Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis A Meta-analysis of Individual Patient Data from Randomized Trials

Rationale: Optimization of beta-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis. Objectives: In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of beta-lactam antibiotics. Methods: We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of beta-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis. Measurements and Main Results: We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6% versus 26.3% (relative risk, 0.74; 95% confidence interval, 0.56-1.00; P = 0.045) and 55.4% versus 46.3% (relative risk, 1.20; 95% confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent beta-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous beta-lactam administration was not independently associated with clinical cure. Conclusions: Compared with intermittent dosing, administration of beta-lactam antibiotics by continuous infusion in critirally ill patients with severe sepsis is associated with decreased hospital mortality.