DISCUSSION
hyperpigmentation, Hyperpigmentation, erythema, pain, PD, bruising, infusion-site, NRS
HYPERPIGMENTATION, HYPERPIGMENTATION, ERYTHEMA, RHD, HYPERMELANOSIS
Subcutaneous infusion of high-dose BPG (SCIP) is tolerable and safe. Despite all participants experiencing some degree of infusion-site reaction, they all resolved spontaneously with no serious adverse outcomes. While pain is a subjective experience, the maximum reported pain at injection was severe (NRS 8), requiring analgesia, in only one participant; moderate pain (NRS 4–7) was experienced by another 11 participants in the first 2 days; nevertheless, the median cohort pain scores were all in the mild (1–3) category. Although we did not directly compare SCIP with intramuscular BPG, similar median or mean pain scores have been reported in other studies involving an intramuscular dose of 1.2 MIU of BPG in healthy adults (Participant experience of the infusion-site reaction indicated by modified Skindex-16 scores was variable, ranging from very little (zero) to fairly severe (75) “bother,” but severity categories have not been defined in literature. Nonetheless, the median scores all fall within the mild–moderate (0.8–12.5) categories, and the impact resolved within 3 days. Hyperpigmentation persisted beyond the first week and was reflected by scores in the emotional domain. As described in literature, hyperpigmentation was more common in darker-skinned participants in the study and carried some emotional stress, worsened by uncertainty and delayed resolution (Despite the high dose delivered in SCIP, the peak concentration was well below concentrations achieved with standard doses of intravenous penicillin G. Simulations from the PK model indicate that penicillin concentrations above the PK/pharmacodynamics (PD) target for While the participants found SCIP safe and tolerable, adults and children living with RHD will determine the acceptability of SCIP as they will have had experience with standard IM injections and an expectation of what is acceptable pain, erythema, or inconvenience related to function and emotional burden. Adolescents may experience difficulty with being unable to expose their abdomen for prolonged periods after SCIP and coping with the possible distress should hyperpigmentation develop. Less exposed sites for SCIP should be investigated along with the feasibility of earlier topical treatment for hypermelanosis.Younger patients with more pliant subcutaneous tissue may tolerate SCIP better than older patients, but this should be balanced with closer attention to the spring-loaded pump and flow control adjustment to prevent excessive pressure and bruising at the site.The limitations of this study include that the study was conducted in healthy adults without RHD, and women were under-represented. While we were able to deliver SCIP using the spring-loaded pump and a variable flow control device, there was limited scope for fine-controlling the flow of BPG because it only flowed with the highest settings. An improved flow control device is needed. While the sample size was adequate for PK modeling, it restricted subgroup analysis. Lastly, most people with RHD live in resource-constrained countries where pre-suspended BPG is not available and therefore will not have access to SCIP. There is an urgent need to explore SCIP using reconstituted powdered BPG formulations or improve access to pre-filled BPG preparations if SCIP is to be widely implemented.