Cracking the nut of clinical trials to test interventions for life threatening gram-positive toxin-mediated syndromes — ASN Events
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  3. Cracking the nut of clinical trials to test interventions for life threatening gram-positive toxin-mediated syndromes

Cracking the nut of clinical trials to test interventions for life threatening gram-positive toxin-mediated syndromes (#140)

Hadar Mudrik-Zohar 1 2 , Joshua Osowicki 3 4 5 , Elyssia Bourke 6 7 , Jim Buttery 4 5 8 , Gerardo L Dimaguila 5 9 , Timothy Fazio 10 11 12 , Ben Gelbart 5 7 13 14 , Elliot Long 5 7 14 15 , Michael Marks 16 17 18 , Erin K McCreary 19 , Emily G McDonald 20 , Jonathan Ryder 21 , Sile Smith 7 13 14 , Steven YC Tong 1 2
  1. Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne , Victoria, Australia
  2. Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
  3. Tropical Diseases Research Group, Murdoch Children's Research Institute , Melbourne, Victoria, Australia
  4. Department of Infectious Diseases, Royal Children's Hospital, Melbourne, Victoria, Australia
  5. Department of Paediatrics, Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia
  6. Department of Emergency Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  7. Department of Critical Care, Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia
  8. Epidemiology Informatics Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
  9. Epidemiology Informatics, Centre for Health Analytics, Melbourne Children's Campus, Melbourne, Victoria, Australia
  10. Clinical Informatics Centre, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  11. EMR Team, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  12. Department of Medicine, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia
  13. Paediatric Intensive Care Unit, Royal Children’s Hospital, Melbourne, Victoria, Australia
  14. Clinical Sciences, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
  15. Department of Emergency Medicine, The Royal Children’s Hospital, Melbourne, Victoria, Australia
  16. Clinical research department, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
  17. Hospital for Tropical Diseases, University College London Hospital, London , United Kingdom
  18. Division of Infection and Immunity, University College London, London , United Kingdom
  19. Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh , Pennsylvania, USA
  20. Division of General Internal Medicine, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
  21. Division of Infectious Diseases, Department of Internal Medicine, University of Nebraska Medical Centre, Omaha, Nebraska, USA

Background: 

There is limited evidence to guide the management of patients with life-threatening invasive gram-positive infections, such as toxic shock syndrome and necrotizing fasciitis, caused by Streptococcus pyogenes and Staphylococcus aureus. While adjunctive clindamycin is commonly used to inhibit bacterial toxin synthesis, emerging observational data suggest linezolid as a promising alternative with much lower resistance rates and reduced adverse effects. Seemingly insurmountable design challenges have prevented definitive head-to-head comparisons. Recent clinical trial innovations, such as waiver of consent for electronic health record (EHR)-based randomisation, may overcome key barriers to timely enrolment.

 Methods:

We are undertaking a retrospective analysis using 5 years of real-world data from 2 tertiary hospitals in Melbourne, Australia, to inform a planned pragmatic multicentre randomised controlled trial (RCT) comparing adjunctive clindamycin and linezolid. Potential EHR-based structured data triggers for randomisation will be evaluated for their ability to identify paediatric and adult patients with suspected invasive gram-positive toxin-mediated infections. Sensitivity, specificity, and predictive values of these triggers will be assessed at various time points within 48 hours of emergency department presentation.

Results:

This study will optimise EHR-based randomisation processes and assess their feasibility for real-time patient identification and recruitment. Insights from this analysis will guide the design of a pilot RCT, refine recruitment strategies, and improve treatment allocation.  

Conclusion:

The preliminary retrospective analysis will assess EHR-based randomisation processes to inform design of a pilot RCT, paving the way for a full-scale trial to address enduring knowledge gaps in the management of difficult-to-study and challenging-to-treat life-threatening toxin-mediated infections.  

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