Could late-latent syphilis be treated with a single subcutaneous infusion of long-acting penicillin?

An estimated 19.9 million people are living with syphilis globally.¹ The World Health Organization has set a key strategic target for elimination of congenital syphilis via mother-to-child transmission (MTCT) in 50 countries by 2025. Currently only 15 countries have achieved this, highlighting the need for improved treatments.² The Australian syphilis epidemic continues and a national target to eliminate congenital syphilis by 2022 was not achieved.³

For those with late-latent or syphilis infection of unknown duration, three intramuscular (i.m.) injections of benzathine penicillin G (BPG; 2.4 million units [MU]) given on consecutive weeks are recommended, a regimen which has changed little since the 1950s.⁴ Data are scarce on multi-dose completion rates, but appear low (43–69%), likely owing to the associated pain and the need for multiple clinic visits, which impede the overall efforts to reduce global burden and MTCT of syphilis.^5,6 Pharmacokinetic modelling suggests that current three-dose regimen given a week apart (using Bicillin®L-A formulation, Pfizer) result in penicillin plasma concentrations above 18 ng/mL (a historical therapeutic target) for approximately 6 weeks (Fig. 1; orange).^7–9

Fig. 1.

Simulation of 7.2 MU subcutaneous infusion of benzathine penicillin (as Bicillin®L-A) compared to three separate weekly 2.4 MU intramuscular injections modelled from Kado et al.⁹ MU, million units; SCIP, subcutaneous infusion of penicillin.

Subcutaneous (SC) delivery of BPG, delivered to the lower abdominal area using a SC catheter at a rate of 0.5–1 mL/min, delays systemic absorption of penicillin which could be exploited to deliver the entire treatment course at a single visit.⁹ Here we show the pharmacological profiles following SC infusion of 7.2 MU BPG (SCIP), delivered in 10 healthy adult volunteers who participated in a Phase I study⁹ (Fig. 1; blue), which focused on secondary prophylaxis for acute rheumatic fever, a condition for which BPG is also indicated. Compared with standard treatment, SCIP leads to increased time (7 extra days) above 18 ng/mL. There were no serious adverse events throughout the 16 weeks follow-up and majority reported minimal pain, substantiated via quantitative pain scores and qualitative interviews.^9,10

Therefore, SCIP appears safe and tolerable for syphilis, potentially providing a more sustained therapeutic penicillin exposure and less pain compared to standard i.m. therapy. In late-latent or syphilis of unknown duration, it confers added benefit of treatment completion at a single visit, emphasising patient-centred delivery to improve treatment completion rates. Equivalent drug costs can be assumed as the total dose delivered is the same (7.2 MU), while the additional low cost of a SC catheter is offset by reduced demand on material and personnel resources from reduced number of visits. Further evaluation is currently underway in a Phase IIa trial to explore safety, tolerability, and treatment efficacy of SCIP in non-central nervous system syphilis (ACTRN12622000349741), the results of which have the potential to improve syphilis treatment and adherence.