Continuous Infusion Compared with Intermittent Intravenous Infusion of Beta-Lactam Antibiotics for Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Trials

Abstract Background: The pathophysiologic changes during critical illness and high minimal inhibitory concentration (MIC) pathogens are important risk factors of mortality and bacterial eradication in critical care. Beta-lactam antibiotics have a time-dependent effect on bactericidal activity. The continuous infusion (CIF) of beta-lactam antibiotics achieves sufficient drug concentration above the MIC, especially for critically ill patients. However, the superiority of CIF over intermittent infusion (IIF) of beta-lactam antibiotics is yet to be clearly established. Thus, we aimed to investigate the effects on mortality of CIF of beta-lactams antibiotics in comparison to those of IIF of beta-lactams antibiotics in patients with sepsis admitted to the intensive care unit (ICU).Methods: We systematically searched PUBMED, MEDLINE, Cochrane Library, EMBASE, Web of Science, and ICTRP for randomized controlled trials (RCTs) comparing CIF with IIF of beta-lactam antibiotics in critically ill populations. All RCTs published until October 2019 were eligible. The primary outcome measure was the relative risk (RR) of mortality, while the secondary outcome measures were bacterial eradication rate, length of ICU stay, and length of admission. Results: In total, 6 RCTs comprising 974 patients were analyzed. We found a significantly lower mortality for critically ill patients on CIF (RR: 0.79; 95% CI: 0.63, 0.98) compared with those on IIF of beta-lactam antibiotics. The pooled RR for the bacterial eradication rate was 1.16 (95% CI: 1.03, 1.29) for CIF compared with IIF administration. Conclusion: CIF of beta-lactam antibiotics for critically ill patients significantly reduces mortality and yields a better bacterial eradication rate than IIF. These findings support the clinical and bacterial eradication benefits in adult critically ill patients, and may guide clinical discussions and decisions.