A randomised, double-blinded, placebo-controlled human challenge trial to establish the lowest penicillin concentration to prevent <em>Streptococcus pyogenes</em> pharyngitis (CHIPS). — ASN Events
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  2. Plenary 5 - Interventions for Prevention
  3. A randomised, double-blinded, placebo-controlled human challenge trial to establish the lowest penicillin concentration to prevent Streptococcus pyogenes pharyngitis (CHIPS).

A randomised, double-blinded, placebo-controlled human challenge trial to establish the lowest penicillin concentration to prevent Streptococcus pyogenes pharyngitis (CHIPS). (118511)

Thel Hla 1 , Joshua Osowicki 2 , julie Marsh 1 , Sam Salman 3 , Madhu Page-Sharp 4 , Okhee Yoo 1 , Kristy Azzopardi 2 , Michael Morici 1 , Kevin Batty 4 , Stephanie Enkel 1 , Lara Hatchuel 5 , Andrew Steer 2 , Joseph Kado 1 , Alma Fulurija 1 , James McCarthy 6 , Tom Snelling 7 , Jonathan Carapetis 1 , Laurens Manning 1 3 8
  1. END RHD, The Kids Institute, Perth, WA, Australia
  2. Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia
  3. University of Western Australia, Shenton Park, WA, Australia
  4. School of Pharmacy, Curtin University, Bentley, WA, Australia
  5. Linear Clinical Research, Perth, WA, Australia
  6. University of Melbourne, Melbourne, WA, Australia
  7. University of Sydney, Sydney, WA, Australia
  8. Department of Infectious Diseases, Fiona Stanley Hospital, Perth, WA, Australia

Background

The in vivo plasma concentration of penicillin needed to prevent Streptococcus pyogenes pharyngitis, recurrent acute rheumatic fever, and rheumatic heart disease is not known. We used a human challenge model to fill this knowledge gap.

Methods

In this randomised, double-blinded, placebo-controlled, human challenge trial, healthy adult volunteers were randomly assigned to target steady-state penicillin plasma concentrations (0, 3, 6, 9, 12, or 20 ng/mL). Participants and site staff were blinded to treatment allocation and outcomes. Individualised 5-day continuous intravenous infusions of penicillin were commenced 12 hours prior to pharyngeal application of an emm75 S. pyogenes inoculum (MIC=12 ng/mL). The primary endpoint was clinical pharyngitis.

Findings

Sixty participants were randomised, with 57 included in the analysis. The pharyngitis endpoint was met in 8/14 of the placebo group, followed by 4/9, 4/9, 0/8, 0/8, and 0/9 in each of the groups assigned 3, 6, 9, 12, and 20 ng/mL, respectively. No severe (grade 3) or serious adverse events occurred. Using Bayesian concentration-response modelling, the minimum steady-state plasma concentration of penicillin where 90% of participants would avoid clinical pharyngitis was 8.1 ng/mL (95% credible interval 6.1-10.9 ng/mL). The penicillin concentration where 90% of participants avoid an elevation in CRP of >20mg/L was 7.6 ng/mL (95% credible interval 5.8-10.3 ng/mL).

 

Interpretation

When steady state penicillin concentrations are greater than 9 ng/mL, few people will develop experimental emm75 S. pyogenes pharyngitis. These data will inform efforts to improve long-acting penicillin preparations and dosage regimens to prevent recurrent rheumatic fever and rheumatic heart disease.

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