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Optimising Treatment Outcomes for Children and Adults Through Rapid Genome Sequencing of Sepsis Pathogens. A Study
Adam D Irwin1,2, Lachlan J M Coin3,4, Patrick N A Harris1
1UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia.
Insights
Rapid pathogen sequencing and personalized antibiotic dosing can improve sepsis treatment. This pilot study assesses its feasibility and accuracy in ICU patients, aiming to reduce mortality and hospital stays.
Area of Science:
- Medical Microbiology
- Genomic Medicine
- Clinical Pharmacology
Background:
- Sepsis significantly impacts global morbidity and mortality, with Australia reporting 20,000 cases and 5,000 deaths annually.
- Conventional sepsis diagnostics are slow, delaying appropriate antibiotic therapy and leading to poorer outcomes.
- Nanopore technology offers rapid DNA sequencing for real-time pathogen identification.
Purpose of the Study:
- To evaluate the feasibility and diagnostic accuracy of direct pathogen sequencing from clinical samples in sepsis patients.
- To assess the impact of integrated rapid sequencing and software-guided dosing on time to effective antimicrobial therapy.
- To inform future sepsis research by providing key feasibility data.
Main Methods:
- The DIRECT study is a pilot prospective, non-randomized multicentre trial involving children and adults with sepsis in intensive care units (ICUs).
- Phase 1 involves Oxford Nanopore Technologies MinION sequencing from blood in 50 sepsis patients.
- Phase 2 combines MinION sequencing with Bayesian software-guided (ID-ODS) personalized antimicrobial dosing in another 50 patients.
Main Results:
- Primary outcome: time to effective antimicrobial therapy (drug concentration > pathogen's MIC).
- Secondary outcomes: diagnostic accuracy of MinION sequencing, time to pathogen identification and susceptibility testing.
- Data from this pilot study will guide larger, essential sepsis trials.
Conclusions:
- Rapid pathogen sequencing and personalized dosing software hold potential to improve upon conventional diagnostics.
- Reduced time to optimal antimicrobial therapy may decrease sepsis mortality and ICU length of stay.
- This study provides crucial feasibility data for advancing sepsis management strategies.
Background:
Sepsis contributes significantly to morbidity and mortality globally. In Australia, 20,000 develop sepsis every year, resulting in 5,000 deaths, and more than AUD$846 million in expenditure. Prompt, appropriate antibiotic therapy is effective in improving outcomes in sepsis. Conventional culture-based methods to identify appropriate therapy have limited yield and take days to complete. Recently, nanopore technology has enabled rapid sequencing with real-time analysis of pathogen DNA. We set out to demonstrate the feasibility and diagnostic accuracy of pathogen sequencing direct from clinical samples, and estimate the impact of this approach on time to effective therapy when integrated with personalised software-guided antimicrobial dosing in children and adults on ICU with sepsis.
Methods:
The DIRECT study is a pilot prospective, non-randomized multicentre trial of an integrated diagnostic and therapeutic algorithm combining rapid direct pathogen sequencing and software-guided, personalised antibiotic dosing in children and adults with sepsis on ICU.
Participants And Interventions:
DIRECT will collect microbiological and pharmacokinetic samples from approximately 200 children and adults with sepsis admitted to one of four ICUs in Brisbane. In Phase 1, we will evaluate Oxford Nanopore Technologies MinION sequencing direct from blood in 50 blood culture-proven sepsis patients recruited from consecutive patients with suspected sepsis. In Phase 2, a further 50 consecutive patients with suspected sepsis will be recruited in whom MinION sequencing will be combined with Bayesian software-guided (ID-ODS) personalised antimicrobial dosing.
Outcome Measures:
The primary outcome is time to effective antimicrobial therapy, defined as trough drug concentrations above the MIC of the pathogen. Secondary outcomes are diagnostic accuracy of MinION sequencing from whole blood, time to pathogen identification and susceptibility testing using sequencing direct from whole blood and from positive blood culture broth.
Discussion:
Rapid pathogen sequencing coupled with antimicrobial dosing software has great potential to overcome the limitations of conventional diagnostics which often result in prolonged inappropriate antimicrobial therapy. Reduced time to optimal antimicrobial therapy may reduce sepsis mortality and ICU length of stay. This pilot study will yield key feasibility data to inform further, urgently needed sepsis studies. Phase 2 of the trial protocol is registered with the ANZCTR (ACTRN12620001122943).
Trial Registration:
Registered with the Australia New Zealand Clinical Trials Registry Number ACTRN12620001122943.
