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

Jason A. Roberts, Mohd-Hafiz Abdul-Aziz, Joshua S. Davis, Joel M. Dulhunty, Menino O. Cotta, John Myburgh, Rinaldo Bellomo, Jeffrey Lipman

Background In this individual patient-data meta-analysis including 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 (RCTs) 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. RESULTS We identified 3 RCTs that recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, gender and illness severity. The rates of hospital mortality and clinical cure for the continuous and intermittent infusion groups were 19.6% versus 26.3% (RR 0.74 [95% CI 0.56-1.00], P = 0.045) and 55.4% versus 46.3% (RR 1.20 [95% CI 1.03-1.40], P = 0.021), respectively. In a multivariable model, intermittent beta-lactam administration, higher APACHE II score, use of renal replacement therapy and infection by non-fermenting Gram negative bacilli were significantly associated with hospital mortality; continuous beta-lactam administration was not independently associated with clinical cure. CONCLUSIONS Administration of beta-lactam antibiotics by continuous infusion in critically ill patients with severe sepsis is associated with decreased hospital mortality compared with intermittent dosing.