Personalised antibiotics dosing to treat severe infections

Developing faster and more accurate diagnosis of sepsis

Sepsis is a life-threatening condition that occurs when the body's response to an infection damages its own tissues. Early recognition and treatment can improve the chance of survival.

The Optimising Treatment Outcomes for Children and Adults Through Rapid Genome Sequencing of Sepsis Pathogens (DIRECT) study set out to describe the feasibility of an integrated diagnostic and therapeutic intervention, using whole genome sequencing and antibiotic dosing software, to reduce the time to effective antibiotic exposure in critically ill children and adults with sepsis.

Outcomes

• The study recruited 156 children and adults with suspected sepsis across 4 intensive care units (ICUs) from participating sites at Royal Brisbane and Women’s Hospital, The Prince Charles Hospital, Princess Alexandra Hospital and Queensland Children’s Hospital.
• The study demonstrated that in those patients who failed to achieve therapeutic antibiotic exposures in the first 24 hours of sepsis treatment, the use of dosing software reduced the time to achieve antibiotic targets by more than 48 hours.
• Rapid pathogen sequencing from whole blood samples did not prove feasible, but the study successfully demonstrated accurate pathogen identification using metagenomic sequencing from 56 positive blood cultures, along with accurate predictions of antibiotic susceptibility.
• Health economic impact assessment is still pending.

Through the DIRECT study, the project team has demonstrated the feasibility of metagenomic sequencing of pathogens from positive blood cultures and of the impact of antibiotic dosing software in a multi-centre trial in ICUs. The results of the trial highlight the potential for these diagnostic and therapeutic innovations in the management of critically ill children and adults with sepsis.

Project investigators

The project team included expertise from partners within universities, research institutes, and hospital and health services around Queensland.

• Professor Jason Roberts, The University of Queensland Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Metro North Health (Lead, advice on dosing strategy)
• Associate Professor Luregn Schlapbach, Children’s Health Queensland, The University of Queensland Centre for Child Health Research (Senior Staff Specialist Paediatric ICU, Medical Lead Paediatric Critical Care Research Group, Project Lead and Paediatric ICU Lead, Queensland Children’s Hospital)
• Dr Adam Irwin, Children’s Health Queensland, The University of Queensland Centre for Clinical Research (Project Manager, paediatric infectious diseases specialist)
• Professor Lachlan Coin, The University of Queensland Institute for Molecular Bioscience (Group Leader, bioinformatic expert)
• Dr Patrick Harris, The University of Queensland Centre for Clinical Research, Pathology Queensland (Pathology Queensland Microbiology Lead, microbiology specialist)
• Dr Menino Osbert Cotta, The University of Queensland Centre for Clinical Research (Clinical Pharmacist and Postdoctoral Research Fellow)
• Dr Brian Forde, The University of Queensland Centre for Clinical Research (bioinformatics)
• Professor Jeff Lipman, Royal Brisbane and Women’s Hospital (ICU Research Director, Royal Brisbane Women’s Hospital ICU Lead)
• Associate Professor Peter Kruger, Princess Alexandra Hospital (Prince Alexandra Hospital ICU Lead)
• Associate Professor Kiran Shekar, The Prince Charles Hospital (ICU Lead)
• Kara Brady, The Prince Charles Hospital (Research Coordinator)
• Associate Professor David Whiley, The University of Queensland, The Queensland Paediatric Infectious Diseases group (laboratory diagnostics)
• Dr Seweryn Bialasiewicz, The Queensland Paediatric Infectious Diseases group (laboratory diagnostics)
• Associate Professor Scott Beatson, The University Queensland, School of Chemistry and Molecular Bioscience (bioinformatics)
• Professor David Paterson, The University of Queensland Centre for Clinical Research (infectious diseases)
• Associate Professor Julia Clark, Queensland Children’s Hospital (paediatric infectious diseases)
• Krispin Hajkowicz, Royal Brisbane and Women’s Hospital (Director Infectious Diseases Unit)
• Dr Sainath Raman, Queensland Children’s Hospital (Paediatric ICU)
• Luminita Vlad, Centre of Research Excellence Manager, UQCCR, The University of Queensland (Project Manager)

This project was supported by funding from the Australian Government under the Medical Research Future Fund’s RART 2.1 and RART 2.2 grant schemes.  These results relate to research work completed under both grants (2.1 and 2.2).