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.

Presentaciones de la sífilis anorrectal: la gran simuladora / Anorectal syphilis presentations: the great pretender

Antecedentes: La sífilis es una infección sexualmente transmisible sistémica crónica que afecta a docenas de millones de personas al año. A nivel anorrectal, su manifestación polimórfica obliga al diagnóstico diferencial con enfermedades anorrectales benignas y malignas. Objetivo: Describir las diferentes presentaciones de la sífilis anorrectal a propósito de 5 casos clínicos. Método: Estudio observacional, retrospectivo, descriptivo. Resultados: La mayoría de los pacientes fueron VIH positivos en edad sexual activa. Las manifestaciones registradas, al igual que las reportadas en la bibliografía fueron las fisuras, úlceras perianales y pseudotumores. Conclusiones: La sífilis es considerada "la gran simuladora". En la localización anorrectal se requiere una alta sospecha diagnóstica para diferenciarla de presentaciones similares de otras enfermedades anales benignas, la enfermedad inflamatoria intestinal y el cáncer anorrectal, con el fin de evitar el consiguiente riesgo de sobretratamiento. (AU)

Background: Syphilis is a chronic systemic sexually transmitted infection that affects tens of millions of people annually. At the anorectal level, its polymorphic manifestation requires differential diagnosis with benign and malignant anorectal diseases. Objective: To review the presentation of anorectal syphilis from 5 clinical cases. Methods: Observational, retrospective, descriptive study. Results: Most of the patients were HIV positive in sexually active age. The manifestations recorded and reported in the literature were fissures, perianal ulcers, and pseudotumors. Conclusions: Syphilis is considered "the great pretender". In anorectal syphilis, a high diagnostic suspicion is needed to differentiate it from similar presentations due to other anal conditions, inflammatory bowel disease, and anorectal cancer, to avoid the consequent risk of overtreatment. (AU)

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.

Antibiotics to eradicate Streptococcus pyogenes pharyngeal carriage in asymptomatic children and adults: A systematic review.

Streptococcus pyogenes (S. pyogenes) is a Gram-positive bacteria which causes a spectrum of diseases ranging from asymptomatic infection to life-threatening sepsis. Studies report up to 2000 times greater risk of invasive S. pyogenes disease in close contacts of index cases within 30-days of symptom onset. Despite this, there is variability in the management of asymptomatic carriage of S. pyogenes and those at risk of secondary cases of invasive S. pyogenes infection. OBJECTIVE: Our systematic review assessed the efficacy of different antibiotic regimens used for eradication of S. pyogenes from the pharynx in asymptomatic individuals. METHODS: We searched Pubmed, EMBASE (1974-), OVID Medline (1948-) and the Cochrane CENTRAL registry. We included randomised controlled trials (RCTs) with asymptomatic participants with >50% with pharyngeal cultures positive with S. pyogenes at baseline. Only studies with microbiological methods including culture (+/- polymerase chain reaction, PCR) were included. We included studies published in English. Each included study was assessed by two independent reviewers for data extraction and risk of bias. RESULTS: Of 1166 unique records identified, three RCTs were included in the review. Two of the three included RCTs found oral clindamycin for 10-days was the most efficacious regimen, compared to intramuscular benzathine penicillin G followed by 4 days of oral rifampicin, or monotherapy using benzathine penicillin, phenoxymethylpenicillin or erythromycin. Two RCTs were assessed as being at high risk of bias, with the third study demonstrating low/some risk of bias. CONCLUSIONS: Current available evidence for the optimal antibiotic in eradicating pharyngeal S. pyogenes carriage is limited. Future RCTs should include penicillin, first-generation cephalosporins, rifampicin, macrolides (such as azithromycin) and clindamycin.

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.

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.

A 25-Year-Old Military Recruit with Isolated Myositis Following Routine Chemoprophylaxis with Intramuscular Benzathine Penicillin G.

BACKGROUND Myositis is an inflammatory myopathy that can be caused by a variety of drugs, diseases, and toxins. The U.S. military uses chemoprophylaxis with intramuscular penicillin G to prevent group A streptococcal infection. We present a case of penicillin G-induced myositis, a rare cause of drug-induced myositis with limited discussion in the medical literature. CASE REPORT A 25-year-old man with no pertinent medical history presented to the Emergency Department with right hip and leg pain after receiving a single dose of intramuscular penicillin G as part of standard prophylaxis for group A streptococcal infection during basic military training. He reported pain and leg weakness that was exacerbated by physical exertion and weight bearing but had no systemic symptoms, such as fevers or chills. Initial radiographs of the hip were normal; however, subsequent magnetic resonance imaging of the hip revealed intramuscular edema and features consistent with myositis of the right proximal thigh and hip musculature. He was admitted for isolated right gluteal myositis, attributed to his preceding local penicillin injection. He recovered with symptomatic care over the following 2 weeks, with return to baseline function. CONCLUSIONS This case highlights a rare complication of intramuscular penicillin G as a cause of acute isolated myositis. It serves to inform physicians of this rare complication and to recommend the consideration of intramuscular penicillin G as a causative etiology in individuals presenting with myositis and recent penicillin G exposure.

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.

Subcutaneous infusion of high-dose benzathine penicillin G is safe, tolerable, and suitable for less-frequent dosing for rheumatic heart disease secondary prophylaxis: a phase 1 open-label population pharmacokinetic study.

Since 1955, the recommended strategy for rheumatic heart disease (RHD) secondary prophylaxis has been benzathine penicillin G [BPG; 1.2 MU (900 mg)] injections administered intramuscularly every 4 weeks. Due to dosing frequency, pain, and programmatic challenges, adherence is suboptimal. It has previously been demonstrated that BPG delivered subcutaneously at a standard dose is safe and tolerable and has favorable pharmacokinetics, setting the scene for improved regimens with less frequent administration. The safety, tolerability, and pharmacokinetics of subcutaneous infusions of high-dose BPG were assessed in 24 healthy adult volunteers assigned to receive either 3.6, 7.2, or 10.8 MU (three, six, and nine times the standard dose, respectively) as a single subcutaneous infusion. The delivery of the BPG to the subcutaneous tissue was confirmed with ultrasonography. Safety assessments, pain scores, and penicillin concentrations were measured for 16 weeks post-dose. Subcutaneous infusion of penicillin (SCIP) was generally well tolerated with all participants experiencing transient, mild infusion-site reactions. Prolonged elevated penicillin concentrations were described using a combined zero-order (44 days) and first-order (t1/2 = 12 days) absorption pharmacokinetic model. In simulations, time above the conventionally accepted target concentration of 20 ng/mL (0.02 µg/mL) was 57 days for 10.8 MU delivered by subcutaneous infusion every 13 weeks compared with 9 days of every 4-weekly dosing interval for the standard 1.2 MU intramuscular dose (i.e., 63% and 32% of the dosing interval, respectively). High-dose SCIP (BPG) is safe, has acceptable tolerability, and may be suitable for up to 3 monthly dosing intervals for secondary prophylaxis of RHD.

Case Report: Detection of Treponema phagedenis in cerebrospinal fluid of a neurosyphilis patient by metagenomic next-generation sequencing.

Treponema phagedenis, a human commensal spirochete, has been reported world-wide as a key factor in the pathogenesis of bovine digital dermatitis. Here we report a case of T. phagedenis sequence detection in the cerebrospinal fluid (CSF) of a patient. The patient was diagnosed with neurosyphilis, and T. phagedenis was detected as the only microorganism in his CSF by metagenomic sequencing. The patient went through a round of penicillin therapy previously (2.4 million units of Benzathine Penicillin intramuscularly once a week for three weeks) that did not resolve the symptoms; after the diagnosis of neurosyphilis he was treated with Penicillin G Sodium 4.0 million units q4h intravenous for 14 days then his symptoms resolved. To the best of our knowledge, T. phagedenis has never been reported to be detected in a human's CSF before. This was also the first time it was detected by metagenomic next-generation sequencing. We propose that more etiological tests should be performed including culture and sequencing for more patients with syphilis, which will contribute to a deeper understanding of the pathogenicity of the spirochete.

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.

Longitudinal Variations in the tprK Gene of Treponema pallidum in an Amoy Strain-Infected Rabbit Model.

Heterogeneous tprK sequences have been hypothesized to be an important factor for persistent infection of Treponema pallidum subsp. pallidum (T. pallidum) in humans. Previous research has only explored tprK diversity using a rabbit model infected with almost clonal isolates, which is inconsistent with the fact that infected human isolates contain multiple heterogeneous tprK sequences. Here, we used the T. pallidum Amoy strain with heterogeneous tprK sequences to establish a rabbit infection model and explore longitudinal variations in the tprK gene under normal infection, immunosuppression treatment, and benzathine penicillin G (BPG) treatment using next-generation sequencing. The diversity of the tprK gene was high in all three groups but was highest in the control group and lowest in the BPG group. Interestingly, the overall diversity of tprK in all three groups decreased during infection, exhibiting a "more to less" trend, indicating that survival selection may be an important factor affecting tprK variation in the later infection stage. BPG treatment appeared to reduce the diversity of tprK but increased the frequency of predominant sequence changes, which might facilitate the escape of T. pallidum from the host immune clearance. Furthermore, the original predominant V region sequence did not disappear with disease progression but retained a relatively high proportion within the population, suggesting a new direction for tprK-related vaccine research. This study provides insights into longitudinal variations within the highly heterogeneous tprK gene sequences of T. pallidum and will contribute to further exploration of the pathogenesis of syphilis. IMPORTANCE The tprK variations are an important factor in persistent T. pallidum infection. A nearly clonal isolate has been used previously to investigate the mechanism of tprK gene variations; however, clinical T. pallidum isolates in infected humans exhibit multiple heterogeneous tprK sequences. Here, we use next-generation sequencing to explore longitudinal variations in the tprK gene under normal infection and immunosuppression and benzathine penicillin G treatment in a rabbit model infected with the Amoy strain with heterogeneous tprK sequences. The overall diversity of tprK in all three groups was high and decreased during infection, exhibiting a "more to less" trend. Benzathine penicillin G treatment reduced the diversity of tprK but increased the frequency of predominant sequence changes. Moreover, the original predominant V region sequence did not disappear as the disease progressed but remained at a relatively high proportion within the population. The research results give us a new understanding about tprK variation.

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).