"Hurts less, lasts longer"; a qualitative study on experiences of young people receiving high-dose subcutaneous injections of benzathine penicillin G to prevent rheumatic heart disease in New Zealand.

BACKGROUND: Four-weekly intramuscular (IM) benzathine penicillin G (BPG) injections to prevent acute rheumatic fever (ARF) progression have remained unchanged since 1955. A Phase-I trial in healthy volunteers demonstrated the safety and tolerability of high-dose subcutaneous infusions of BPG which resulted in a much longer effective penicillin exposure, and fewer injections. Here we describe the experiences of young people living with ARF participating in a Phase-II trial of SubCutaneous Injections of BPG (SCIP). METHODOLOGY: Participants (n = 20) attended a clinic in Wellington, New Zealand (NZ). After a physical examination, participants received 2% lignocaine followed by 13.8mL to 20.7mL of BPG (Bicillin-LA®; determined by weight), into the abdominal subcutaneous tissue. A Kaupapa Maori consistent methodology was used to explore experiences of SCIP, through semi-structured interviews and observations taken during/after the injection, and on days 28 and 70. All interviews were recorded, transcribed verbatim, and thematically analysed. PRINCIPAL FINDINGS: Low levels of pain were reported on needle insertion, during and following the injection. Some participants experienced discomfort and bruising on days one and two post dose; however, the pain was reported to be less severe than their usual IM BPG. Participants were 'relieved' to only need injections quarterly and the majority (95%) reported a preference for SCIP over IM BPG. CONCLUSIONS: Participants preferred SCIP over their usual regimen, reporting less pain and a preference for the longer time gap between treatments. Recommending SCIP as standard of care for most patients needing long-term prophylaxis has the potential to transform secondary prophylaxis of ARF/RHD in NZ and globally.

Pharmacokinetics and Safety of Intramuscular Injectable Benzathine Penicillin G in Japanese Healthy Participants.

An intramuscular (IM) suspension of benzathine penicillin G (BPG) has been used as first-line therapy for the treatment of syphilis worldwide since its approval in the 1950s. However, there are limited reports about the pharmacokinetics of BPG. A Phase 1 study was conducted on eight Japanese healthy participants to investigate the pharmacokinetics (samples collected predose to 648 h post-dose) and safety of 2.4 million units of BPG after a single IM injection. Following administration, penicillin G, the active moiety of BPG, was absorbed slowly from the injection site with a median time to Cmax (tmax) of 48 h post-dose. After the achievement of Cmax, concentrations of penicillin G declined slowly in a monophasic fashion with a mean apparent terminal half-life of 189 h. Geometric mean AUCinf and Cmax were 50770 ng•h/mL and 259 ng/mL, respectively. Median time (range) above the well-accepted therapeutic concentration (18 ng/mL) for syphilis treatment was 561 h (439-608 h [18-25 days]), which reached and exceeded the necessary duration of 7-10 days for syphilis treatment. Two participants were underdosed with residual drug left in the syringe due to the high viscosity of the drug product. Only one (12.5%) participant reported a mild adverse event of nasopharyngitis, which was considered not related to the study treatment. The study results supported BPG approval in Japan as an option for syphilis treatment.

Intramuscular versus enteral penicillin prophylaxis to prevent progression of rheumatic heart disease: Study protocol for a noninferiority randomized trial (the GOALIE trial).

BACKGROUND: Rheumatic Heart Disease (RHD) persists as a major cardiovascular driver of mortality and morbidity among young people in low-and middle-income countries. Secondary antibiotic prophylaxis (SAP) with penicillin remains the cornerstone of RHD control, however, suboptimal treatment adherence undermines most secondary prevention programs. Many of the barriers to optimal SAP adherence are specific to the intramuscular form of penicillin and may potentially be overcome by use of oral penicillin. This noninferiority trial is comparing the efficacy of intramuscular to oral penicillin SAP to prevent progression of mild RHD at 2 years. METHODS/DESIGN: The Intramuscular vs Enteral Penicillin Prophylaxis to Prevent Progression of Rheumatic Heart Disease (GOALIE) trial is randomizing Ugandan children aged 5 to 17 years identified by echocardiographic screening with mild RHD (Stage A or B as defined by 2023 World Heart Federation criteria) to Benzathine Benzyl Penicillin G (BPG arm, every-28-day intramuscular penicillin) or Phenoxymethyl Penicillin (Pen V arm, twice daily oral penicillin) for a period of 2 years. A blinded echocardiography adjudication panel of 3 RHD experts and 2 cardiologists is determining the echocardiographic stage of RHD at enrollment and will do the same at study completion by consensus review. Treatment adherence and study retention are supported through peer support groups and case management strategies. The primary outcome is the proportion of children in the Pen V arm who progress to more advanced RHD compared to those in the BPG arm. Secondary outcomes are patient-reported outcomes (treatment acceptance, satisfaction, and health related quality of life), costs, and cost-effectiveness of oral compared to intramuscular penicillin prophylaxis for RHD. A total sample size of 1,004 participants will provide 90% power to demonstrate noninferiority using a margin of 4% with allowance for 7% loss to follow-up. Participant enrollment commenced in October 2023 and final participant follow-up is expected in December 2026. The graphical abstract (Fig. 1) summarizes the flow of echocardiographic screening, participant enrollment and follow-up. DISCUSSION: The GOALIE trial is critical in global efforts to refine a pragmatic approach to secondary prevention for RHD control. GOALIE insists that the inferiority of oral penicillin be proven contemporarily and against the most important near-term clinical outcome of progression of RHD severity. This work also considers other factors that could influence the adoption of oral prophylaxis and change the calculus for acceptable efficacy including patient-reported outcomes and costs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05693545.

Patient preferences for prophylactic regimens requiring regular injections in children and adolescents: a systematic review and thematic analysis.

BACKGROUND: At present, limited literature exists exploring patient preferences for prophylactic treatment of acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Given low treatment completion rates to this treatment in Australia, where the burden of disease predominantly affects Aboriginal and Torres Strait Islander people, an improved understanding of factors driving patient preference is required to improve outcomes. Due to limited available literature, this review sought to explore treatment preferences for conditions for which the findings might be generalisable to the ARF/RHD context. OBJECTIVE: Explore treatment preferences of patients, parents/caregivers and healthcare providers towards regular injection regimens in paediatric and adolescent populations for any chronic condition. Findings will be applied to the development of benzathine penicillin G (BPG) prophylactic regimens that are informed by treatment preferences of patients and their caregivers. This in turn should contribute to optimisation of successful BPG delivery. METHODS: A systematic review of databases (Medline, Embase and Global Health) was conducted using a search strategy developed with expert librarian input. Studies were selected using a two-stage process: (1) title and abstract screen and (2) full text review. Data were extracted using a reviewer-developed template and appraised using the JBI Critical Appraisal tool. Data were synthesised according to a thematic analytical framework. RESULTS: 1725 papers were identified by the database search, conducted between 12 February 2022 and 8 April 2022, and 25 were included in the review. Line-by-line coding to search for concepts generated 20 descriptive themes. From these, five overarching analytical themes were derived inductively: (1) ease of use, (2) tolerability of injection, (3) impact on daily life, (4) patient/caregiver agency and (5) home/healthcare interface. CONCLUSIONS: The findings of this review may be used to inform the development of preference-led regular injection regimens for paediatric and adolescent patient cohorts-specifically for BPG administration in ARF/RHD secondary prophylaxis. TRIAL REGISTRATION NUMBER: Patient, parent and health personnel preferences towards regular injection regimes in paediatric and adolescent populations-a protocol for a systematic review. PROSPERO 2021 CRD42021284375. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021284375.

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)

Secondary Antibiotic Prophylaxis for Latent Rheumatic Heart Disease.

BACKGROUND: Rheumatic heart disease affects more than 40.5 million people worldwide and results in 306,000 deaths annually. Echocardiographic screening detects rheumatic heart disease at an early, latent stage. Whether secondary antibiotic prophylaxis is effective in preventing progression of latent rheumatic heart disease is unknown. METHODS: We conducted a randomized, controlled trial of secondary antibiotic prophylaxis in Ugandan children and adolescents 5 to 17 years of age with latent rheumatic heart disease. Participants were randomly assigned to receive either injections of penicillin G benzathine (also known as benzathine benzylpenicillin) every 4 weeks for 2 years or no prophylaxis. All the participants underwent echocardiography at baseline and at 2 years after randomization. Changes from baseline were adjudicated by a panel whose members were unaware of the trial-group assignments. The primary outcome was echocardiographic progression of latent rheumatic heart disease at 2 years. RESULTS: Among 102,200 children and adolescents who had screening echocardiograms, 3327 were initially assessed as having latent rheumatic heart disease, and 926 of the 3327 subsequently received a definitive diagnosis on the basis of confirmatory echocardiography and were determined to be eligible for the trial. Consent or assent for participation was provided for 916 persons, and all underwent randomization; 818 participants were included in the modified intention-to-treat analysis, and 799 (97.7%) completed the trial. A total of 3 participants (0.8%) in the prophylaxis group had echocardiographic progression at 2 years, as compared with 33 (8.2%) in the control group (risk difference, -7.5 percentage points; 95% confidence interval, -10.2 to -4.7; P<0.001). Two participants in the prophylaxis group had serious adverse events that were attributable to receipt of prophylaxis, including one episode of a mild anaphylactic reaction (representing <0.1% of all administered doses of prophylaxis). CONCLUSIONS: Among children and adolescents 5 to 17 years of age with latent rheumatic heart disease, secondary antibiotic prophylaxis reduced the risk of disease progression at 2 years. Further research is needed before the implementation of population-level screening can be recommended. (Funded by the Thrasher Research Fund and others; GOAL ClinicalTrials.gov number, NCT03346525.).

Case report of gastric syphilis in Korea: Clinical features, pathology, management, and prognosis.

RATIONALE: Syphilis is a contagious infectious disease caused by Treponema pallidum. Gastric involvement of syphilis is rare and has nonspecific gastrointestinal symptoms and endoscopic findings. To date, 16 cases have been reported in Korea. Here, we report 2 additional cases of gastric syphilis in men in their 30 second. PATIENTS CONCERNS: Two 35- and 33-year-old men presented with epigastric pain. DIAGNOSIS: The serum venereal disease research laboratory and fluorescent treponemal antibody absorption tests were positive. Esophagogastroduodenoscopy showed multiple variable-sized flat elevated lesions and geographic ulcers with whitish exudates in the antrum and body. Warthin-Starry silver staining of endoscopic biopsy specimens confirmed gastric syphilis. INTERVENTIONS: The patients were treated with an intramuscular injection of 2.4 million units of benzathine penicillin once a week for 3 weeks. OUTCOMES: Clinical symptoms and gastric lesions were completely resolved. LESSONS: First, gastric syphilis, despite its rarity and nonspecific symptoms and endoscopic findings, should be considered in a rare extracutaneous presentation of syphilis. Second, a high index of clinical suspicion and an accurate diagnosis based on a combination of clinical, radiological, endoscopic, serologic, and histopathologic findings provide an opportunity to identify and treat patients with gastric syphilis.

High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.

INTRODUCTION: Intramuscular benzathine penicillin G (BPG) injections are a cornerstone of secondary prophylaxis to prevent acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Uncertainties regarding inter-ethnic and preparation variability, and target exposure profiles of BPG injection are key knowledge gaps for RHD control. METHODS: To evaluate BPG pharmacokinetics (PK) in patients receiving 4-weekly doses in Ethiopia, we conducted a prospective cohort study of ARF/RHD patients attending cardiology outpatient clinics. Serum samples were collected weekly for one month after injection and assayed with a liquid chromatography-mass spectroscopy assay. Concentration-time datasets for BPG were analyzed by nonlinear mixed effects modelling using NONMEM. RESULTS: A total of 190 penicillin concentration samples from 74 patients were included in the final PK model. The median age, weight, BMI was 21 years, 47 kg and 18 kg/m2, respectively. When compared with estimates derived from Indigenous Australian patients, the estimate for median (95% confidence interval) volume of distribution (V/F) was lower (54.8 [43.9-66.3] l.70kg-1) whilst the absorption half-life (t1/2-abs2) was longer (12.0 [8.75-17.7] days). The median (IQR) percentage of time where the concentrations remained above 20 ng/mL and 10 ng/mL within the 28-day treatment cycle was 42.5% (27.5-60) and 73% (58.5-99), respectively. CONCLUSIONS: The majority of Ethiopian patients receiving BPG as secondary prophylaxis to prevent RHD do not attain target concentrations for more than two weeks during each 4-weekly injection cycle, highlighting the limitations of current BPG strategies. Between-population variation, together with PK differences between different preparations may be important considerations for ARF/RHD control programs.

Secondary syphilis mimicking tinea cruris in an HIV infected patient: a case report.

Syphilis is known as the great imitator with various clinical presentations which often lead to confusion and misdiagnosis. A 28-year-old male presented with non-pruritic and painless erythematous patches around the anus and scrotum. Initial differential diagnosis with tinea cruris. Fungal examination was negative. Serological tests for syphilis were positive and anti-HIV screening was reactive. A diagnosis of secondary syphilis was established and the patient was given intramuscular injection of 2.4 million unit of benzathine penicillin. The skin lesions improved significantly 1 week after treatment, confirming a diagnosis of secondary syphilis with HIV. Annular skin lesions in secondary syphilis are uncommon and often misleading. This case emphasizes the importance of considering secondary syphilis in the differential diagnosis of annular lesions.

Dermatosis IgA lineal asociada a sífilis secundaria / Linear IgA bullous dermatosis associated secondary syphilis

La dermatosis IgA lineal del adulto es una enfermedad que pertenece al grupo de las dermatosis ampollares adquiridas. De etiología desconocida e infrecuente, se presenta en adultos mayores y se asocia a múltiples fármacos, neoplasias y enfermedades autoinmunes e infecciosas. Se presenta el caso de un paciente con una dermatosis IgA lineal asociada a una sífilis secundaria.

Linear bullous IgA dermatosis of adult is a disease that belongs to the group of acquired bullous dermatoses. It is of unknown aetiology and infrequent in adults and is associated with drugs, neoplasms, autoimmune and infectious diseases. We present a case of a male patient in whom a linear IgA dermatosis and secondary syphilis coexist.

Syphilitic Pulmonary Inflammatory Pseudotumor: A Diagnostic Challenge.

A 46-year-old man presented with nonproductive cough and lower limb swelling. Chest radiograph showed a left lower lobe lung mass and multiple subpleural nodules. Other investigations revealed that he had nephrotic syndrome. Core biopsies of the left lower lobe lung mass showed features of inflammatory pseudotumor with endarteritis obliterans and a lymphoplasmacytic infiltrate. Immunohistochemical stain for Treponema pallidum was positive. Resolution of the lung mass and nephrotic syndrome was achieved after treatment with intramuscular benzathine benzylpenicillin. The differential diagnosis of pulmonary inflammatory pseudotumor, manifestations of pulmonary syphilis, and a literature review of secondary syphilis of the lung are discussed.

Team adherence to rapid prenatal testing and administration of benzathine penicillin in primary healthcare. / Adesão das equipes aos testes rápidos no pré-natal e administração da penicilina benzatina na atenção primária.

OBJECTIVE: To identify the factors related to the work process regarding the adherence of Primary Healthcare teams to the rapid test for HIV, syphilis, hepatitis B and C during prenatal care and administration of benzathine penicillin in primary healthcare. METHOD: A descriptive, exploratory and quantitative study conducted between the months of July and November 2018, with professionals from the Family Health Strategy teams of the Seridó Norte-Rio-Grandense region in Rio Grande do Norte State, Brazil. RESULTS: There were 18 municipalities, 94 Basic Health Units and 100 Family Health Strategy teams which participated in the study. The nurse was the main person involved in the testing service, and 93% of the interviewed teams offered the test in the service routine. Of these teams, 97.8% underwent prenatal testing, 51.6% offered the test to the pregnant woman at the beginning of the third trimester, and 57% offered the rapid test to sexual partners. Benzantine penicillin was available in 87.1% of the teams; however, 49.5% did not administer the medication in primary healthcare. CONCLUSION: The testing process proved to be fragile because even if the test was available in prenatal care, the other activities linked to the work process did not occur properly.

More than meets the eye: Papilledema from syphilis posing as idiopathic intracranial hypertension.

Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, is a diagnosis of exclusion. Elevated intracranial pressure (ICP) can result from a variety of inflammatory and structural causes affecting cerebrospinal fluid production and absorption. First described in 1935, syphilis is a well-established cause of elevated ICP, referred to as syphilitic hydrocephalus. We report a case of a 49-year-old man presenting with vision changes and headache who was treated for IIH without resolution of symptoms, and eventually diagnosed with syphilitic hydrocephalus. Syphilis should be considered as a cause of elevated ICP prior to a diagnosis of IIH.

Recognizing and limiting syphilis to prevent congenital syphilis.

Syphilis is on the rise in every age and ethnicity group across the United States. The rate of congenital syphilis has started to rise as well, increasing the need for syphilis screening before pregnancy occurs. Raising awareness for syphilis screening, especially among sexually active women, is important, as the implications of this disease have lifelong effects for mother and child.

Nicolau Syndrome, Masquerader of Postinjection Sciatic Nerve Injury: Case Report and Review of Literature.

BACKGROUND: Sciatic nerve injury after inadvertent intramuscular gluteal injection is a well-described entity. We have presented a case of a rare and probably underdiagnosed pathological entity, Nicolau syndrome, which can be confused with injection palsy. CASE DESCRIPTION: We report the case of a 13-year-old boy who had presented with foot drop and urinary and fecal incontinence after an intramuscular injection of benzathine penicillin in the left gluteal region. On examination, the patient had multiple ecchymoses over the left gluteal region and back of the thigh, mild swelling of the left lower limb, and left foot drop. Meticulous examination also revealed a subtle weakness of the opposite limb. Nerve conduction studies revealed axonopathy involving multiple bilateral lower limb nerves. These unusual neurological-dermatological signs and electrophysiological findings raised the concern for an alternative pathology, which was later diagnosed as Nicolau syndrome. The patient experienced clinical and electrophysiological recovery after a course of oral steroids and physiotherapy during the next few months. CONCLUSIONS: Before diagnosing injection sciatic nerve injury, the possibility of medically treatable Nicolau syndrome should be considered. Neurosurgeons' familiarity with this pathology and a timely diagnosis is essential to plan appropriate treatment strategies.

Nodular secondary syphilis in three HIV-positive patients: a case series.

Nodular secondary syphilis is an uncommon variant of secondary syphilis. We identified three cases of nodular secondary syphilis at our institution. The first patient presented with a diffuse nodular rash that included his scrotum and penis. The second patient had disseminated skin-colored nodules with serosanguinous crust on his face, trunk, and extremities. The third patient had a pruritic papular and nodular rash with overlying crust. All three patients had a reactive rapid plasma reagin and tested positive for fluorescent treponemal antibody absorption. All were eventually confirmed to be human immunodeficiency virus-positive. Histopathological examination demonstrated inflammatory infiltrate in the dermis composed of lymphocytes, histiocytes, and plasma cells, and treponemal staining highlighted spirochetes in the dermis. The patients were successfully treated with intramuscular penicillin benzathine G. Physicians should be aware of nodular syphilis as a less common cutaneous manifestation of secondary syphilis. Prompt diagnosis of secondary syphilis can expedite resolution of the infection and avoid progression to tertiary syphilis.

Tinidazole: Another Therapeutic Option for Syphilis?

After the incidental observation of an almost complete resolution of maculopapular eruption in a patient having simultaneously secondary syphilis and trichomonas vaginalis infection, we extended the treatment with tinidazole (500 mg 4 times daily for 7 days) to 10 other early syphilis patients before the start of the conventional penicillin treatment. All patients showed marked improvement of their lesions in a few days. After the introduction of the conventional penicillin regimen, the lesions further improved and VDRL titers declined at least 4-fold within 6 months in all patients. Tinidazole is a 5-nitroimidazole derivative as well as metronidazole but with a longer plasma half-life. It is activated intracellularly by bacterial/parasitic enzymes to a redox cytotoxic intermediate that damages large protein molecules and inhibits repair and transcription of DNA affecting also the cell wall. With this action, tinidazole might also have a synergic action with penicillin and doxycycline, facilitating the entry of such drugs. It is possible that tinidazole has the same bactericidal action on spirochetes other than Borrelia, such as Treponema pallidum, explaining its rapid therapeutic action on the lesions of early syphilis. Whether this action could be confirmed by studies on larger series of patients, tinidazole might be considered in case of allergy to penicillin or other antibiotics usually prescribed in syphilis.

Secondary syphilis presenting as Syphilide psoriasiforme: lessons from the older syphilology literature.

It is essential for health care providers to be familiared with the full spectrum of clinical presentations of syphilis. We present herein a case of syphilide psoriasiforme, an uncommon but well recognized clinical presentation of secondary syphilis. A 46-year-old HIV-infected female patient was referred to our attention with a presumptive diagnosis of palmoplantar psoriasis. On examination, there were exuberant pinkish-red papules and plaques covered with a thick silvery scale in the palms, flexor surfaces of the wrists, and the medial longitudinal arches of the feet. Serological and histopathological analyses uncovered the diagnosis of syphilis. Clinical remission was obtained after treatment. A detailed review of the literature on syphilide psoriasiforme, including descriptions from older syphilology textsis provided. The present case report emphasizes the need for clinicians to have a heightened awareness of the varied and unusual clinical phenotypes of syphilis.