Prevalence and Predictors of Oral Treponema pallidum Detection by Quantitative Polymerase Chain Reaction in Early Syphilis.

BACKGROUND: Treponema pallidum prevalence and burden at oral and lesion sites in adults with early syphilis were assessed by quantitative polymerase chain reaction (qPCR). Factors associated with oral shedding were also examined. METHODS: Pretreatment oral and lesion swabs were collected from adults with early syphilis in a US multicenter syphilis treatment trial. Oral swabs were collected in the presence and absence of oral lesions. Following DNA extraction, qPCR and whole-genome sequencing (WGS) were performed to assess burden and strain variability. RESULTS: All 32 participants were male, mean age was 35 years, and 90.6% with human immunodeficiency virus (HIV). T. pallidum oral PCR positivity varied by stage: 16.7% primary, 44.4% secondary, and 62.5% in early latent syphilis. Median oral T. pallidum burden was highest in secondary syphilis at 63.2 copies/µL. Lesion PCR positivity was similar in primary (40.0%) and secondary syphilis (38.5%). Age 18-29 years was significantly associated with oral shedding (vs age 40+ years) in adjusted models. WGS identified 2 distinct strains. CONCLUSIONS: T. pallidum DNA was directly detected at oral and lesion sites in a significant proportion of men with early syphilis. Younger age was associated with oral shedding. Ease of oral specimen collection and increased PCR availability suggest opportunities to improve syphilis diagnostic testing. Clinical Trials Registration. NCT03637660.

High-throughput nanopore sequencing of Treponema pallidum tandem repeat genes arp and tp0470 reveals clade-specific patterns and recapitulates global whole genome phylogeny.

Sequencing of most Treponema pallidum genomes excludes repeat regions in tp0470 and the tp0433 gene, encoding the acidic repeat protein (arp). As a first step to understanding the evolution and function of these genes and the proteins they encode, we developed a protocol to nanopore sequence tp0470 and arp genes from 212 clinical samples collected from ten countries on six continents. Both tp0470 and arp repeat structures recapitulate the whole genome phylogeny, with subclade-specific patterns emerging. The number of tp0470 repeats is on average appears to be higher in Nichols-like clade strains than in SS14-like clade strains. Consistent with previous studies, we found that 14-repeat arp sequences predominate across both major clades, but the combination and order of repeat type varies among subclades, with many arp sequence variants limited to a single subclade. Although strains that were closely related by whole genome sequencing frequently had the same arp repeat length, this was not always the case. Structural modeling of TP0470 suggested that the eight residue repeats form an extended α-helix, predicted to be periplasmic. Modeling of the ARP revealed a C-terminal sporulation-related repeat (SPOR) domain, predicted to bind denuded peptidoglycan, with repeat regions possibly incorporated into a highly charged ß-sheet. Outside of the repeats, all TP0470 and ARP amino acid sequences were identical. Together, our data, along with functional considerations, suggests that both TP0470 and ARP proteins may be involved in T. pallidum cell envelope remodeling and homeostasis, with their highly plastic repeat regions playing as-yet-undetermined roles.

Coinfection With Chlamydial and Gonorrheal Infection Among US Adults With Early Syphilis.

ABSTRACT: Among 865 adults with early syphilis considered for a multicenter treatment trial, 234 (27%) were excluded before enrollment because of bacterial sexually transmitted infection coinfection. Coinfection with Neisseria gonorrhoeae (29%), Chlamydia trachomatis (22%), or both (23%) was common. Study findings highlight the need for comprehensive bacterial sexually transmitted infection screening in patients with syphilis.

Multicenter Comparison of Nucleic Acid Amplification Tests for the Diagnosis of Rectal and Oropharyngeal Chlamydia trachomatis and Neisseria gonorrhoeae Infections.

Research using nucleic acid amplification tests (NAATs) have repeatedly found rectal and oropharyngeal infections with Chlamydia trachomatis and Neisseria gonorrhoeae to be common and potentially more difficult to treat than genital infections. Unfortunately, public health and patient care efforts have been hampered by the lack of FDA-cleared NAATs with claims for anorectal or oropharyngeal samples. At the time of the initiation of this study, no commercially available assays had these claims. We formed a novel partnership among academic institutions and diagnostic manufacturers to address this public health need. From May 2018 through August 2019, we recruited 1108 women, 1256 men, and 26 transgender persons each of whom provided 3 anal and 3 oropharyngeal swab specimens. The 3 anal swabs were pooled into a single transport tube as were the 3 oropharyngeal swabs. The performance of each of three study assays was estimated by comparison to the composite result and relative to one another. Percent positivity for chlamydia was 5.9 and 1.2% from anal and oropharyngeal specimens, respectively, compared to 4.2 and 4.1% for gonorrhea. Sensitivity for chlamydia detection ranged from 81.0 to 95.1% and 82.8 to 100% for anal and oropharyngeal specimens, respectively. Gonorrhea sensitivity ranged from 85.9 to 99.0% and 74.0 to 100% for anal and oropharyngeal samples, respectively. Specificity estimates were ≥ 98.9% for all assays, organisms, and sample types. Although there was heterogeneity between sensitivity estimates, these assays offer better ability to detect extragenital infections than culture and potential solutions for providing appropriate sexual health care for populations in which these infections are of concern.

Chlamydial Pgp3 Seropositivity and Population-Attributable Fraction Among Women With Tubal Factor Infertility.

BACKGROUND: Chlamydial infection is associated with tubal factor infertility (TFI); however, assessment of prior chlamydial infection and TFI is imperfect. We previously evaluated a combination of serological assays for association with TFI. We now describe the chlamydial contribution to TFI using a newer Chlamydia trachomatis Pgp3-enhanced serological (Pgp3) assay. METHODS: In our case-control study of women 19 to 42 years old with hysterosalpingogram-diagnosed TFI (cases) and non-TFI (controls) in 2 US infertility clinics, we assessed possible associations and effect modifiers between Pgp3 seropositivity and TFI using adjusted odds ratios with 95% confidence intervals (CIs) stratified by race. We then estimated the adjusted chlamydia population-attributable fraction with 95% CI of TFI. RESULTS: All Black (n = 107) and 618 of 620 non-Black women had Pgp3 results. Pgp3 seropositivity was 25.9% (95% CI, 19.3%-33.8%) for non-Black cases, 15.2% (95% CI, 12.3%-18.7%) for non-Black controls, 66.0% (95% CI, 51.7%-77.8%) for Black cases, and 71.7% (95% CI, 59.2%-81.5%) for Black controls. Among 476 non-Black women without endometriosis (n = 476), Pgp3 was associated with TFI (adjusted odds ratio, 2.6 [95% CI, 1.5-4.4]), adjusting for clinic, age, and income; chlamydia TFI-adjusted population-attributable fraction was 19.8% (95% CI, 7.7%-32.2%) in these women. Pgp3 positivity was not associated with TFI among non-Black women with endometriosis or among Black women (regardless of endometriosis). CONCLUSIONS: Among non-Black infertile women without endometriosis in these clinics, 20% of TFI was attributed to chlamydia. Better biomarkers are needed to estimate chlamydia TFI PAF, especially in Black women.

Report From the National Academies of Sciences, Engineering and Medicine-STI: Adopting a Sexual Health Paradigm-A Synopsis for Sexually Transmitted Infection Practitioners, Clinicians, and Researchers.

ABSTRACT: Despite decades of medical, diagnostic, and public health advances related to diagnosis and management of sexually transmitted infections (STIs), rates of reportable STIs continue to grow. A 2021 National Academies of Sciences, Engineering, and Medicine report on the current state of STI management and prevention in the United States, entitled Sexually Transmitted Infections: Adopting a Sexual Health Paradigm, offers recommendations on future public health programs, policy, and research. This new report builds upon the 1997 Institute of Medicine report, The Hidden Epidemic: Confronting Sexually Transmitted Diseases, and provides 11 recommendations organized under 4 action areas: (1) adopt a sexual health paradigm, (2) broaden ownership and accountability for responding to STIs, (3) bolster existing systems and programs for responding to STIs, and (4) embrace innovation and policy change to improve sexual health. We present our interpretive synopsis of this report, highlighting elements of particular interest to STI and sexual health practitioners, including clinicians, researchers, disease intervention specialists, community outreach workers, and public health staff. The report asserts that it is possible to create a healthier and more equitable future where fewer adolescents and adults are infected, fewer babies are born with STIs, and people entering their sexual debut and continuing throughout the life span are taught the language and skills to conceptualize and enact their own vision for what it means to be sexually healthy.

Treponema pallidum genome sequencing from six continents reveals variability in vaccine candidate genes and dominance of Nichols clade strains in Madagascar.

In spite of its immutable susceptibility to penicillin, Treponema pallidum (T. pallidum) subsp. pallidum continues to cause millions of cases of syphilis each year worldwide, resulting in significant morbidity and mortality and underscoring the urgency of developing an effective vaccine to curtail the spread of the infection. Several technical challenges, including absence of an in vitro culture system until very recently, have hampered efforts to catalog the diversity of strains collected worldwide. Here, we provide near-complete genomes from 196 T. pallidum strains-including 191 T. pallidum subsp. pallidum-sequenced directly from patient samples collected from 8 countries and 6 continents. Maximum likelihood phylogeny revealed that samples from most sites were predominantly SS14 clade. However, 99% (84/85) of the samples from Madagascar formed two of the five distinct Nichols subclades. Although recombination was uncommon in the evolution of modern circulating strains, we found multiple putative recombination events between T. pallidum subsp. pallidum and subsp. endemicum, shaping the genomes of several subclades. Temporal analysis dated the most recent common ancestor of Nichols and SS14 clades to 1717 (95% HPD: 1543-1869), in agreement with other recent studies. Rates of SNP accumulation varied significantly among subclades, particularly among different Nichols subclades, and was associated in the Nichols A subclade with a C394F substitution in TP0380, a ERCC3-like DNA repair helicase. Our data highlight the role played by variation in genes encoding putative surface-exposed outer membrane proteins in defining separate lineages, and provide a critical resource for the design of broadly protective syphilis vaccines targeting surface antigens.

The National Academies Report on Sexually Transmitted Infections: Implications for Clinical Training, Licensing, and Practice Guidelines.

Sexually transmitted infections (STIs) represent a sizable, longstanding, and growing challenge and a national public health priority. A recent National Academies report outlines new directions for STI prevention and control, including the adoption of a new sexual health paradigm and broader ownership and accountability for addressing sexual health and STIs among diverse clinical and nonclinical actors. These recommendations have important implications for infectious disease providers with STI and human immunodeficiency virus (HIV) expertise. As part of the envisioned shift toward greater prioritization of sexual health across systems for healthcare and health promotion, STI and HIV specialty providers will need to increasingly take on responsibilities as leaders in the provision of STI-related training; provision of technical assistance; and alignment of clinical training curricula, licensing criteria, and practice guidelines for healthcare generalists.

Tubal Factor Infertility, In Vitro Fertilization, and Racial Disparities: A Retrospective Cohort in Two US Clinics.

BACKGROUND: Nearly 14% of US women report any lifetime infertility which is associated with health care costs and psychosocial consequences. Tubal factor infertility (TFI) often occurs as a result of sexually transmitted diseases and subsequent pelvic inflammatory disease. We sought to evaluate for and describe potential racial disparities in TFI and in vitro fertilization (IVF) prevalence. METHODS: Records of women aged 19 to 42 years in our retrospective cohort from 2 US infertility clinics were reviewed. We calculated TFI prevalence, IVF initiation prevalence, and prevalence ratios (PRs), with 95% confidence intervals (CIs) for each estimate, overall and by race. RESULTS: Among 660 infertile women, 110 (16.7%; 95% CI, 13.8-19.5%) had TFI which was higher in Black compared with White women (30.3% [33/109] vs 13.9% [68/489]; PR, 2.2 [95% CI, 1.5-3.1]). For women with TFI, IVF was offered to similar proportions of women by race (51.5% [17/33] vs 52.9% [36/68] for Black vs White women); however, fewer Black than White women with TFI started IVF (6.7% [1/15] vs 31.0% [9/29]; PR, 0.2 [95% CI, 0-1.0]), although the difference was not statistically different. CONCLUSIONS: Tubal factor infertility prevalence was 2-fold higher among Black than White women seeking care for infertility. Among women with TFI, data suggested a lower likelihood of Black women starting IVF than White women. Improved sexually transmitted disease prevention and treatment might ameliorate disparities in TFI.

Limited Utility of Reverse Algorithm Syphilis Testing in HIV Clinic Among Men Who Have Sex With Men.

BACKGROUND: The reverse algorithm for syphilis diagnosis consists of a treponemal antibody screening immunoassay followed by confirmatory nontreponemal antibody testing. It is increasingly used in the United States despite studies suggesting limited cost-effectiveness in high-prevalence groups. METHODS: In this retrospective cross-sectional study, we included men who have sex with men tested with the reverse algorithm in an Alabama HIV clinic between March 2015 and February 2017. Trep-Sure enzyme immunoassay (EIA) was used for the initial screen, followed by reflex nontreponemal reactive rapid plasma reagin (RPR) testing of specimens with positive results. Sociodemographic and clinical data were extracted from the electronic medical record and stratified according to EIA screen positivity. Quantitative EIA antibody index values were collected to assess test performance at various thresholds. RESULTS: Among 1693 men tested for syphilis with the reverse algorithm in HIV clinic, 808 (48%) had a positive initial EIA screen. A majority (53%) of men with subsequent RPR testing had a nonreactive RPR (EIA+/RPR-), and 19% (19/98) of these EIA+/RPR- samples tested had a negative confirmatory Treponema pallidum particle agglutination testing result. Analysis of quantitative EIA index values using a receiver operating characteristics curve suggested that a threshold >8 (rather the current threshold of antibody index 1.2) improved the performance of the test. CONCLUSIONS: Among men who have sex with men tested in HIV clinic, the syphilis reverse algorithm was inefficient because of high rates of prior syphilis and false-positive EIA screening. Frequent syphilis screening in high-prevalence populations is an important part of the US epidemic response, and the traditional algorithm is preferred.

Optimising treatments for sexually transmitted infections: surveillance, pharmacokinetics and pharmacodynamics, therapeutic strategies, and molecular resistance prediction.

Progressive antimicrobial resistance in Neisseria gonorrhoeae, Mycoplasma genitalium, and Trichomonas vaginalis has created a pressing need for treatment optimisations for sexually transmitted infections (STIs). In this Review, we aim to highlight urgent needs in global STI management, including: (1) improved surveillance to monitor antimicrobial resistance and clinical outcomes; (2) systematic pharmacokinetic and pharmacodynamic evaluations to ensure resistance suppression and bacterial eradication at all sites of infection; (3) development of novel, affordable antimicrobials; and (4) advancements in new molecular and point-of-care tests to detect antimicrobial resistance determinants. Antimicrobial resistance among STIs is a global public health crisis. Continuous efforts to develop novel antimicrobials will be essential, in addition to other public health interventions to reduce the global STI burden. Apart from prevention through safer sexual practices, the development of STI vaccines to prevent transmission is a crucial research priority.

Gonococcal vaccines: Public health value and preferred product characteristics; report of a WHO global stakeholder consultation, January 2019.

Renewed interest in developing vaccines against Neisseria gonorrhoeae has been sparked by the increasing threat of gonococcal antimicrobial resistance (AMR) and growing optimism that gonococcal vaccines are biologically feasible. Evidence suggests serogroup B Neisseria meningitidis vaccines might provide some cross-protection against N. gonorrhoeae, and new gonococcal vaccine candidates based on several approaches are currently in preclinical development. To further stimulate investment and accelerate development of gonococcal vaccines, greater understanding is needed regarding the overall value that gonococcal vaccines might have in addressing public health and societal goals in low-, middle-, and high-income country contexts and how future gonococcal vaccines might be accepted and used, if available. In January 2019, the World Health Organization (WHO) convened a multidisciplinary international group of experts to lay the groundwork for understanding the potential health, economic, and societal value of gonococcal vaccines and their likely acceptance and use, and for developing gonococcal vaccine preferred product characteristics (PPCs). WHO PPCs describe preferences for vaccine attributes that would help optimize vaccine value and use in meeting the global public health need. This paper describes the main discussion points and conclusions from the January 2019 meeting of experts. Participants emphasized the need for vaccines to control N. gonorrhoeae infections with the ultimate goals of preventing adverse sexual and reproductive health outcomes (e.g., infertility) and reducing the impact of gonococcal AMR. Meeting participants also discussed important PPC considerations (e.g., vaccine indications, target populations, and potential immunization strategies) and highlighted crucial research and data needs for guiding the value assessment and PPCs for gonococcal vaccines and advancing gonococcal vaccine development.

Characteristics of Mycoplasma genitalium Urogenital Infections in a Diverse Patient Sample from the United States: Results from the Aptima Mycoplasma genitalium Evaluation Study (AMES).

Data from a large prospective multicenter clinical validation study of a nucleic acid amplification in vitro diagnostic test for Mycoplasma genitalium were analyzed to describe the prevalence of M. genitalium infection, risk factors, and disease associations in female and male patients seeking care in diverse geographic regions of the United States. Among 1,737 female and 1,563 male participants, the overall prevalence of M. genitalium infection was 10.3% and was significantly higher in persons ages 15 to 24 years than in persons ages 35 to 39 years (for females, 19.8% versus 4.7% [odds ratio {OR} = 5.05; 95% confidence interval {CI} = 3.01 to 8.46]; for males, 16.5% versus 9.4% [OR = 1.91; 95% CI = 1.20 to 3.02]). The risk for M. genitalium infection was higher in black than in white participants (for females, 12.0% versus 6.8% [OR = 1.88; 95% CI = 1.30 to 2.72]; for males, 12.9% versus 6.9% [OR = 2.02; 95% CI = 1.38 to 2.96]) and higher in non-Hispanic than in Hispanic participants (for females, 11.2% versus 6.0% [OR = 1.97; 95% CI = 1.25 to 3.10]; for males, 11.6% versus 6.8% [OR = 1.80; 95% CI = 1.14 to 2.85]). Participants reporting urogenital symptoms had a significantly elevated risk of M. genitalium infection compared to that for asymptomatic individuals (for females, OR = 1.53 [95% CI = 1.09 to 2.14]; for males, OR = 1.42 [95% CI = 1.02 to 1.99]). Women diagnosed with vaginitis and cervicitis had a higher prevalence of M. genitalium infection than women without those diagnoses, although this was statistically significant only for vaginitis (for vaginitis, OR = 1.88 [95% CI = 1.37 to 2.58]; for cervicitis, OR = 1.42 [95% CI = 0.61 to 2.96]). A diagnosis of urethritis in men was also significantly associated with M. genitalium infection (OR = 2.97; 95% CI = 2.14 to 4.13). Few characteristics distinguished asymptomatic from symptomatic M. genitalium infections. These results from persons seeking care in the United States suggest that M. genitalium infection should be considered in young persons presenting with urogenital symptoms.

Development of New Antimicrobials for Urogenital Gonorrhea Therapy: Clinical Trial Design Considerations.

Gonorrhea remains a major public health challenge, and current recommendations for gonorrhea treatment are threatened by evolving antimicrobial resistance and a diminished pipeline for new antibiotics. Evaluations of potential new treatments for gonorrhea currently make limited use of new understanding of the pharmacokinetic and pharmacodynamic contributors to effective therapy, the prevention of antimicrobial resistance, and newer designs for clinical trials. They are hampered by the requirement to utilize combination ceftriaxone/azithromycin therapy as the comparator regimen in noninferiority trials designed to seek an indication for gonorrhea therapy. Evolving gonococcal epidemiology and clinical trial design constraints hinder the enrollment of those populations at the greatest risk for gonorrhea (adolescents, women, and persons infected with antibiotic-resistant Neisseria gonorrhoeae). This article summarizes a recent meeting on the evaluation process for antimicrobials for urogenital gonorrhea treatment and encourages the consideration of new designs for the evaluation of gonorrhea therapy.

Gonorrhoea.

The bacterium Neisseria gonorrhoeae causes the sexually transmitted infection (STI) gonorrhoea, which has an estimated global annual incidence of 86.9 million adults. Gonorrhoea can present as urethritis in men, cervicitis or urethritis in women, and in extragenital sites (pharynx, rectum, conjunctiva and, rarely, systemically) in both sexes. Confirmation of diagnosis requires microscopy of Gram-stained samples, bacterial culture or nucleic acid amplification tests. As no gonococcal vaccine is available, prevention relies on promoting safe sexual behaviours and reducing STI-associated stigma, which hinders timely diagnosis and treatment thereby increasing transmission. Single-dose systemic therapy (usually injectable ceftriaxone plus oral azithromycin) is the recommended first-line treatment. However, a major public health concern globally is that N. gonorrhoeae is evolving high levels of antimicrobial resistance (AMR), which threatens the effectiveness of the available gonorrhoea treatments. Improved global surveillance of the emergence, evolution, fitness, and geographical and temporal spread of AMR in N. gonorrhoeae, and improved understanding of the pharmacokinetics and pharmacodynamics for current and future antimicrobials in the treatment of urogenital and extragenital gonorrhoea, are essential to inform treatment guidelines. Key priorities for gonorrhoea control include strengthening prevention, early diagnosis, and treatment of patients and their partners; decreasing stigma; expanding surveillance of AMR and treatment failures; and promoting responsible antimicrobial use and stewardship. To achieve these goals, the development of rapid and affordable point-of-care diagnostic tests that can simultaneously detect AMR, novel therapeutic antimicrobials and gonococcal vaccine(s) in particular is crucial.