Benzathine benzylpenicillin G (BPG), given as an intramuscular injection every 3-4 weeks has remained the cornerstone of secondary prophylaxis for nearly 70 years. The current dose (1.2 MU; 900mg) was determined from studies of healthy military recruits, rather than in patients at risk of acute rheumatic fever and subsequent rheumatic heart disease (RHD). There are significant gaps in our understanding of the optimal delivery route, dose and dose interval, particularly in those groups most at-risk. It is assumed that the best pharmacological surrogate for efficacy is the time that concentrations remain above a target of 20 ng/mL between injections, yet despite some evidence for protective efficacy in patients adherent to monthly injections, breakthrough infections occur and the majority of patients do not maintain target concentrations.
Recent pharmacokinetic studies in populations at risk of RHD have provided some interesting insights into the pharmacology of BPG, particularly in relation to site of delivery and duration of effect. Subcutaneous delivery of BPG has very different absorption characteristics which has been exploited in early phase trials. Implants remain a technological challenge, large due to size constraints. Human challenge studies to determine the minimum effective protective concentrations are underway. Whilst individualised approaches to secondary prophylaxis might be possible, all of the new opportunities need confirmation in high risk populations and should be contextualised within the global supply chain. Each will need to be underpinned by robust implementation science exploring patient preferences and health sector delivery.