Obstetrics and Gynaecology - Research Publications
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ItemNo Preview AvailableImpact of 16S rRNA Single Nucleotide Polymorphisms on Mycoplasma genitalium Organism Load with Doxycycline Treatment(AMER SOC MICROBIOLOGY, 2022-05-17)Doxycycline targets the 16S rRNA and is widely used for the treatment of sexually transmitted infections. While it is not highly effective at eradicating Mycoplasma genitalium infections, it can reduce organism load. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in the 16S rRNA gene of M. genitalium and change in organism load. M. genitalium samples were collected from 56 men prior to commencing doxycycline and at a median of 13 of 14 doses. These were sequenced for the 16S rRNA, and the association between 16S rRNA SNPs and change in organism load was determined. 16S rRNA sequences were available for 52/56 (92.9%) M. genitalium-infected men, of which 20 (38.5%) had an undetectable load, 26 (50.0%) had a decrease in M. genitalium load (median change of 105-fold), and 6 (11.5%) had an increase in load (median change of 5-fold). The most common SNPs identified were A742G (10/52 [19.2%]), GG960-961TT/C (7/52 [13.5%]), and C1435T (28/52 [53.8%]) (M. genitalium numbering). None were associated with a change in organism load (P = 0.76, 0.16, and 0.98, respectively). Using pooled published data from 28 isolates, no clear relationship between the SNPs and doxycycline MIC was identified. In conclusion, the low efficacy of doxycycline against M. genitalium does not appear to be due to variation in the 16S rRNA gene.
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ItemNo Preview AvailableparC Variants in Mycoplasma genitalium: Trends over Time and Association with Moxifloxacin Failure(AMER SOC MICROBIOLOGY, 2022-05-17)Prevalence, trends, and treatment outcome estimates were generated for parC variants in macrolide-resistant Mycoplasma genitalium. Among 539 cases, the most common amino acid change was S83I, which increased from 13% in 2012 to 2013, to 23% in 2019 to 2020 (Ptrend = 0.046). From 381 moxifloxacin treatments, failure occurred in 58.7% (95% confidence interval [CI], 46.7 to 69.9) of cases with S83I. Other changes affecting S83 or D87 were uncommon and minor contributors to failure. The absence of S83I was highly predictive of moxifloxacin cure (96.4%; 95% CI, 93.7 to 98.2), highlighting diagnostic potential.
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ItemThe Urethral Microbiota of Men with and without Idiopathic Urethritis(AMER SOC MICROBIOLOGY, 2022-10-26)Nongonococcal urethritis (NGU) is a common genital tract syndrome in men, and up to 50% of cases are considered idiopathic, i.e., no etiological agent is identified. This poses challenges for clinicians in the diagnosis and treatment of NGU and often results in antibiotic misuse and overuse. Therefore, to identify potential infectious causes of urethritis and inform clinical management of urethritis cases, we characterized and compared the urethral microbiota of men with and without idiopathic urethritis. Participants were derived from a case-control study that examined viral and bacterial pathogens and sexual practices associated with NGU. Men with NGU who tested negative for established causes of NGU (Chlamydia trachomatis, Mycoplasma genitalium, Trichomonas vaginalis, adenoviruses, herpes simplex virus [HSV]-1, and/or HSV-2) were classified as idiopathic cases, and the controls were men reporting no current urethral symptoms. Men provided a urine sample that was used to characterize the urethral microbiota using 16S rRNA gene sequencing. Bacterial taxa associated with idiopathic urethritis were identified using analysis of compositions of microbiomes with bias correction. When stratified by sex of sexual partner, we found that the abundance of Haemophilus influenzae was significantly increased in men who have sex with men with idiopathic urethritis, and the abundance of Corynebacterium was significantly increased in men who have sex with women with idiopathic urethritis. Other taxa, including Ureaplasma, Staphylococcus haemolyticus, Streptococcus pyogenes, Escherichia, and Streptococcus pneumoniae/pseudopneumoniae, dominated the urethral microbiota of idiopathic urethritis cases but not controls, suggesting that these organisms may also contribute to urethritis. Importantly, the taxa we identified represent biologically plausible causes of urethritis and should be prioritized for future study. IMPORTANCE Nongonococcal urethritis (NGU) is the commonest genital tract syndrome in men and is nearly universally presumptively treated with an antibiotic. Common causes of NGU include Chlamydia trachomatis and Mycoplasma genitalium, but in more than 50% of cases, an infectious cause is not identified. In this case-control study, we found that the urethral microbiota composition differed between men with and without idiopathic urethritis and differed by sex of sexual partner. We identified specific bacterial taxa that were associated with idiopathic urethritis, including Haemophilus influenzae and Corynebacterium. These data, together with the finding that key bacterial taxa were found to dominate the urethral microbiota of cases but not controls, suggest that a range of bacteria contribute to urethritis and that these organisms may be influenced by sexual practices. Through identifying the infectious causes of urethritis, we can inform appropriate targeted diagnostic and treatment practices and importantly reduce misuse and overuse of antibiotics.
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ItemPrevalence of Mycoplasma genitalium fluoroquinolone-resistance markers, and dual- class- resistance markers, in asymptomatic men who have sex with men(MICROBIOLOGY SOC, 2021)Introduction. Failure of fluoroquinolones, the principal treatment option for macrolide-resistant Mycoplasma genitalium infections, has recently emerged. This is of particular concern for men who have sex with men (MSM), who have high proportions of macrolide-resistant M. genitalium infections. Treatment failure with moxifloxacin is likely the result of single nucleotide polymorphisms (SNPs) in parC, whilst concurrent gyrA mutations may play a role.Gap Statement. The levels of fluoroquinolone resistance and dual-class (i.e. macrolide and fluoroquinolone) resistance in M. genitalium among asymptomatic MSM is unknown.Aim. To (i) determine the proportion of fluoroquinolone resistance and dual-class resistance in M. genitalium infections among asymptomatic MSM, (ii) explore any clinical and behavioural associations with fluoroquinolone resistance, and (iii) determine the distribution of antibiotic resistance among M. genitalium mgpB sequence types (STs).Methodology. M. genitalium positive samples (N=94) were obtained from 1001 asymptomatic MSM enrolled in a study at Melbourne Sexual Health Centre (Carlton, Australia) between August 2016 and September 2017. Sanger sequencing was performed to determine the proportion of M. genitalium infections with SNPs in parC that have previously been associated with failure of moxifloxacin (corresponding to amino changes S83I, D83R, D87Y and D87N) and in gyrA (corresponding to amino acid changes M95I, D99N, D99Y and D99G). Associations between clinical/behavioural factors and parC SNPs were examined. Strain typing was performed by sequencing a portion of the mgpB gene.Results. The proportion of MSM with infections harbouring parC and gyrA SNPs was 13.0 % [95 % confidence interval (CI): 6.8-23.2 %] and 4.7 % (95 % CI: 1.1-13.4 %), respectively; dual-class resistance was 13.0 %. No significant clinical/behavioural associations were found. Antibiotic resistance was not restricted to specific mgpB STs.Conclusion. One in eight (13 %) of asymptomatic MSM with M. genitalium had an infection with dual-class-resistance mutations. Typing by mgpB sequence suggested fluoroquinolone resistance is arising from independent mutation events. This study illustrates that asymptomatic MSM may act as a reservoir for antibiotic-resistant M. genitalium.
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ItemNo Preview AvailableEvaluation of ResistancePlus MG FleXible, a 'near- patient' test for the detection of Mycoplasma genitalium and macrolide resistance mutations, using freshly collected clinical samples(MICROBIOLOGY SOC, 2021)Introduction. Mycoplasma genitalium is a sexually transmitted pathogen with increasing resistance to first- and second-line antimicrobials. The 'near-patient test' ResistancePlus MG FleXible (SpeeDx) detects M. genitalium plus four macrolide resistance mutations (MRMs), facilitating same-day patient follow up.Hypothesis/Gap Statement. This assay has not been assessed on freshly collected samples.Aim. Our goal was to evaluate the performance of the ResistancePlus MG FleXible test against the standard of care open platform test.Methods. ResistancePlus MG FleXible (analysed on the Cepheid GeneXpert platform) was evaluated on freshly collected samples and compared to the standard of care open platform test ResistancePlus MG (SpeeDx) analysed on the LightCycler 480 II (Roche).Results. For 270 valid tests, ResistancePlus MG FleXible yielded a high positive per cent agreement (PPA) of 94.1% [96/102; 95 % confidence interval (CI): 87.6-97.8 %] and negative per cent agreement (NPA) of 95.2% (160/168; 95 % CI: 90.8-97.9%) for M. genitalium detection compared to the reference assay (kappa for test concordance of 0.89; 95 % CI: 0.83-0.95). Performance was similar across different sample types. For the detection of MRMs, ResistancePlus MG FleXible had a PPA of 97.1% (66/68; 95% CI: 89.8-99.6) and NPA of 78.6% (22/28; 95 % CI: 59.0-91.7), with test comparison kappa of 0.79 (95 % CI: 0.65-0.93). Notably, of six discordant results (i.e. determined to be wild type by the reference assay), five were positive for MRMs by Sanger sequencing, indicating that the ResistancePlus MG FleXible assay has an improved performance for mutation detection.Conclusion. ResistancePlus MG FleXible had comparable test performance for M. genitalium detection as the open platform assay, with improved detection of MRMs. The ResistancePlus MG FleXible 'near-patient' assay can deliver a rapid result to expedite appropriate treatment.
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ItemThe Effect of Exogenous Sex Steroids on the Vaginal Microbiota: A Systematic Review(FRONTIERS MEDIA SA, 2021-11-12)BACKGROUND: Exogenous sex steroids within hormonal contraception and menopausal hormone therapy (MHT) have been used for family planning and management of menopausal symptoms, without consideration of their effects on the vaginal microbiota. This is largely because their use predates our understanding of the importance of the vaginal microbiome on human health. We conducted a systematic review (PROSPERO: CRD42018107730) to determine the influence of exogenous sex steroids, stratified by oestrogen-containing or progestin-only types of contraception, and MHT on the vaginal microbiome, as measured by molecular methods. METHODS: Embase, PubMed and Medline were searched for relevant literature published through to December 1st 2020. Eligible studies reported on the effect of specific exogenous sex steroids on the vaginal microbiome using a molecular method. Data regarding the 'positive', 'negative' or 'neutral' effect of each type of contraceptive or MHT on the vaginal microbiome was extracted and summarised. A positive effect reflected sex steroid exposure that was associated with increased abundance of lactobacilli, a change to, or maintenance of, an optimal vaginal microbiota composition, or a decrease in bacterial diversity (specifically reflecting a low-diversity optimal microbiota state), relative to the control group. An exogenous sex steroid was designated as having a negative effect on the vaginal microbiome if it resulted in opposing effects (i.e. loss of lactobacilli, a non-optimal microbiota state). When no significant change was found, this was considered neutral/inconclusive. RESULTS: We identified 29 manuscripts reporting on the effect of exogenous sex steroids on the vaginal microbiome; 25 investigating hormonal contraceptives, and 4 investigating MHT. Oestrogen-containing contraception, particularly reflecting the combined oestrogen and progestin-containing contraceptive pill, had a positive effect on the composition of the vaginal microbiota. Progestin-only contraception, particularly reflecting depo-medroxyprogesterone acetate, had mixed effects on the microbiota. Among post-menopausal women using MHT, exogenous oestrogen applied topically was associated with increased prevalence of lactobacilli. CONCLUSION: Our findings suggest that oestrogen-containing compounds may promote an optimal vaginal microbiota, which could have clinical applications. The impact of progestin-only contraceptives on the vaginal microbiota is less clear; more data is needed to determine how progestin-only contraceptives contribute to adverse reproductive and sexual health outcomes.
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ItemA Prospective, Open-Label Pilot Study of Concurrent Male Partner Treatment for Bacterial Vaginosis(AMER SOC MICROBIOLOGY, 2021-10-26)Up to 50% of women receiving first-line antibiotics for bacterial vaginosis (BV) experience recurrence within 12 weeks. Evidence suggests that reinfection from an untreated regular sexual partner contributes to recurrence. We conducted a pilot study of 34 heterosexual couples to describe the impact of concurrent partner treatment on the composition of the genital microbiota over a 12-week period. We also determined the acceptability and tolerability of concurrent partner treatment and obtained preliminary estimates of the efficacy of the intervention to inform a randomized controlled trial (RCT). Women received first-line antibiotic treatment for BV (i.e., oral metronidazole or intravaginal clindamycin), and their male partner received oral metronidazole, 400 mg, and 2% clindamycin cream applied topically to penile skin, both twice daily for 7 days. The genital microbiota was characterized at three anatomical sites (women, vaginal; men, cutaneous penile and first-pass urine [representing the urethra]) using 16S rRNA gene sequencing. Immediately posttreatment, concurrent partner treatment significantly reduced the abundance of BV-associated bacteria (false-discovery rate [FDR] corrected P value < 0.05) and altered the overall microbiota composition of all three anatomical sites (P = 0.001). Suppression of BV-associated bacteria was sustained in the majority (81%) of women over the 12-week period (FDR P value < 0.05), despite BV-associated bacteria reemerging at both genital sites in men. In this cohort of women at high risk for recurrence, five recurred within 12 weeks of treatment (17%; 95% confidence interval [CI], 6 to 34%). Importantly, men tolerated and adhered to combination therapy. Our findings provide support for an RCT of combined oral and topical male partner treatment for BV. IMPORTANCE Recurrence of BV following standard treatment is unacceptably high. Posttreatment recurrence is distressing for women, and it imposes a considerable burden on the health care system. Recurrences result in multiple presentations to clinical services and repeated antibiotic use, and the associated obstetric and gynecological sequelae are significant. New treatments to improve long-term BV cure are urgently needed. Here, we used 16S rRNA gene sequencing to investigate changes in the microbiota composition at three genital sites (vagina, penile skin, and male urethra) of heterosexual couples undergoing concurrent partner treatment for bacterial vaginosis (BV). We found that concurrent partner treatment immediately and significantly altered the composition of the genital microbiota of both partners, with a reduction in BV-associated bacteria seen at all three sites. BV cure at 12 weeks posttreatment was higher than expected. These microbiological data provide evidence for continued investigation of partner treatment as a strategy to improve BV cure.
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ItemTreating male partners of women with bacterial vaginosis (StepUp): a protocol for a randomised controlled trial to assess the clinical effectiveness of male partner treatment for reducing the risk of BV recurrence(BMC, 2020-11-11)BACKGROUND: Bacterial vaginosis (BV) is estimated to affect 1 in 3 women globally and is associated with obstetric and gynaecological sequelae. Current recommended therapies have good short-term efficacy but 1 in 2 women experience BV recurrence within 6 months of treatment. Evidence of male carriage of BV-organisms suggests that male partners may be reinfecting women with BV-associated bacteria (henceforth referred to as BV-organisms) and impacting on the efficacy of treatment approaches solely directed to women. This trial aims to determine the effect of concurrent male partner treatment for preventing BV recurrence compared to current standard of care. METHODS: StepUp is an open-label, multicentre, parallel group randomised controlled trial for women diagnosed with BV and their male partner. Women with clinical-BV defined using current gold standard diagnosis methods (≥3 Amsel criteria and Nugent score (NS) = 4-10) and with a regular male partner will be assessed for eligibility, and couples will then be consented. All women will be prescribed oral metronidazole 400 mg twice daily (BID) for 7 days, or if contraindicated, a 7-day regimen of topical vaginal 2% clindamycin. Couples will be randomised 1:1 to either current standard of care (female treatment only), or female treatment and concurrent male partner treatment (7 days of combined antibiotics - oral metronidazole tablets 400 mg BID and 2% clindamycin cream applied topically to the glans penis and upper shaft [under the foreskin if uncircumcised] BID). Couples will be followed for up to 12 weeks to assess BV status in women, and assess the adherence, tolerability and acceptability of male partner treatment. The primary outcome is BV recurrence defined as ≥3 Amsel criteria and NS = 4-10 within 12 weeks of enrolment. The estimated sample size is 342 couples, to detect a 40% reduction in BV recurrence rates from 40% in the control group to 24% in the intervention group within 12 weeks. DISCUSSION: Current treatments directed solely to women result in unacceptably high rates of BV recurrence. If proven to be effective the findings from this trial will directly inform the development of new treatment strategies to impact on BV recurrence. TRIAL REGISTRATION: The trial was prospectively registered on 12 February 2019 on the Australian and New Zealand Clinical Trial Registry (ACTRN12619000196145, Universal Trial Number: U1111-1228-0106, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376883&isReview=true ).