Poster Presentation Lancefield International Symposium for Streptococci and Streptococcal Diseases 2025

Population pharmacokinetics of penicillin G: insights into increased clearance at low concentrations to guide development of improved long-acting formulations for syphilis and prevention of rheumatic fever (#30)

Okhee Yoo 1 2 3 , Sam Salman 1 4 5 , Thel K Hla 1 4 6 , Joshua Osowicki 7 8 9 , Madhu Page-Sharp 10 , Julie A Marsh 1 4 , Renae Barr 1 , Kristy Azzopardi 7 , Michael Morici 1 , Kevin T Batty 10 11 , Stephanie Enkel 1 4 , Joseph Kado 1 4 , Lara Hatchuel 12 , Alma Fulurija 1 , James S McCarthy 13 , Thomas L Snelling 14 , Andrew Steer 7 8 9 , Jonathan Carapetis 1 4 15 , Laurens Manning 1 4 6
  1. Wesfarmers Centre for Vaccines and Infectious Diseases, The Kids Research Institute, Nedlands, WA, Australia
  2. Pharmacy, School of Allied Health, University of Western Australia, Perth, WA, Australia
  3. Institute for Paediatric Perioperative Excellence, University of Western Australia, Perth, WA, Australia
  4. Medical School, University of Western Australia, Crawley, WA, Australia
  5. Clinical Pharmacology and Toxicology Unit, PathWest, Perth, WA, Australia
  6. Department of Infectious Diseases, Fiona Stanley Hospital, Perth, WA, Australia
  7. Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
  8. Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
  9. Infectious Diseases Unit, Department of General Medicine, The Royal Children's Hospital, Melbourne, Victoria, Australia
  10. Curtin Medical School, Curtin University, Bentley, WA, Australia
  11. Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia
  12. Linear Clinical Research, Perth, WA, Australia
  13. The Doherty Institute, University of Melbourne, Melbourne, Victoria, Australia
  14. Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
  15. Perth Children’s Hospital, Nedlands, WA, Australia

Background/Objectives: While benzylpenicillin (penicillin G) is listed by the WHO as an Essential Medicine, dose optimisation is a persistent challenge, especially for long-acting IM formulations like benzathine benzylpenicillin. Maintaining sustained antibiotic exposure at target concentra-tions is crucial for secondary chemoprophylaxis of rheumatic heart disease and treatment of syphilis. This study compared the pharmacokinetic profile of continuous low-dose benzylpenicillin infusions with a standard-dose bolus, and evaluated which renal function marker (serum creatinine, cystatin C, or combined eGFR) best predicted clearance.

Methods: Healthy adult volunteers received a single 600 mg IV benzylpenicillin bolus followed by randomisation to continuous infusions targeting steady-state concentrations of 3, 6, 9, 12, or 20 ng/ml. Plasma benzylpenicillin concentrations were measured by liquid chromatography–mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM by incorporating both bolus and infusion data, while various GFR estimations were evaluated as covariates for clearance.

Results: Data from 72 participants were analysed, including 504 bolus and 389 continuous infusion samples. A two-compartment model improved fit when the ratio of central volume of distribution between bolus and low-dose infusion was incorporated, and clearance differences at steady state plasma concentration of 3 ng/mL were accounted for. Of the GFR estimations, cystatin C–based eGFR significantly enhanced model fit compared to creatinine-based equations.

Conclusions: Benzylpenicillin pharmacokinetics at very low concentrations demonstrated both a higher volume of distribution and increased clearance. Cystatin C–based eGFR may more accurately predict benzylpenicillin clearance, enabling precision dosing for long-acting preparations used for treatment of syphilis and prevention of rheumatic fever.