Rheumatic heart disease (RHD) results from untreated and often repetitive episodes of Rheumatic Fever (RF), which in turn is caused by uncontrolled group A beta-hemolytic streptococcal (GAS) infection in a susceptible host. In endemic areas for RHD the disease starts during childhood or adolescence, thus requiring continuous linkage to the health system for its management and prevention of complications across the lifespan. Antibiotics are essential to prevent recurrences of RF (secondary prophylaxis) and for treatment of symptomatic GAS infections (primary prevention). Since the 1950s, prophylaxis has been achieved via intramuscular (IM) administration of benzathine penicillin G (BPG), a crystalline powder formed through the fusion of 2 penicillin G molecules and characterized by very low solubility and in vivo hydrolysis. These features together with the absence of known GAS resistance to BPG in vitro and with slow absorption from IM injection e producing prolonged therapeutic serum concentrations e result in long halflife, providing prolonged bactericidal protection and making it particularly effective for primary and secondary prevention of GAS infections. However, the mechanism for the apparent persistent susceptibility of GAS to BPG is relatively poorly understood.