F2F Poster 21st Lancefield International Symposium for Streptococci and Streptococcal Diseases 2022

Protocol for a controlled human infection of penicillin against Streptococcus pyogenes: a double-blinded, placebo controlled, randomised trial in healthy adult volunteers (the CHIPS trial) (#347)

Thel K Hla 1 2 , Joshua Osowicki 3 4 5 , Sam Salman 1 2 6 , Kevin Batty 7 , Julie Marsh 1 , Joseph Kado 1 2 , Renae Barr 1 , Stephanie Enkel 1 2 , Tom Snelling 8 , James McCarthy 9 , Andrew Steer 3 4 5 , Jonathan Carapetis 1 2 10 , Laurens Manning 1 2 11
  1. Telethon Kids Institute, Nedlands, WA, Australia
  2. Medical School, University of Western Australia, Crawley, WA, Australia
  3. Tropical Diseases, Murdoch Children's Research Institute, Melbourne, VIC, Australia
  4. Dept of paediatrics, University of Melbourne, Melbourne, VIC, Australia
  5. Infectious Diseases, The Royal Children's Hospital, Melbourne, VIC, Australia
  6. Clinical Pharmacology and Toxicology Unit, PathWest, Perth, WA, Australia
  7. Curtin Medical School, Curtin University, Bentley, WA, Australia
  8. School of Public Health, University of Sydney, Sydney, NSW, Australia
  9. University of Melbourne, Melbourne, VIC, Australia
  10. Perth Children's Hospital, Nedlands, WA, Australia
  11. Fiona Stanley Hospital, Perth, WA, Australia

Background: Regular intramuscular benzathine penicillin G (BPG) injections remain the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since 1950’s. As the clinically important penicillin pharmacokinetic target remains unknown, it is difficult to suggest evidence-based changes to this established regime. Determining the minimum effective penicillin exposure to prevent Streptococcus pyogenes infection will accelerate development of improved long-acting penicillins for RHD prevention. The CHIPS Trial will address this knowledge gap, directly testing protection afforded by steady state plasma concentrations of benzylpenicillin in an established model of experimental human S. pyogenes pharyngitis.

Methods: The CHIPS Trial is a double-blinded, placebo-controlled, randomised experimental human infection study. Sixty healthy adult volunteers aged 18 to 40 years will be recruited and randomised 1:1:1:1:1 to continuous intravenous benzylpenicillin infusions targeting 5 different steady state plasma concentrations of 0 (placebo), 3, 6, 12 and 20 ng/mL via a midline catheter. During an initial day admission, individual penicillin pharmacokinetic parameters will be established to refine dosing for a continuous infusion. The subsequent inpatient challenge admission involves confinement up to 6 days, with oral antibiotic treatment at its conclusion and periodic outpatient follow-up for one month.

Results: The minimum effective steady-state plasma penicillin concentration required to prevent pharyngitis will be determined as the primary objective. Secondary objectives will explore systemic and mucosal immuno-inflammatory responses during pharyngitis, bacterial colonisation dynamics, environmental contamination, and include the qualitative evaluation of the participant experience.

Conclusion: This presentation will highlight key aspects of the innovative study design and discuss important elements of the protocol.