Combination empirical antimicrobial therapy, including agents that target Gram-negative bacteria, have been reported to lower mortality and morbidity in patients with severe sepsis. Investigators from the German-based SepNet trials group performed a randomized, open-label, parallel-group study to compare the effect of combination therapy with meropenem and moxifloxacin (combination therapy) versus meropenem alone (monotherapy) for empirical treatment of patients with severe sepsis. Results were published in the June issue of The Journal of the American Medical Association.

After randomization with a modified Pocock minimization algorithm, 551 patients from 44 intensive care units were included in the study. Of those, 273 received meropenem alone, while 278 received combination therapy. The primary end point was sepsis-related organ dysfunction, as measured by Sequential Organ Failure Assessment (SOFA) scores recorded daily for 14 days. Multiple secondary endpoints also were studied, and all analyses followed the intention-to-treat principle. A power calculation was performed a priori to detect a 10% mortality difference and a change by 1.1 points in mean SOFA scores.

Gram-positive organisms were recovered in 54% of all patients. Escherichia coli and Klebsiella species were the two most common Gram-negative organisms recovered. The mean SOFA score in the combination group was 8.3 (95% confidence interval [CI], 7.8-8.8) and 7.9 (95% CI, 7.5-8.4) in the monotherapy group (P=0.36). Mortality rates were not statistically significantly different at 28 days and 90 days. More study-related adverse events were reported in the combination therapy group, but there was no difference in the number of serious adverse events between the groups. The authors concluded that, among adult patients with severe sepsis, empirical treatment with meropenem and moxifloxacin is no better than monotherapy with meropenem alone.

Clinically relevant antimicrobial synergism has been shown to be beneficial in other serious infections; one meta-regression suggested a beneficial effect of combination therapy for critically ill patients with septic shock. These studies used different antimicrobial regimens, including β-lactams in combination with other agents.

This well-designed study may be limited by different regional microbial patterns in Germany. Moreover, patients were treated aggressively according to the guidelines of the German Sepsis Society, and antibiotics in both treatment arms were started early (within 1.5 hours of enrollment). Interestingly, patients also were treated with procalcitonin-guided algorithms, with a median treatment duration of eight days. The patient population, microbial epidemiology and treatment protocols should be considered when interpreting the results of this study.

Concise Critical Appraisal is a regular feature authored by SCCM member Samuel M. Galvagno Jr., DO, PhD. Each installment highlights journal articles most relevant to the critical care practitioner.