Are empirical combinations of antibiotics beneficial in severe sepsis?

Christine Ma, Faculty of Medicine, University of New South Wales, Sydney, Australia

International sepsis guidelines recommend that empirical combination antibiotic therapy be used for the treatment of gram-negative infections (1). This is to increase the chance that the organism will be sensitive to at least one therapy, to prevent superinfection and to encourage more effective bacterial clearance (2). However, the efficacy of this approach has not been clinically proven for patients with severe sepsis – a subpopulation with altered pharmacokinetics. This study compares the effects of combination vs. monotherapy for patients with severe sepsis (3).

600 patients from 44 German ICUs were recruited to the study. They were randomised to receive either 1g meropenem 8 hourly and 400mg moxifloxacin daily, or 1g meropenem 8 hourly alone, for 7-14 days, or until discharge from the ICU or death. The primary end point was patient scores on the Sequential Organ Failure Assessment (SOFA) over 14 days. There were no statistically significant differences found in this primary end point between the two groups. However, respiratory SOFA scores varied, with 2.5 points in the combination group and 2.4 points in the monotherapy group. Furthermore, the rate of antibiotic resistance to meropenem was higher in the monotherapy group compared to the combination group – 9.1% vs. 1.3% respectively. Other subgroups, duration of hospital stay and mortality showed no significant differences (3).

This study revealed that combination therapy of meropenem and moxifloxacin did not result in decreased organ failure (except for respiratory failure) compared to monotherapy of meropenem for patients with severe sepsis. However, monotherapy did lead to more incidences of antibiotic resistance, and so dual therapy may still be indicated. Further studies into different antibiotic combinations and/or specific infections may be warranted, as this study was not powered for analysis of organ dysfunction from specific organisms

References: 

1. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Medicine. 2008;34(1):17-60. doi:10.1007/s00134-007-0934-2

2. Klastersky J, Zinner SH. Synergistic combinations of antibiotics in gram-negative bacillary infections. Clin Infect Dis. 1982;4(2):294-301. doi:10.1093/clinids/4.2.294

3. Brunkhorst FM, Oppert M, Marx G, Bloos F, Ludewig K, Putensen C, et al. Effect of Empirical Treatment with Moxifloxacin and Meropenem vs Meropenem on Sepsis-Related Organ Dysfunction in Patients with Severe Sepsis JAMA. 307(22): 2390-2399. doi:10.1001/jama.2012.5833

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