Jul 092012

In the first randomized trial of its kind, patients with severe sepsis or septic shock who were given meropenem alone had equivalent clinical outcomes to patients who were given combination therapy including meropenem and moxifloxacin. The results, reported in JAMA, provide ethical support to critical care physicians who prefer to be conservative antibiotic stewards. But given the near-infinite complexity of the “bugs and drugs” game in the ICU, authors warn against overgeneralization of their findings.

What They Did

Authors randomized 600 patients with severe sepsis or septic shock at 44 ICUs in Germany to receive either intravenous meropenem, 1 g every 8 hours, or meropenem and moxifloxacin, 400 mg per day. Antibiotics were recommended to be provided for 7 days at least, up to 14 days at the clinician's discretion. Primary outcome was Sequential Organ Failure Assessment (SOFA) score, with secondary outcomes of mortality at 28 and 90 days. Physicians determined when to de-escalate antibiotics, often using procalcitonin measurements to do so.

What They Found

There were no statistically significant differences in outcomes between groups: SOFA scores at 14 days were 8.3 in the combination therapy group versus 7.9 in the meropenem-only group; 28 day mortality was 24% in the combination therapy group vs. 22% in the meropenem-only group. At 90 days, mortality was 35% in the combination-therapy group and 32% in the meropenem-alone group. (This was among the 551 patients remaining to be evaluated.)

Combination therapy appeared to be unnecessary in this trial, at least according to culture data: all 58 organisms isolated in the combination therapy group were susceptible to meropenem. In the meropenem monotherapy group, 65 of 69 were susceptible to meropenem; those four bugs that “got away” apparently did not cause enough harm to affect measurable outcomes.

Use of combination antibiotic therapy appeared to decrease the emergence of resistant organisms, albeit to a small extent: eight patients in the meropenem monotherapy group developed positive cultures for organisms resistant to meropenem, versus one in the combination therapy group.

What It Means

The theoretical rationale for combination antibiotic therapy is strong: Adding an antibiotic with a distinct microbial killing mechanism could increase the likelihood of coverage for the infecting organism; prevent superinfections from emerging; or synergistically improve microbial killing, resulting in a faster cure.

But does combination antibiotic therapy improve outcomes in critically ill patients? No one really knows: as stated, this is the 1st randomized trial to test the question in patients with severe sepsis or septic shock. It was resoundingly negative, and two previous meta-analyses did also not show a benefit of combination antibiotic therapy (beta-lactams + aminoglycosides) in patients with sepsis and/or gram-negative bacteremia. (On the other hand, a few randomized trials in patients with specific, severe infections including endocarditis, bacteremia with gram-negative organisms, and sepsis in patients with neutropenia have suggested that combination antibiotic therapy might be beneficial.)

Surviving Sepsis guidelines recommend combination therapy targeting gram-negative bacteria be used (especially if Pseudomonas is suspected), but  “no study or meta-analysis has convincingly demonstrated that combination therapy produces a superior clinical outcome for individual pathogens in a particular patient group,” those guidelines' authors openly acknowledge.

Authors of the JAMA paper rightly urge caution in extrapolating their results. This study proves nothing about combination antibiotic therapy in general, testing as it did only these 2 antibiotics. Further, although their high-quality methods and large multicenter design would seem to enhance validity, bacteriology and antimicrobial sensitivity are extremely local phenomena, sometimes varying widely even between hospitals in the same city. These local factors, along with the circumstances of the individual patient and likely primary source of infection, should always be the primary determinants of antibiotic therapy.

Nevertheless, their findings should give courage to those physicians who seek to limit the overuse of antibiotics both for their own patients individually, and to reduce pressure for the emergence of resistant organisms in society at large. Even when the severity of a patient's septic shock seems to demand combination antibiotics, the closeness in outcomes between groups seen here would also seem to support early de-escalation of combination antibiotics according to culture results, in accordance with the recommendations of by expert groups like ATS and IDSA.

Clinical Takeaway:  It's possible that combination antibiotic therapy could be unnecessary in patients with severe sepsis or septic shock, but it would take several more large trials using various antibiotic combinations to demonstrate that convincingly.

Taken together, the hyperlocal nature of bacteriology/epidemiology and antimicrobial resistance patterns, and the ethical and intuitive rationale for combination antibiotics in deathly ill patients (not to mention the professional guidelines advising their use), provide strong pressure for physicians to continue to use combination antibiotic therapy for initial management of patients with septic shock, unless multiple studies were to show that such treatment is clearly harmful. De-escalation of antibiotics -- reducing the number and spectrum of drugs being used, according to culture results and changes in the patient's condition -- should be done as soon as feasible, for all patients.

Brunkhorst FM et al. Effect of Empirical Treatment With Moxifloxacin and Meropenem vs Meropenem on Sepsis-Related Organ Dysfunction in Patients With Severe Sepsis. A Randomized Trial. JAMA 2012;307:2390-2399.

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Meropenem + moxifloxacin: no improvement over meropenem alone in severe sepsis (RCT)