Severe adverse events following benzathine penicillin G injection for rheumatic heart disease prophylaxis: cardiac compromise more likely than anaphylaxis

Abstract

ObjectiveSecondary prophylaxis through long-term antibiotic administration is essential to prevent the progression of acute rheumatic fever to rheumatic heart disease (RHD). Benzathine penicillin G (BPG) has been shown to be the most efficacious antibiotic for this purpose; however, adverse events associated with BPG administration have been anecdotally reported. This study therefore aimed to collate case reports of adverse events associated with BPG administration for RHD prophylaxis.Study designA literature review was used to explore reported adverse reactions to BPG and inform development of a case report questionnaire. This questionnaire was circulated through professional networks to solicit retrospective reports of adverse events from treating physicians. Returned surveys were tabulated and thematically analysed. Reactions were assessed using the Brighton Collaboration case definition to identity potential anaphylaxis.ResultsWe obtained 10 case reports from various locations, with patients ranging in age from early-teens to adults. All patients had clinical or echocardiogram-obtained evidence of valvular disease. The majority of patients (80%) had received BPG prior to the event with no previous adverse reaction. In eight cases, the reaction was fatal; in one case resuscitation was successful and in one case treatment was not required. Only three cases met Level 1 Brighton criteria consistent with anaphylaxis.ConclusionThese results indicate that anaphylaxis is not a major cause of adverse reactions to BPG. An alternative mechanism for sudden death following BPG administration in people with severe RHD is proposed.

Quality of benzathine penicillin G: A multinational cross‐sectional study

“…Adverse events following BPG are rare. Given such reactions generally occur in patients with severe valvular pathology, the disease process itself is much more likely to be responsible 8 . If BPG had an unidentified immunogenic contaminant/s we would expect significant clusters of events, which have not been reported.…”

“…Given such reactions generally occur in patients with severe valvular pathology, the disease process itself is much more likely to be responsible. 8 The low water solubility of BPG results in manufacturers adding emulsifying agents to improve mixing and suspension after reconstitution with an aqueous diluent. Lecithin, which is present in Bicillin L-A ® (and some batches of BPG powder for injection), has been linked previously to adverse events, although testing to prove such an allergy is often not available in the low resource setting.…”

“…The significant difference in particle size distribution (D 50 12.5 µm vs 24.4 µm) between two of the manufacturers and the observed clumping in 10% of samples tested (aggregation or incomplete suspension of powder, which was improved by sonication) indicated some heterogeneity in the BPG crystals, despite these batches meeting a range of standard pharmacopeial requirements. Clumping of particles may explain the issue of needle blockage, which has led to the use of excessive diluent volumes (up to 10 mL) for fear of wastage, 8 as well as concerns about inferior quality of the BPG powder for injection 10,16 . As the elimination of clumping or caking of the powder and a tighter particle size distribution may improve delivery (syringeability), sonication of the reconstituted BPG immediately prior to injection could be an achievable solution for many clinical settings.…”

“…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 However, 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.…”

“…Severe adverse reactions following BPG are rare, but occasionally fatal. Usually 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 .…”