Could late-latent syphilis be treated with a single subcutaneous infusion of long-acting penicillin?

Syphilis is an important global health threat and little has changed in its treatment since the mid-20th century. For late-latent or syphilis infection of unknown duration, the standard treatment of multiple intramuscular injections of benzathine penicillin G (BPG) are associated with significant pain and distress to clients and caregivers, negatively impacting on treatment completion. Based on pharmacokinetic modelling from a Phase I study of subcutaneous infusion of high dose BPG (SCIP), we present its feasibility, safety and tolerability for treatment of syphilis in a single infusion. SCIP leads to more sustained penicillin concentrations above the desired target with less reported pain and reduced clinic visits.

Unilateral tonsillitis due to primary syphilis with gram-negative corkscrew-like spirochaetes confirmed by Gram stain of pus.

A man in his 40s presented with pharyngeal pain and right cervical lymphadenopathy that persisted for 1 month. His right tonsil was swollen and covered with exudate; however, a rapid streptococcal antigen test was negative. Rapid plasma reagin and Treponema pallidum antibody were positive. Gram staining of the pus confirmed the presence of gram-negative corkscrew-like spirochaetes. The patient had unprotected oral intercourse. He did not have any skin lesions. He was diagnosed with primary syphilis and treated with benzathine penicillin G. In adults, the differential diagnosis of tonsillitis should include sexually transmitted diseases. A rapid streptococcal antigen test is not sufficient for such a case; a syphilis test is necessary, and Gram staining, which is rapid and does not need any special equipment, can support the diagnosis.

Diagnostic and Therapeutic Approaches for a Diabetic Patient Presenting with Secondary Syphilis and Severe Odynophagia.

Syphilis, an infectious disease caused by the spirochete Treponema pallidum, represents a pervasive global epidemic. Secondary syphilis is typically marked by the emergence of highly contagious mucocutaneous manifestations, including non-pruritic rashes on the palms and soles of the feet, alopecia, mucous patches, and condyloma lata. Here, we report a rare case of a 30-year-old male with newly discovered type 2 diabetes mellitus who presented with severe odynophagia due to secondary syphilis, confirmed by both nontreponemal VDRL/RPR and treponemal TPHA tests. Following the administration of a single-dose intramuscular injection of benzathine penicillin G 2.4 million units, the symptoms gradually decreased, allowing the patient to regain his health.

Access to Benzathine Penicillin G Treatment for Persons With Syphilis, Maricopa County, Arizona, 2021.

BACKGROUND: As the incidence of syphilis continues to increase, examining benzathine penicillin G (BPG) treatment data provides valuable insight for public health strategies. This study analyzed the trends of where BPG is administered relative to the initial clinical site of syphilis diagnosis. Our findings are timely in the context of recent national BPG shortages. METHODS: The analysis included persons diagnosed with any syphilis stage in Maricopa County, Arizona, from January 1, 2021, to December 31, 2021. The Arizona surveillance database (PRISM) was the source of demographic, testing, and treatment data. RESULTS: Of a total of 4028 persons with syphilis, 3038 (75.4%) received at least 1 injection of BPG. Among persons who received an initial BPG injection, only 1719 (56.6%) were diagnosed and treated at the same clinical site type. The Maricopa County Sexually Transmitted Disease Clinic administered BPG to 48.8% (n = 1483) of persons with syphilis who received an initial injection. CONCLUSIONS: Our findings analyze trends in BPG administration that are likely due to treatment referral practices and medication cost. Administration of BPG is not guaranteed at the clinical site of diagnosis, highlighting concerns regarding access to BPG. A burden is placed on patients who are required to leave their diagnosing provider to seek syphilis treatment at other health facilities that administer BPG.

Oral linezolid compared with benzathine penicillin G for treatment of early syphilis in adults (Trep-AB Study) in Spain: a prospective, open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Management of syphilis, a sexually transmitted infection (STI) with increasing incidence, is challenged by drug shortages, scarcity of randomised trial data, an absence of non-penicillin alternatives for pregnant women with penicillin allergy (other than desensitisation), extended parenteral administration for neurosyphilis and congenital syphilis, and macrolide resistance. Linezolid was shown to be active against Treponema pallidum, the causative agent of syphilis, in vitro and in the rabbit model. We aimed to assess the efficacy of linezolid for treating early syphilis in adults compared with the standard of care benzathine penicillin G (BPG). METHODS: We did a multicentre, open-label, non-inferiority, randomised controlled trial to assess the efficacy of linezolid for treating early syphilis compared with BPG. We recruited participants with serological or molecular confirmation of syphilis (either primary, secondary, or early latent) at one STI unit in a public hospital and two STI community clinics in Catalonia (Spain). Participants were randomly allocated in a 1:1 ratio using a computer-generated block randomisation list with six participants per block, to receive either oral linezolid (600 mg once per day for 5 days) or intramuscular BPG (single dose of 2·4 million international units) and were assessed for signs and symptoms (once per week until week 6 and at week 12, week 24, and week 48) and reagin titres of non-treponemal antibodies (week 12, week 24, and week 48). The primary endpoint was treatment response, assessed using a composite endpoint that included clinical response, serological response, and absence of relapse. Clinical response was assessed at 2 weeks for primary syphilis and at 6 weeks for secondary syphilis following treatment initiation. Serological cure was defined as a four-fold decline in rapid plasma reagin titre or seroreversion at any of the 12-week, 24-week, or 48-week timepoints. The absence of relapse was defined as the presence of different molecular sequence types of T pallidum in recurrent syphilis. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference in rates of treatment response was higher than -10%. The primary analysis was done in the per-protocol population. The trial is registered at ClinicalTrials.gov (NCT05069974) and was stopped for futility after interim analysis. FINDINGS: Between Oct 20, 2021, and Sept 15, 2022, 62 patients were assessed for eligibility, and 59 were randomly assigned to linezolid (n=29) or BPG (n=30). In the per-protocol population, after 48 weeks' follow-up, 19 (70%) of 27 participants (95% CI 49·8 to 86·2) in the linezolid group had responded to treatment and 28 (100%) of 28 participants (87·7 to 100·0) in the BPG group (treatment difference -29·6, 95% CI -50·5 to -8·8), which did not meet the non-inferiority criterion. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (five [17%] of 29, 95% CI 5·8 to 35·8 in the linezolid group vs five [17%] of 30, 5·6 to 34·7, in the BPG group). No serious adverse events were reported during follow-up. INTERPRETATION: The efficacy of linezolid at a daily dose of 600 mg for 5 days did not meet the non-inferiority criteria compared with BPG and, as a result, this treatment regimen should not be used to treat patients with early syphilis. FUNDING: European Research Council and Fondo de Investigaciones Sanitarias.

Use of ceftriaxone as an alternative treatment method in pregnant women diagnosed with syphilis - a single centre experience.

BACKGROUND: There are few data on the use of ceftriaxone in pregnant women diagnosed with syphilis. The aim of this study was to investigate the safety and efficacy of ceftriaxone as an alternative treatment option for syphilis during pregnancy. METHODS: A retrospective analysis of 79 pregnant women diagnosed with syphilis and treated with ceftriaxone was conducted. RESULTS: No cases of intolerance, Jarisch-Herxheimer reactions, or allergic reactions were recorded. The average time to seronegativation for secondary syphilis with symptoms was 6.14 months ± 2.76, and for latent forms, it was 7.52 months ± 1.84. Patients received no additional treatment. No serious adverse drug reactions were reported. CONCLUSIONS: Data from our study support the use of ceftriaxone as an effective and safe alternative treatment for pregnant women diagnosed with syphilis when penicillin therapy is contraindicated or unavailable.

A 4-fold or greater decrease in TPPA titers may indicate effective BPG treatment in primary syphilis.

BACKGROUND: In the majority of clinical environments, the treponema pallidum particle agglutination (TPPA) test is known for its higher specificity compared to the rapid plasma reagin (RPR) test and is commonly employed for the diagnosis of syphilis, but their use for serological monitoring after syphilis therapy is controversial. OBJECTIVES: We aim to evaluate whether the TPPA titers is suitable for monitoring syphilis treatment efficacy. METHODS: At first, 232 patients with primary syphilis were recruited. Serological testing was performed at baseline (initial visit) and at 6 months (±1 month) after benzathine penicillin G (BPG) treatment. Second, New Zealand white male rabbits were infected with Treponema pallidum (T. pallidum) to evaluate the changes in TPPA titers after BPG therapy. Finally, we compared the TPPA titers in the culture supernatant of rabbit splenocytes stimulated with T. pallidum with or without BPG. RESULTS: After 6 months of treatment, 150 (64.7%) of 232 primary syphilis patients achieved serological cure, and 82 (35.3%) had adverse outcomes. Among 110 patients with TPPA titers decreased by more than fourfold, 109 of them were serological cure patients (≥4-fold decrease in RPR titers) (P ＜ 0.0001). In the rabbit model of syphilis, the TPPA titers was significantly decreased in the treatment subgroup (P = 0.016) and remained constant (±2-fold) or increased (≥4-fold) in the nontreatment subgroup. In addition, T. pallidum resulted in a positive TPPA titers in the culture supernatant of splenocytes (median titers was 1: 80), while BPG could directly reduce the TPPA titers in the culture supernatant (median titers was 1: 40) (P = 0.032). CONCLUSIONS: A 4-fold or greater decrease in TPPA titers may indicate effective treatment in primary syphilis. Combining TPPA titers with RPR titers results may potentially aid in the early diagnosis of syphilis.

Syphilis as the great mimicker: A case of full-house pattern membranous nephropathy.

Syphilis is a known cause of membranous nephropathy. We describe a case of a patient presenting with nephrotic syndrome whose renal biopsy demonstrated a 'full house' immunohistochemical pattern with positive IgG, IgM, C1q, IgA, C3c, and C4d staining. He was treated with immunosuppressive agents for minimal change nephropathy and subsequently class V lupus nephritis, before syphilis infection was confirmed. Following treatment with a single dose of intramuscular benzathine penicillin there was complete and rapid resolution of nephrotic syndrome. With progressive rising incidence in the western world, syphilis is an important and under-recognised differential diagnosis in cases of nephrotic syndrome.

The aetiology and incidence of infective endocarditis in people living with rheumatic heart disease in tropical Australia.

PURPOSE: To define the incidence and microbiological aetiology of infective endocarditis (IE) in patients with rheumatic heart disease (RHD) in tropical Australia. METHODS: A retrospective study that examined all episodes of IE between January 1998 and June 2021 among individuals on the RHD register in Far North Queensland, Australia. RESULTS: There were 1135 individuals with a diagnosis of RHD on the register during the study period, representing 10962 patient-years at risk. Overall, there were 18 episodes of definite IE occurring in 16 individuals, although only 7 episodes occurred in native valves (11 occurred in prosthetic valves) equating to 0.7 episodes of native valve IE/1000 patient-years. No patient with mild RHD - and only one child with RHD - developed IE during the study period. Despite the study's tropical location, the causative organism was usually typical skin or oral flora. Among individuals with an indication for benzathine penicillin G (BPG) prophylaxis, only 1/6 episodes of IE due to a penicillin-susceptible organism received BPG in the month before presentation. CONCLUSION: Although RHD predisposes individuals to IE, the absolute risk of IE in native valve disease in tropical Australia is low and might be reduced further by improved adherence to secondary BPG prophylaxis.

Development of a sustained release implant of benzathine penicillin G for secondary prophylaxis of rheumatic heart disease.

BACKGROUND: Regular intramuscular (i.m.) benzathine penicillin G (BPG) injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. Patient adherence to IM BPG is poor, largely due to pain, the need for regular injections every 3-4 weeks and health sector delivery challenges in resource-limited settings. There is an urgent need for new approaches for secondary prophylaxis, such as an implant which could provide sustained penicillin concentrations for more than 6 months. METHODS: In this study we developed and evaluated a slow release implant with potential for substantially extended treatment. The side wall of a solid drug rich core was coated with polycaprolactone which acts as an impermeable barrier. The exposed surfaces at the ends of the implant defined the release surface area, and the in vitro release rate of drug was proportional to the exposed surface area across implants of differing diameter. The in vivo pharmacokinetics and tolerability of the implants were evaluated in a sheep model over 9 weeks after subcutaneous implantation. RESULTS: The absolute release rates obtained for the poorly water-soluble benzathine salt were dependent on the exposed surface area demonstrating the impermeability of the wall of the implant. The implants were well-tolerated after subcutaneous implantation in a sheep model, without adverse effects at the implantation site. Gross structural integrity was maintained over the course of the study, with erosion limited to the dual-exposed ends. Steady release of penicillin G was observed over the 9 weeks and resulted in approximately constant plasma concentrations close to accepted target concentrations. CONCLUSION: In principle, a long acting BPG implant is feasible as an alternative to i.m. injections for secondary prophylaxis of RHD. However, large implant size is currently a significant impediment to clinical utility and acceptability.

Combination of Amoxicillin 3000 mg and Probenecid Versus 1500 mg Amoxicillin Monotherapy for Treating Syphilis in Patients With Human Immunodeficiency Virus: An Open-Label, Randomized, Controlled, Non-Inferiority Trial.

BACKGROUND: Amoxicillin plus probenecid is an alternative to intramuscular benzathine penicillin G for treating syphilis in the United Kingdom. Low-dose amoxicillin is an alternative treatment option used in Japan. METHODS: We conducted an open-label, randomized, controlled, non-inferiority trial between 31 August 2018, and 3 February 2022, to compare 1500 mg low-dose amoxicillin monotherapy with the combination of 3000 mg amoxicillin and probenecid (non-inferiority margin 10%). Patients with human immunodeficiency virus (HIV) infection and syphilis were eligible. The primary outcome was the cumulative serological cure rate within 12 months post-treatment, measured using the manual rapid plasma reagin card test. Secondary outcomes included safety assessment. RESULTS: A total of 112 participants were randomized into 2 groups. Serological cure rates within 12 months were 90.6% and 94.4% with the low-dose amoxicillin and combination regimens, respectively. Serological cure rates for early syphilis within 12 months were 93.5% and 97.9% with the low-dose amoxicillin and combination regimens, respectively. Non-inferiority of low-dose amoxicillin compared with amoxicillin plus probenecid overall and for early syphilis was not confirmed. No significant side effects were detected. CONCLUSIONS: This is the first randomized controlled trial to demonstrate a high efficacy of amoxicillin-based regimens for treating syphilis in patients with HIV infection, and the non-inferiority of low-dose amoxicillin compared with amoxicillin plus probenecid was not seen. Therefore, amoxicillin monotherapy could be a good alternative to intramuscular benzathine penicillin G with fewer side effects. However, further studies comparing with benzathine penicillin G in different populations and with larger sample sizes are needed. TRIALS REGISTRATION: (UMIN000033986).

Luetic (syphilitic) hepatitis: the great imitator persists in the 21st century.

A male patient in his 20s was referred to the hepatology team with jaundice, pruritus and drenching night sweats. Investigations revealed an acute hepatitis with negative autoimmune and viral serology. Liver biopsy demonstrated severe pan-lobular hepatitis, and an extended diagnostic screen included a positive treponemal antibody test, with an RPR titre of 64, indicating active syphilis infection. He was treated with 2.4 million units of intramuscular benzathine penicillin as a single dose which led to complete resolution of the abnormal liver tests and symptoms. Diagnostic and management challenges, including the role of good history taking, appropriate investigations and role of multidisciplinary team, are discussed.

Syphilis.

Syphilis is a curable systemic infectious disease with a clear increase in incidence in recent years. The disease presents with a broad clinical spectrum and challenges clinicians due to the long incubation period and the sometimes complex interpretation of serological test results. Penicillin G remains the treatment of choice in all stages of syphilis.

Case Series of Stillbirths Due to Syphilis in Edmonton, Alberta, Canada.

BACKGROUND: Data on the incidence and characteristics of stillbirths attributed to congenital syphilis were collected. METHODS: We extracted data on stillbirths in the Edmonton Zone on January 1, 2015, through June 30, 2021, born to persons diagnosed with infectious syphilis (primary, secondary, early latent, or early neurosyphilis) during pregnancy or at the time of delivery. RESULTS: Of 314 infants documented to be exposed to infectious syphilis during gestation, 16 (5.1%) were stillborn. Three of the 16 females with stillbirths were diagnosed with syphilis during pregnancy but not treated, 12 were diagnosed only at the time of stillbirth (1 of whom was treated early in pregnancy and presumably reinfected), and 1 had a stillbirth in the week after one dose of benzathine penicillin G. CONCLUSIONS: Stillbirths due to congenital syphilis were all due to failure to treat syphilis in pregnancy. Innovative strategies to prevent syphilis in the community and to reach those experiencing barriers to care are urgently required to not miss opportunities to diagnose and treat syphilis as early as possible during pregnancy.

Qualitative assessment of healthy volunteer experience receiving subcutaneous infusions of high-dose benzathine penicillin G (SCIP) provides insights into design of late phase clinical studies.

INTRODUCTION: Secondary prophylaxis to prevent rheumatic heart disease (RHD) progression, in the form of four-weekly intramuscular benzathine benzylpenicillin G (BPG) injections, has remained unchanged since 1955. Qualitative investigations into patient preference have highlighted the need for long-acting penicillins to be delivered less frequently, ideally with reduced pain. We describe the experience of healthy volunteers participating in a phase-I safety, tolerability and pharmacokinetic trial of subcutaneous infusions of high-dose benzathine penicillin G (BPG)-the SCIP study (Australian New Zealand Clinical Trials Registry ACTRN12622000916741). METHODS: Participants (n = 24) received between 6.9 mL to 20.7 mL (3-9 times the standard dose) of BPG as a single infusion into the abdominal subcutaneous tissues via a spring-driven syringe pump over approximately 20 minutes. Semi-structured interviews at four time points were recorded, transcribed verbatim and thematically analysed. Tolerability and specific descriptors of the experience were explored, alongside thoughts on how the intervention could be improved for future trials in children and young adults receiving monthly BPG intramuscular injections for RHD. RESULTS: Participants tolerated the infusion well and were able describe their experiences throughout. Most reported minimal pain, substantiated via quantitative pain scores. Abdominal bruising at the infusion site did not concern participants nor impair normal activities. Insight into how SCIP could be improved for children included the use of topical analgesia, distractions via television or personal devices, a drawn-out infusion time with reduced delivery speed, and alternative infusion sites. Trust in the trial team was high. CONCLUSION: Qualitative research is an important adjunct for early-phase clinical trials, particularly when adherence to the planned intervention is a key driver of success. These results will inform later-phase SCIP trials in people living with RHD and other indications.

Syphilis screening coverage and positivity by HIV treatment status among South African pregnant women enrolled in the 2019 antenatal HIV sentinel survey.

We describe coverage of maternal syphilis screening, syphilis positivity, coverage of treatment and their association with maternal HIV infection and antiretroviral treatment (ART) status among pregnant women attending South African antenatal clinics. The 2019 antenatal care sentinel survey was a cross-sectional survey conducted from 1 October to 15 November 2019 at 1589 sentinel sites in all nine provinces of the country and aimed to enrol 36,000 pregnant women ages 15-49 years regardless of HIV, ART or syphilis status. Data collection procedures included obtaining written informed consent, a brief interview, medical record review and blood specimen collection. Completed data collection forms and specimens were sent to designated regional laboratories for data capture and HIV serology testing. Data analysis determined four outcomes i) syphilis screening coverage ii) syphilis positivity iii) coverage of any treatment and iv) with Benzathine penicillin G (BPG). Multivariable logistic regression models with or without interaction between HIV infection and ART status with province were used to determine factors associated with syphilis positivity. Of the 41 598 women enrolled, 35 900 were included in the analysis for syphilis screening coverage. The weighted syphilis screening coverage was 96.4% [95% Confidence Interval (CI) 95.9-96.7%] nationally and was lowest among HIV positive women not on ART at 93.5% (95% CI 92.2-94.5%). Syphilis positivity was 2.6% (95% CI 2.4-2.9%) nationally. Among those who were syphilis positive, 91.9% (95% CI 89.8-93.7%) had documentation of syphilis treatment status, of whom 92.0% (95% CI 89.8-93.9%) were treated, with the majority treated with one or more doses of BPG [92.2% (95% CI 89.8-94.3%)]. HIV-positive women, not on ART [adjusted odd ratio (aOR) 2.24 (95% 1.71-2.93)] and those on ART [aOR 2.25 (95% CI 1.91-2.64)] were more likely to be syphilis positive compared to those who were HIV negative. The national syphilis screening coverage met the global screening target of 95%. Syphilis positivity was higher among HIV positive women compared to negative women. Introduction of rapid syphilis testing and ensuring a universal supply of appropriate treatment for syphilis will reduce the likelihood of mother-to-child transmission of syphilis.

[Nicolau syndrome]. / Síndrome de Nicolau.

Nicolau syndrome is a rare complication of the parenteral application of various drugs. It is characterized by the appearance of pain, followed by edema, erythema, and then a necrotic plaque. We present the case of a 31-year-old male with this syndrome, after the application of intramuscular benzathine penicillin. The diagnosis was supported by the biopsy. He received treatment with enoxaparin and cilostazol with subsequent improvement.

El síndrome de Nicolau es una complicación infrecuente de la aplicación parenteral de diversos fármacos. Se caracteriza por la aparición de dolor, seguido de edema, eritema y luego una placa necrótica. Se reporta el caso de un hombre de 31 años que presenta este síndrome luego de la aplicación de penicilina benzatínica intramuscular. La biopsia apoyó el diagnóstico. Recibió tratamiento con enoxaparina y cilostazol con posterior mejoría.

Treatment Completion With Three-Dose Series of Benzathine Penicillin Among People Diagnosed With Late Latent and Unknown Duration Syphilis, Maricopa County, Arizona.

BACKGROUND: Syphilis is a public health concern as cases are rising each year. If untreated, syphilis is associated with significant morbidity and risk of vertical transmission during pregnancy. For people with late latent and unknown duration stages, 3 injections of benzathine penicillin G (BPG) at 1-week intervals are recommended. Our study quantified treatment for people diagnosed with late latent and unknown duration syphilis in Maricopa County, Arizona with a secondary analysis of pregnant women to assess completion of 3 injections of BPG in multiple time intervals. METHODS: Maricopa County syphilis case data were extracted from the state-run database (PRISM). Records were reviewed for people with late latent and unknown duration syphilis during January 1, 2016, to December 31, 2021. Treatment types and time intervals between treatments were analyzed. RESULTS: Of a total of 14,924 people with syphilis reported in Maricopa County, 5372 (36.0%) were staged as late latent or unknown duration syphilis. Completion of 3 BPG injections in the time frame of 7 to 9 days was 42.9% (n = 2302). Completion among pregnant women (n = 406) with 3 injections was 68.7% (n = 279). CONCLUSIONS: The completion rate of 3 BPG injections for people with late latent or unknown duration syphilis is low. An unmet need exists to identify barriers to treatment including access to BPG and public health follow-up after the first injection. Prioritized effort is needed to identify and classify patients as having earlier stages of syphilis that require only 1 BPG injection.

Challenges and outcomes of implementing a national syphilis follow-up system for the elimination of congenital syphilis in Cambodia: a mixed-methods study.

OBJECTIVES: We aimed to describe the challenges and outcomes of implementing a national syphilis follow-up system to improve syphilis management in maternal and child health (MCH) services in Cambodia. DESIGN: Operational study; quantitative cohort data and cross sectional qualitative data. SETTING: Public health facilities at national level and in four provinces with high syphilis prevalence in Cambodia. PARTICIPANTS: Pregnant women screened for syphilis; MCH health care providers and managers. METHODS: We conducted an operational research using syphilis screening and treatment data collected from a national follow-up system (cohort data) and reported in the health management information system (HMIS) between 2019 and 2020. We also conducted indepth interviews with 16 pregnant women and focus group discussions with 37 healthcare providers and managers. Descriptive statistics and thematic content analysis were used. OUTCOME MEASURES: Syphilis testing and treatment results and perceptions regarding these services. RESULTS: A total of 470 pregnant women who tested positive in rapid syphilis testing were recorded in the national syphilis follow-up system in 2019-2020. Of these, 71% (332 of 470) received a rapid plasma reagin (RPR) test and 95% (n=315) tested positive; 78% (246 of 315) received any syphilis treatment and only 28% (88 of 315) were treated adequately with benzathine penicillin G (BPG). Data from four provinces with high syphilis prevalence (more closely monitored) showed higher testing and treatment rates than at the national level. HMIS aggregated data reported a higher number of pregnant women screened and treated for syphilis than the follow-up system during the same period. Barriers to syphilis testing and treatment included late antenatal care, long distance to RPR testing and treatment, partners' lack of support to reach the health facility, BPG stockout and poor adherence to oral treatment in the absence of BPG. Providers and managers reported a lack of communication across services, insufficient skills to treat infants and absence of clear guidance regarding the revised follow-up system. Study findings contributed to changes in operating procedures nationwide to facilitate access to syphilis testing and adequate treatment and a systematic follow-up of pregnant women and exposed infants. CONCLUSIONS: Study results contributed to informing improvements to syphilis management in MCH services in Cambodia.