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Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: A propensity-matched analysis*

Kumar, Anand MD; Zarychanski, Ryan MD; Light, Bruce MD; Parrillo, Joseph MD; Maki, Dennis MD; Simon, Dave MD; Laporta, Denny MD; Lapinsky, Steve MD; Ellis, Paul MD; Mirzanejad, Yazdan MD; Martinka, Greg MD; Keenan, Sean MD; Wood, Gordon MD; Arabi, Yaseen MD; Feinstein, Daniel MD; Kumar, Aseem PhD; Dodek, Peter MD; Kravetsky, Laura BSc; Doucette, Steve MSc

doi: 10.1097/CCM.0b013e3181eb3ccd
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Background: Septic shock represents the major cause of infection-associated mortality in the intensive care unit. The possibility that combination antibiotic therapy of bacterial septic shock improves outcome is controversial. Current guidelines do not recommend combination therapy except for the express purpose of broadening coverage when resistant pathogens are a concern.

Objective: To evaluate the therapeutic benefit of early combination therapy comprising at least two antibiotics of different mechanisms with in vitro activity for the isolated pathogen in patients with bacterial septic shock.

Design: Retrospective, propensity matched, multicenter, cohort study.

Setting: Intensive care units of 28 academic and community hospitals in three countries between 1996 and 2007.

Subjects: A total of 4662 eligible cases of culture-positive, bacterial septic shock treated with combination or monotherapy from which 1223 propensity-matched pairs were generated.

Measurements and Main Results: The primary outcome of study was 28-day mortality. Using a Cox proportional hazards model, combination therapy was associated with decreased 28-day mortality (444 of 1223 [36.3%] vs. 355 of 1223 [29.0%]; hazard ratio, 0.77; 95% confidence interval, 0.67-0.88; p = .0002). The beneficial impact of combination therapy applied to both Gram-positive and Gram-negative infections but was restricted to patients treated with β-lactams in combination with aminoglycosides, fluoroquinolones, or macrolides/clindamycin. Combination therapy was also associated with significant reductions in intensive care unit (437 of 1223 [35.7%] vs. 352 of 1223 [28.8%]; odds ratio, 0.75; 95% confidence interval, 0.63-0.92; p = .0006) and hospital mortality (584 of 1223 [47.8%] vs. 457 of 1223 [37.4%]; odds ratio, 0.69; 95% confidence interval, 0.59-0.81; p < .0001). The use of combination therapy was associated with increased ventilator (median and [interquartile range], 10 [0-25] vs. 17 [0-26]; p = .008) and pressor/inotrope-free days (median and [interquartile range], 23 [0-28] vs. 25 [0-28]; p = .007) up to 30 days.

Conclusion: Early combination antibiotic therapy is associated with decreased mortality in septic shock. Prospective randomized trials are needed.

From Section of Critical Care Medicine (AK, RZ, BL, LK), Health Sciences Centre/St. Boniface Hospital, University of Manitoba, Winnipeg, Manitoba, Canada; Cancer Care Manitoba (RZ), University of Manitoba, Winnipeg, Manitoba, Canada; Cooper Hospital/University Medical Center (AK, JP), Robert Wood Johnson Medical School, UMDNJ, Camden, New Jersey; Section of Infectious Diseases (DM), University of Wisconsin, Madison, Madison, WI; Section of Infectious Diseases (DS), Rush University, Chicago, Illinois; Section of Critical Care Medicine (DL), Jewish General Hospital, McGill University, Montreal, Quebec City, Canada; Section of Critical Care Medicine (SL), Mount Sinai Hospital, University of Toronto, Toronto, Ontario Canada; Department of Emergency Medicine (PE), University Health Network, University of Toronto, Toronto, Ontario, Canada; Surrey Memorial Hospital (YM), Surrey, British Columbia, Canada; Richmond General Hospital (GM), Vancouver, British Columbia, Canada; Royal Columbian Hospital (SK), Vancouver, British Columbia, Canada; Royal Jubilee Hospital/Victoria General Hospital (GW), University of British Columbia, Victoria, British Columbia, Canada; Intensive Care Department (YA), King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; Moses H. Cone Memorial Hospital (DF), Greensboro, North Carolina; Laurentian University (AK), Biomolecular Sciences Program and Department of Chemistry and Biochemistry, Sudbury, Ontario, Canada; Section of Critical Care Medicine (PD), St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Ottawa Health Research Centre (SD), Ottawa, Ontario, Canada.

Dr. Kumar has received grants from Wyeth, AstraZeneca, Pfizer, and Roche. Dr. Parrillo consulted with Sangart, Artisan, Philips, and Immunetrics. He received a grant from the Robert Wood Johnson Foundation. Dr. Mirjanezad consulted for the advisory boards of Schering-Plough Corporation and Pfizer. He received honoraria/speaking fees from Merck, Schering-Plough Corporation, Bayer, and Wyeth. He also received grants from Par101, C.diff, and INC Research. All other authors have no potential conflicts of interest to disclose.

None of the authors have financial or personal relationships or affiliations that could influence (or bias) the decision regarding the analysis or manuscript in any regard.

Funding for this work was provided by the Manitoba Health Research Council, Health Sciences Centre Foundation, and the Alfred Deacon Foundation. Additional support was provided by through unrestricted grants from Eli-Lilly, Pfizer, Astellas Pharma, Merck, Wyeth, Bayer, Bristol-Myers-Squibb, and Astra-Zeneca. Funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Dr. Kumar had full access to all the data in the study is responsible for the integrity of the database and the accuracy of the data analysis.

This specific research concept, the septic shock database, and manuscript were developed by Dr. Kumar. Dr. Kumar and Mr. Doucette were responsible for the methodological design issues and data analysis. All authors assisted with data interpretation and manuscript revisions.

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© 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins