Wednesday, May 23, 2012

More antibiotics NOT more better in sepsis

There is a meme in antibiotic therapy for all infectious disease clinical syndromes that earlier and more antibiotics lead to lower mortality. I'm not sure that this meme is supported by data from good studies, but it has been so effectively spread through the establishment that its very existence goes unnoticed (check this abstract's first sentence). I think this unproven belief threatens effective antimicrobial stewardship and is partially responsible for the emergence of antimicrobial resistant organisms, but I digress...

Published online in JAMA this week is a randomized trial of dual antibiotic vs monotherapy in sepsis funded through the German Sepsis Research Network (SepNet). The 2.5 year study in 44 German ICUs compared meropenem monotherapy (n=298) with meropenem+moxifloxacin (n=278) in patients with sepsis or septic shock. Patients were treated for 7 to 14 days or until discharge or death and duration was informed by a procalcitonin-guided treatment protocol on study days 7 and 10. The primary outcome was mean of daily total Sequential Organ Failure Assessment (SOFA) scores over 14-days with similar scores in both monotherapy (7.9 points) and dual therapy (8.3 points) patients, p=0.36. 28-day mortality was 22% in the mero and 24% in mero+moxi patients (p=0.58) and 90-day mortality was 32% in the mero and 35% in the mero+moxi patients (p=0.43).

Groups were similar and infections were predominately pneumonia, intra-abdominal and GU. Blood cultures were positive in 33% of patients with Escherichia coli and MSSA being the most commonly isolated, while 18 had MRSA from any source. 100% of cultures tested were susceptible to the mero+moxi combination while 94% of specimens were susceptible to meropenem monotherapy.

This is an important study and one that should make us question current empiric therapy dogma. However, it doesn't answer the question whether antibiotics overall made a difference and whether other therapeutic options including source control might be more important.  It's nice to see clinical ID slowly emerge into the modern evidence-based medicine era even if so few studies are completed in the US.

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  1. I don't understand the point of this study. The investigators compared two treatments which used either one or two antibiotics. However, the 2 antibiotics chosen have very similar spectrum of activity, and to my knowledge the combination has not been shown to be synergistic. It's kind of like comparing meropenem monotherapy to dual therapy with meropenem + imipenem. So, I suspect most clinicians could have accurately predicted the outcome of the study, and I don't think the authors really addressed the question of whether dual therapy is better than monotherapy. Also, at least in the US, in critically ill patients, I can't imagine anyone not specifically including MRSA coverage.

  2. I guess with the pneumonia predominance in sepsis this wasn't so obvious to me. Also, I've seen this combination quite often in sepsis. With clinicians avoiding amino glycosides this past decade, quinolones are often added.

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