UK leads: Professor Marlies Ostermann (MO) and Dr Dagan Lonsdale (DL)
Project Summary
In late 2024 Sepsis Research FEAT approved support for a new research study into antibiotic treatment of sepsis. This project will help researchers to understand whether they are currently using the correct doses of medicines to treat infection in adults and children who are life-threateningly ill in intensive care.
Having an infection in intensive care is linked to a high chance of death; around 1 in 3 people die following an infection in intensive care. The study team would like to find out whether the doses of medicines currently used to treat infections raise the levels of drugs in the blood stream significantly enough to kill bacteria. They are seeking to understand whether in the past ten years there has been any improvement to the way medicines are given to patients in the treatment of infection. They are also keen to establish whether a low level of drugs in the system is bad for people with serious infections, so that they are able to design new ways to administer medicines to treat infection that optimise drug levels in the system.
In 2012 DALI-1 demonstrated that in a large number of critically ill adult patients in intensive care, the blood levels of drugs used to treat infection were too low or too high. Since then, a number of changes have been made to the way that drugs are prescribed.
In this second phase of the project (DALI-2), the team is seeking to find out whether the changes made in the last decade have made a difference. They also now believe that it is important to include children in their study. The project will include a large number of patients globally. Sepsis Research FEAT is pleased to have approved funding for the UK arm of the work, where the team anticipates enrolling 100-150 adults and children to its study.
Researchers will ask for a very small amount of blood from adults and children being treated for infection in intensive care units in the UK and across the world. They will measure the level (concentration) of medicines in this blood sample to establish whether levels are high enough to kill the bacteria that cause infection, and will compare this to those found in DALI-1. Observing what happens to people with high and low levels of medicine will help them to understand whether having a low level is a bad thing (which they currently think it is likely to be).
Data provided by this project will demonstrate what improvements have been made in dosing medicines to treat infection and will allow researchers to design new ways to give these medicines more effectively. The hope is that improving the way these medicines are given will make a difference to patients by reducing the risk of death from sepsis.
Background
Ensuring the optimal levels of antibiotic dosages for individual patients is essential to ensuring the best outcomes – in terms of effectiveness of treatment and the avoidance of antibiotic toxicity and AMR (antimicrobial resistance).
A considerable risk of mortality is associated with infections in intensive care unit (ICU) patients globally [1]. Antibiotic dosing can be challenging in this cohort of patients due to pharmacokinetic (PK) variability observed when compared with non-critically ill patients [2, 3]. In 2012, the international DALI (Defining Antibiotic Levels in Intensive care unit patients) study demonstrated that contemporary beta-lactam antibiotic dosing achieved a therapeutic target of 100% fT>MIC in only 60% (218/361) patients, and that clinical outcomes were improved when this therapeutic target was achieved as compared to lower concentrations [3]. Several UK sites participated in this study. Of note, DALI only included 8 beta-lactam antibiotics and did not include paediatric populations. A two minute video from the original DALI project lead, Professor Jason Roberts, explains more about the origins of the DALI studies here.
Since the original DALI study was conducted, literature supporting alternative antibiotic dosing strategies has progressed, leading to guidelines endorsing PK/PD focused antibiotic dosing and change in practice [4-7]. DALI-2 now seeks to understand the translation of antibiotic optimisation research into clinical practice, include more antibiotics and extend our knowledge to children. DALI-2 is an international collaborative project that will involve participants across 6-continents. The team believes that it is important for the UK to participate again in this study, in order to ensure the results are generalizable for the people they look after. They believe that the DALI-2 study is essential for determining whether action is required to change existing antibiotic prescribing practices for critically ill adults and children in the UK and across the world.
Research Aims
DALI-2 is a prospective, multi-national, PK/PD point prevalence study describing whether contemporary antibiotic dosing for critically ill patients achieves pre-defined concentrations associated with maximal activity.
Primary Aim:
To describe the achievement of therapeutic antibiotic exposures (concentrations) in critically ill patients. The project will look at 35 different antibiotics.
Secondary Aims:
To describe the relationship between achievement of target antibiotic exposures and patient-related outcomes including: outcome of treatment, mortality and emergence of antibiotic resistance. Several subgroups will be studied that include socio-demographics and those undergoing personalised dose-optimisation.
Research Methods
Participants will be adults and children in intensive care who are being treated with one of the study drugs and who have an indwelling arterial or venous catheter placed as part of routine care. Following assent or consent as appropriate for patient groups, enrolled participants will have three small (3 mL adults, 0.5 mL children) blood samples drawn during one dosing interval. Samples will be stored on ice and transported to Australia where all samples from across the world will have drug concentrations measured in a batch process. Participants will be asked to provide data on demographics, microbiological samples and outcome following infection. This will include the minimum inhibitory concentration of any bacteria isolated as causing infection. A full statistical analysis plan is available on request but in short will be descriptive in describing achieved antibiotic concentrations. Regression models will be constructed to identify variables associated with attainment of adequate drug concentration. Non-compartmental modelling of pharmacokinetic data will be undertaken to allow individual pharmacokinetic profiling of study antibiotics (particularly those with less well described kinetics in critical illness).
DALI-2 intends to recruit up to 3000 participants from across the globe. The study was presented at the critical care research forum in early 2024 where there was support for the study. 24 sites in the UK have expressed a formal interest in participating. It is anticipated that the UK will contribute at least 10 sites with each site contributing 10-30 participants.
Recruitment will occur over a 3-month period in 2026.
Anticipated outcomes
- Largest description of efficacy of current antibiotic dosing in adults and children
- Evidence of efficacy (or lack of efficacy) of optimised dosing strategies
- Potential therapeutic strategies for dose optimisation for future studies
Future directions and funding intentions
There are a wide range of possible future directions and funding intentions for this project, fundamentally arising from the fact that it will study 35 drugs. In current practice, only meropenem, piperacillin-tazobactam, vancomycin and aminoglycosides have optimised strategies in widespread use in adults. There is significant scope for future trials in a number of the other study drugs, of which the UK is well placed to investigate co-amoxiclav (less well used across the globe). The paediatric field is in particular need. DL and MO have ongoing research projects in this space and are well placed to lead future pharmacokinetic or dose optimisation studies.
Project Leads
Professor Marlies Ostermann, PhD, MD, EDIC, FRCP is a Consultant in Critical Care & Nephrology at Guy’s & St Thomas’ Hospital, London
Dr Dagan Lonsdale is a Consultant in Intensive Care Medicine and Senior lecturer in Clinical Pharmacology at St George’s University Hospitals, London
References
1. Vincent, J.-L., et al., Prevalence and Outcomes of Infection Among Patients in Intensive Care Units in 2017. JAMA, 2020. 323(15): p. 1478-1487.
2. Roberts, J.A., et al., Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis, 2014. 14(6): p. 498-509.
3. Roberts, J.A., et al., DALI: Defining antibiotic levels in intensive care unit patients: Are current ß-lactam antibiotic doses sufficient for critically ill patients? Clinical Infectious Diseases, 2014. 58(8): p. 1072-1083.
4. Evans, L., et al., Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Critical Care Medicine, 2021.
5. Kalil, A.C., et al., Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clinical Infectious Diseases, 2016. 63(5): p. e61-e111.
6. Dulhunty, J.M., et al., Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial. JAMA, 2024. 332(8): p. 629-637.
7. Abdul-Aziz, M.H., et al., Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis. JAMA, 2024. 332(8): p. 638-648.
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