Prolonged infusion versus intermittent infusion dosing of beta-lactam antibiotics in critically ill patients with sepsis: a protocol for a systematic review and meta-analysis of randomised controlled trials
Authors: Abdul-Aziz Mohd H. , Hammond Naomi E , Brett Stephen J. , Cotta Menino O. , De Waele Jan J. , Di Tanna Gian Luca , Dulhunty Joel M. , Elkady Hatem , Eriksson Lars , Hasan M. Shahnaz , Lipman Jeffrey , Monti Giacomo , Myburgh John , Novy Emmanuel , Rajbhandari Dorrilyn , Roger Claire , Santos Joseph Alvin , Sjövall Fredrik , Zaghi Irene , Zangrillo Alberto , Delaney Anthony , Roberts Jason A. 
Published: May 2023

Introduction

In vitroandin vivopharmacokinetic/pharmacodynamic data describe improved activity of beta-lactam antibiotics when administered by prolonged infusion compared with standard intermittent infusion. There remains insufficient robust clinical trial data to support a widespread practice change. Patients with sepsis and septic shock are a population in whom prolonged infusion of beta-lactam antibiotics may improve survival. Two large multicentre randomised controlled trials (RCTs) comparing prolonged versus intermittent infusion of beta-lactam antibiotics in critically ill patients with sepsis or septic shock are due for completion in 2023. With existing RCT evidence, this systematic review and meta-analysis will include these new data to measure the clinical benefits of prolonged beta-lactam infusion in critically ill patients with sepsis.

Methods and analysis

This protocol has been prepared according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) statement. This systematic review and meta-analysis will include RCTs that compare prolonged infusion with intermittent infusion of beta-lactam antibiotics in critically ill adult patients with sepsis. Medline (via PubMed), CINAHL, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and other clinical trials registries will be searched to identify eligible RCTs for review. Two reviewers will perform the study selection and extraction processes with disagreements resolved by discussion or referral to a third reviewer if needed. The Cochrane Collaboration’s Risk-of-Bias Tool for Randomised Trials version 2 (RoB 2) will be used to evaluate the quality of included studies. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach will be used to evaluate the overall quality of evidence for each outcome measures Thea prioriprimary outcome is all-cause 90-day mortality. Secondary outcomes include intensive care unit (ICU) mortality, ICU length of stay, clinical cure, microbiological cure, and the development of adverse events. Bayesian random-effects meta-analyses will be conducted, with frequentist analyses planned for sensitivity analysis.

Ethics and dissemination

Human research ethics approval is not required as the study involves the use of existing collections of data that are de-identified. It is expected that findings will be presented at national and international intensive care and infectious diseases meetings, and will be submitted to a peer-reviewed journal for publication.

PROSPERO Registration Number: CRD42023399434