There is an unmet need for developing drugs for the treatment of gonorrhea due to rapidly evolving resistance of Neisseria gonorrhoeae against antimicrobial drugs used for empiric therapy, an increase in globally reported multidrug-resistant cases, and the limited available therapeutic options. Furthermore, few drugs are under development. Development of antimicrobials is hampered by challenges in clinical trial design, limitations of available diagnostics, changes in and varying standards of care, lack of robust animal models, and clinically relevant pharmacodynamic targets. On 23 April 2021, the US Food and Drug Administration, Centers for Disease Control and Prevention, and National Institute of Allergy and Infectious Diseases of the National Institutes of Health co-sponsored a workshop with stakeholders from academia, industry, and regulatory agencies to discuss the challenges and strategies, including potential collaborations and incentives, to facilitate the development of drugs for the treatment of gonorrhea. This article provides a summary of that workshop.

Background:Congenital syphilis rates in the United States have increased significantly over the past decade. Syphilis is a curable infection with the potential for lifelong sequelae in the absence of timely diagnosis and treatment. Routine serologic syphilis screening is universally recommended during prenatal care with the traditional or the reverse diagnostic algorithm. False positive syphilis serologic testing in pregnancy can occur and comparative performance data for recommended algorithms in pregnancy are limited. Primary objective:To compare the performance of the traditional algorithm and the reverse algorithm for the diagnosis of syphilis in pregnancy. Study design:This retrospective analysis included pregnant women who delivered at our tertiary care center in the Southeastern United States during a period of increasing syphilis rates with testing performed between November 1, 2012 and December 31, 2019. We evaluated results according to the diagnostic algorithm used by facility laboratories at the time of syphilis screening (traditional 2012-2014 and reverse 2015-2019). Screen positivity, false positive test results, confirmed infection, and pregnancy outcomes were compared between the two periods. For secondary outcomes, multivariable logistic regression models were conducted to identify factors associated with false positive screening results and confirmed infection including maternal age, race, insurance status, test timing and location, and human immunodeficiency virus/sexually transmitted infection coinfection. Results:Of 26,519 pregnant women tested for syphilis during the study period, 8781 were evaluated using the traditional algorithm and 17,738 were evaluated using the reverse algorithm. Mean age was 27.9 years, 85.3% of women were initially screened in the first trimester, and the mean number of syphilis testing episodes in pregnancy was 2.3. Screen positivity was 0.6% among women screened using the traditional algorithm compared to 1.6% for those tested with the reverse algorithm (p < 0.001). The proportion diagnosed with confirmed infection was similar in both algorithms: 0.2% traditional algorithm versus 0.3% reverse algorithm. Among those who screened positive with follow-up testing performed, 52.4% and 60.4% were classified as falsely positive with negative confirmatory testing with the traditional algorithm and the reverse algorithms, respectively. In an adjusted model, delayed testing in pregnancy (odds ratio [OR], 22.8; 95% confidence interval [CI], 14.1-36.8 for ≥28 weeks compared to <14 weeks), inpatient or ER screening location (OR, 22.7; 95% CI, 13.4-38.4 vs. clinic), Black race (OR, 5.4; 95% CI, 3.2-9.2) compared to White, other sexually transmitted infection in pregnancy (OR, 2.2; 95% CI, 1.2-4.1]), and lack of private insurance (OR, 1.8; 95% CI, 1.2-2.9) were associated with false positive syphilis screening. The same factors were associated with confirmed syphilis in pregnancy except for STI coinfection. The reverse algorithm was only associated with false positive screening in the crude model (OR, 2.2; 95% CI, 1.4-3.5). Conclusion:Syphilis screen positivity rates in pregnancy were nearly twice as high with the reverse algorithm compared to the traditional algorithm. Since false positive screening tests were common, improved diagnostic testing for active infection in pregnancy is needed.

Importance Syphilis rates have been increasing in the US for the past decade. The incidence of the Jarisch-Herxheimer reaction (JHR) after penicillin treatment for early syphilis is reported to range from 8% to 56%. Objectives To prospectively assess the incidence of JHR signs and symptoms among adults with early syphilis treated with benzathine penicillin G and to document factors associated with JHR and benzathine penicillin G treatment response outcomes. Design, Setting, and Participants The main study was designed as a phase 4 randomized clinical trial to compare the treatment efficacy of 1 vs 3 doses of benzathine penicillin G in adults with early syphilis, measured as serologic response at 6 months. A total of 249 adults with or without HIV were screened and enrolled between October 31, 2018, and March 3, 2020. Participants were screened and enrolled at 10 US study sites in the Sexually Transmitted Infections Clinical Trials Group. Statistical analysis for this secondary analysis took place between March 2023 and August 2024. Intervention Participants received a first dose of benzathine penicillin G, 2.4 million units intramuscularly, at the enrollment visit. The JHR assessment window was day 1 to day 7 after the first dose of benzathine penicillin G. Main Outcomes and Measures Primary outcomes in this study were the incidence of symptoms consistent with JHR within 7 days after benzathine penicillin G treatment. Unelicited and elicited symptoms were assessed by participant self-report using a standardized checklist during contact made by a study clinician. Factors associated with JHR were collected at baseline, and serologic treatment response was assessed at 6 months. Posttreatment incident JHR symptoms were captured as safety outcomes for this trial. Analysis was performed on an intention-to-treat basis. Results Of 249 participants, the median age was 32 years (IQR, 27-41 years), 242 (97.2%) were men, and 153 (61.4%) were living with HIV. One or more JHR symptoms occurred in 59 participants (23.7%) treated for early syphilis, with a median symptom onset at 4.9 hours (IQR, 3.0-9.2 hours) and a median duration of 12.8 hours (IQR, 5.0-24.0 hours). Symptom onset was within 12 hours of treatment for 49 of 57 participants (86.0%). Among 59 symptomatic participants, myalgias (30 [50.8%]), chills (27 [45.8%]), weakness (23 [39.0%]), and feverishness (21 [35.6%]) were most common. In adjusted models, JHR was associated with secondary syphilis (adjusted odds ratio [AOR], 2.91 [95% CI, 1.51-5.61]) and the absence of HIV (AOR for living with HIV, 0.49 [95% CI, 0.26-0.94]). The proportion of participants with a serologic treatment response to benzathine penicillin G at 6 months was higher among participants with JHR (84.7% [50 of 59] vs 68.9% [131 of 190] without JHR). Conclusions and Relevance In this prespecified secondary analysis of a randomized clinical trial of early syphilis treatment wtih benzathine penicillin G in adults, approximately 1 in 4 participants experienced short-lived JHR symptoms, which were associated with secondary syphilis stage, lack of HIV, and successful treatment outcomes at 6 months. These messages could be used in patient counseling. Trial Registration ClinicalTrials.gov Identifier: NCT03637660

BACKGROUND:For people who have anal and/or oral sex, many programs recommend genital and extragenital (defined here as anorectal and oropharyngeal) screening for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) to identify all potential sites of infection. METHODS:We assessed genital and extragenital CT and NG prevalence among people reporting extragenital sexual exposure. RESULTS:Among 343 gay and bisexual men who reported sex with men (GBMSM), 42 (12.2%) had CT with positivity of 3.5%, 9.3%, and 1.8% in the genital, anal, and oral samples, respectively. In this same group, 55 (16.0%) had NG with positivity of 5.2%, 8.5%, and 7.6% in the genital, anal, and oral samples, respectively. If only genital screening had been performed, 71.4% of CT infections and 67.3% of NG infections in GBMSM would have gone undetected. Among 96 men who only have sex with women (MSW), 10 (10.4%) had chlamydial infection-all detected in genital samples with no extragenital infections detected. Nine gonococcal infections (9.4%) were detected in MSW, with positivity of 6.3%, 2.1%, and 3.1% in the genital, anal, and oral samples, respectively. If only genital testing had been performed, no CT infections would have been missed among MSW; however, 33.3% of NG infections would have been missed. Among 329 cisgender women, 35 (10.6%) had CT with positivity of 7.9%, 6.1%, and 1.8% in the genital, anal, and oral samples, respectively. In the same group, 17 (5.2%) had NG with positivity of 4.0%, 2.1%, and 2.4% in the genital, anal, and oral samples, respectively. Among these women, 25.7% and 23.5% of CT and NG infections, respectively, would not have been detected. CONCLUSIONS:The increased case finding when including extragenital testing for GBMSM and women was confirmed in this analysis. However, the benefit-cost ratio and the clinical or public health value of extragenital screening in these different populations require further study.

Importance:Syphilis rates have been increasing in the US for the past decade. The incidence of the Jarisch-Herxheimer reaction (JHR) after penicillin treatment for early syphilis is reported to range from 8% to 56%. Objectives:To prospectively assess the incidence of JHR signs and symptoms among adults with early syphilis treated with benzathine penicillin G and to document factors associated with JHR and benzathine penicillin G treatment response outcomes. Design, Setting, and Participants:The main study was designed as a phase 4 randomized clinical trial to compare the treatment efficacy of 1 vs 3 doses of benzathine penicillin G in adults with early syphilis, measured as serologic response at 6 months. A total of 249 adults with or without HIV were screened and enrolled between October 31, 2018, and March 3, 2020. Participants were screened and enrolled at 10 US study sites in the Sexually Transmitted Infections Clinical Trials Group. Statistical analysis for this secondary analysis took place between March 2023 and August 2024. Intervention:Participants received a first dose of benzathine penicillin G, 2.4 million units intramuscularly, at the enrollment visit. The JHR assessment window was day 1 to day 7 after the first dose of benzathine penicillin G. Main Outcomes and Measures:Primary outcomes in this study were the incidence of symptoms consistent with JHR within 7 days after benzathine penicillin G treatment. Unelicited and elicited symptoms were assessed by participant self-report using a standardized checklist during contact made by a study clinician. Factors associated with JHR were collected at baseline, and serologic treatment response was assessed at 6 months. Posttreatment incident JHR symptoms were captured as safety outcomes for this trial. Analysis was performed on an intention-to-treat basis. Results:Of 249 participants, the median age was 32 years (IQR, 27-41 years), 242 (97.2%) were men, and 153 (61.4%) were living with HIV. One or more JHR symptoms occurred in 59 participants (23.7%) treated for early syphilis, with a median symptom onset at 4.9 hours (IQR, 3.0-9.2 hours) and a median duration of 12.8 hours (IQR, 5.0-24.0 hours). Symptom onset was within 12 hours of treatment for 49 of 57 participants (86.0%). Among 59 symptomatic participants, myalgias (30 [50.8%]), chills (27 [45.8%]), weakness (23 [39.0%]), and feverishness (21 [35.6%]) were most common. In adjusted models, JHR was associated with secondary syphilis (adjusted odds ratio [AOR], 2.91 [95% CI, 1.51-5.61]) and the absence of HIV (AOR for living with HIV, 0.49 [95% CI, 0.26-0.94]). The proportion of participants with a serologic treatment response to benzathine penicillin G at 6 months was higher among participants with JHR (84.7% [50 of 59] vs 68.9% [131 of 190] without JHR). Conclusions and Relevance:In this prespecified secondary analysis of a randomized clinical trial of early syphilis treatment wtih benzathine penicillin G in adults, approximately 1 in 4 participants experienced short-lived JHR symptoms, which were associated with secondary syphilis stage, lack of HIV, and successful treatment outcomes at 6 months. These messages could be used in patient counseling. Trial Registration:ClinicalTrials.gov Identifier: NCT03637660.

BACKGROUND:Controversy persists regarding the appropriate duration of therapy with benzathine penicillin G in persons with early (i.e., primary, secondary, or early latent) syphilis (Treponema pallidum infection). METHODS:In a multicenter, randomized, controlled, noninferiority trial, we assigned persons who had early syphilis, with or without human immunodeficiency virus (HIV) infection, to receive intramuscular injections of benzathine penicillin G in a one-time dose of 2.4 million units or in doses of 2.4 million units administered at three successive weekly intervals. The primary end point was seroreversion to nonreactive status or a decrease in the rapid plasma reagin titer by two or more dilutions at 6 months, referred to here as a serologic response (noninferiority margin, 10 percentage points). A key secondary end point was a serologic response within subgroups defined according to HIV status, also assessed in a noninferiority analysis. RESULTS:A total of 249 persons with early syphilis were enrolled. Most participants were men (97%), 62% were Black, and 153 (61%) were living with HIV infection. The distribution according to syphilis stage was 19% with primary syphilis, 47% with secondary syphilis, and 33% with early latent syphilis. The percentage of participants with a serologic response at 6 months was 76% (95% confidence interval [CI], 68 to 82) in the single-dose group and 70% (95% CI, 61 to 77) in the three-dose group (difference, -6 percentage points; 90% CI, -15 to 3, indicating noninferiority). No clinical relapse or treatment failure occurred in either group. In the one-dose group, a serologic response at 6 months was observed in 76% of participants who had HIV infection and 76% of those who did not, and in the three-dose group, a serologic response at 6 months was observed in 71% of participants who had HIV infection and 70% of those who did not. Most participants in each group had local injection-site pain and tenderness with treatment (76% with a single dose and 85% with three doses). CONCLUSIONS:Treatment with one dose of 2.4 million units of benzathine penicillin G was noninferior to treatment with three doses with regard to serologic response 6 months after treatment. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03637660.).

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.

Abstract Background Syphilis rates in the United Stated (U.S.) have increased steadily for over a decade. Despite over 75 years as the drug of choice for syphilis treatment, controversy persists on optimal duration of therapy with benzathine penicillin G (BPG) for persons with early(primary, secondary, and early latent) syphilis, particularly for persons co-infected with HIV. Given the ongoing national shortages of BPG, optimizing duration of therapy is an urgent concern. Methods We conducted a multicenter RCT comparing a single intramuscular (IM) injection of BPG, 2.4 million units to BPG administered for three successive weeks for treatment of early syphilis in persons with and without HIV. The primary outcome of the study was a > 4-fold decline in RPR titer measured at 6 months. Intention to treat (ITT) and per protocol analyses were performed and were similar. ITT analyses are presented here. Results A total of 249 persons with early syphilis were enrolled at 10 participating sites. Most (97%) participants were were categorized as male sex, black race (62%), and 153 (64%) were living with HIV. The syphilis stage distribution was 19% primary, 47% secondary, and 33% early latent and did not differ significantly by HIV status. Serologic response (> 4-fold decline in RPR titer) at 6 months was 76% (95% Confidence Interval (CI) 0.68-0.82) in the single dose group and did not differ significantly from the three-dose group (70%, 95% CI 0.61-0.77). There were no treatment failures (> 4-fold increase in RPR titer). Among persons with and without HIV there was no significant difference in RPR response at 6 months: 76% in the single-dose group vs. 71% in the 3-dose group (95% CI 0.05-0.17). Most participants experienced mild to moderate local injection site pain and tenderness. Conclusion Treatment of persons with early syphilis with more than a single dose of 2.4 million units of BPG offers no therapeutic benefit irrespective of HIV infection status and was associated with increased rates of injection site discomfort. Disclosures Edward W. Hook, III, FIDSA, GARPD (Global Antibiotic Resistance Program: Advisor/Consultant|Talis Biomedical: Advisor/Consultant|VISBY Diagnostics: Advisor/Consultant Candice J. McNeil, MD, MPH, BARDA/GSK: Grant/Research Support|Becton Dickinson: Grant/Research Support|Cepheid: Grant/Research Support|Gilead: Grant/Research Support|Hologic: Grant/Research Support|Lupin: study product Julia C. Dombrowski, MD, MPH, Hologic: Grant/Research Support|Mayne Pharmaceuticals: Grant/Research Support

The 15th International Symposium on Human Chlamydial Infections (ISHCI) was convened at the Menger hotel in San Antonio, Texas, June 19–24, 2022. This was the first in-person international meeting on Chlamydia since the start of the COVID pandemic and Julius Schachter's passing. Despite these tragedies we regained our strength and gathered in the Alamo city for commemorating Dr Schachter's many contributions to the Chlamydia field. The meeting has been renamed “The Julius Schachter-International Symposium on Human Chlamydial Infections (JS-ISHCI). Julius Schachter was among the first to recognize Chlamydia trachomatis as a common infectious agent that causes sexually transmitted disease. He also reported the first case of chlamydia-induced pneumonia in infants, which triggered screening and intervention programs to prevent pulmonary infection of newborns. By 1981, he and his team members, including Jeanne Moncada, isolated C. trachomatis from nasopharyngeal and rectal swabs from children in a trachoma-endemic area, which led to the proposal of a multicenter trial using oral azithromycin to eliminate blinding trachoma. Julius also significantly improved the laboratory diagnosis of human chlamydial infections by using less invasive urine and vaginal swab sampling, making patient self-collection possible for the diagnosis and treatment of asymptomatic infections. Besides his own research on C. trachomatis human infections, Julius was deeply involved in the organization and production of every ISHCI. Since the first meeting in 1962 at Lake Placid, the ISHCI has remained a highly respected quadrennial symposium for all chlamydial researchers to exchange scientific findings and ideas and explore collaboration opportunities. The meeting began by commemorating the members of the Chlamydia family who recently passed away, including Joseph Igietseme (USA), Byron Batteiger (USA), Pekka Saikku and Maija Leinonen (Finland). Two living legends were recognized: Dr. Sheila West (USA) for her contributions to trachoma research and Dr. Robert C. Brunham (Canada) for his contributions to both clinical and basic research of sexually transmitted chlamydial infections. As revealed in the Supplemental Material (https://links.lww.com/OLQ/A888), a very robust scientific program was developed for the symposium, which started with the clinical challenges caused by chlamydial infections in both human genital and ocular tissues. Most of the week was used to reveal new findings on diagnostics and the mechanisms of chlamydial biology and its interactions with host cells, as well as host responses. Finally, the program ended with presentations on how to use what we have learnt about Chlamydia and model systems, particularly animal models, to promote the development of vaccines for protecting humans from chlamydial infections and diseases. The program was organized into 7 research tracks with a keynote lecture for introducing each track. The success of the 15th JS-ISHCI was because of the collective efforts by everyone in the chlamydia community. The International Scientific Committee together with other scientists formed a review board, which carefully reviewed the abstracts and made constructive suggestions, ensuring the high scientific quality of the symposium. The local organizing committee members effectively worked together with others in the community to ensure that every step was executed according to the plan. The steering committee provided strong logistical guidance and ensured financial support. Important contributions to the success of the symposium came from the ~100 attendees. As revealed in the presentations and during the discussions at the 15th JS-ISHCI, the Chlamydia field has made significant progresses in both research and clinical applications since last meeting in the Netherlands in 2018. We have learned more about Chlamydia genetics, making the manipulation of the chlamydial genome more efficient for supporting subsequent functional studies. The combination of Chlamydia mutants with in vitro and in vivo research models has allowed us to gain new insights into the intricate molecular networks between Chlamydia and its host at the molecular, cellular and tissue levels. Both new chlamydial mechanisms and host response patterns unique to chlamydial infections have been identified. The exciting findings may motivate more biologists to take advantage of the unique chlamydial evolutionary niches to uncover host mechanisms that are otherwise difficult to discover. More importantly, the basic research achievements will help address the clinical challenges of human chlamydial infections. One of the clinical challenges is to understand why some C. trachomatis–infected women can spontaneously clear infection within 2 weeks1 and remain resistant to subsequent infections2 while others allow persistent C. trachomatis infection. Although clinical studies have identified some correlates,3,4 the mechanisms remain largely unknown. At the conference, a mouse model-based study reported a cGAS-STING signaling-dependent mechanism for inhibiting C. trachomatis infection in the lower genial tract,5 which has not only validated previous in vitro observations on chlamydial activation of the cGAS-STING pathway6,7 but also provided the urgently needed mechanistic information for designing new clinical studies. This and other exciting findings have been published in the symposium proceedings.8 Many attendees have realized that a fundamental understanding of Chlamydia and its interactions with its natural hosts in the context of mucosal microbiome may hold the key for designing an effective and safe Chlamydia vaccine. The intimate format of the meeting successfully served as a platform for attendees to exchange ideas, establish collaborations, develop out of the box thinking and strategize synergistic research plans, all of which will enable the field as a whole to make new discoveries in chlamydial research in the coming 4 years. Hopefully, when we meet again at the 16th, we may be closer to an effective vaccine for protecting humans from chlamydial infections and diseases.

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 β-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.

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.

Abstract Background Treponema pallidum (T. pallidum) is transmitted from person to person by direct contact with widespread dissemination early after acquisition. Current syphilis diagnostic testing is limited to darkfield microscopy from visible lesions and serologic antibody detection. T. pallidum molecular diagnostics are urgently needed. Methods As part of a multicenter US syphilis treatment trial that completed enrollment in March 2022 (NCT 3637660), we randomized 249 adults with early syphilis infection to 1 vs 3 weekly doses of benzathine penicillin G to compare treatment response at 6 months. In a small substudy (n=32) presented here, consenting participants at the University of Alabama at Birmingham (UAB) and Emory University had pre-treatment oral (buccal mucosa and posterior pharynx) and lesion swab samples collected. Following DNA extraction, T. pallidum burden in samples was quantified by targeting the tp0574 gene. Syphilis was staged by experienced providers according to physical examination and serology. Results Study participants were men (100%) and most were living with HIV (91%) with mean CD4 count 477 cells/mm3. Syphilis stage was categorized as primary in 6 (19%), secondary in 18 (56%) and early latent in 8 (25%). Oral swab qPCR positivity rates were 17% in primary disease, 44% in secondary disease, and 63% in early latent disease (see Figure). Lesion PCR positivity was similar in primary and secondary syphilis (40% and 38.5%). Mean treponemal burden was highest on oral swabs of participants with early latent syphilis (13,128,969) and lesion swabs of participants with secondary syphilis (2,033,309). Conclusion Among adult males, many living with HIV, data suggest a role for oral and lesion swabs for the molecular detection of T. pallidum. Widespread availability of PCR, the relative ease of oral specimen collection, and the opportunity to directly demonstrate T. pallidum in persons with early latent syphilis suggest the opportunity for PCR testing to enhance and refine syphilis diagnostic testing. The elevated proportion of positive oral samples and significant organism burden in secondary and early latent syphilis is consistent with potential for transmission. Disclosures All Authors: No reported disclosures.

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.

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 ofMedicine report, The Hidden Epidemic: Confronting Sexually TransmittedDiseases, 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 futurewhere 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.

Genital herpes simplex virus (HSV) infections are among the most common sexually transmitted infections encountered by humans and, in 2018, were estimated to occur in approximately 27% of US adults.1 There is no cure for HSV infection; consequently, infection can be transmitted from individual to individual, most often because of asymptomatic viral shedding. Thus, the reservoir of individuals infected with HSV continues to increase. For the most part, knowledge about genital HSV infections is predicated on studies of infections caused by HSV-2. However, over the past 2 decades, HSV-1 has been recognized as an increasing cause of genital infections and accounts for an estimated greater than 50% of new infections among some subpopulations, such as college students and heterosexual women.2-4 Differences in the shedding patterns, clinical manifestations, and management between genital herpes caused by HSV-1 and HSV-2 are poorly described. Although currently available serology can determine the overall prevalence of HSV-2 infections, commercially available serological tests for HSV-1 perform relatively poorly,5 and no serologic test has been developed to distinguish individuals who have genital HSV-1 infection from those with oropharyngeal HSV-1 infection. Thus, the true prevalence of and optimal management strategies for HSV-1 genital infection are lacking. Until now, knowledge of the natural history of genital HSV-1 infections has been limited to observational studies with small numbers of patients. In this issue of JAMA, Johnston and colleagues begin to address this knowledge gap by providing data to inform clinical care and highlighting persistent research questions through a prospective cohort study of volunteers with first-episode genital HSV-1 infections.6 Between 2013 and 2018, a total of 82 individuals (median age, 26 years; 54 [65.8%] women) with first-episode infection were recruited to the study, including 42 with primary (seronegative) infection and 22 with initial genital infection (preexisting antibodies to HSV-1). HSV was detected from the genital tract of 53 individuals (64.6%) and from the mouth of 24 individuals (29.2%). All study participants were HIV and HSV-2 seronegative. Of note, 18 participants (22%) who were initially enrolled withdrew from participation during follow-up or were lost to follow-up. Regardless, and despite the relatively small study population (n = 82), this report represents the largest cohort of individuals with first-episode infection and the 2 years of intense follow-up supplemented by polymerase chain reaction (PCR) testing for detection of asymptomatic HSV DNA shedding provide important insights for clinicians. Shedding frequency was determined at 2 and 11 months after enrollment by PCR testing of anogenital swabs collected daily for 30 days. Participants with evidence of viral shedding at 11 months were followed up for up to 2 years. Oropharyngeal swabs assessed shedding from the mouth as well. In this study cohort, genital HSV-1 shedding was relatively common soon after infection but decreased relatively rapidly, from 12.1% (detected on 275 of 2264 days) at the 2-month assessment period to 7.1% (detected on 122 of 1719 days) at the 11-month assessment period. Most shedding occurred in the absence of symptoms. Shedding from the mouth was significantly lower, with HSV detected on 88 of 2223 days (3.9%). Shedding was considerably higher among individuals with primary infection (17.2%) compared with those with nonprimary infection (6.9%). Long-term shedding was uncommon. Shedding, and thus transmission risk, decrease rapidly during the first year after infection. However, HSV shedding still occurs and therefore viral transmission can still occur, particularly because shedding occurs predominantly in the absence of symptoms. Further, symptomatic recurrences were much less likely following initial genital HSV-1 than reported for HSV-2 infections. Taken together, these data appear to validate the sense that risk for genital transmission of HSV-1 may decline rapidly following initial infection, but it is not zero. Shedding of HSV-1 from the mouth was constant at about 3% at each interval. Unreported studies of shedding of HSV-1 from the oropharynx performed both in dental clinics and in nursing populations indicate an overall shedding rate of approximately 1% based on culture and not the more sensitive method of PCR.7 Thus, this rate of oral shedding may be higher than that in previous prospective studies that used culture could detect and raises the point that the mouth is a source of HSV-1 for transmission with oral-genital sex. To put these data in perspective, shedding with HSV-2 is significantly greater and associated with a higher percentage of symptoms, although asymptomatic shedding is common and unpredictable with HSV-1 as well, particularly in the months soon after acquisition of infection. However, seroprevalence of HSV-2 infection is decreasing in the US.3 As such, these data from Johnston et al6 can guide clinicians in patient counseling and recommendations for the use of suppressive antiviral therapy. For example, in the absence of better readily available serological tests, suppressive therapy might be offered to those with initial HSV-1 infections to reduce the probability of transmission.3 Although the study by Johnston et al6 did not include pregnant individuals, the findings also may have implications for management of HSV-1 in pregnancy. HSV is a common cause Related article Opinion

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.

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.