Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis
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This study aims to determine if continuous infusion (CI) is associated with better clinical and pharmacokinetic/pharmacodynamic (PK/PD) outcomes compared to intermittent bolus (IB) dosing in critically ill patients with severe sepsis.
This was a two-centre randomised controlled trial of CI versus IB dosing of beta-lactam antibiotics, which enrolled critically ill participants with severe sepsis who were not on renal replacement therapy (RRT). The primary outcome was clinical cure at 14 days after antibiotic cessation. Secondary outcomes were PK/PD target attainment, ICU-free days and ventilator-free days at day 28 post-randomisation, 14- and 30-day survival, and time to white cell count normalisation.
A total of 140 participants were enrolled with 70 participants each allocated to CI and IB dosing. CI participants had higher clinical cure rates (56 versus 34 %, p = 0.011) and higher median ventilator-free days (22 versus 14 days, p < 0.043) than IB participants. PK/PD target attainment rates were higher in the CI arm at 100 % fT >MIC than the IB arm on day 1 (97 versus 70 %, p < 0.001) and day 3 (97 versus 68 %, p < 0.001) post-randomisation. There was no difference in 14-day or 30-day survival between the treatment arms.
In critically ill patients with severe sepsis not receiving RRT, CI demonstrated higher clinical cure rates and had better PK/PD target attainment compared to IB dosing of beta-lactam antibiotics. Continuous beta-lactam infusion may be mostly advantageous for critically ill patients with high levels of illness severity and not receiving RRT.
Malaysian National Medical Research Register ID: NMRR-12-1013-14017.
KeywordsAntibiotics Critically ill Intermittent bolus Pharmacokinetics Pharmacodynamics Prolonged infusion
We would like to thank ICU research coordinators Nurhafizah Zarudin and Siti Nabilah Mohd Zanidin (Tengku Ampuan Afzan Hospital) and Nurul Syazwani Muhtar and Kay Shannu Stanislaus Asirvatham (University Malaya Medical Centre); ICU pharmacists Aida Roziana Ramlan (Tengku Ampuan Afzan Hospital) and Yeap Li Ling and Lim Ka Yin (University Malaya Medical Centre); Suzanne Parker-Scott and Jenny Lisette Ordonez Mejia at The Burns, Trauma and Critical Care Research Centre, The University of Queensland for laboratory analysis; and Dr Joel Dulhunty at The Royal Brisbane and Women’s Hospital, Brisbane for statistical analysis advice. Mohd H. Abdul-Aziz and Azrin N. Abd Rahman would like to acknowledge the support of the Ministry of Education, Malaysia in the form of scholarships. Jason A. Roberts is funded by a Career Development Fellowship from the National Health and Medical Research Council of Australia (APP1048652). We wish to acknowledge funding from the Australian National Health and Medical Research Council for Centre of Research Excellence (APP1099452).
Compliance with ethical standards
Conflicts of interest
All of the other authors declare that there are no conflicts of interest.
This project has received funding from the International Islamic University of Malaysia (IIUM) Research Endowment Grant (Grant Number EDW B 11-148-0626). IIUM had no role in study design, analysis or drafting of the manuscript.
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