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Drug Combo Failed to Beat Monotherapy for Severe Sepsis

SAN FRANCISCO – Treating a new diagnosis of severe sepsis or septic shock with a combination of moxifloxacin and meropenem did not decrease the risk of sepsis-related organ dysfunction, compared with meropenem monotherapy, in a randomized, open-label trial.

On the contrary, there were statistical hints suggesting that the monotherapy regimen may be safer than the dual-drug strategy, Dr. Tobias Welte and his associates reported at an international conference of the American Thoracic Society.

Dr. Tobias Welte

Mean daily scores on the SOFA (Sequential Organ Failure Assessment) for 551 patients with evaluable data did not differ significantly between groups (a score of 8 in both) during treatment for 7-14 days or until discharge from the ICU or death, said Dr. Welte of Hannover (Germany) Medical School. Subscores on the SOFA for cardiovascular, respiratory, coagulation, renal, or hepatic failure also were similar between groups.

Among secondary outcomes, mortality rates at 28 days were 24% with the combination therapy and 22% with monotherapy. Mortality rates at 90 days were 35% with combination therapy and 32% with monotherapy. Those differences between groups were not significant, he said.

The combination therapy group had a significantly higher rate of treatment-related adverse events (9%), compared with the monotherapy group (4%).

The study was published online on May 21 in JAMA (doi:10.1001/jama.2012.5833).

The investigators had expected that the combination regimen would improve clinical outcomes. Use of empirical therapy with combined antibiotics has been controversial and is more common in the United States than in Europe.

Germany has a relatively low rate of antibiotic-resistant organisms, and the study had a relatively low rate of drug resistance. In patients with a first episode of severe sepsis or septic shock without risk factors for resistance to multiple antibiotics, monotherapy with a drug like meropenem is a good choice, Dr. Welte said.

"What we need for the future is a better characterization of patients who are at risk for multiresistant organisms," he said. "If you do it like the Americans do it, every patient is at risk for multiresistancy."He said he believes that with more precise risk stratification, more than half of U.S. patients with severe sepsis or septic shock might be candidates for monotherapy. Both groups averaged 8 days of treatment, showing that "8 days of treatment are enough even in patients with severe sepsis or septic shock," Dr. Welte said. One of the reasons for increased rates of multidrug-resistant organisms in the United States is overuse of antibiotics, he added. If treatment for severe sepsis were limited to one drug for only 7-8 days in areas with low rates of resistance, drug use in these cases could be reduced twofold, he suggested.

The MaxSep (Treatment of Severe Sepsis and Septic Shock) study included patients from 44 ICUs in Germany between October 2007 and March 2010. Intravenous infusions delivered 1-g meropenem every 8 hours plus moxifloxacin 400 mg every 24 hours, or meropenem alone. Survivors were followed for 90 days.

Baseline characteristics were similar between groups. After treatment, the results were similar between groups in ICU or hospital length of stay, median intervention-free days, and rate of secondary infection.

Notably, half of the infections were community acquired, which adds to the generalizability of the findings, Dr. Welte said.

In previous retrospective cohort studies, survival in severe sepsis significantly improved with a combination of beta-lactam antibiotics plus aminoglycosides, fluoroquinolones, macrolides, or clindamycin, compared with monotherapy (Crit. Care Med. 2010;38:1651-64).

Dr. Frank M. Brunkhorst of Friedrich Schiller University Jena (Germany) was the lead investigator in the study.

The study was funded by German government ministries and foundations. AstraZeneca and Bayer HealthCare provided the drugs for the study. Dr. Welte reported financial relationships with AstraZeneca, Bayer HealthCare, Astellas, GlaxoSmithKline, Novartis, and Pfizer. Some of his associates in the study reported relationships with these and other pharmaceutical companies.

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SAN FRANCISCO – Treating a new diagnosis of severe sepsis or septic shock with a combination of moxifloxacin and meropenem did not decrease the risk of sepsis-related organ dysfunction, compared with meropenem monotherapy, in a randomized, open-label trial.

On the contrary, there were statistical hints suggesting that the monotherapy regimen may be safer than the dual-drug strategy, Dr. Tobias Welte and his associates reported at an international conference of the American Thoracic Society.

Dr. Tobias Welte

Mean daily scores on the SOFA (Sequential Organ Failure Assessment) for 551 patients with evaluable data did not differ significantly between groups (a score of 8 in both) during treatment for 7-14 days or until discharge from the ICU or death, said Dr. Welte of Hannover (Germany) Medical School. Subscores on the SOFA for cardiovascular, respiratory, coagulation, renal, or hepatic failure also were similar between groups.

Among secondary outcomes, mortality rates at 28 days were 24% with the combination therapy and 22% with monotherapy. Mortality rates at 90 days were 35% with combination therapy and 32% with monotherapy. Those differences between groups were not significant, he said.

The combination therapy group had a significantly higher rate of treatment-related adverse events (9%), compared with the monotherapy group (4%).

The study was published online on May 21 in JAMA (doi:10.1001/jama.2012.5833).

The investigators had expected that the combination regimen would improve clinical outcomes. Use of empirical therapy with combined antibiotics has been controversial and is more common in the United States than in Europe.

Germany has a relatively low rate of antibiotic-resistant organisms, and the study had a relatively low rate of drug resistance. In patients with a first episode of severe sepsis or septic shock without risk factors for resistance to multiple antibiotics, monotherapy with a drug like meropenem is a good choice, Dr. Welte said.

"What we need for the future is a better characterization of patients who are at risk for multiresistant organisms," he said. "If you do it like the Americans do it, every patient is at risk for multiresistancy."He said he believes that with more precise risk stratification, more than half of U.S. patients with severe sepsis or septic shock might be candidates for monotherapy. Both groups averaged 8 days of treatment, showing that "8 days of treatment are enough even in patients with severe sepsis or septic shock," Dr. Welte said. One of the reasons for increased rates of multidrug-resistant organisms in the United States is overuse of antibiotics, he added. If treatment for severe sepsis were limited to one drug for only 7-8 days in areas with low rates of resistance, drug use in these cases could be reduced twofold, he suggested.

The MaxSep (Treatment of Severe Sepsis and Septic Shock) study included patients from 44 ICUs in Germany between October 2007 and March 2010. Intravenous infusions delivered 1-g meropenem every 8 hours plus moxifloxacin 400 mg every 24 hours, or meropenem alone. Survivors were followed for 90 days.

Baseline characteristics were similar between groups. After treatment, the results were similar between groups in ICU or hospital length of stay, median intervention-free days, and rate of secondary infection.

Notably, half of the infections were community acquired, which adds to the generalizability of the findings, Dr. Welte said.

In previous retrospective cohort studies, survival in severe sepsis significantly improved with a combination of beta-lactam antibiotics plus aminoglycosides, fluoroquinolones, macrolides, or clindamycin, compared with monotherapy (Crit. Care Med. 2010;38:1651-64).

Dr. Frank M. Brunkhorst of Friedrich Schiller University Jena (Germany) was the lead investigator in the study.

The study was funded by German government ministries and foundations. AstraZeneca and Bayer HealthCare provided the drugs for the study. Dr. Welte reported financial relationships with AstraZeneca, Bayer HealthCare, Astellas, GlaxoSmithKline, Novartis, and Pfizer. Some of his associates in the study reported relationships with these and other pharmaceutical companies.

SAN FRANCISCO – Treating a new diagnosis of severe sepsis or septic shock with a combination of moxifloxacin and meropenem did not decrease the risk of sepsis-related organ dysfunction, compared with meropenem monotherapy, in a randomized, open-label trial.

On the contrary, there were statistical hints suggesting that the monotherapy regimen may be safer than the dual-drug strategy, Dr. Tobias Welte and his associates reported at an international conference of the American Thoracic Society.

Dr. Tobias Welte

Mean daily scores on the SOFA (Sequential Organ Failure Assessment) for 551 patients with evaluable data did not differ significantly between groups (a score of 8 in both) during treatment for 7-14 days or until discharge from the ICU or death, said Dr. Welte of Hannover (Germany) Medical School. Subscores on the SOFA for cardiovascular, respiratory, coagulation, renal, or hepatic failure also were similar between groups.

Among secondary outcomes, mortality rates at 28 days were 24% with the combination therapy and 22% with monotherapy. Mortality rates at 90 days were 35% with combination therapy and 32% with monotherapy. Those differences between groups were not significant, he said.

The combination therapy group had a significantly higher rate of treatment-related adverse events (9%), compared with the monotherapy group (4%).

The study was published online on May 21 in JAMA (doi:10.1001/jama.2012.5833).

The investigators had expected that the combination regimen would improve clinical outcomes. Use of empirical therapy with combined antibiotics has been controversial and is more common in the United States than in Europe.

Germany has a relatively low rate of antibiotic-resistant organisms, and the study had a relatively low rate of drug resistance. In patients with a first episode of severe sepsis or septic shock without risk factors for resistance to multiple antibiotics, monotherapy with a drug like meropenem is a good choice, Dr. Welte said.

"What we need for the future is a better characterization of patients who are at risk for multiresistant organisms," he said. "If you do it like the Americans do it, every patient is at risk for multiresistancy."He said he believes that with more precise risk stratification, more than half of U.S. patients with severe sepsis or septic shock might be candidates for monotherapy. Both groups averaged 8 days of treatment, showing that "8 days of treatment are enough even in patients with severe sepsis or septic shock," Dr. Welte said. One of the reasons for increased rates of multidrug-resistant organisms in the United States is overuse of antibiotics, he added. If treatment for severe sepsis were limited to one drug for only 7-8 days in areas with low rates of resistance, drug use in these cases could be reduced twofold, he suggested.

The MaxSep (Treatment of Severe Sepsis and Septic Shock) study included patients from 44 ICUs in Germany between October 2007 and March 2010. Intravenous infusions delivered 1-g meropenem every 8 hours plus moxifloxacin 400 mg every 24 hours, or meropenem alone. Survivors were followed for 90 days.

Baseline characteristics were similar between groups. After treatment, the results were similar between groups in ICU or hospital length of stay, median intervention-free days, and rate of secondary infection.

Notably, half of the infections were community acquired, which adds to the generalizability of the findings, Dr. Welte said.

In previous retrospective cohort studies, survival in severe sepsis significantly improved with a combination of beta-lactam antibiotics plus aminoglycosides, fluoroquinolones, macrolides, or clindamycin, compared with monotherapy (Crit. Care Med. 2010;38:1651-64).

Dr. Frank M. Brunkhorst of Friedrich Schiller University Jena (Germany) was the lead investigator in the study.

The study was funded by German government ministries and foundations. AstraZeneca and Bayer HealthCare provided the drugs for the study. Dr. Welte reported financial relationships with AstraZeneca, Bayer HealthCare, Astellas, GlaxoSmithKline, Novartis, and Pfizer. Some of his associates in the study reported relationships with these and other pharmaceutical companies.

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