Prevention of rheumatic heart disease in New Zealand: High-dose subcutaneous benzathine penicillin is cost-saving compared with traditional intramuscular injections

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. 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. 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. 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.

Effectivity and adherence of secondary prevention on clinical outcome of rheumatic heart disease in high-burden setting: a systematic review and meta-analysis

BackgroundFour-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-doseSubCutaneous Infusions of BPG (SCIP) 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 SCIP trial.MethodologyParticipants (n=20) attended a clinic in Wellington, New Zealand (NZ). After a physical examination, participants received 2% lignocaine followed by 13.8mL (6 vials) to 20.7mL (9 vials) of BPG (Bicillin-LA®; determined by weight), into the abdominal subcutaneous tissue. Semi-structured interviews and observations were taken during and after the infusion, as well as on days 28 and 70. All interviews were recorded, transcribed verbatim, and thematically analysed.Principal FindingsLow levels of pain were reported on needle insertion, during and following the infusion. 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 overwhelming majority preferred to continue with SCIP.ConclusionsParticipants 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 ARF/RHD prophylaxis has the potential to transform secondary prophylaxis of ARF/RHD in NZ and globally.SynopsisAcute rheumatic fever (ARF) is a preventable inflammatory disease that occurs as a delayed sequelae to group A streptococcus (GAS) infection. ARF and its complication rheumatic heart disease (RHD) have significant negative effects on health, often resulting in chronic illness and premature death. For 70 years, the only proven way to prevent ARF progression has been benzathine penicillin G (BPG), given as a monthly intramuscular (IM) injection for a minimum of 10 years. The effectiveness of this approach is limited by pain and the frequency of injection which leads to suboptimal adherence. There is an urgent need to improve penicillin formulations for all children living with ARF and RHD. Here we describe the experiences of 20 young people living with ARF participating in a Phase-II trial delivering high-doseSubCutaneous Infusions ofPenicillin (SCIP) in order to provide longer effective penicillin exposure, and therefore fewer injections. Participants in the trial overwhelmingly preferred high-dose SCIP over their usual monthly IM penicillin regimen, reporting less pain and a preference for the longer time gap (28 versus 70 days) between treatments. Reducing injection frequency from 13 to four-or-five per year, may improve adherence and reduce disease progression. Offering widespread SCIP to ARF/RHD patients to evaluate long-term adherence, preferences and disease progression has the potential to transform secondary prophylaxis of ARF/RHD both in New Zealand and globally.

To the Editor : Rheumatic heart disease (RHD) is a consequence of untreated group A beta-haemolytic streptococcal pharyngitis in a susceptible individual who is likely to live under social conditions of poverty. There are over 30 million people with the disease, which is associated with over 300 000 deaths per year worldwide. In Mozambique and South Africa, RHD is estimated to affect 20 - 30/1 000 asymptomatic schoolchildren. Intramuscular penicillin is more effective than oral penicillin in the secondary prevention of acute rheumatic fever (ARF), and is highly effective for the primary prevention of ARF in children and young adults with pharyngitis. Intramuscular benzathine penicillin G (BPG) is therefore a first-line drug for primary and secondary prevention of ARF and RHD.

Primary prevention of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) encompasses the timely diagnosis and adequate treatment of the superficial group A Streptococcus (GAS) infections pharyngitis and impetigo....

Introduction: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are significant causes of morbidity and mortality. Ethiopia has a high RHD prevalence but has no national strategic guidelines for preventing RHD and no data on the status of secondary prevention in children with RHD. Generating local information is essential to designing effective prevention and control strategies. This study describes the status of secondary RHD prevention in Ethiopian children. Methods: A multicenter, cross-sectional study was performed in children aged 5-17 years with an echocardiogram-based RHD diagnosis. Participants with congenital heart disease and a recent RHD diagnosis (<1 year) were excluded. Good adherence was defined as at least 80% completion of intramuscular benzathine penicillin (BPG) or oral Amoxicillin within the previous year. The primary outcome measure was adherence to prophylaxis, expressed as a proportion. Covariates included socio-demographics, type and severity of RHD, and ARF recurrence. Chi-square test and Student’s t-test were used to assess differences. Multivariate logistic regression was performed. Results: We included 337 participants with a mean age (±standard deviation) of 12.9±2.6 years. The majority were females (54%) and 73% had severe aortic/mitral disease. BPG (80%) and Amoxicillin (20%) were the prophylaxis of choice. Predictors of good adherence were 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, P<0.008). Running out of medicines (35%), interrupted follow-up (27%), and the COVID pandemic (26%) were the three most common reasons for missing prophylaxis. Recurrence of ARF was higher in participants on Amoxicillin (40% vs. 16%, P<0.001) and in those with poor adherence (36.8% vs. 17.9%, P=0.005). Type and duration of prophylaxis (OR 0.5, P =0.02; OR=1.1, P =0.04, respectively), and sex (OR=1.9, P =0.03) were independent predictors of poor adherence. Conclusion: Poor adherence is prevalent in Ethiopian children with RHD. Amoxicillin is a suboptimal option for prophylaxis associated with lower adherence and a higher rate of ARF recurrence.

Out-of-pocket expenditure for administration of benzathine penicillin G injections for secondary prophylaxis in patients with rheumatic heart disease: A registry-based data from a tertiary care center in Northern India

This prospective study was aimed at answering two important questions: 1) Is a biweekly schedule of 1.2 million U intramuscular benzathine penicillin G (BPG) superior to a 4-week one in the prevention of upper respiratory Group A beta-hemolytic streptococcal (GABHS) infections and rheumatic fever (RF) recurrences? 2) Is there a difference in the bioavailability of BPG obtained from different manufacturers? Three hundred sixty rheumatic patients aged 4 to 20 years were randomly assigned to either a biweekly (190 patients) or 4-week (160 patients) BPG prophylactic schedule and were followed-up monthly for 2 years by clinical examination, throat swab culture for GABHS and measurement of antistreptolysin O titer to detect GABHS infection and/or recurrences of RF (according to revised Jones' Criteria). Thereafter, 34 rheumatic subjects, aged 8 to 16 years were randomly assigned to receive a 4-week injection of 1.2 million U of either a locally manufactured BPG brand (22 patients) or an imported one (12 patients). Sera of all patients were tested for penicillin level by plate diffusion method on days 1, 2, 3, 4, 5, 6, 7, 14, 21, and 28 after the intramuscular injection of BPG. The GABHS infection rate was found to be 0.2% and 0.3% for patients on the biweekly and 4-week BPG schedules, respectively, with no significant differences between them. However, the RF recurrence rate/patient/year for the 4-week schedule patients (0.12) was double that for the biweekly schedule ones (0.06). Estimation of the bioavailability of the two different brands of BPG demonstrated a difference in their pharmacokinetics and a decrease in the serum penicillin concentration below the minimum inhibitory concentration 3 weeks after the injection of either brand. Although a biweekly schedule may not be superior in preventing upper respiratory GABHS infection, it may play a role in preventing the sequelae of such infections. The short duration of penicillinemia explains the superiority of the 2-week schedule in RF prophylais. The difference in the pharmacokinetics of penicillin brands might contribute to the high recurrence rate of RF reported in Egypt.

IntroductionIntramuscular 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.MethodsTo 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.ResultsA 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.ConclusionsThe 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.

Acute Rheumatic Fever (ARF) is the autoimmune condition triggered by untreated Group A Streptococcal (GAS) infection of the upper respiratory tract (and possibly skin). Severe and recurrent untreated attacks of ARF can cause cardiac damage, known as Rheumatic Heart Disease (RHD). RHD remains a significant cause of morbidity and mortality globally and in Australia, New Zealand (NZ) and the Pacific Region, the disease burden of ARF and RHD amongst Indigenous and Pacific communities is one of the highest in the world, usually affecting children and young adults. The most effective recommended preventative measure for ARF requires painful monthly intramuscular injections of Benzathine Penicillin G (BPG) for 10 years or more. Known as secondary prophylaxis, these injections aim to prevent GAS infections that may lead to recurrence of ARF and either cause or worsen RHD. Adherence to secondary prophylaxis remains a challenge in many settings and improved understanding of barriers and a BPG reformulation that is more appropriate are urgently needed. This work sought to explore the BPG reformulation preferences and perspectives of predominantly Māori and Pacific children/teens in New Zealand currently receiving monthly BPG intramuscular injections, their families and healthcare providers using three software applications developed for this purpose. A total of 82 participants comprised of children/teens, family members and health professionals have thus far participated in this research project. This is the first time software applications have been successfully developed to collect qualitative and quantitative data on individual preferences for BPG formulations and dosing regimens in New Zealand.

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). 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 Māori 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. 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. 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.

Over 46 million people are living with rheumatic heart disease (RHD) globally, resulting in 380 000 premature deaths each year. Effective RHD prevention strategies are known but their implementation in low-resource settings has lagged. This study evaluated the feasibility and effectiveness of integrating secondary antibiotic prophylaxis into primary health centres to improve access and adherence to RHD care. We conducted a hybrid type III study using a mixed-method, pre-post design to evaluate a package of implementation strategies centred on decentralised RHD care and use of an electronic medical record in Gulu and Lira, Uganda. We combined clinical and programmatic data with provider and patient interviews to assess effectiveness, adoption and acceptability. The mean difference in the annualised percentage of days adherent to benzathine penicillin G (BPG) monthly injections predecentralisation and postdecentralisation was calculated using linear mixed effect regression. Thematic analysis was used to analyse qualitative data. We decentralised 151 patients (median age 17.9 years, 64% female) from district hospitals to eight primary health centres. The percentage of days adherent to BPG was 77.2% predecentralisation and 80.5% postdecentralisation (mean difference 3.25, (95% CI -0.72 to 6.86), p=0.081), which was statistically non-inferior at the -10% non-inferiority margin. Interview data identified knowledge, confidence and intrinsic motivation as major determinants of provider adoption. Patients expressed mixed feelings towards pain control and provider services, but convenience and financial savings resulted in a high level of acceptability. The electronic registry presented challenges in a naive environment but showed a strong potential as an oversight tool at the district level. This study is the first to demonstrate that decentralised RHD care is effective in sub-Saharan Africa. Lessons learnt provide a platform for future integration of RHD services countrywide, with implications for increasing access to and scale-up of secondary prevention measures for RHD care in Uganda.

Background and Aims: Awareness raising is an important component of primary prevention of RHD. Data are lacking on primary prevention activities for rheumatic heart disease (RHD) prevention in Nepal. The aim of this study is to assess the effectiveness of various awareness raising activities on increasing knowledge about throat infection (TI), acute rheumatic fever (ARF) and RHD and their impact on RHD prevention.
 Methods: Fourteen randomly selected government health facilities in Lalitpur were enrolled in this study. A baseline study conducted in early 2015 analyzed the level of knowledge about RHD among care seekers attending health facilities in Lalitpur. An expansive public awareness raising activities on RHD were performed for 2.5 years starting from February 2015. Data were collected using structured interviews, and review of health facility records. Data were analyzed to compare the postintervention status with the baseline status.
 Results: The mean knowledge about ARF and RHD increased by over 71% (1.82 to 3.12) and 124% (0.37 to 0.83) respectively in post intervention group. There was significant difference in knowledge about TI, ARF and RHD among baseline and post intervention group (p-value<0.0001). The number of throat infection cases presented at health facilities increased by 30.39% from fiscal year (FY) 2071/72 to FY 2072/073 and by 4.69% in the next FY. 
 Conclusions: Awareness raising interventions are effective in increasing knowledge about TI, ARF and RHD which further can produce positive impact in the primary prevention of ARF and RHD.

A secondary level of prophylaxis has proven to be the most successful in Nepal, a country with an endemic rate of rheumatic heart disease, in combating the severe issues associated with rheumatic heart disease. The use of benzathine penicillin G in secondary prophylaxis of rheumatic heart disease, recommended by several guidelines, has been increasingly abandoned in Nepal due to a lack of national guidelines and the termination of the prior programs. The use of oral penicillin and alternative oral antibiotics, which are less effective in preventing the recurrence of acute rheumatic fever, is on the rise. Nepal urgently needs to develop new national guidelines and ensure their effective implementation in order to slow the increase in the number of rheumatic heart disease patients. In this article, we explore the limitations, challenges, and advantages of using the consensus-supported intramuscular benzathine penicillin G as the first-line drug for the secondary prevention of rheumatic heart disease.

Rheumatic heart disease (RHD) is a severe, chronic condition arising from acute rheumatic fever (ARF), a complication of untreated group A - Streptococcus infections. RHD results in progressive damage to the heart valves, leading to significant morbidity and mortality. While RHD has declined in high-income countries due to effective prophylaxis, it remains a major health issue in developing regions. Approximately 15 million people worldwide are affected by RHD, impacting quality of life and healthcare systems. This narrative review evaluates the efficacy and safety of high-dose subcutaneous benzathine penicillin G (BPG) injections as a preventive strategy for RHD. Traditionally administered intramuscularly, the review explores the subcutaneous route’s benefits. Subcutaneous BPG is effective in preventing ARF recurrences and managing RHD progression. It maintains therapeutic penicillin levels over extended periods, potentially reducing injection frequency. This method is associated with less pain and improved patient adherence compared to intramuscular injections. However, subcutaneous BPG administration has challenges. Adverse effects, such as allergic reactions and anaphylaxis, though infrequent, require careful management. Consistent drug supply is also essential. Future research should explore innovative delivery methods, such as implantable devices or transdermal systems, to further improve patient outcomes. In conclusion, high-dose subcutaneous BPG injections offer a promising option for RHD prophylaxis, combining efficacy with a favorable safety profile. Addressing administration and side effect challenges is crucial for optimizing treatment effectiveness.