Effect of Empirical Treatment With Moxifloxacin andMeropenemvsMeropenemonSepsis-Related

Frank M. Brunkhorst, MD Michael Oppert, MD Gernot Marx, MD Frank Bloos, MD, PhD Katrin Ludewig, MD Christian Putensen, MD Axel Nierhaus, MD Ulrich Jaschinski, MD Andreas Meier-Hellmann, MD Andreas Weyland, MD Matthias Gründling, MD Onnen Moerer, MD Reimer Riessen, MD Armin Seibel, MD Maximilian Ragaller, MD Markus W. Büchler, MD Stefan John, MD Friedhelm Bach, MD Claudia Spies, MD Lorenz Reill, MD Harald Fritz, MD Michael Kiehntopf, MD Evelyn Kuhnt, MSc Holger Bogatsch, MD Christoph Engel, MD Markus Loeffler, MD, PhD Marin H. Kollef, MD Konrad Reinhart, MD Tobias Welte, MD for the German Study Group Competence Network Sepsis (SepNet) INAPPROPRIATE INITIAL ANTIMICRObial therapy (defined as an antimicrobial regimen that lacks in vitro activity against the isolated organisms responsible for the infection) is associated with increased mortality Author Affiliations and a list of the German Study Group Competence Network Sepsis investigators appear at the end of this article. Corresponding Author: Tobias Welte, MD, Klinik für Pneumologie, Medizinische Hochschule Hannover, Carl Neuberg Str 1, D-30625 Hannover, Germany (welte .tobias@mh-hannover.de). Context Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The role of empirical combination therapy comprising at least 2 antibiotics of different mechanisms remains controversial. Objective To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction. Design, Setting, and Patients A randomized, open-label, parallel-group trial of 600 patients who fulfilled criteria for severe sepsis or septic shock (n=298 for monotherapy and n=302 for combination therapy). The trial was performed at 44 intensive care units in Germany from October 16, 2007, to March 23, 2010. The number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. Interventions Intravenous meropenem (1 g every 8 hours) and moxifloxacin (400 mg every 24 hours) or meropenem alone. The intervention was recommended for 7 days and up to a maximum of 14 days after randomization or until discharge from the intensive care unit or death, whichever occurred first. Main Outcome Measure Degree of organ failure (mean of daily total Sequential Organ Failure Assessment [SOFA] scores over 14 days; score range: 0-24 points with higher scores indicating worse organ failure); secondary outcome: 28-day and 90day all-cause mortality. Survivors were followed up for 90 days. Results Among 551 evaluable patients, there was no statistically significant difference in mean SOFA score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8-8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5-8.4 points) (P=.36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%-29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%-27.4%) in the monotherapy group (P=.58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%-41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%-38.1%) in the monotherapy group (P=.43). Conclusion Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure. Trial Registration clinicaltrials.gov Identifier: NCT00534287 JAMA. 2012;307(22):2390-2399 Published online May 21, 2012. doi:10.1001/jama.2012.5833 www.jama.com