Continuous Infusion of Beta-lactams for Sepsis Improves Outcomes.

Continuous Infusion of Beta-lactams for Sepsis Improves Outcomes.

Watkins Richard R

Infectious Disease Alert

2013

2013-03

Despite notable advances in critical care medicine, mortality from severe sepsis remains unacceptably high. With current therapeutic strategies, nothing has proven more crucial than early and effective antibiotics. Among the most commonly utilized antibiotics in intensive care units (ICUs) are beta-lactams, such as piperacillin-tazobactam and meropenem. These agents are usually administered by intermittent bolus dosing. However, pharmocodynamic data have shown that continuous infusion administration results in greater blood and fluid exposure with more time above the minimum inhibitory concentration (MIC) compared to intermittent dosing. Dulhunty and colleagues sought to determine the clinical and pharmacokinetic differences between continuous and intermittent bolus dosing of beta-lactam antibiotics in patients with severe sepsis. The study was a prospective, double-blind, randomized controlled trial conducted at several hospitals in Australia and Hong Kong between April 2010 and November 2011. Patient inclusion criteria included \textgreater 18 years of age, severe sepsis in the preceding 24 hours, treatment within the previous 24 hours with ticarcillin-clavulanate, piperacillin-tazobactam or meropenem, and expected or actual ICU stay greater than 24 hours. Patients were excluded if they were on continuous renal replacement therapy, lacked a central access catheter with at least 3 lumens, or received the study drug for \textgreater 24 hours. They were randomized to receive active infusion and placebo boluses (intervention group), or placebo infusion and active boluses (control group). On days 3 and 4 blood samples were taken to ascertain plasma trough levels. The primary endpoint was the time that antibiotic concentration was above the MIC. Secondary endpoints were clinical response at days 7 to 14 after study drug cessation, time to clinical resolution, status at ICU and hospital discharge, and number of days alive and free of ICU admission in the first 28 days post-randomization. Sixty patients were enrolled, 30 in the continuous infusion group and 30 in the intermittent bolus group. The most common source of infection in both groups was lung, followed by blood, intra-abdominal, skin or skin structure, urinary tract, and central nervous system. The patients who received continuous infusion compared to intermittent bolus administration achieved higher times above the MIC (82% vs. 29%, P = .001) and higher clinical cure (76.7% vs. 50%, P = .032). Moreover, there was less time to clinical resolution (11 days vs. 16.5 days, P = .14), lower ICU length of stay (7.5 days vs. 9 days, P = .50), better hospital survival (90% vs 80% P = .47), and higher ICU survival (93.3% vs. 86.7%, P = .67) in the continuous infusion group, but these did not reach statistical significance. Plasma antibiotic concentration of meropenem was greater than the MIC in 100% of patients who received continuous infusion compared to 22% in the intermittent bolus group. Piperacillin-tazobactam and ticarcillin-clavulanate continuous infusions resulted in concentrations above the MIC 75% and 50% of the time, respectively. The corresponding- intermittent bolus administration achieved concentrations above the MIC 36% and 0% of the time with piperacillin-tazobactam and ticarcillin-clavulanate.

Prospective Studies; Human; Multicenter Studies; Infusions; Microbial Culture and Sensitivity Tests; Randomized Controlled Trials; Double-Blind Studies; Antibiotics – Administration and Dosage; Intravenous – Utilization; Sepsis – Drug Therapy

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