitalium: a review GM Daley1, DB Russell1–3, SN Tabrizi4–6 and J McBride1 International Journal of STD & AIDS 0(0) 1–13 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462413515196 std.sagepub.com Abstract Mycoplasma genitalium (M. genitalium) was first isolated from the urethral swabs of two symptomatic men with urethritis in 1980. Published prevalence rates vary greatly between populations studied. A number of urogenital conditions have been ascribed to M. genitalium, which is recognised to cause a sexually transmitted infection. The association of M. genitalium with non-specific urethritis is now well established, but the evidence supporting its role in both male and female infertility remains inconclusive. Laboratory methods are challenging and there is a lack of test standardisation. The recommended treatment of the infection is azithromycin as a single 1 gm dose. However, in recent years a macrolide resistance has been observed. More studies are required to establish the clinical importance of M. genitalium in urogenital conditions, particularly infertility, and to establish the role for screening and treatment in high-risk populations. Keywords Mycoplasma genitalium, prevalence, diagnosis, treatment, resistance, screening Date received: 29 July 2013; accepted: 5 November 2013 Introduction A small parasitic bacterium, Mycoplasma genitalium (M. genitalium), was ﬁrst isolated in 1980 from the urethral swabs of two symptomatic men with non-gonococcal urethritis (NGU).1 Since its discovery, M. genitalium has been associated with urogenital consequences such as male and female urethritis, balanoposthitis, prostatitis, cervicitis, pelvic inﬂammatory disease (PID) and both male and female infertility.2 M. genitalium may be associated with obstetric complications such as preterm delivery and has been reported in extra-genital infections.3–5 While the association with NGU is strong and well accepted, the evidence for association with infertility is inconclusive. The organism may also play a role in increasing the risk of human immunodeﬁciency virus (HIV) infection.6 Diagnosis of M. genitalium has improved considerably since the use of polymerase chain reaction (PCR) technology and is now reaching high sensitivity rates. Laboratory methods, specimen collection and specimen handling will be discussed. Treatment has become an important discussion point relating to this infection due to the emergence of macrolide resistance and whether or not to screen for M. genitalium infection will be addressed. Methodology This is a selective review conduced in a systematic way. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for conducting a literature search were used.7 A literature search was conducted using the databases PubMed, Medline and The Cochrane Library. The search term ‘‘Mycoplasma genitalium’’ was used in each search engine. A total of 843 articles from 1980 to present in peer-reviewed journals were reviewed once duplicates had been removed. Of these articles, those not written in English or not relevant to the topics covered in this review were excluded. The inclusion of articles was based on quality of the study and relevance to this review. References from articles retrieved were examined and included if not found in the original search strategy. 1 School of Medicine and Dentistry, James Cook University, Cairns, Australia 2 Sexual Health Service, Cairns, QLD, Australia 3 School of Population Health, University of Melbourne, Melbourne, Australia 4 Department of Microbiology and Infectious Diseases, The Royal Women’s Hospital, Melbourne, Australia 5 Department of Molecular Microbiology, Murdoch Children’s Research Institute, Melbourne, Australia 6 Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia Corresponding author: Gemma Daley, School of Medicine & Dentistry, Block A Level 2, Cairns Base Hospital, The Esplanade, Cairns, QLD, Australia 4870. Email: [email protected] Downloaded from std.sagepub.com at Pres Ospedaliero S Anna PARENT on March 21, 2014 2 International Journal of STD & AIDS 0(0) Epidemiology Prevalence Compared to other sexually transmitted infections (STIs) such as those caused by Chlamydia trachomatis, there have been few studies published to determine the prevalence of M. genitalium. This may be because M. genitalium is diﬃcult to culture and before polymerase chain reaction (PCR) was readily available there was no convenient test method to detect the organism.8 Since laboratory assays for M. genitalium using PCR have been described and evaluated, there has been an increasing number of prevalence studies conducted globally (Table 1). Although these studies have added signiﬁcantly to understanding the prevalence and pathogenesis of M. genitalium, it is diﬃcult to apply the ﬁndings across all populations due to variability in prevalence, sampling method/site and laboratory assays used. Many of the sample populations studied include individuals with urogenital symptoms and/or sexual health presentations, where the expected prevalence of STIs is higher, and thus, a biased sample. The existing literature reports that the prevalence rate of M. genitalium ranges from 0% to 47.5% in different population samples (Table 1). This variation is thought to be multi-factorial.39 The samples used include urine, semen and various swabs, all of which have diﬀering sensitivities. The specimens were either self-collected or collected by the clinician and storage conditions varied. Some studies had restricted enrolment criteria; for example, the inclusion of women with PID, men with urethritis or sex workers. McGowin and Anderson-Smits,39 in a comprehensive but not systematic review, assessed the prevalence rate of M. genitalium in 48 published studies involving over 27,000 women in total. These studies were divided into two groups based on whether the study included highrisk subjects or low-risk subjects. Risk was assessed based on symptoms and to which type of health facility individuals were presenting. The prevalence rate was 2.0% in the low-risk group compared to 7.3% in the high-risk group suggesting that M. genitalium is probably more prevalent than may have been appreciated. Transmission and risk factors It is now accepted that M. genitalium can cause an STI. Keane et al.40 were the ﬁrst to examine concordance rates of couples with M. genitalium. They studied 39 couples attending a genitourinary clinic consisting of men with NGU and their female partners. Of the 12 men with NGU testing positive for M. genitalium, seven of their respective female partners also tested positive. This concordance rate of 58% was similar to that for C. trachomatis, also sexually transmitted, in which there was 43% concordance. Other studies have since conﬁrmed this high concordance rate. There are contradictory data in relation to risk factors for M. genitalium infections. Such variation may be a result of diﬀerences in populations studied. According to a recent study in China in which M. genitalium was sought in women sex workers, infection was associated with lack of education, being single, living alone or with partners rather than husbands, migrant background and absence of symptoms.13 Manhart et al.41 found that after adjusting for confounding factors M. genitalium was strongly associated with sexual behaviours in a group of young adults. Those who reported ever having partaken in vaginal intercourse were more likely to test positive than those who had never done so, with a further 10% increase in prevalence with each vaginal intercourse partner in the last year. Furthermore, those who had lived with a sexual partner were 11 (95% [CI] 3.17–39.50) times more likely to have M. genitalium than those who had never. Men who have sex with men. A cross-sectional study of men who have sex with men (MSM) in men-only saunas in Australia revealed that in a sample of this population M. genitalium was less common than Neisseria gonorrhoeae or C. trachomatis.12 Further, the authors found it was most likely to be detected in asymptomatic rectal or urethral infections, was absent from the pharynx and there were no demographic or behavioural risk factors identiﬁed. In contrast, in other studies of MSM there was a signiﬁcant relationship between M. genitalium positive-urethral specimens and dysuria.42–44 In addition, from the literature it may be seen that HIVpositive MSM have been M. genitalium positive more often than HIV-negative men.42,44 Role of M. genitalium in the transmission of HIV. Montagnier et al.45 ﬁrst postulated the possibility that M. genitalium may be involved in both HIV acquisition and transmission when M. genitalium was identiﬁed in the blood of a patient with HIV. They also reported that some mycoplasmas might play a role in the replication and pathogenicity of HIV. It has also been demonstrated that adherence of mycoplasmas to HIV-infected cells can increase HIV virus release.46 There are several possible explanations for the observed association between HIV and M. genitalium. It is possible that as both infections are sexually transmitted the association is just related to high-risk individuals being exposed to both infections or confounded by sexual behaviour.47,48 It is also possible that HIV infection increases the risk of M. genitalium in the immuno-compromised host or that M. genitalium is a risk factor for HIV acquisition and transmission. If the later hypothesis were true, it would be worth exploring Downloaded from std.sagepub.com at Pres Ospedaliero S Anna PARENT on March 21, 2014 2009 Not available 1981–1983 1979–1980 2004–2006 China 2012 Denmark 1993 1985 1984 England 2010 2001–2002 2009 2007–2011 Australia 2013 2007–2008 2001–2002 Africa 2006 2011 Data collection Location Year Downloaded from std.sagepub.com at Pres Ospedaliero S Anna PARENT on March 21, 2014 17 16 15 14 13 12 11 10 9 References Table 1. Past prevalence studies of M. genitalium. Retrospective and longitudinal study Retrospective prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Longitudinal study Cross-sectional prevalence study Randomised, controlled trial Study design n ¼ 2378 Stored self-collected vaginal swabs n ¼ 99 PCR of urethral, rectal and throat swabs n ¼ 106 Micro-immunoflorescence of serum to detect antibodies to M. genitalium n ¼ 31 Microimmunoflorescence of serum to detect antibodies to M. genitalium n ¼ 810 PCR of cervical swabs n ¼ 1116 PCR of self-collected vaginal swabs n ¼ 521 PCR urine, rectal and pharyngeal swabs n ¼ 1182 PCR of FVU n ¼ 826 PCR of cervical swab Number tested (n) Method used 3.3% (78/2378) 38.7% (12/31) 17% (17/99) urethral 0% (0/99) rectal and throat 25% (32/106) 13.2% (107/810) 2.1% (11/521) 2.4% (27/1116) 8.1% (96/1182) 26.3% (216/826) Prevalence (continued) Female university students Women with acute PID with no antibodies to C. trachomatis or M. hominis Women with a history of infertility for 2 or more years Men attending an STI clinic Female sex workers MSM in men-only saunas Men with self-reported dysuria and/or urethral discharge presenting to a sexual health clinic Females presenting to primary health clinics Female sex workers in Ghana and Benin Comments Daley et al. 3 2006 2010–2011 Not available 1998–1999 Not available 2011 Honduras 2012 Iran 2011 Israel 1988 Italy 2000 Japan 2000 New Zealand 2013 1994–1996 France 2002 2008–2009 Not available 1993 Greenland 2012 Not available Data collection 2004 Location Year Table 1. Continued Downloaded from std.sagepub.com at Pres Ospedaliero S Anna PARENT on March 21, 2014 27 26 25 24 23 22 21 20 19 18 References Cross-sectional prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Prospective prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Study design n ¼ 261 PCR of cervical swabs n ¼ 264 PCR of endocervical swab n ¼ 201 178 symptomatic 23 asymptomatic PCR of urethral swabs n ¼ 513 Culture of urethral swab n ¼ 196 PCR of urine samples n ¼ 726 PCR of vaginal swabs n ¼ 297 PCR of self-collected urine and vaginal swab n ¼ 170 PCR of cervical, vaginal and urethral samples n ¼ 78 PCR of FVU n ¼ 103 PCR of urethral swab Number tested (n) Method used 8.4% (22/261) 12.6% (22/174) female sex workers 1.1% (1/90) controls 29.2% (52/178) symptomatic men 4.3% (1/23) asymptomatic men 0% (0/513) 1.02% (2/196) 18.3% (133/726) 9.8% (29/297) 38% (65/170) 23% (24/103) 21% (16/78) Prevalence (continued) Women attending an STI clinic Female sex workers and asymptomatic pregnant women Men attending an STI clinic Patients with ‘‘urogenital inflammations’’ Pregnant women Female sex workers Random sample aged 15–65 years Women with abnormal vaginal discharge attending an STI clinic Men with a history of chronic urethritis Men attending an STI clinic with NGU Comments 4 International Journal of STD & AIDS 0(0) Downloaded from std.sagepub.com at Pres Ospedaliero S Anna PARENT on March 21, 2014 Not available 2007–2009 Turkey 2005 United States 2011 Not available 1997–1998 2000 1988 2000 2004 1999–2001 2002–2004 2006 2010 2003–2008 Sweden 2012 2002–2005 2005–2006 2008 2011 2006–2008 Data collection 2010 Location Year Table 1. Continued 38 37 36 35 34 33 32 31 30 29 28 References Cross-sectional prevalence study Retrospective prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Cross-sectional prevalence study Prospective cohort study Cross-sectional prevalence study Prospective cohort study Case-control study Study design n ¼ 367 PCR of urethral swabs and urine samples n ¼ 324 PCR of urine and vaginal and cervical swabs n ¼ 216 PCR of frozen (-70 C) urine samples n ¼ 31 DNA probe n ¼ 64 PCR of unspecified urine sample n ¼ 512 PCR of FVU n ¼ 318 (233 men, 85 women) PCR of urethral and cervical swabs n ¼ 5519 PCR of FVU and cervical samples n ¼ 78 PCR of FVU n ¼ 300 PCR of vaginal swab n ¼ 103 PCR of urethral swab Number tested (n) Method used 13% (4/31) 5.6% (12/216) 9.9% (32/324) 12.5% (46/367) 6.3% (4/64) 7% (18/233) men 3.5% (3/85) women 7% (34/512) 41% (32/78) 2.1% (116/5519) 10% (21/209) men with NGU 2% (4/199) controls 8.7% (26/300) Prevalence Men attending STI clinic with NGU Young pregnant women HIV-positive women Men with non-gonococcal urethritis Men with urethritis Symptomatic women at gynaecological outpatient service Men with persistent or symptomatic non-chlamydial NGU Men attending an STI clinic Men and women attending an STI clinic Men attending an STI clinic with symptomatic NGU Women under 25 presenting for termination of pregnancy Comments Daley et al. 5 6 International Journal of STD & AIDS 0(0) whether treatment of M. genitalium would lead to a lower risk of HIV acquisition and/or transmission. Symptoms Symptoms and signs in men Urethritis. The most common clinical manifestation of M. genitalium infection in men is that of acute and chronic urethritis. For the purpose of this review, urethritis is deﬁned as inﬂammation of the urethra producing symptoms such as dysuria (pain on urination) or vague urethral discomfort.49 Taylor-Robinson and Jensen established the role of M. genitalium in the clinical entity of urethritis in 2001 and it is now accepted to be an important cause of non-chlamydial NGU, accounting for about 15–20% of cases of NGU.50,51 Manhart et al.52 recently evaluated data from a total of 34 studies published from 1993 to 2010 inclusive utilising PCR to establish the diagnosis. In this review, 834 of 6732 men (12.3%) with NGU had a positive PCR for M. genitalium and symptomatic men were more likely to have a positive PCR than asymptomatic individuals. Moreover, quantitative PCR demonstrated that pathogen counts in the urine were high in symptomatic men. Balanoposthitis and prostatitis. Horner and TaylorRobinson53 found that in a study of 114 men with acute NGU, M. genitalium was signiﬁcantly associated (p ¼ 0.01) with balanitis and/or posthitis (inﬂammation of the head of the penis and foreskin, respectively), collectively termed balanoposthitis.53 They found that even after adjusting for C. trachomatis and urethral discharge the odds ratio was 4.1 (95% [CI] 1.2–13.5). This may have important consequences for HIV transmission in these individuals. There is a paucity of literature on the relationship between M. genitalium and chronic prostatitis/chronic pelvic pain syndrome in men.49 Krieger and Riley investigated this association and found M. genitalium in the semen of 18 out of 38 men with chronic pelvic pain syndrome and inﬂammatory inﬁltrate in the prostate-speciﬁc specimens.54 This is an area of research that needs to be further investigated in order to determine its signiﬁcance and impact on management and screening for M. genitalium in men. Symptoms and signs in women Vaginal discharge, urethritis and cervicitis. A common symptom or sign of M. genitalium infection is vaginal discharge. M. genitalium can also present with urethritis and/or cervicitis.55,56 In a review by McGowin and Anderson-Smits,39 of 14 studies of lower genital tract inﬂammation, seven had M. genitalium associated with urethritis, vaginal discharge, microscopic cervicitis and mucopurulent cervical discharge. This study also revealed that in three of six studies from 2002 to 2010 there was a signiﬁcant association between M. genitalium and vaginal discharge. One of the studies adjusted for bacterial vaginosis but still found a signiﬁcant association between M. genitalium and vaginal discharge. In contrast to this, Thurman et al.,57 in a similar population, found no signiﬁcant association. These inconsistencies may be due to the deﬁnition of pathological vaginal discharge and/or the subjectivity of patient symptoms. The relationship between M. genitalium and cervicitis also requires further investigation. Manhart et al.55 conducted a study examining 719 cervical secretions archived from 1984 to 1986. The authors concluded that M. genitalium infection was an independent cause of cervicitis (OR 3.1; 95% [CI] 1.5–6.8). This conclusion was established after a multivariate logistic regression analysis correcting for confounding factors and excluding participants with C. trachomatis and/or N. gonorrhoeae. The study had an attributable risk of 70% suggesting that among the women with cervicitis and M. genitalium, 70% of the cervicitis was caused by M. genitalium independently.2 Nevertheless, there are diﬃculties in comparing studies because of the inconsistency in deﬁning cervicitis. A standard deﬁnition is required for comparison. Effect on female reproductive health PID C. trachomatis and N. gonorrhoeae are well established as factors in the aetiology of PID, the term referring to infection of the upper reproductive tract in women that can lead to chronic pelvic pain, ectopic pregnancy and tubal infertility. However in a high proportion of PID the causative organism remains unknown. It is diﬃcult to make a microbiological diagnosis of PID.58 In 1987 Taylor-Robinson et al. demonstrated that after inoculating primates with this bacterium both salpingitis and lower genital tract pathology resulted.59 Since this time, many studies have supported the theory that M. genitalium may play a role in the aetiology of PID. This is a logical consequence of cervicitis when considering the pathogenesis of PID is the result of an ascending lower genital tract infection. Several authors have published studies examining a relationship between M. genitalium and PID in geographically diverse populations. Recently Bjartling et al.60 conducted a study in Sweden in which they examined 2079 women presenting to the hospital obstetrics and gynaecology department. Of the 49 Downloaded from std.sagepub.com at Pres Ospedaliero S Anna PARENT on March 21, 2014 Daley et al. 7 women with PID, 12.2% were positive for M. genitalium compared to 2.4% of the 168 female controls.60 After adjusting for confounding factors including age and the presence of C. trachomatis the relative risk was 6.29 (95% [CI] 1.56–25.2). Conversely, Cohen et al.61 conducted a cohort study of 258 female sex workers in Kenya and did not ﬁnd a positive association between M. genitalium and PID after 36 months of follow-up (95% [CI] 0.43–1.13). These results are in contrast to those reported by Haggerty et al.62 who, using samples from the PID Evaluation and Clinical Health (PEACH) Study, described the positive association of M. genitalium with endometritis and short-term PID treatment failure.62 One of the major issues in PID research is that laparoscopy is considered the ‘‘gold standard’’ for diagnosis. However, it is not commonly used in clinical practice for this purpose.63 0.46-44.72) and furthermore, in a subset of the women with idiopathic infertility after laparoscopy, this relative risk increased to 9.06 (95% CI (1.02–80.89). Obstetric complications and infertility The laboratory testing for M. genitalium has proven particularly diﬃcult and has led to inaccuracies in deﬁning global prevalence rates and diﬃculties in comparing prevalence rates between populations. M. genitalium contains 521 genes in total with 482 of these genes able to encode proteins.50,69,70 The ﬁrst assay to detect this organism was described by both Palmer et al.71 and Jensen et al.72 Table 2 outlines a number of assays used for detection. A lack of standardisation of assays for M. genitalium remains a problem and there is a need for a gold standard assay. The potential to cause adverse obstetric outcomes and infertility is another critical aspect in determining the importance of M. genitalium. The literature surrounding the association between M. genitalium and obstetric complications is inconsistent. Some studies support a positive relationship between the infection and preterm delivery. Oakeshott et al.3 demonstrated an association between M. genitalium and pre-term birth (OR ¼ 2.6, 95% [CI] 0.12-46.8) in a group of 915 women from the UK. Likewise, Hitti et al.4 found a very similar adjusted odds ratio of 2.5 (95% [CI] 1.2–5.0) in a group of 1328 women in Peru. Others studies have concluded there is no positive association between M. genitalium and adverse obstetric outcomes. Labbe et al.64 conducted a case-control study of 1014 women in Ginnea-Bissau and found no association between M. genitalium and adverse pregnancy outcomes.64 Likewise, Short et al.37 examined a group of 216 American women and found no increased risk of spontaneous abortion, with an odds ratio of 0.9 (95% [CI] 0.2–3.8). However, they did ﬁnd a positive association between M. genitalium and infertility.37 In contrast, the relationship between M. genitalium and infertility is better understood and consistent in regards to women. Clausen et al.65 examined 308 women presenting to an infertility clinic in Denmark using tubal occlusion diagnosed laparoscopically as the diagnostic criterion. The results showed that the relative risk of tubal factor infertility in women with M. genitalium was 3.8 (95% [CI] 1.7–9.4). Grzesko et al.66 supported this strong association in a population of 74 women attending an infertility clinic in Poland. They found the overall relative risk of infertility in patients with M. genitalium was 5.37 (95% [CI] Male infertility M. genitalium has been isolated from samples of semen and has been observed attaching to the human spermatozoa.54,67 Al-Sweih et al.68 examined samples of semen from 127 infertile and 188 fertile men in Kuwait. They concluded that there was no signiﬁcant association between M. genitalium infection and fertility. They did, however, note that genital mycoplasmas appeared to ‘‘negatively inﬂuence semen quality.’’68 Diagnosis Laboratory methods Specimen collection There is still no consensus as to which specimens are preferable in detecting M. genitalium. The sensitivities vary between vaginal swabs, ﬁrst void urine (FVU) and rectal swabs and are reported as 85.7%, 97.4% and 24.3%, respectively (refer to Table 3). In women, combination of swabs from two sites results in a better detection rate: 95.7% for combined vaginal and endocervical swabs and 95% when an endocervical swab and FVU specimen are used together.82,83 Some centres allow patients to obtain their own rectal and vaginal swab specimens because this method of collection has been shown to be as eﬀective as swabs obtained by clinical staﬀ.84–86 Rectal swabs for primarily menwho-have-sex-with-men (MSM) has been utilised.82 Specimen handling There is accumulating evidence to suggest that specimen handling is crucial. In view of the thermolability/ fragility of DNA it is important to promptly process the specimens. If handled appropriately the specimens can be stored for long periods: storage at 20 C for 18 Downloaded from std.sagepub.com at Pres Ospedaliero S Anna PARENT on March 21, 2014 8 International Journal of STD & AIDS 0(0) Table 2. Comparison of assay methods for detection of M. genitalium. Assay Target of assay Detection limit Assay time Reference LCRT-PCR PCR PCR PCR PCR PCR Multiplex PCR reverse line blot Multiple steps: Including cell culture & PCR G3PDH Mg219 MgPa MgPa 16 S rRNA 16 S rRNA MgPa MgPa <2.5 gene copies 0.5 pg DNA or 825 gene copies >23 or <5 gene copies <1 CFU 0.5–5 CFU <50 to >6 gene copies 2 108 ng DNA >106 dilution 50 min 60 min 60 min 70, 73 Table 3. The sensitivities of different specimens for the detection of M. genitalium. Specimen site and type Sensitivity (PCR) First voided urine Combined vaginal and endocervical swab Endocervical and urine Vaginal swab Rectal swab 97.4% 95.7% 82 95% 85.7% 24.3% 83 Reference 82 82 82 months resulted in a 90% sensitivity compared to fresh specimens.87 Treatment Antibiotic treatment Treatment strategies for M. genitalium are based on the knowledge that it is susceptible to antibiotics belonging to the drug classes of macrolides, tetracyclines and quinolones.88 Before the discovery of M. genitalium, tetracyclines were used to treat NGU. Recent studies (refer to Table 4) have shown that a single 1-g dose of azithromycin is more eﬀective than an extended dose of doxycycline. It has replaced the use of tetracyclines which were the ﬁrst agents used to treat NGU before the recognition of M. genitalium.62,92 Failure of tetracyclines or older quinolones to treat M. genitalium-associated male urethritis has been recognised and persistent infection from poor eﬃcacy has resulted in chronic NGU.2,31,33,95 Empirical treatment of NGU with azithromycin was demonstrated to be at least as eﬀective as doxycycline 100 mg twice daily for 7 days.96 One study showed 85% eﬃcacy after a single 1-g dose of azithromycin.92 The popular use of azithromycin in clinical practice may have already resulted in resistance to a 1-g single 70, 74 75, 76 77 90 min 4h 4h 20 days 77 78, 79 80 81 dose. This has been observed in M. genitalium-infected patients. Resistance to 1-g single dose azithromycin in patients with conﬁrmed M. genitalium has been shown to range from 15% to 30%.70 The macrolide resistance has been identiﬁed as being related to multiple-point mutations in region 5 of 23 S-rRNA and L4 and L22 ribosomal proteins, the latter inﬂuencing conformation of the macrolide binding site. It is likely that the widespread and often inappropriate use of macrolides for respiratory tract infections is contributing to the problem of macrolide resistance.97–99 There is concern that single doses of azithomycin are more likely to lead to resistant strains which is leading to recommendations for treatment including a ﬁve-day course. Treatment with 1.5 g azithromycin over 5 days given as 500 mg on day 1 and 250 mg per day on days 2 to 5 has been shown to have excellent eﬃcacy with clearance rates of 96 to 100%.92,95 Moxiﬂoxacin has been demonstrated to be eﬀective in >95% of patients with macrolide-resistant strains of M. genitalium.72 Fluoroquinolone resistance, however, has also been described, including resistance to moxiﬂoxacin.72 Antibiotic resistance Azithromycin has previously been the treatment of choice for M. genitalium and to some extent still is. However, a resistance to azithromycin has emerged and in such cases moxiﬂoxacin has been helpful. Fluoroquinolones, particularly moxiﬂoxacin, are recommended for infections resulting from azithromycinresistant strains.70,94,100 It should be noted that some ﬂuoroquinolones such as levoﬂoxacin and gatiﬂoxacin have an unacceptably low eﬃcacy with reported eradication rates of 60% and 83%, respectively.101,102 These data are supported by studies examining the minimal inhibitory concentrations (MIC) which have shown only moderate anti-M. genitalium activity of levoﬂoxacin.103 In general a 10 - to 14-day course of moxiﬂoxacin, 400 mg/day, is recommended for patients Downloaded from std.sagepub.com at Pres Ospedaliero S Anna PARENT on March 21, 2014 Daley et al. 9 Table 4. Summary of previous studies examining antibiotic efficacies in treating M. genitalium infection. % Efficacy (infections cleared/total treated) Study details Population Number (n) Treatment(s) used 2012, Japan89 Retrospective, single-centre study Women with M. genitalium positive cervicitis 257 Azithromycin extended release formulation 2 g single dose Azithromycin 1 g single dose Clarithromycin 400 mg/day for 7 days Clarithromycin 400 mg/day for 14 days Moxifloxacin 400 mg/day for 7 days Moxifloxacin 400 mg/day for 14 days Levofloxacin 500 mg/day for 7 days Levofloxacin 500 mg/day for 14 days Sitafloxacin 200 mg/day for 7 days Sitafloxacin 200 mg/day for 14 days Azithromycin 1 g single dose 90.5% (19/21) Azithromycin 1 g single dose Doxycycline 100 mg BD for 7 days Azithromycin 1 g single dose Doxycycline 200 mg day 1 and 100 mg days 2-9 Azithromycin 1 g single dose Moxifloxacin 400 mg OD for 10 days in patients with resistant infection Azithromycin 1 g single dose OR 1 g once per week for 3 weeks Moxifloxacin given to azithromycin resistant cases 400 mg OD for 10 days Azithromycin 1 g single dose OR 1.5 g over 5 days 87% (20/23) 45% (14/31) 2012, Australia90 Retrospective study 2009, United States91 Randomised, controlled trial Stored samples 111 Symptomatic men attending an STI clinic 54 2008, Scandinavia92 Randomised, controlled trial Men and women attending an STI clinic 159 2008, Australia93 Prospective cohort study Symptomatic men and women attending an STI clinic 192 2006, Australia94 Case control study Men and women attending an STI clinic 31 2006, Sweden31 Prospective cohort study 20 2003, Sweden95 Prospective cohort study Men with persistent or symptomatic non-chlamydial NGU Men and women attending an STI clinic 1993, England19 Prospective cohort study Men attending an STI clinic with NGU 14 66 Tetracyclines (doxycycline and lymecycline) used empirically as initial treatment Azithromycin used as initial empirical treatment 500 mg on day 1, 250 mg OD for 4 days Doxycycline 200 mg on day 1, 100 mg OD for 13 days Note. All medications were taken orally. Downloaded from std.sagepub.com at Pres Ospedaliero S Anna PARENT on March 21, 2014 85.7% (36/42) 65% (13/20) 85% (17/20) 90.5% (38/42) 100% (42/42) 54.5% (12/22) 71.4% (15/21) 78.6% (11/14) 92.3% (12/13) 69% (77/111) 85.7% (48/56) 22.3% (23/103) 84% (101/120) 100% (11/11) 72% (23/31) 100% (8/8) 100% (20/20) 28.6% (4/14) women 37.5 (6/16) men 100% (36/36) 71.4% (10/14) 10 International Journal of STD & AIDS 0(0) who have failed therapy with azithromycin as a stat dose or as an extended dose.50 A resistance to moxiﬂoxacin has also been observed. The development of resistance to the ﬂuoroquinolones has shown to be linked to mutations in the gyr A and par C genes.104 Conflict of interest The authors declare no conﬂict of interest. Funding This research received no speciﬁc grant from any funding agency in the public, commercial, or not-for-proﬁt sectors. Screening At present the guidelines on screening for M. genitalium are non-uniform, varying between geographical locations and even between clinics within a certain location. This may be due to the variable prevalence of M. genitalium between studies and the relatively recent association between this infection and adverse urogenital outcomes, some of which are yet to be adequately established. When compared to that of other sexually transmitted organisms, the prevalence of M. genitalium in the general population is often somewhere between the prevalence of N. gonorrhoeae and C. trachomatis with N. gonorrhoeae being less common and C. trachomatis more common than M. genitalium.11,42,105 As N. gonorrhoeae is routinely screened for in sexual health clinics and consistently less prevalent in studies comparing N. gonorrhoeae and M. genitalium it would be reasonable to consider screening as both infections have adverse outcomes.106 Conclusion M. genitalium is an important sexually transmitted organism. Prevalence studies have been hampered by diﬃculty with laboratory testing. Treatment is problematic. Tetraclycines were the ﬁrst agents used but have poor eﬃcacy. Azithromycin as a single dose of 1 g has been demonstrated to have unsatisfactory eﬃcacy in recent years and moreover, may be associated with an increase in resistance to the macrolides. 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