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Mycoplasma genitalium is now recognised as an important bacterial sexually transmitted infection. We summarised data from studies of mutations associated with macrolide and fluoroquinolone resistance in M genitalium to establish the prevalence of resistance. We also investigated temporal trends in resistance and aimed to establish the association between resistance and geographical location. In this systematic review and meta-analysis, we searched PubMed, Embase, and MEDLINE for studies that included data for the prevalence of mutations associated with macrolide and fluoroquinolone resistance in M genitalium published in any language up to Jan 7, 2019. We defined prevalence as the proportion of M genitalium samples positive for key mutations associated with azithromycin resistance (23S rRNA gene, position 2058 or 2059) or moxifloxacin resistance (S83R, S83I, D87N, or D87Y in parC), or both, among all M genitalium samples that were successfully characterised. We used random-effects meta-analyses to calculate summary estimates of prevalence. Subgroup and meta-regression analyses by WHO region and time period were done. This study was registered with PROSPERO, number CRD42016050370. Overall, 59 studies from 21 countries met the inclusion criteria for our study: 57 studies of macrolide resistance (8966 samples), 25 of fluoroquinolone resistance (4003 samples), and 22 of dual resistance to macrolides and fluoroquinolones (3280 samples). The summary prevalence of mutations associated with macrolide resistance among M genitalium samples was 35·5% (95% CI 28·8–42·5); prevalence increased from 10·0% (95% CI 2·6–20·1%) before 2010, to 51·4% (40·3–62·4%) in 2016–17 (p<0·0001). Prevalence of mutations associated with macrolide resistance was significantly greater in samples in the WHO Western Pacific and Americas regions than in those from the WHO European region. The overall prevalence of mutations associated with fluoroquinolone resistance in M genitalium samples was 7·7% (95% CI 4·5–11·4%). Prevalence did not change significantly over time, but was significantly higher in the Western Pacific region than in the European region. Overall, the prevalence of both mutations associated with macrolide resistance and those associated with fluoroquinolone resistance among M genitalium samples was 2·8% (1·3–4·7%). The prevalence of dual resistance did not change significantly over time, and did not vary significantly by geographical region. Global surveillance and measures to optimise the efficacy of treatments—including resistance-guided strategies, new antimicrobials, and antimicrobial combination approaches—are urgently needed to ensure cure in a high proportion of M genitalium infections and to prevent further spread of resistant strains. Australian National Health and Medical Research Council.

Treating Mycoplasma genitalium with a sequence of first doxycycline to reduce bacterial load, and then using a resistance assay to choose either high-dose azithromycin or sitafloxacin, cured >92% of infections in a population with high levels of antibiotic resistance. Abstract Background Rising macrolide and quinolone resistance in Mycoplasma genitalium necessitate new treatment approaches. We evaluated outcomes of sequential antimicrobial therapy for M. genitalium guided by a macrolide-resistance assay. Methods In mid-2016, Melbourne Sexual Health Centre switched from azithromycin to doxycycline (100 mg twice daily for 7 days) for nongonococcal urethritis, cervicitis, and proctitis. Cases were tested for M. genitalium and macrolide-resistance mutations (MRMs) by polymerase chain reaction. Directly after doxycycline, MRM-negative infections received 2.5 g azithromycin (1 g, then 500 mg daily for 3 days), and MRM-positive infections received sitafloxacin (100 mg twice daily for 7 days). Assessment of test of cure and reinfection risk occurred 14-90 days after the second antibiotic. Results Of 244 evaluable M. genitalium infections (52 women, 68 heterosexual men, 124 men who have sex with men) diagnosed from 20 June 2016 to 15 May 2017, MRMs were detected in 167 (68.4% [95% confidence interval {CI}, 62.2%-74.2%]). Treatment with doxycycline decreased bacterial load by a mean 2.60 log10 (n = 56; P < .0001). Microbiologic cure occurred in 73 of 77 MRM-negative infections (94.8% [95% CI, 87.2%-98.6%]) and in 154 of 167 MRM-positive infections (92.2% [95% CI, 87.1%-95.8%]). Selection of macrolide resistance occurred in only 2 of 76 (2.6% [95% CI, .3%-9.2%]) macrolide-susceptible infections. Conclusions In the context of high levels of antimicrobial resistance, switching from azithromycin to doxycycline for presumptive treatment of M. genitalium, followed by resistance-guided therapy, cured ≥92% of infections, with infrequent selection of macrolide resistance.

Abstract First isolated in 1981, Mycoplasma genitalium is now well recognized as a frequent cause of urethritis and several other urogenital syndromes in both men and women. The cytoadhesins P110 (MgpC) and P140 (MgpB), located in the terminal organelle of the bacterium, mediate the establishment and persistence of M. genitalium infection in the reproductive tract tissues. This adhesion complex exposes a large extracellular domain, mediating bacterial adhesion to the anogenital tissue. The antigenic variation promoted by reciprocal recombination contribute to the efficient colonization of the urogenital environment and the immune evasion strategy of the bacterium. Although M. genitalium was traditionally detected in ano-genital samples, sexual transmission was not postulated until the early 2000s. Now, it is well accepted that M. genitalium can lead to a sexually transmitted infection. While vaginal sex may constitute the primary transmission route in terms of risk, anal intercourse in men who have sex with men is likely the most common cause of spread. Acknowledging the exquisite adaptation of the bacterium to diverse ecological niches in the human body, the unique features of the proteins P110 and P140 may influence transmission, dissemination and disease. Cytadhesins P110 and P140 are key for the pathogenesis and transmission of Mycoplasma genitalium infection

The 2058T macrolide resistance-associated mutation in 23S rRNA has emerged in Mycoplasma genitalium in France. Using mgpB typing, we documented the spread of a macrolide- and moxifloxacin-resistant ST159 clone, harboring the A2058T and ParC Ser83Ile mutations. In France, that clone is likely circulating among men who have sex with men.

Background Although Mycoplasma genitalium is a common sexually transmitted pathogen causing clinically distinct diseases both in male and females, few genomes have been sequenced up to now, due mainly to its fastidious nature and slow growth. Hence, we lack a robust phylogenetic framework to provide insights into the population structure of the species. Currently our understanding of the nature and diversity of M. genitalium relies on molecular tests targeting specific genes or regions of the genome and knowledge is limited by a general under-testing internationally. This is set against a background of drug resistance whereby M. genitalium has developed resistance to mainly all therapeutic antimicrobials. Results We sequenced 28 genomes of Mycoplasma genitalium from temporally (1980–2010) and geographically (Europe, Japan, Australia) diverse sources. All the strain showed essentially the same genomic content without any accessory regions found. However, we identified extensive recombination across their genomes with a total of 25 regions showing heightened levels of SNP density. These regions include the MgPar loci, associated with host interactions, as well as other genes that could also be involved in this role. Using these data, we generated a robust phylogeny which shows that there are two main clades with differing degrees of genomic variability. SNPs found in region V of 23S rRNA and parC were consistent with azithromycin/erythromycin and fluoroquinolone resistances, respectively, and with their phenotypic MIC data. Conclusions The sequence data here generated is essential for designing rational approaches to type and track Mycoplasma genitalium as antibiotic resistance increases. It represents a first approach to its population genetics to better appreciate the role of this organism as a sexually transmitted pathogen.

Protein glycosylation has been reported in all forms of life. The genus Mycoplasma is composed of highly genome-streamlined bacterial symbionts, making them model organisms for investigating minimal genome concepts. Previous work from our group showed mycoplasmas scavenge hexoses from exogenous oligosaccharides to glycosylate surface proteins at serine, threonine, asparagine, and glutamine residues without utilizing a consensus sequence as seen in canonical glycosylation systems. We report here that this surface protein hexosylation system is conserved in Mycoplasma genitalium , a human urogenital pathogen with a 580-kbp genome that can be cultured axenically. We also report this modification is found in the ruminant pathogen Mycoplasma mycoides subsp. capri and is conserved in JCVI-Syn3A, a nonpathogenic mycoplasma with a synthetic minimal M. mycoides genome containing genes that are essential for survival and robust growth under axenic culture conditions. In contrast to known glycoproteins, we have detected evidence of glycosylation of aspartic acid and glutamic acid residues, which expands the pool of potential glycosyl acceptors in bacteria to include the acidic amino acids.

Macrolide or fluoroquinolone-resistant Mycoplasma genitalium is spreading worldwide. We aimed to determine the influence of single nucleotide polymorphisms (SNPs) in the quinolone resistance determining regions (QRDR) of parC and gyrA in cultured M. genitalium strains. In addition, we examined the prevalence of macrolide- and fluoroquinolone resistance mediating mutations in specimens collected from Japanese male patients with urethritis in two time-periods between 2005-2009 and 2010-2017, respectively, by sequencing the QRDR of parC and gyrA and domain V of the 23S rRNA gene. The minimum inhibitory concentrations (MIC) of moxifloxacin, sitafloxacin, ciprofloxacin, levofloxacin, doxycycline, minocycline, azithromycin and clarithromycin were determined in 23 M. genitalium strains. Three cultured strains had elevated MICs for moxifloxacin at 16, 4 and 2 mg/L and had SNPs with the amino-acid change Ser83→Ile in ParC (p<0.001) and 3 kinds of SNPs with amino-acid changes Asp99→Asn, Gly93→Cys and Met95→Ile in GyrA, respectively. Among a total of 148 M. genitalium positive urine specimens, the prevalence of A2058G and A2059G SNPs in the 23S rRNA gene and any SNPs in ParC increased from 4.8% and 22.6% in 2005-2009 to 42.2% and 53.1% in 2010-2017, respectively. If M. genitalium is considered multi-drug resistant in clinical specimens carrying SNPs in the 23S rRNA gene and Ser83→Ile in ParC, the prevalence of multi-drug resistance is 12.5% in 2010-2017 in Japan. In conclusion, the SNP resulting in Ser83→Ile in ParC is closely related to moxifloxacin resistance even though other factors may also affect treatment outcomes by moxifloxacin. The prevalence of circulating multi-drug resistant M. genitalium strains with macrolide- and fluoroquinolone-resistance is dramatically increasing in Japan.

ObjectiveTo systematically review and appraise published data, to determine the prevalence of Mycoplasma genitalium (MG) in men who have sex with men (MSM) tested at each anatomical site, that is, at the urethra, rectum and/or pharynx.DesignSystematic review and meta-analysis.Data sourcesOvid Medline, PubMed, Embase were searched for articles from 1st January 1981 (the year MG was first identified) to 1st June 2018.Review methodsStudies were eligible for inclusion if they reported MG prevalence in MSM tested at the urethra, rectum and/or pharynx, in at least 50 MSM, using nucleic acid amplification testing. Data were extracted by anatomical site, symptom and HIV status. Summary estimates (95% CIs) were calculated using random-effects meta-analysis. Subgroup analyses were performed to assess heterogeneity between studies.ResultsForty-six studies met inclusion criteria, with 34 reporting estimates of MG prevalence at the urethra (13 753 samples), 25 at the rectum (8629 samples) and 7 at the pharynx (1871 samples). MG prevalence was 5.0% (95% CI 3.5 to 6.8; I2=94.0) at the urethra; 6.2% (95% CI 4.6 to 8.1; I2=88.1) at the rectum and 1.0% (95% CI 0.0 to 5.1; I2=96.0) at the pharynx. The prevalence of MG was significantly higher at urethral and rectal sites in symptomatic versus asymptomatic MSM (7.1% vs 2.2%, p<0.001; and 16.1% vs 7.5%, p=0.039, respectively). MG prevalence at the urethra was significantly higher in HIV-positive compared with HIV-negative MSM (7.0% vs 3.4%, p=0.006).ConclusionMG was common in MSM, particularly at urethral and rectal sites (5% to 6%). MG was more commonly detected in symptomatic men at both sites, and more common in HIV-positive men at the urethra. MG was uncommonly detected in the pharynx. Site-specific estimates are similar to those for chlamydia and will be helpful in informing testing practices in MSM.PROSPERO registration numberCRD42017058326.

Background. We evaluated the impact of extended azithromycin (1.5g over 5 days) on selection of macrolide resistance and microbiological cure in men with Mycoplasma genitalium urethritis during 2013–2015 and compared this to cases treated with azithromycin 1g in 2012–2013. Methods. Microbiological cure was determined for men with M. genitalium urethritis treated with azithromycin 1.5g using quantitative polymerase chain reaction specific for M. genitalium DNA on samples 14–100 days post-treatment. Pre- and post-treatment macrolide resistance mutations were detected by sequencing the 23 S gene. Results. There was no difference in proportions with microbiological cure between azithromycin 1.5g and 1g: 62/106 (58%; 95% confidence interval [CI], 49%, 68%) and 56/107 (52%; 95%CI 42–62%), P = .34, respectively. Also, there was no difference in the proportion of wild-type 23 S rRNA (presumed macrolide sensitive) infections cured after 1.5g and azithromycin 1g: 28/34 (82%; 95%CI 65–92%) and 49/60 (82%; 95%CI 70–90%), P=1.0, respectively. There was no difference between 1.5g and 1g in the proportions of wild-type infections with post-treatment resistance mutations: 4/34 (12%; 95%CI 3–27%) and 11/60 (18%; 95%CI 10–30%), respectively, P = .40. Pre-treatment resistance was present in 51/98 (52%; 95%CI 42–62%) cases in 2013–2015 compared to 47/107 (44%; 95%CI 34–54%) in 2012–2013, P = .25. Conclusions. Extended azithromycin 1.5g was no more effective than a single 1g dose at achieving cure of M. genitalium urethritis and importantly did not reduce the selection of macrolide resistance. Nonmacrolide and new approaches for the treatment of M. genitalium urethritis are required.

Mycoplasma genitalium , Ureaplasma urealyticum and Mycoplasma hominis are bacterial pathogens found in the genitourinary tract, implicated in a range of infections. In women, these infections including pelvic inflammatory disease, vaginitis, infertility, and cervical cancer, while in men, they can cause non-gonococcal urethritis, prostate cancer, among other conditions. These infections are a global health concern, with China identified as a country with a high prevalence. This review provides a comprehensive overview of the epidemiology, causative factors, and diagnostic methods for these three Mycoplasma species with in China. The rise of multi-drug resistance, driven by antibiotics overuse, poses a significant challenge to treatment, complicating patient management. These Mycoplasma species employ unique adhesion mechanisms that trigger a cascade of signal transduction, culminating to inflammatory responses, tissue damage, and the release of toxic metabolites. Here, we delineate the mechanisms of underlying Mycoplasma resistance and propose key therapeutic strategies for these three mycoplasmas in China. This includes a summary of effective antibiotic treatment strategies, and potential combinations of therapeutic to improve cure rates, and a discussion of potential therapeutic approaches using traditional Chinese medicine.