Continuous infusion of beta-lactams may be superior to bolus therapy

Jan 9th – Continuous infusion of beta-lactam antibiotics yielded a higher plasma concentration and higher rates of clinical cure in patients with severe sepsis. [tabs tab1=”2MM Rundown” tab2=”Full 2MM Report” tab3=”About the Authors”]

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Image: PD

1.  Continuous infusion of beta-lactam antibiotics yielded a higher plasma concentration and higher rates of clinical cure than bolus therapy in patients with severe sepsis.

 2.  Survival to hospital discharge was greater in patients who received continuous infusion, though this result was not statistically significant.

This is the first multicenter randomized control trial comparing continuous and intermittent administration of beta-lactams in critically ill patients.  The results suggest a benefit in administering beta-lactams continuously in order to maintain plasma concentrations above the MIC.  This study’s limitations primarily stem from the small cohort of patients enrolled, confounding by unmeasured factors, and lack of power to evaluate an effect on survival.  However, this study demonstrates the feasibility of performing a larger multicenter trial in an effort to determine the optimal method of administering beta-lactams in critically ill patients.

Click to read the study in CID

Click to read an accompanying editorial in CID

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Image: PD

1.  Continuous infusion of beta-lactam antibiotics yielded a higher plasma concentration and higher rates of clinical cure than bolus therapy in patients with severe sepsis.

2.  Survival to hospital discharge was greater in patients who received continuous infusion, though this result was not statistically significant.

Primer:  Sepsis is a systemic condition resulting from infection that is a significant cause of mortality worldwide.  In the United States, more than 650,000 cases of sepsis are diagnosed annually.  Estimated mortality rates from severe sepsis can range from 20-50%.  Treating sepsis involves early administration of antibiotics, fluid resuscitation, and often, mechanical ventilation.  The most common bacteriocidal antibiotics used in the setting of sepsis are beta-lactams, which kill bacteria by inhibiting cell wall synthesis.  The longer beta-lactam levels in the blood are above the drug’s Minimum Inhibitory Concentration (MIC – the lowest concentration of drug in which bacteria are unable to grow) the more effective they are at killing bacteria.  Therefore, continuously infusing beta lactams into the blood in order to maintain a steady concentration should yield better results than intermittently bolusing a drug.  The authors of this study compared continuous infusion therapy with bolus therapy in septic patients.

Background reading:

1. Clinical Outcomes with Extended or Continuous Versus Short-term Intravenous Infusion of Carbapemens and Piperacillin/Tazobactam: A systematic Review and Meta-analysis

2.  Uptodate: Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis

This [double-blind, randomized controlled] study enrolled a total of 60 patients who were in severe sepsis between 2010 and 2011.  Patients were randomized to receive either continuous infusion therapy with piperacillin-tazobactam, meropenem, or ticarcillin-clavulanate or bolus therapy with the same drugs.  Total drug dosages were similar between forms of therapy.  The researchers then measured plasma antibiotic concentrations, clinical cure, ICU length of stay, and hospital survival rates.  The proportion of patients in the intervention group who had a plasma concentration above MIC on days 3 and 4 was 82%, compared to 29% in the control group (p=0.001).  Clinical cure was higher in the intervention group (p= 0.032).  While ICU length of stay and hospital survival were both more favorable in the intervention group, these results were not statistically significant.

In sum: This is the first multicenter randomized control trial comparing continuous and intermittent administration of beta-lactams in critically ill patients.  The results suggest a benefit in administering beta-lactams continuously in order to maintain plasma concentrations above the MIC.  This study’s limitations primarily stem from the small cohort of patients enrolled, confounding by unmeasured factors, and lack of power to evaluate an effect on survival.  However, this study demonstrates the feasibility of performing a larger multicenter trial in an effort to determine the optimal method of administering beta-lactams in critically ill patients.

Click to read the study in CID

Click to read an accompanying editorial in CID

By [AS] and [MP]

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Akira Shishido: Aki is a 4th year M.D. candidate at Harvard Medical School.

Mitalee Patil: Mitalee is a 4th year M.D. candidate at Harvard Medical School.

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