AUTHOR=Irwin Adam D. , Coin Lachlan J. M. , Harris Patrick N. A. , Cotta Menino Osbert , Bauer Michelle J. , Buckley Cameron , Balch Ross , Kruger Peter , Meyer Jason , Shekar Kiran , Brady Kara , Fourie Cheryl , Sharp Natalie , Vlad Luminita , Whiley David , Beatson Scott A. , Forde Brian M. , Paterson David , Clark Julia , Hajkowicz Krispin , Raman Sainath , Bialasiewicz Seweryn , Lipman Jeffrey , Schlapbach Luregn J. , Roberts Jason A. TITLE=Optimising Treatment Outcomes for Children and Adults Through Rapid Genome Sequencing of Sepsis Pathogens. A Study Protocol for a Prospective, Multi-Centre Trial (DIRECT) JOURNAL=Frontiers in Cellular and Infection Microbiology VOLUME=11 YEAR=2021 URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2021.667680 DOI=10.3389/fcimb.2021.667680 ISSN=2235-2988 ABSTRACT=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