Abstract
Benzathine penicillin G (BPG) is used as first‐line treatment for most forms of syphilis and as secondary prophylaxis against rheumatic heart disease (RHD). Perceptions that poor quality of BPG is linked to reported adverse effects and therapeutic failure may impact syphilis and RHD control programs. Clinical networks and web‐based advertising were used to obtain vials of BPG from a wide range of countries. The quality of BPG was assessed using a high performance liquid chromatography assay capable of detecting relevant impurities and degradation products. Tests for water content, presence of heavy metals and physical characteristics of BPG, including particle size analysis and optical microscopy, also were conducted. Thirty‐five batches of BPG were sourced from 16 countries across 4 WHO regions. All batches passed the US Pharmacopeia requirements for BPG injection (content), with no evidence of breakdown products or other detected contaminants. Water content and heavy metal analysis (n = 11) indicated adherence to regulatory standards and Good Manufacturing Practice. Particle size analysis (n = 20) found two batches with aggregated particles (>400 µm) that were dispersed following sonication. Current batches of BPG were of satisfactory pharmaceutical quality but aggregated particles were found in a modest proportion of samples. Future studies should focus on the physical characteristics of BPG which may contribute to variations in plasma penicillin concentrations an observed needle blockages in clinical practice. Pharmacopeial monographs could be revised to include standards on particle size and crystal morphology of BPG.
Highlights
Benzathine penicillin G (BPG) has been on the World Health Organization (WHO) essential medications list since 1977 and is currently recommended as first-line treatment of syphilis and for secondary prophylaxis for recurrent rheumatic fever.[1,2,3,4] Following intramuscular injection of BPG, the crystalline combination of penicillin G and benzathine is slowly absorbed and results in prolonged plasma concentrations of penicillin G.5,6 Depending on the indication, BPG may be administered as weekly or monthly injections.[7]Severe adverse reactions following BPG are rare, but occasionally fatal
As our investigation focussed on the quality of BPG for community-based end users in a range of international clinical settings, no information was available on the conditions for storage and transportation of vials prior to acquisition for the present study
The significant difference in particle size distribution (D50 12.5 μm vs 24.4 μm) between two of the manufacturers and the observed clumping in 10% of samples tested indicated some heterogeneity in the BPG crystals, despite these batches meeting a range of standard pharmacopeial requirements
Summary
Benzathine penicillin G (BPG) has been on the World Health Organization (WHO) essential medications list since 1977 and is currently recommended as first-line treatment of syphilis and for secondary prophylaxis for recurrent rheumatic fever.[1,2,3,4] Following intramuscular injection of BPG, the crystalline combination of penicillin G and benzathine (in a 2:1 molar ratio) is slowly absorbed and results in prolonged plasma concentrations of penicillin G.5,6 Depending on the indication, BPG may be administered as weekly or monthly injections.[7]. Severe adverse reactions following BPG are rare, but occasionally fatal This occurs at the “end of the needle” and is assumed to be anaphylaxis.[8] These reactions occur almost exclusively in the setting of significant rheumatic heart disease (RHD), rather than syphilis, suggesting a disease-related mechanism or other patient factors, rather than a reaction to the BPG components.[8,9] anecdotal reports of poor quality BPG have been linked to severe adverse effects and needle blockages.[7,10] Any perceptions that BPG is a low-quality medication are likely to impact on national syphilis and RHD control programs.[10,11]. Despite reports of needle blockages, few publications report the quality and physical characteristics of BPG.[7,15] A clinical study undertaken in the 1990s compared two brands of BPG in Egypt (one local and one imported) and reported significant pharmacokinetic differences between the formulations, using a microbiological assay (plate diffusion method). We conducted a thermal stability assessment of Bicillin L-A®, due to anecdotal reports of this product being discarded after short periods outside refrigeration
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