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.

Sub-clinical rheumatic heart disease (RHD) detected by hand-held echocardiogram in children participating in a school-based RHD prevention program in Tanzania.

BACKGROUND: Rheumatic Heart Disease (RHD) continues to cause suffering and premature deaths in many sub-Saharan Africa (SSA) countries, where the disease is still endemic. RHD is largely preventable and determining its community burden is an important critical step in any RHD prevention program. METHODS: We conducted a cross-sectional study of 5-16 years old pupils from 11 primary schools participating in an RHD prevention program in 4 districts in Tanzania, between 2018 and 2019. At the school, all children were invited to participate after receiving consent from their parents/guardians. Participating children filled a questionnaire and were auscultated for cardiac murmurs. Echocardiographic screening was done by two experienced cardiologists, using a hand-held machine (V-Scan, GE®). All positive screening tests were stored for further examination by the same two cardiologists to reach to a consensus of definite, borderline or no RHD, using a modified World Heart Federation (WHF) criterion. RESULTS: Of the 6895 children invited, 4738 (68.7%) were screened and 4436 (64.3%) had complete data. The mean (SD) age was 10.04 (2.43) years, and 2422 (54.6%) were girls. Fifty three (1.2%) children were found to have a murmur. The proportion of children with trace or mild valvular regurgitation, sub-valvular/chordal thickening and valvular thickening/deformity were 8.3%, 1.3%, and 1.0%, respectively. Sub-clinical RHD was found in 95 children (59 definite and 36 borderline), giving a prevalence of 2.1%, [95% CI 1.7% - 2.6%]. Sub-clinical RHD was independently associated with female sex (aOR 1.83, 95% CI 1.18-2.85, p = 0.007), older age groups (aOR 1.73, 95% CI 1.10-2.72, p = 0.018 for age group 11-14 years; and aOR 3.02 95% CI 1.01-9.05, p = 0.048 for age group 15-16 years), as well as presence of a cardiac murmur, aOR 5.63 95% CI 2.31-13.69, p < 0.0001. None of the studied socio- or economic factors was associated with the presence of sub-clinical RHD in this study. CONCLUSION: The prevalence of sub-clinical RHD among primary school children in Tanzania is 2.1%, similar to previous reports in SSA. Efforts to prevent and control RHD in our communities are highly warranted.

Population pharmacokinetic study of benzathine penicillin G administration in Indigenous children and young adults with rheumatic heart disease in the Northern Territory, Australia.

BACKGROUND: Benzathine penicillin G (BPG) is the cornerstone of secondary prophylaxis to prevent Streptococcus pyogenes infections, which precede acute rheumatic fever (ARF). The paucity of pharmacokinetic (PK) data from children and adolescents from populations at the highest risk of ARF and rheumatic heart disease (RHD) poses a challenge for determining the optimal dosing and frequency of injections and undermines efforts to develop improved regimens. METHODS: We conducted a 6 month longitudinal PK study of young people receiving BPG for secondary prophylaxis. Throat and skin swabs were collected for microbiological culture along with dried blood spot (DBS) samples for penicillin concentrations. DBSs were assayed using LC-MS/MS. Penicillin concentration datasets were analysed using non-linear mixed-effects modelling and simulations performed using published BMI-for-age and weight-for-age data. RESULTS: Nineteen participants provided 75 throat swabs, 3 skin swabs and 216 penicillin samples. Throat cultures grew group C and G Streptococcus. Despite no participant maintaining penicillin concentration >20 ng/mL between doses, there were no S. pyogenes throat infections and no ARF. The median (range) observed durations >20 ng/mL for the low- and high-BMI groups were 14.5 (11.0-24.25) and 15.0 (7.5-18.25) days, respectively. CONCLUSIONS: Few patients at highest risk of ARF/RHD receiving BPG for secondary prophylaxis maintain penicillin concentrations above the target of 20 ng/mL beyond 2 weeks during each monthly dosing interval. These PK data suggest that some high-risk individuals may get inadequate protection from every 4 week dosing. Future research should explore this gap in knowledge and PK differences between different populations to inform future dosing schedules.

Secondary prevention of rheumatic heart disease in Ethiopia: a multicenter study.

BACKGROUND: Ethiopia has a high acute rheumatic fever (ARF) and rheumatic heart disease (RHD) prevalence, and to our knowledge, there are no data on the status of secondary prevention in children with RHD. This study describes the status of secondary RHD prevention. METHODS: A multicenter, prospective study was performed on children aged 5-17 years with RHD in Ethiopia. Good adherence was defined as at least 80% completion of benzathine penicillin (BPG) or oral Amoxicillin within the previous year. The primary outcome measure was adherence to prophylaxis, expressed as a proportion. Socio-demographics, severity of RHD, and ARF recurrence were evaluated. RESULTS: A total of 337 children with a mean age of 12.9 ± 2.6 years were included. The majority (73%) had severe aortic/mitral disease. Participants were on BPG (80%) or Amoxicillin (20%) prophylaxis. Female sex (P = 0.04) use of BPG (0.03) and shorter mean duration of prophylaxis in months (48.5 ± 31.5 vs. 60.7 ± 33, respectively, P < 0.008) predicted good adherence. Running out of medications (35%), interrupted follow-up (27%), and the COVID-19 pandemic (26%) were the most common reasons for missing prophylaxis. Recurrence of ARF was higher in participants on Amoxicillin compared with BPG (40% vs. 16%, P < 0.001) and in those with poor adherence compared with good adherence (36.8% vs. 17.9%, respectively, P = 0.005). Type and duration of prophylaxis (OR 0.5, CI = 0.24, 0.9, P = 0.02; OR = 1.1, CI = 1.1, 1.2, P = 0.04, respectively), and sex (OR = 1.9, CI = 1.1, 3.4, P = 0.03) were independent predictors of poor adherence. CONCLUSION: Poor adherence is prevalent in Ethiopian children living with RHD. Amoxicillin is a suboptimal option for prophylaxis as its use is associated with lower adherence and a higher rate of ARF recurrence.

Persisting burden and challenges of rheumatic heart disease.

Rheumatic heart disease (RHD) is the result of episodes of acute rheumatic fever with valvular (and other cardiac) damage caused by an abnormal immune response to group A streptococcal infections, usually during childhood and adolescence. As a result of improved living conditions and the introduction of penicillin, RHD was almost eradicated in the developed world by the 1980s. However, being a disease of poverty, its burden remains disproportionately high in the developing world, despite being a fundamentally preventable disease. Rheumatic heart disease generates relatively little attention from the medical and science communities, in contrast to other common infectious problems (such as malaria, HIV, tuberculosis), despite the major cardiovascular morbidity/mortality burden imposed by RHD. This relative neglect and paucity of funding have probably contributed to limited fundamental medical advances in this field for over 50 years. Given the importance of prevention before the onset of major valvular damage, the main challenges for RHD prevention are improving social circumstances, early diagnosis, and effective delivery of antibiotic prophylaxis. Early identification through ultrasound of silent, subclinical rheumatic valve lesions could provide an opportunity for early intervention. Simple echocardiographic diagnostic criteria and appropriately trained personnel can be valuable aids in large-scale public health efforts. In addition, a better understanding of the immunogenic determinants of the disease may provide potential routes to vaccine development and other novel therapies.

Pediatric Rheumatic Heart Disease in a Middle-Income Country: A Population-Based Study.

INTRODUCTION: Rheumatic heart disease (RHD), a debilitating complication from rheumatic fever, remains a problem in low- and middle-income countries. This study describes the incidence, prevalence, modifiable risk factors for severe RHD and immediate outcome of pediatric RHD. METHODS: This population-based and observational cohort study reviewed pediatric RHD patients (0-18 years) from the Sabah Pediatric Rheumatic Heart Registry from 2015 till 2018. RESULTS: A total of 188 RHD were reviewed with 120 new cases. The incidence of RHD is 2.19 [95% confidence interval (CI): 1.83-2.61] per 100 000 population, with a rising trend over time. Meanwhile, the prevalence of RHD was 13.78 (95% CI: 11.92-15.86) per 100 000 pediatric population. The majority of patients were from indigenous groups (59.0%), male (56.4%) with a mean age of 14.3 (3.31) years. About 77.9% had the lowest household income, and a significant proportion lived in overcrowded conditions. At diagnosis, 59% were diagnosed with severe RHD. There is heightened risk but no statistical significance between modifiable factors (low weight and height percentile at diagnosis, lowest income group, renting a house, overcrowding and healthcare access of more than 5 km) with severe RHD. Severe RHD is significantly associated with risk for intervention (p = 0.016). Sixteen (13.8%) patients required surgical intervention. About 97.6% of patients were on intramuscular benzathine penicillin G with 84.5% compliance. CONCLUSION: The rising prevalence and incidence of pediatric RHD in Sabah, with the most being severe RHD at diagnosis, necessitates the development of an echocardiographic screening and a comprehensive national disease program.

Community Advocacy and Capacity Building of Community Health Workers on Rheumatic Heart Disease in Osun State, Nigeria.

Rheumatic heart disease (RHD) is one of the leading causes of cardiovascular diseases in the world. The study aimed to assess awareness and capacity building on the diagnosis and prevention of RHD among Community Health Workers (CHWs) Nigeria. It was an interventional study, where 300 CHWs from public Primary Health Care (PHC) facilities were selected pre-assessed on the diagnosis and prevention of RHD before their training on RHD. Also, a post-test evaluation was done to reassess the CHWs awareness on RHD. Data were analyzed and RHD knowledge was scored and graded. Results showed, at pre-test evaluation, that 49% of the CHWs had good knowledge, 49.7% had fair knowledge while 4.1% had poor knowledge on the diagnosis and prevention of RHD, while post-test evaluation revealed that 100% of the CHWs had good knowledge. Awareness of the CHWs about the diagnosis and prevention of RHD was fair in the pre-test and improved after the training with all the CHWs having good knowledge. This showed the training was impactful. Intermittent assessment of the awareness and simultaneous training of the CHWs on RHD may be scaled up into a significant and effective measure in the armamentarium of community prevention of the disease.

La cardiopathie rhumatismale est l'une des principales causes de maladies cardiovasculaires dans le monde. L'étude visait à évaluer la sensibilisation et le renforcement des capacités sur le diagnostic et la prévention de la cardiopathie rhumatismale chez les agents de santé communautaire (ASC). au Nigeria. Il s'agissait d'une étude interventionnelle, dans le cadre de laquelle 300 ASC des établissements publics de soins de santé primaires (PHC) ont été sélectionnés et pré-évalués sur le diagnostic et la prévention des RHD avant leur formation sur les RHD.. De plus, une évaluation post-test a été réalisée pour réévaluer la connaissance des ASC sur la RHD. Les données ont été analysées et les connaissances sur la RHD ont été notées et évaluées. Les résultats ont montré, lors de l'évaluation du pré-test, que 49% des ASC avaient une bonne connaissance, 49,7 % une connaissance moyenne et 4,1 % une mauvaise connaissance du diagnostic et de la prévention de RHD, tandis que l'évaluation du post-test a révélé que 100% des ASC avaient de bonnes connaissances. La connaissance des ASC sur le diagnostic et la prévention de la RHD était moyenne dans le pré-test et s'est améliorée après la formation, tous les ASC ayant de bonnes connaissances. Cela montre que la formation a eu un impact. L' évaluation intermittente de la sensibilisation et la formation simultanée des ASC sur la RHD peut devenir une mesure significative et efficace dans l'arsenal de prévention communautaire de la maladie. Mots-clés: Cardiopathie rhumatismale, Agents de santé communautaire, service de santé, prévention.

Diagnosis, management, and prevention of acute rheumatic fever in the United States.

ABSTRACT: Acute rheumatic fever is a multisystem autoimmune disease caused by infection with group A streptococcus. The condition most commonly affects children ages 5 to 14 years who are from low-income populations. The diagnosis is clinical; however, the 2015 Jones Criteria can help support it. Acute rheumatic fever poses a significant health risk secondary to rheumatic heart disease. Although acute rheumatic fever is rare in the United States, outbreaks still occur, and certain populations continue to be at increased risk. This article describes how to identify acute rheumatic fever and provides prompt management and prevention strategies to reduce patient risk for lifelong complications.

Contemporary Diagnosis and Management of Rheumatic Heart Disease: Implications for Closing the Gap: A Scientific Statement From the American Heart Association.

The global burden of rheumatic heart disease continues to be significant although it is largely limited to poor and marginalized populations. In most endemic regions, affected patients present with heart failure. This statement will seek to examine the current state-of-the-art recommendations and to identify gaps in diagnosis and treatment globally that can inform strategies for reducing disease burden. Echocardiography screening based on World Heart Federation echocardiographic criteria holds promise to identify patients earlier, when prophylaxis is more likely to be effective; however, several important questions need to be answered before this can translate into public policy. Population-based registries effectively enable optimal care and secondary penicillin prophylaxis within available resources. Benzathine penicillin injections remain the cornerstone of secondary prevention. Challenges with penicillin procurement and concern with adverse reactions in patients with advanced disease remain important issues. Heart failure management, prevention, early diagnosis and treatment of endocarditis, oral anticoagulation for atrial fibrillation, and prosthetic valves are vital therapeutic adjuncts. Management of health of women with unoperated and operated rheumatic heart disease before, during, and after pregnancy is a significant challenge that requires a multidisciplinary team effort. Patients with isolated mitral stenosis often benefit from percutaneous balloon mitral valvuloplasty. Timely heart valve surgery can mitigate the progression to heart failure, disability, and death. Valve repair is preferable over replacement for rheumatic mitral regurgitation but is not available to the vast majority of patients in endemic regions. This body of work forms a foundation on which a companion document on advocacy for rheumatic heart disease has been developed. Ultimately, the combination of expanded treatment options, research, and advocacy built on existing knowledge and science provides the best opportunity to address the burden of rheumatic heart disease.

The American Heart Association's Call to Action for Reducing the Global Burden of Rheumatic Heart Disease: A Policy Statement From the American Heart Association.

Rheumatic heart disease (RHD) affects ≈40 million people and claims nearly 300 000 lives each year. The historic passing of a World Health Assembly resolution on RHD in 2018 now mandates a coordinated global response. The American Heart Association is committed to serving as a global champion and leader in RHD care and prevention. Here, we pledge support in 5 key areas: (1) professional healthcare worker education and training, (2) technical support for the implementation of evidence-based strategies for rheumatic fever/RHD prevention, (3) access to essential medications and technologies, (4) research, and (5) advocacy to increase global awareness, resources, and capacity for RHD control. In bolstering the efforts of the American Heart Association to combat RHD, we hope to inspire others to collaborate, communicate, and contribute.

The 2020 Australian guideline for prevention, diagnosis and management of acute rheumatic fever and rheumatic heart disease.

INTRODUCTION: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) cause significant morbidity and premature mortality among Australian Aboriginal and Torres Strait Islander peoples. RHDAustralia has produced a fully updated clinical guideline in response to new knowledge gained since the 2012 edition. The guideline aligns with major international ARF and RHD practice guidelines from the American Heart Association and World Heart Federation to ensure best practice. The GRADE system was used to assess the quality and strength of evidence where appropriate. MAIN RECOMMENDATIONS: The 2020 Australian guideline details best practice care for people with or at risk of ARF and RHD. It provides up-to-date guidance on primordial, primary and secondary prevention, diagnosis and management, preconception and perinatal management of women with RHD, culturally safe practice, provision of a trained and supported Aboriginal and Torres Strait Islander workforce, disease burden, RHD screening, control programs and new technologies. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINE: Key changes include updating of ARF and RHD diagnostic criteria; change in secondary prophylaxis duration; improved pain management for intramuscular injections; and changes to antibiotic regimens for primary prevention. Other changes include an emphasis on provision of culturally appropriate care; updated burden of disease data using linked register and hospitalisations data; primordial prevention strategies to reduce streptococcal infection addressing household overcrowding and personal hygiene; recommendations for population-based echocardiographic screening for RHD in select populations; expanded management guidance for women with RHD or ARF to cover contraception, antenatal, delivery and postnatal care, and to stratify pregnancy risks according to RHD severity; and a priority classification system for presence and severity of RHD to align with appropriate timing of follow-up.

Rheumatic heart disease in The Gambia: clinical and valvular aspects at presentation and evolution under penicillin prophylaxis.

BACKGROUND: Rheumatic heart disease (RHD) remains the leading cause of cardiac-related deaths and disability in children and young adults worldwide. In The Gambia, the RHD burden is thought to be high although no data are available and no control programme is yet implemented. We conducted a pilot study to generate baseline data on the clinical and valvular characteristics of RHD patients at first presentation, adherence to penicillin prophylaxis and the evolution of lesions over time. METHODS: All patients registered with acute rheumatic fever (ARF) or RHD at two Gambian referral hospitals were invited for a clinical review that included echocardiography. In addition, patients were interviewed about potential risk factors, disease history, and treatment adherence. All clinical and echocardiography information at first presentation and during follow-up was retrieved from medical records. RESULTS: Among 255 registered RHD patients, 35 had died, 127 were examined, and 111 confirmed RHD patients were enrolled, 64% of them females. The case fatality rate in 2017 was estimated at 19.6%. At first presentation, median age was 13 years (IQR [9; 18]), 57% patients had late stage heart failure, and 84.1% a pathological heart murmur. Although 53.2% of them reported history of recurrent sore throat, only 32.2% of them had sought medical treatment. A history suggestive of ARF was reported by 48.7% patients out of whom only 15.8% were adequately treated. Two third of the patients (65.5%) to whom it was prescribed were fully adherent to penicillin prophylaxis. Progressive worsening and repeated hospitalisation was experienced by 46.8% of the patients. 17 patients had cardiac surgery, but they represented only 18.1% of the 94 patients estimated eligible for cardiac surgery. CONCLUSION: This study highlights for the first time in The Gambia the devastating consequences of RHD on the health of adolescents and young adults. Our findings suggest a high burden of disease that remains largely undetected and without appropriate secondary prophylaxis. There is a need for the urgent implementation of an effective national RHD control programto decrease the unacceptably high mortality rate, improve case detection and management, and increase community awareness of this disease.

Early diagnosis of acute rheumatic fever and rheumatic heart disease as part of a secondary prevention strategy: Narrative review.

Acute rheumatic fever (ARF) and its sequela rheumatic heart disease (RHD) remain significant causes of morbidity and mortality. In New Zealand, ARF almost exclusively affects Indigenous Maori and Pacific children. This narrative review aims to present secondary interventions to improve early and accurate diagnosis of ARF and RHD, in order to minimise disease progression in New Zealand. Medline, EMBASE and Scopus databases were searched as well as other electronic publications. Included were 56 publications from 1980 onwards. Diagnosing ARF and RHD as early as possible is central to reducing disease progression. Recent identification of specific ARF biomarkers offer the opportunity to aid initial diagnosis and portable echocardiography has the potential to detect undiagnosed RHD in high-risk areas. However, further research into the benefits and risks to children with subclinical RHD is necessary, as well as an economic evaluation.

Relationship between patient understanding and timeliness of penicillin prophylaxis in rheumatic heart disease prevention programmes in American Samoa.

AIM: While mostly eradicated in developed nations, rheumatic heart disease (RHD) is still the leading cause of preventable cardiovascular disease in children. RHD and its antecedent acute rheumatic fever remain endemic in many low to middle income countries, as well as in vulnerable communities in wealthy ones. Evidence-based interventions are particularly important in resource-poor settings. We sought to determine if efforts directed at patient and family education impact degree of participation in community-based prevention measures, and with short-term disease progression. METHODS: We performed an observational, cross-sectional study of children with RHD aged 5-19 years, along with their parents, in American Samoa. A survey was administered in November 2016 to assess patient and parent knowledge of RHD. Scores were compared to percent timeliness of penicillin prophylaxis via chart review. RESULTS: We collected a total of 70 surveys of child-parent dyads with a patient mean age of 14.28 years ±2.71. An increased knowledge score was predictive of increased penicillin compliance for both children (12.70% increase in compliance per 1-unit increase in score (P = 0.0004)) and parents (10.10% increase in compliance per 1-unit increase in score (P = 0.0012)). CONCLUSIONS: A clear relationship exists between patient and parent knowledge of RHD and timeliness of penicillin prophylaxis doses. This study was the first to link patient understanding of RHD to engagement with preventative measures.

A community-based program to reduce acute rheumatic fever and rheumatic heart disease in northern Australia.

BACKGROUND: In Australia's north, Aboriginal peoples live with world-high rates of rheumatic heart disease (RHD) and its precursor, acute rheumatic fever (ARF); driven by social and environmental determinants of health. We undertook a program of work to strengthen RHD primordial and primary prevention using a model addressing six domains: housing and environmental support, community awareness and empowerment, health literacy, health and education service integration, health navigation and health provider education. Our aim is to determine how the model was experienced by study participants. METHODS: This is a two-year, outreach-to-household, pragmatic intervention implemented by Aboriginal Community Workers in three remote communities. The qualitative component was shaped by Participatory Action Research. Yarning sessions and semi-structured interviews were conducted with 14 individuals affected by, or working with, ARF/RHD. 31 project field reports were collated. We conducted a hybrid inductive-deductive thematic analysis guided by critical theory. RESULTS: Aboriginal Community Workers were best placed to support two of the six domains: housing and environmental health support and health navigation. This was due to trusting relationships between ACWs and families and the authority attributed to ACWs through the project. ACWs improved health literacy and supported awareness and empowerment; but this was limited by disease complexities. Consequently, ACWs requested more training to address knowledge gaps and improve knowledge transfer to families. ACWs did not have skills to provide health professionals with education or ensure health and education services participated in ARF/RHD. Where knowledge gain among participant family members was apparent, motivation or structural capability to implement behaviour change was lacking in some domains, even though the model was intended to support structural changes through care navigation and housing fixes. CONCLUSIONS: This is the first multi-site effort in northern Australia to strengthen primordial and primary prevention of RHD. Community-led programs are central to the overarching strategy to eliminate RHD. Future implementation should support culturally safe relationships which build the social capital required to address social determinants of health and enable holistic ways to support sustainable individual and community-level actions. Government and services must collaborate with communities to address systemic, structural issues limiting the capacity of Aboriginal peoples to eliminate RHD.

The Global Impact of Rheumatic Heart Disease.

PURPOSE OF REVIEW: Rheumatic heart disease (RHD) is a neglected disease of poverty, which presents challenges for patients, communities, and health systems. These effects are magnified in low resource countries, which bear the highest disease burden. When considering the impact of RHD, it is imperative that we widen our lens in order to better understand how RHD impacts the over 40 million people currently living with this preventable condition and their communities. We aimed to perform an updated literature review on the global impact of RHD, examining a broad range of aspects from disease burden to impact on healthcare system to socioeconomic implications. RECENT FINDINGS: RHD accounts for 1.6% of all cardiovascular deaths, resulting in 306,000 deaths yearly, with a much higher contribution in low- and middle-income countries, where 82% of the deaths occurred in 2015. RHD can result in severe health adverse outcomes, markedly heart failure, arrhythmias, stroke and embolisms, and ultimately premature death. Thus, preventive, diagnostic and therapeutic interventions are required, although insufficiently available in undersourced settings. As examples, anticoagulation management is poor in endemic regions - and novel oral anticoagulants cannot be recommended - and less than 15% of those in need have access to interventional procedures and valve replacement in Africa. RHD global impact remains high and unequally distributed, with a marked impact on lower resourced populations. This preventable disease negatively affects not only patients, but also the societies and health systems within which they live, presenting broad challenges and high costs along the pathway of prevention, diagnosis, and management.

Subcutaneous administration of benzathine benzylpenicillin G has favourable pharmacokinetic characteristics for the prevention of rheumatic heart disease compared with intramuscular injection: a randomized, crossover, population pharmacokinetic study in healthy adult volunteers.

BACKGROUND: Benzathine penicillin G has been used as monthly deep intramuscular (IM) injections since the 1950s for secondary prevention of acute rheumatic fever and rheumatic heart disease (RHD). Injection frequency and pain are major programmatic barriers for adherence, prompting calls for development of better long-acting penicillin preparations to prevent RHD. We hypothesized that subcutaneous (SC) administration of benzathine penicillin G could delay penicillin absorption when compared with IM injections. METHODS: To compare the pharmacokinetic profile and tolerability of benzathine penicillin G according to different routes of administration, 15 healthy males participated in a randomized crossover study to receive benzathine penicillin G by either SC or IM routes, with a 10 week washout period before the second dose by the alternative route. Ultrasound guidance confirmed injection location. Penicillin concentrations and pain scores were measured for 6 weeks following injections. RESULTS: SC administration was well tolerated with no significant differences in pain scores. Following SC injection, the principal absorption half-life (95% CI) was 20.1 (16.3-29.5) days and 89.6% (87.1%-92.0%) of the drug was directed via this pathway compared with 10.2 (8.6-12.5) days and 71.3% (64.9%-77.4%) following IM administration. Lower peak and higher trough penicillin concentrations resulted following SC injection. Simulations demonstrated that SC infusion of higher doses of benzathine penicillin G could provide therapeutic penicillin concentrations for 3 months. CONCLUSIONS: SC administration of benzathine penicillin G is safe and significantly delays penicillin absorption. High-dose benzathine penicillin G via the SC route would fulfil many product characteristics required for the next generation of longer-acting penicillins for use in RHD.

Acute rheumatic fever prophylaxis in high-income countries: clinical observations from an Italian multicentre, retrospective study.

OBJECTIVES: The aim of the study is to evaluate the compliance rate to secondary prophylaxis and the presence of rheumatic heart disease (RHD) in a cohort of Italian patients with acute rheumatic fever (ARF). METHODS: This is a multicentre retrospective study. The patients were divided into two groups by the presence or absence at last follow-up of RHD. Clinical features, ARF recurrences and the rate of compliance to secondary prophylaxis were evaluated. RESULTS: Two-hundred and ninety patients were enrolled (137 females; 153 males). Carditis at onset was present in 244 patients (84.7%). At the end of follow-up, 173 patients manifested RHD. Adherence to secondary prophylaxis was low in 26% of patients. The presence of RHD at follow-up was associated with the presence of carditis and its severity at onset (p=0.001), but it was not related to secondary prophylaxis adherence (p=NS). No association between prophylaxis adherence and ARF recurrence was found (p=NS) nor between ARF recurrence and RHD at the end of follow-up (p=NS). CONCLUSIONS: Poor adherence to secondary prophylaxis does not seem to be associated with increased risk of RHD in developed countries. Further studies are needed to confirm our data in a larger population.