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

Introduction In vitro and in vivo pharmacokinetic/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 Collaborations 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 The a priori primary 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 ### Competing Interest Statement Some of the authors are management committee members of a trial that is eligible for inclusion in this review ### Clinical Protocols ### Funding Statement This systematic review and meta-analysis will be conducted without specific funding support. The investigators are grateful to The George Institute for Global Health and the Centre of Research Excellence Personalising Antimicrobial Dosing to Reduce Resistance (CRE RESPOND; Australian National Health and Medical Research Council Centre of Research Excellence, APP2007007), The University of Queensland, for providing in-kind support for this work. Naomi E. Hammond, John Myburgh and Jason A. Roberts are supported by National Health and Medical Research Council (NHMRC) Investigators Grant. Jan De Waele is supported by a Senior Clinical Investigator Fellowship from the Flanders Research Foundation (FWO). Fredrik Sjovall is supported by a grant from the Swedish Research Council. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data sharing requests will be handled in accordance with The George Institute for Global Health (TGI) data sharing policy (https://www.georgeinstitute.org.au/data-sharing-policy).