A Narrative Review on Spontaneous Clearance of Urogenital Chlamydia trachomatis: Host, Microbiome, and Pathogen-Related Factors.

ABSTRACT: Chlamydia trachomatis (CT) is the most commonly reported sexually transmitted infection in the United States. Untreated urogenital infection in women can result in adverse sequelae such as pelvic inflammatory disease and infertility. Despite national screening and treatment guidelines, rates continue to rise; because most infections are asymptomatic, the actual prevalence of CT infection is likely significantly higher than reported. Spontaneous clearance of CT in women (in the absence of antibiotic treatment) has been described in multiple epidemiologic studies. Given the serious consequences and high prevalence of CT infection, there is growing interest in understanding this phenomenon and factors that may promote CT clearance in women. Spontaneous CT clearance is likely the result of complex interactions between CT, the host immune system, and the vaginal microbiota (i.e., the communities of bacteria inhabiting the vagina), which has been implicated in CT acquisition. Herein, we briefly review current literature regarding the role of each of these factors in spontaneous CT clearance, identify knowledge gaps, and discuss future directions and possible implications for the development of novel interventions that may protect against CT infection, facilitate clearance, and prevent reproductive sequelae.

State-of-the-Art Review: Neurosyphilis.

We review key concepts in the diagnosis, treatment, and follow-up of individuals with neurosyphilis. We describe the epidemiology of syphilis in the United States, highlight populations that are markedly affected by this infection, and attempt to estimate the burden of neurosyphilis. We describe the cardinal clinical features of early and late (tertiary) neurosyphilis and characterize the clinical significance of asymptomatic neurosyphilis in the antibiotic era. We review the indications for cerebrospinal fluid (CSF) examination and the performance characteristics of different CSF assays including treponemal and lipoidal antibodies, white cell count, and protein concentration. Future biomarkers and the role of imaging are briefly considered. We review preferred and alternative treatments for neurosyphilis and evidence for their use, including evidence for the use of enhanced intramuscular benzathine penicillin G to supplement intravenous penicillin.

A patient with secondary syphilis following incomplete treatment of primary infection.

Syphilis is a bacterial infection caused by Treponema pallidum and is primarily transmitted via skin-to-skin or mucosal contact during sexual encounters, or through vertical transmission during pregnancy. Cases continue to rise globally across various demographic groups despite effective treatment and prevention interventions. We discuss the case of a 28-year-old cisgender man who presented with secondary syphilis 1 month after being inadequately treated for primary syphilis. Individuals can present with symptoms and signs of syphilis to clinicians of various subspecialties due to diverse clinical presentation. All health-care providers should be able to identify the common and less common manifestations of this infection, and adequate treatment and follow-up are crucial to preventing serious sequelae. Novel biomedical prevention interventions, such as doxycycline post-exposure prophylaxis, are on the horizon.

Bacterial Vaginosis and Spontaneous Clearance of Chlamydia trachomatis in the Longitudinal Study of Vaginal Flora.

BACKGROUND: Up to 26% of urogenital Chlamydia trachomatis infections spontaneously resolve between detection and treatment. Mechanisms governing natural resolution are unknown. We examined whether bacterial vaginosis (BV) was associated with greater chlamydia persistence versus spontaneous clearance in a large, longitudinal study. METHODS: Between 1999 and 2003, the Longitudinal Study of Vaginal Flora followed reproductive-age women quarterly for 1 year. Baseline chlamydia screening and treatment were initiated after ligase chain reaction testing became available midstudy, and unscreened endocervical samples were tested after study completion. Chlamydia clearance and persistence were defined between consecutive visits without chlamydia-active antibiotics (n = 320 persistence/n = 310 clearance). Associations between Nugent score (0-3, no BV; 4-10, intermediate/BV), Amsel-BV, and chlamydia persistence versus clearance were modeled with alternating and conditional logistic regression. RESULTS: Of chlamydia cases, 48% spontaneously cleared by the next visit (310/630). Nugent-intermediate/BV was associated with higher odds of chlamydia persistence (adjusted odds ratio [aOR] = 1.89; 95% confidence interval [CI], 1.30-2.74), and the findings were similar for Amsel-BV (aOR 1.39; 95% CI, .99-1.96). The association between Nugent-intermediate/BV and chlamydia persistence was stronger in a within-participant analysis of 67 participants with both clearance/persistence intervals (aOR = 4.77; 95% CI, 1.39-16.35). BV symptoms did not affect any results. CONCLUSIONS: BV is associated with greater chlamydia persistence. Optimizing the vaginal microbiome may promote chlamydia clearance.

Association of Pregnancy and HIV Status With Molecular-Bacterial Vaginosis in Indian Women.

BACKGROUND: Bacterial vaginosis (BV) is a highly prevalent disorder of the cervicovaginal microbiota. Molecular-BV may put women at increased risk for adverse reproductive and obstetric outcomes. We investigated the association of HIV and pregnancy on the vaginal microbiota and associations with molecular-BV in women of reproductive age from Pune, India. SETTING: We studied vaginal samples from N = 170 women, including N = 44 nonpregnant HIV seronegative, N = 56 pregnant seronegative, N = 47 nonpregnant women with HIV (WWH), and N = 23 pregnant WWH, and collected data on clinical, behavioral, and demographic factors. METHODS: We used 16S rRNA gene amplicon sequencing to characterize the composition of the vaginal microbiota. We classified the vaginal microbiota of these women into community state types based on bacterial composition and relative abundance and further categorized them into molecular-BV versus Lactobacillus -dominated states. To determine associations between pregnancy and HIV status with outcome of molecular-BV, logistic regression models were used. RESULTS: There was a high prevalence of molecular-BV (30%) in this cohort. We found that pregnancy was associated with decreased odds of molecular-BV (adjusted OR = 0.35, 95% CI: 0.14 to 0.87), while HIV was associated with increased odds of molecular-BV (adjusted OR = 2.76, 95% CI: 1.33 to 5.73), even when controlling for multiple relevant factors such as age, number of sexual partners, condom use, and douching. CONCLUSION: Larger and longitudinal studies are needed to further characterize molecular-BV and the vaginal microbiota in pregnant women and WWH and relate these factors to infectious, reproductive, and obstetric outcomes. In the long term, these studies may lead to novel microbiota-based therapeutics to improve women's reproductive and obstetric health.

The Utility of Biomarkers in the Clinical Management of Syphilis: A Systematic Review.

BACKGROUND: Routinely available laboratory tests for Treponema pallidum remain suboptimal for diagnostic, prognostic, predictive, and monitoring purposes. Biomarkers with enhanced performance characteristics can improve diagnostic confidence and facilitate management. We conducted a systematic review to examine the utility of biomarkers in the diagnosis and management of syphilis. METHODS: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses to identify articles for inclusion and independently reviewed them for eligibility and study quality using a 3-stage procedure. The search, conducted by a senior library informationist, used PubMed, Embase, Cochrane Library, and Scopus and included any study published before May 2022. RESULTS: Of the 111 studies identified, 31 (27.9%) were included in our review. Most studies were cross-sectional or prospective. The data were strikingly heterogeneous examining a variety of biomarkers across different syphilis stages, using different methodologies and definitions of treatment success. Available publications chiefly focused on diagnosing various syphilis stages, neurosyphilis and congenital syphilis, serological cure, the serofast state, and reinfection. CONCLUSIONS: Despite increasing attempts to identify novel biomarkers, we found limited evidence to support the use of any biomarker in clinical decision making at this time; the syphilis biomarker literature is heterogenous and lacks measurement of clinically meaningful end points. We recommend the formation of a working group to set priorities for syphilis biomarker research and to guide future study of clinically meaningful biomarkers.

Vaginal Candida albicans: High Frequency of in Vitro Fluconazole Resistance in a Select Population-A Brief Note.

Among clinician-ordered vaginal cultures positive for Candida albicans , 30% exhibited fluconazole resistance. Resistance did not reliably predict future susceptibility. Prospective studies to verify associations with demographic and clinical factors as well as to correlate in vitro resistance with treatment response and longitudinal resistance patterns are needed.

Lactobacillus-dominance and rapid stabilization of vaginal microbiota in combined oral contraceptive pill users examined through a longitudinal cohort study with frequent vaginal sampling over two years.

BACKGROUND: Bacterial vaginosis (BV), a condition in which vaginal Lactobacillus spp. are in low abundance, is associated with vulvovaginal symptoms, obstetric outcomes and urogenital infections. Recurrent BV is difficult to manage, and emerging data indicate a reduced risk of BV with the use of hormonal contraception (HC). Despite widespread use, little longitudinal data is available on whether, and in what timeframe, combined oral contraceptive pills (COCs) may act to affect vaginal microbiota stability and Lactobacillus dominance. METHODS: We compared the vaginal microbiota of reproductive-age cisgender women during intervals on combined estrogen and progestin COCs with non-use intervals in a 2-year observational study. Vaginal microbiota were characterized by 16S rRNA gene amplicon sequencing. FINDINGS: COC users were more likely to have Lactobacillus-dominated microbiota and more stable microbiota over time. Stability increased and then plateaued four weeks after COC initiation. The associations between COCs and Lactobacillus spp. dominance, and microbiota stability, were statistically significant for White, but not African American women; however sample size was limited for African American participants. Findings were similar for other forms of HC and when excluding samples collected during menses. INTERPRETATION: Our study provides a methodologic framework to evaluate observational longitudinal microbiota data with exposure crossovers. We found COCs are associated with vaginal microbiota stability and a Lactobacillus-dominated state. COCs appear to impact stability within a month of initiation. Our findings have clinical implications for how soon benefits can be expected in (at least White) patients initiating COCs, and support the need for larger prospective trials to verify our results in ethnically diverse populations. FUNDING: R01-AI089878.

Enacted Sexual Minority Stigma, Psychological Distress, and Sexual and Drug Risk Behaviors Among Urban Men Who Have Sex with Men (MSM).

Urban Black men who have sex with men (MSM) bear a disproportionate burden of HIV and syphilis in the U.S. Experiences of enacted sexual minority stigma and psychological distress among these men may be associated with HIV/STI sexual and drug risk behaviors. The objective was to determine the associations between enacted sexual minority stigma, psychological distress, and sexual and drug risk behaviors. In an urban prospective cohort study, survey measures assessed past 3-month exposure to enacted sexual minority stigma, psychological distress, and sexual and drug risk behaviors. Multivariable logistic regression models were utilized for hypothesis testing. The Black MSM (N = 140) reported the following: 22.1% experiences of enacted sexual minority stigma, 39% high levels of psychological distress, 48.6% > 1 sex partner, 8.6% transactional sex, and 6% injection drug use (IDU). In models adjusted for age and education, enacted sexual minority stigma significantly increased the odds of reporting > 1 sex partner, transactional sex, and IDU. Adjusting additionally for homelessness, the association between enacted sexual minority stigma and transactional sex remained significant. Adding psychological distress to this model showed a significant association between psychological distress and transactional sex, while the association was no longer significant for transactional sex. These findings highlight some of the complex psycho-social relationships that may be associated with sexual and drug risk behaviors among Black MSM placing them at increased risk for HIV and syphilis.

RESUMEN: Hombres urbanos de raza Negra que tienen sexo con hombres (HSH) sobrellevan una carga desproporcionada de VIH y sífilis en los EE.UU. Experiencias de estigma efectivo de minoría sexual y angustia psicológica entre estos hombres pudiese ser asociado con conductas sexuales de riesgo VIH/ITS y drogas. El objetivo era determinar las asociaciones entre un estigma efectivo de minoría sexual, angustia psicológica, y comportamientos sexuales y de riesgo de drogas. En un estudio de cohortes prospectivo urbano, las medidas de la encuesta evaluada en los últimos tres meses de exposición al estigma efectivo, angustia psicológica, y sus conductas sexuales y comportamientos riesgoso de drogas. Modelos de regresión logística multivariante se utilizaron para la prueba de hipótesis. Los HSH de raza negra (N = 140) reportaron lo siguiente: 22.1% experiencias de estigma efectivo, 39% niveles altos de angustia psicológica, 48.6% y > 1 pareja sexual, 8.6% sexo transaccional, y 6% uso de drogas inyectables (UDI). En modelos ajustados a edad y educación, un estigma efectivo de minoría sexual aumentó de manera significante las probabilidades de reportar y > 1 pareja sexual, sexo transaccional, y UDI. Ajustando adicionalmente para personas sin vivienda, la asociación entre estigma efectivo de minoría sexual y sexo transaccional permaneció significante. La adición de angustia psicológica al modelo mostró una asociación significativa entre angustia psicológica y sexo transaccional, mientras que la asociación ya no era significativa para el sexo transaccional. Estos resultados destacan algunas de las complejas relaciones psicosociales que pudiesen estar asociadas con conductas sexuales y de riesgo de drogas entre HSH de raza negra, poniéndolos a mayor riesgo de contraer VIH y sífilis.

Douching cessation and molecular bacterial vaginosis: a reanalysis of archived specimens.

OBJECTIVES: Observational studies demonstrate an association between vaginal douching and bacterial vaginosis (BV) characterised by Gram stain. We sought to describe the effect of a douching cessation intervention on the composition and structure of the vaginal microbiota and molecular-BV, a state defined by low levels of Lactobacillus spp evaluated by molecular tools. METHODS: 33 women self-collected mid-vaginal swabs twice weekly (982 samples) during a douching observation phase (4 weeks) followed by a douching cessation phase (12 weeks) in a 2005 single crossover pilot study conducted in Baltimore, Maryland. Vaginal microbiota were characterised by 16S rRNA gene amplicon sequencing (V3-V4) and clustered into community state types (CSTs). Conditional logistic regression modelling allowed each participant to serve as their own control. Wilcoxon signed-rank tests were used to evaluate changes in microbiota between phases. Broad-range qPCR assays provided estimates of bacterial absolute abundance per swab in a subsample of seven participants before and after douching. A piecewise linear mixed effects model was used to assess rates of change in bacterial absolute abundance before and after douching. RESULTS: There was no statistically significant change in the odds of molecular-BV versus Lactobacillus-dominated CSTs comparing the douching cessation interval to douching observation (adjusted OR 1.77, 95% CI 0.89 to 3.55). Removal of L. iners-dominated CST III from the outcome did not affect the results. There were no significant changes in the relative abundance of four Lactobacillus spp and no meaningful changes in other taxa investigated. There was no significant change in bacterial absolute abundance between a participant's sample collected 3 days prior to and following douching (p=0.46). CONCLUSIONS: In this pilot study, douching cessation was not associated with major changes in vaginal microbiota. Douching cessation alone may not durably shift the vaginal microbiota and additional interventions may be needed to restore optimal vaginal microbiota among those who douche.

Psychological distress and adherence to anti-retroviral therapy or pre-exposure prophylaxis regimens among Urban Black gay and bisexual men (MSM).

BACKGROUND: Urban Black gay, and bisexual men (MSM) bear a disproportionate burden of HIV in the U.S. Mental health is a barrier to adherence to both antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP). The objective was to determine the association between psychological distress and ART or PrEP adherence among urban Black MSM. METHODS: Using data from a four-year prospective cohort study, adherence to ART was defined as > 95% and PrEP was defined as > 80% of doses taken in the past 30 days. Psychological distress measures included difficulty sleeping; feeling anxious; suicidality; feeling sad or depressed; feeling sick, ill, or not well in the past 3 months; high (vs. low) overall psychological distress was classified as above the median value. Associations were examined using Chi-square, Fisher's exact tests, and logistic regression. RESULTS: Among 165 Black MSM, 44.2% (73) reported high psychological distress. 65.3% (47/72) of participants living with HIV and 39.8% (37/93) of HIV negative participants were ART or PrEP adherent, respectively. Education was significantly associated with PrEP adherence (p = 0.038). Non-injection drug use in the past 3 months (p = 0.008), difficulty sleeping (p = 0.010), feeling anxious (p = 0.003), and feeling sad or depressed (p < 0.001), and overall psychological distress (p < 0.001) were significantly associated with ART adherence. High psychological distress was significantly associated with a reduced odds of ART adherence (aOR 0.23; 95% CI = 0.08-0.70) adjusting for age and non-injection drug use. CONCLUSIONS: Increased psychological distress was significantly associated with ART nonadherence and may represent an important barrier to viral suppression.

Summary of the Fourth Annual American Sexually Transmitted Diseases Association Workshop on Improving Sexually Transmitted Infection Control Efforts Through Cross-Sector Collaboration.

ABSTRACT: The American Sexually Transmitted Diseases Association has, for several years, been conducting a cross-sector workshop to bring together a variety of stakeholders to develop ideas for collaboratively improving the sexually transmitted infection control efforts in the United States. In this summary, we share the content of discussions and ideas of the fourth annual workshop for future research and potential changes to practice with a focus on diagnostic capacity.

Management of Adult Syphilis: Key Questions to Inform the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines.

A panel of experts generated 5 "key questions" in the management of adult syphilis. A systematic literature review was conducted and tables of evidence were constructed to answer these questions. Available data suggest no clinical benefit to >1 dose of benzathine penicillin G for early syphilis in human immunodeficiency virus (HIV)-infected patients. While penicillin remains the drug of choice to treat syphilis, doxycycline to treat early and late latent syphilis is an acceptable alternate option if penicillin cannot be used. There are very limited data regarding the impact of additional antibiotic doses on serologic responses in serofast patients and no data on the impact of additional antibiotic courses on long-term clinical outcomes. In patients with isolated ocular or otic signs and symptoms, reactive syphilis serologic results, and confirmed ocular/otic abnormalities at examination, a diagnostic cerebrospinal fluid (CSF) examination is not necessary, because up to 40% and 90% of patients, respectively, would have no CSF abnormalities. Based on the results of 2 studies, repeated CSF examinations are not necessary for HIV-uninfected patients or HIV-infected patients on antiretroviral therapy who exhibit appropriate serologic and clinical responses after treatment for neurosyphilis. Finally, several important gaps were identified and should be a priority for future research.

Sexually Transmitted Infection Transmission Dynamics During the Coronavirus Disease 2019 (COVID-19) Pandemic Among Urban Gay, Bisexual, and Other Men Who Have Sex With Men.

BACKGROUND: The impact of coronavirus disease 2019 (COVID-19) mitigation measures on sexually transmitted infection (STI) transmission and racial disparities remains unknown. Our objectives were to compare sex and drug risk behaviors, access to sexual health services, and STI positivity overall and by race during the COVID-19 pandemic compared with pre-pandemic among urban sexual minority men (MSM). METHODS: Sexually active MSM aged 18-45 years were administered a behavioral survey and STI testing every 3-months. Participants who completed at least 1 during-pandemic (April 2020-December 2020) and 1 pre-pandemic study visit (before 13 March 2020) that occurred less than 6 months apart were included. Regression models were used to compare during- and pre-pandemic visit outcomes. RESULTS: Overall, among 231 MSM, reports of more than 3 sex partners declined(pandemic-1: adjusted prevalence ratio 0.68; 95% confidence interval: .54-.86; pandemic-2: 0.65, .51-.84; pandemic-3: 0.57, .43-.75), substance use decreased (pandemic-1: 0.75, .61-.75; pandemic-2: 0.62, .50-.78; pandemic-3: 0.61, .47-.80), and human immunodeficiency virus/preexposure prophylaxis care engagement (pandemic-1: 1.20, 1.07-1.34; pandemic-2: 1.24, 1.11-1.39; pandemic-3: 1.30, 1.16-1.47) increased. STI testing decreased (pandemic-1: 0.68, .57-.81; pandemic-2: 0.78, .67-.92), then rebounded (pandemic-3: 1.01, .87-1.18). Nei-ther Chlamydia (pandemic-2: 1.62, .75-3.46; pandemic-3: 1.13, .24-1.27) nor gonorrhea (pandemic-2: 0.87, .46 1.62; pandemic-3: 0.56, .24-1.27) positivity significantly changed during vs pre-pandemic. Trends were mostly similar among Black vs. non-Black MSM. CONCLUSIONS: We observed sustained decreases in STI risk behaviors but minimal change in STI positivity during compared with pre-pandemic. Our findings underscore the need for novel STI prevention strategies that can be delivered without in-person interactions.

Diagnosis and Treatment of Sexually Transmitted Infections: A Review.

Importance: Approximately 1 in 5 adults in the US had a sexually transmitted infection (STI) in 2018. This review provides an update on the epidemiology, diagnosis, and treatment of gonorrhea, chlamydia, syphilis, Mycoplasma genitalium, trichomoniasis, and genital herpes. Observations: From 2015 to 2019, the rates of gonorrhea, chlamydia, and syphilis increased in the US; from 1999 to 2016, while the rates of herpes simplex virus type 1 (HSV-1) and HSV-2 declined. Populations with higher rates of STIs include people younger than 25 years, sexual and gender minorities such as men and transgender women who have sex with men, and racial and ethnic minorities such as Black and Latinx people. Approximately 70% of infections with HSV and trichomoniasis and 53% to 100% of extragenital gonorrhea and chlamydia infections are asymptomatic or associated with few symptoms. STIs are associated with HIV acquisition and transmission and are the leading cause of tubal factor infertility in women. Nucleic acid amplification tests have high sensitivities (86.1%-100%) and specificities (97.1%-100%) for the diagnosis of gonorrhea, chlamydia, M genitalium, trichomoniasis, and symptomatic HSV-1 and HSV-2. Serology remains the recommended method to diagnose syphilis, typically using sequential testing to detect treponemal and nontreponemal (antiphospholipid) antibodies. Ceftriaxone, doxycycline, penicillin, moxifloxacin, and the nitroimidazoles, such as metronidazole, are effective treatments for gonorrhea, chlamydia, syphilis, M genitalium, and trichomoniasis, respectively, but antimicrobial resistance limits oral treatment options for gonorrhea and M genitalium. No cure is available for genital herpes. Effective STI prevention interventions include screening, contact tracing of sexual partners, and promoting effective barrier contraception. Conclusions and Relevance: Approximately 1 in 5 adults in the US had an STI in 2018. Rates of gonorrhea, chlamydia, and syphilis in the US have increased, while rates of HSV-1 and HSV-2 have declined. Ceftriaxone, doxycycline, penicillin, moxifloxacin, and the nitroimidazoles are effective treatments for gonorrhea, chlamydia, syphilis, Mycoplasma genitalium, and trichomoniasis, respectively, but antimicrobial resistance limits oral therapies for gonorrhea and Mycoplasma genitalium, and no cure is available for genital herpes.

HIV Transmission Potential and Sex Partner Concurrency: Evidence for Racial Disparities in HIV Risk Among Gay and Bisexual Men (MSM).

We determined whether racial disparities in HIV infection among gay and bisexual men (MSM) may be partially explained by racial differences in the HIV transmission potential (i.e. mixing of people living with HIV and people not living with HIV or of unknown HIV serostatus) and density (i.e. sex partner concurrency) of sexual networks. Data included a behavioral survey, testing for HIV, and an egocentric sexual network survey. Mixed effects logistic regressions were used for hypothesis testing. Black (vs. non-Black) MSM were more likely to not know their partner's HIV serostatus (21.8% vs. 9.6%). Similar proportions reported sex partner concurrency (67.1% vs. 68.0%). In adjusted analyses, among Black MSM, sex partner concurrency significantly increased the odds of an HIV transmission potential partnership (TPP), and this association was not significant among non-Black indexes. The association between an HIV TPP and sex partner concurrency may help explain persistent racial disparities in HIV prevalence.

RESUMEN: Determinamos si las disparidades raciales en infecciones del VIH entre hombres homosexuales y bisexuales (hombres que tienen sexo con hombres) puede ser parcialmente explicado por diferencias raciales en el potencial de transmisión del VIH (es decir, mezcla de personas viviendo con VIH y personas que no viven con VIH o cuyo estado serológico del VIH es desconocido) y densidad (es decir, concurrencia de pareja sexual) de redes sexuales. Los datos incluyeron una encuesta de comportamiento, pruebas para el VIH y una encuesta de redes sexuales egocéntrica. Regresiones logísticas de efectos mixtos fueron usados para la prueba de hipótesis. HSH negros (vs. HSH no-negros) eran más propensos a no saber el estado serológico del VIH de su pareja (21.8% vs. 9.6%). Proporciones similares reportaron concurrencia de pareja sexual (67.1% vs. 68.0%). En análisis ajustados, entre HSH negros, la concurrencia de pareja sexual aumentó significativamente las probabilidades de una asociación potencial de transmisión del VIH (TPP por sus siglas en inglés), y esta asociación no fue significativa entre índices de no-negros. La asociación entre una TPP VIH y concurrencia de pareja sexual puede ayudar a explicar disparidades raciales persistentes en la prevalencia del VIH.