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Original Contribution |

Effect of Empirical Treatment With Moxifloxacin and Meropenem vs Meropenem on Sepsis-Related Organ Dysfunction in Patients With Severe Sepsis:  A Randomized Trial FREE

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)
[+] Author Affiliations

Author Affiliations: Department of Anesthesiology and Intensive Care Medicine (Drs Brunkhorst, Bloos, Ludewig, and Reinhart) and Institute for Clinical Chemistry and Laboratory Medicine (Dr Kiehntopf), Friedrich-Schiller University, Jena, Germany; Department of Nephrology and Medical Intensive Care, Charité, Campus Virchow-Klinikum, University Medical Center, Berlin, Germany (Dr Oppert); Department of Anesthesiology and Intensive Care Medicine, University of Aachen, Aachen, Germany (Dr Marx); Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Bonn, Germany (Dr Putensen); Department of Critical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (Dr Nierhaus); Department of Anesthesiology and Critical Care Medicine, Klinikum Augsburg, Augsburg, Germany (Dr Jaschinski); Department of Anesthesiology and Intensive Care Medicine, HELIOS Klinikum, Erfurt, Germany (Dr Meier-Hellmann); Department of Anesthesiology and Intensive Care Medicine, Klinikum Oldenburg, Oldenburg, Germany (Dr Weyland); Department of Anesthesiology and Intensive Care Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany (Dr Gründling); Department of Anesthesiology and Intensive Care Medicine, University of Goettingen, Goettingen, Germany (Dr Moerer); Department of Internal Medicine, University of Tübingen, Tübingen, Germany (Dr Riessen); Department of Anesthesiology and Intensive Care Medicine, Jung-Stilling-Krankenhaus, Siegen, Germany (Dr Seibel); Department of Anesthesiology and Intensive Care Medicine, University Hospital of the Technical University of Dresden, Dresden, Germany (Dr Ragaller); Department of Surgery, University of Heidelberg, Heidelberg, Germany (Dr Büchler); Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen and Nuremberg, Germany (Dr John); Department of Anesthesiology and Intensive Care Medicine, Evangelisches Krankenhaus Bielefeld, Bielefeld, Germany (Dr Bach); Department of Anesthesiology and Intensive Care Medicine, Charité, Campus Mitte, University Medical Center, Berlin, Germany (Dr Spies); Department of Cardiology and Intensive Care Medicine, Vivantes Klinikum Neukölln, Berlin, Germany (Dr Reill); Department of Anesthesiology and Intensive Care Medicine, Krankenhaus Martha-Maria Halle, Halle, Germany (Dr Fritz); Clinical Trial Centre Leipzig (Ms Kuhnt and Dr Bogatsch) and Institute for Medical Informatics, Statistics and Epidemiology (Drs Engel and Loeffler), University of Leipzig, Leipzig, Germany; Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, Missouri (Dr Kollef); and Department of Pneumology, Medizinische Hochschule Hannover, Hannover, Germany (Dr Welte).


JAMA. 2012;307(22):2390-2399. doi:10.1001/jama.2012.5833.
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Published online

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 90-day 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

Figures in this Article

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 and morbidity in patients with neutropenic fever and in patients with severe sepsis.13 To decrease the likelihood of inappropriate antimicrobial therapy, recent international sepsis guidelines suggest empirical combination therapy targeting gram-negative bacteria, particularly for patients with suspected Pseudomonas infections.4 However, the authors of this guideline4 state that “no study or meta-analysis has convincingly demonstrated that combination therapy produces a superior clinical outcome for individual pathogens in a particular patient group.”

The basis on which combination therapy provides a potential survival benefit can be related to several mechanisms. These include an increased chance that at least 1 agent with activity against the infecting organism will be susceptible to at least 1 of the components of the regimen; prevention of emergence to a resistant superinfection57; potential beneficial immunomodulatory nonantibiotic effect of the secondary agent8,9; and generation of an additive or even synergistic activity resulting in better bacterial clearance of the combination therapy.1014 In contrast to patients with febrile neutropenia, rigorous randomized trials have not been performed in the most severely ill patients with sepsis, capillary leak syndrome, and multiorgan failure in which both the volume of distribution and metabolism of the antibiotics may be altered.

The primary objective of this trial was to compare the effect of a combination therapy with the effect of a monotherapy on sepsis-related organ dysfunction using 2 broad-spectrum antibiotics for the empirical treatment of patients with severe sepsis. We hypothesized that maximizing the potential benefit and appropriateness of initial antibiotics by using 2 antibiotics would improve clinical outcomes compared with monotherapy.

Experimental Design, Study Organization, and Patients

Severe sepsis and septic shock were defined according to published criteria.15 Patients were eligible for study enrollment if the onset of the syndrome was not more than 24 hours prior to study inclusion. We excluded patients if they had been treated with more than 1 daily dose of a carbapenem or a quinolone within the 4 weeks prior to randomization, had received an antipseudomonal β-lactam antibiotic within the 48 hours prior to randomization, or had contraindications to the study drugs according to the manufacturer's summary of product characteristics. In addition, we excluded patients who were known to be previously infected or colonized with methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus species (not susceptible to study antibiotics), had infections for which the guidelines recommend an antimicrobial therapy other than the study medication (ie, endocarditis), or were expected to die or undergo withdrawal of life support.

The trial was approved by the ethics committee of each participating institution and by Germany's Federal Institute for Drugs and Medical Devices. Written informed consent was obtained from all patients or their legal representative. For patients in whom prior consent could not be obtained because of critical illness or the use of sedative or anesthetic drugs and to enable early antibiotic therapy, the ethics committees approved a provision for delayed consent. In such cases, a surrogate decision maker was fully informed as soon as possible. Either consent was then obtained or the patient was removed from the study and all study procedures ended.

Randomization

Patients were randomly allocated to receive either 1 g of meropenem (AstraZeneca) every 8 hours and 400 mg of moxifloxacin (Bayer HealthCare) every 24 hours (combination therapy) or 1 g of meropenem alone (monotherapy) each administered intravenously over 15 to 30 minutes for meropenem and for 60 minutes for moxifloxacin in an unblinded fashion. The randomization was stratified by the participating centers and performed by the investigators using an Internet-based randomization tool that was provided by the clinical trial center. The modified Pocock minimization algorithm (with a random component) ensures balanced randomization at any time.16 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 (ICU) or death, whichever occurred first.

Data Collection

Clinical, microbiological, and laboratory examinations were performed prior to treatment, at the end of therapy (test-of-cure visit), and at day 21 or at discharge from the ICU, whichever occurred first. Site investigators used standardized definitions to determine the final clinical and microbiological outcomes (eMethods). If Pseudomonas species were cultured, 2 antibiotics with activity against these species were recommended. All patients received sepsis treatment for cardiovascular, respiratory, renal, and metabolic failure according to the guidelines of the German Sepsis Society.17

Outcome Measures and Safety End Points

The primary end point was sepsis-related organ dysfunction as measured by the mean of daily total Sequential Organ Failure Assessment (SOFA)18 scores over a period of 14 days or discharge from the ICU or death, whichever occurred first. The scale of the SOFA score ranges from 0 to 24, with higher scores indicating a greater severity of organ failure. Subscores of SOFA range from 0 to 4 for each of the 6 organ systems, with an aggregate score of 0 to 24. The mean SOFA score was calculated as the mean of all daily SOFA scores during the ICU stay for each patient.

Secondary end points were 28-day and 90-day all-cause mortality; mean SOFA subscores; duration of ICU and hospital stay; clinical and microbiological treatment response; intervention-free days with a ventilator, vasopressor, dialysis, or antibiotic; secondary infections; emergence of antibiotic-resistant bacteria; and adverse events. Adverse events were reported according to the ICH guideline E2A and coded by the Medical Dictionary for Regulatory Activities version 13.1.

Sample Size and Statistical Analysis

The study was planned to detect a difference of 1.1 points in the mean SOFA score between the 2 interventions with a significance level of .05 and a power level of 90%. Such an effect was expected to reduce 28-day mortality from 40% to 30%.18 Assuming an SD of 3.8 points and a dropout rate of about 15%, an enrollment of 600 patients was required. One interim analysis was planned and conducted after recruitment of half of the planned sample size. The significance level was adjusted by the α spending method,19 which was .00288 (as specified by the O’Brien and Fleming20 multiple testing procedure). Hence, the significance level for the final confirmatory analysis was .04712. Annual safety reports were performed and reported to the Federal Institute for Drugs and Medical Devices and the ethics committee of the Friedric-Schiller University of Jena.

The confirmatory analyses followed the intention-to-treat principle based on all patients who were randomized and provided informed consent. Per-protocol analyses excluding patients with protocol violations were performed to investigate the robustness of the results (the definition of protocol violations appear in eMethods). Safety analyses were based on the safety analysis population, which comprises all patients randomized who received at least 1 dose of study medication and who were grouped according to the treatment they actually received.

The t test for independent groups was used to investigate the primary end point of mean SOFA score. The χ2 test, Fisher exact test, and the Mann-Whitney test were applied to analyze the secondary end points of efficacy and safety, as appropriate. Overall survival was estimated using the Kaplan-Meier method. Proportional hazard models and generalized linear models were used to identify factors influencing overall mortality and mean SOFA score. All reported P values are 2-sided. Statistical analyses were performed using SAS version 9.1.3 (SAS Institute Inc).

Between October 16, 2007, and March 23, 2010, 5607 patients were screened in 44 ICUs from different academic tertiary hospitals in Germany; 1088 were eligible and 600 patients were randomized (Figure 1). Delayed informed consent could not be obtained in 49 patients from the patient or the patient's legal representative. These patients were excluded from the intention-to-treat analysis, but were included in the safety analysis.

Place holder to copy figure label and caption
Figure 1. Screening and Inclusion Process for Patients in the Study
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Among the remaining 551 evaluable patients, demographic and baseline characteristics (Table 1), site and source of infection (Table 2), pathogens present at the time of enrollment (Table 3), indicators of severity of disease, and antibiotics used 1 week prior to randomization (eTable 1) were well balanced comparing the combination therapy (meropenem and moxifloxacin) group with the monotherapy (meropenem alone) group. The median time from enrollment to initiation of study antibiotics was 0.7 (interquartile range [IQR], 0.4-1.0) hours in the combination therapy group compared with 0.8 (IQR, 0.5-1.4) hours in the monotherapy group (P = .08).

Table Graphic Jump LocationTable 1. Demographics and Baseline Characteristics
Table Graphic Jump LocationTable 2. Site and Source of Infection
Table Graphic Jump LocationTable 3. Gram-Positive, Gram-Negative, and Fungi Pathogens at Enrollment

The most common pathogens cultured from enrollment specimens appear in Table 3. Blood cultures were positive in 183 patients (33%) with Escherichia coli and methicillin-sensitive S aureus as the most common pathogens. Blood cultures were positive for Pseudomonas species in only 9 patients (5 in the combination therapy and 4 in the monotherapy group). The susceptibility profiles and numbers of study drugs resistant to gram-negative bacteria grown in enrollment specimens appear in eTable 2. Of all patients whose specimens were tested for susceptibility to meropenem, 58 of 58 (100%; 95% CI, 93.8%-100%) were susceptible in the combination therapy group compared with 65 of 69 (94.2%; 95% CI, 85.8%-98.4%) in the monotherapy group (P = .13).

Primary and Secondary Outcomes

The mean SOFA score was 8.3 points (95% CI, 7.8-8.8 points) in the combination therapy group compared with 7.9 points (95% CI, 7.5-8.4 points) in the monotherapy group (P = .36; Table 4 and Figure 2A). In the per-protocol analysis, the mean SOFA score was 7.9 points (95% CI, 7.4-8.5 points) in the combination therapy group compared with 7.6 points (95% CI, 7.0-8.1 points) in the monotherapy group (P = .37; Figure 2B). The respiratory SOFA subscore was statistically significantly different between the 2 study groups; the median score was 2.5 points (IQR, 2.0-2.9 points) in the combination therapy group compared with 2.4 points (IQR, 2.0-2.8 points) in the monotherapy group (P = .02; Table 4).

Place holder to copy figure label and caption
Figure 2. Daily Sequential Organ Failure Assessment (SOFA) Scores
Graphic Jump Location

The data markers indicate means and the error bars indicate 95% CIs.

There were no significant differences comparing combination therapy with monotherapy for the secondary end points of duration of ICU and hospital stay; intervention-free days with a ventilator, vasopressor, dialysis, or antibiotic; the rates of secondary infections (Table 4); or clinical and microbiological treatment response (eTable 4). Antibiotic resistance to meropenem was detected more often in the monotherapy group (8/88; 9.1% [95% CI, 4.0%-17.1%) compared with the combination therapy group (1/78; 1.3% [95% CI, 0.03%-6.9%]; P = .04). However, the number of specimens tested for susceptibility was low (Table 4).

The rates for 28-day and 90-day mortality were not statistically significantly different between the 2 treatment groups (Table 4 and Figure 3A). 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).

Place holder to copy figure label and caption
Figure 3. Overall Survival
Graphic Jump Location

The results of the per-protocol analysis of the 28-day and 90-day mortality rates also did not significantly differ between the 2 study groups (Figure 3B). By day 28, there were 48 deaths (n = 214; 22.4% [95% CI, 17.0%-28.6%]) in the combination therapy group compared with 39 deaths (n = 195; 20.0% [95% CI, 14.6%-26.3%]) in the monotherapy group (P = .55). By day 90, there were 70 deaths (n = 213; 32.9% [95% CI, 26.6%-39.6%]) in the combination therapy group compared with 58 deaths (n = 189; 30.7% [95% CI, 24.2%-37.8%]) in the monotherapy group (P = .64).

Study Treatment

Meropenem was administered initially for a median of 8 days (IQR, 5-10 days) in the combination therapy group and 8 days (IQR, 4-10 days) in the monotherapy group. In the combination therapy group, moxifloxacin was administered for a median of 7 days (IQR, 4-10 days). The total dose of meropenem administered was 18 g (IQR, 8-24 g) in the combination therapy group and 19 g (IQR, 8-25 g) in the monotherapy group. The total dose of moxifloxacin administered was 2.8 g (IQR, 1.6-4.0 g).

Concomitant Treatment

Activated protein C was administered to 8 patients (3%) in the combination therapy group and to 9 patients (3%) in the monotherapy group (P = .78). Low-dose hydrocortisone for septic shock was administered to 111 patients (39.9%) in the combination therapy group and to 91 patients (33.3%) in the monotherapy group (P = .11) at comparable doses (median of mean daily dose: 136 mg [IQR, 99-175 mg] vs 134 mg [IQR, 100-169 mg], respectively; P = .67). Selenium as an adjunctive sepsis treatment was administered to 92 patients (33.1%) in the combination therapy group and to 87 patients (31.9%) in the monotherapy group (P = .76). Immunosuppressive treatment with a prednisolone equivalent was administered at a daily dose of greater than 5 mg to 13 patients (4.7%) in the combination therapy group and to 13 patients (4.8%) in the monotherapy group (P = .96).

Safety End Points

At least 1 adverse event occurred in 85 patients (n = 303; 28.1% [95% CI, 23.1%-33.5%]) in the combination therapy group and in 71 patients (n = 293; 24.2% [95% CI, 19.4%-29.6%]) in the monotherapy group (P = .31). There were significantly more study-related adverse events reported in the combination therapy group (n = 26; 8.6% [95% CI, 5.7%-12.3%]) compared with the monotherapy group (n = 11; 3.8% [95% CI, 1.2%-6.6%]; P = .02). However, there were no differences in the rates of adverse events classified as serious, serious and study-related, resulting in death, or study-related and resulting in death (eTable 3). Adverse events assigned to the system organ class of cardiac disorders were reported in 37 patients (12.2%; 95% CI, 8.8%-16.4%) in the combination therapy group and in 31 patients (10.6%; 95% CI, 7.3%-14.7%) in the monotherapy group (P = .61). Of these patients, 10 patients (3.3%; 95% CI, 1.6%-6.0%) in the combination therapy group and 7 patients (2.4%; 95% CI, 1.0%-4.9%) in the monotherapy group were classified as serious (P = .63). Adverse events assigned to the system organ class of hepatobiliary disorders were reported in 8 patients (2.6%; 95% CI, 1.2%-5.1%) in the combination therapy group and in 3 patients (1.0%; 95% CI, 0.2%-3.0%) in the monotherapy group (P = .22), of whom 1 event was classified as serious in the monotherapy group. The QT interval corrected for heart rate at end of therapy was not different between groups (median, 423 milliseconds; IQR, 400-443 milliseconds in the combination therapy group; median, 417 milliseconds; IQR, 394-447 milliseconds in the monotherapy group; P = .85).

Multivariable Analyses

The risk factors for higher mean SOFA score at 14 days identified by general linear model risk factors were SOFA score at enrollment (regression coefficient per point, 0.6 [95% CI, 0.5-0.7]; P < .001), renal failure at enrollment (regression coefficient, 3.9 [95% CI, 3.1-4.8]; P < .001), and age (regression coefficient per year, 0.02 [95% CI, 0.002-0.04]; P = .03). In Cox regression analysis, independent risk factors for time to death were SOFA score at baseline (hazard ratio [HR] per point, 1.08 [95% CI, 1.03-1.14]; P = .003), renal failure at enrollment (HR, 3.56 [95% CI, 2.51-5.06]; P < .001), and age (HR per year, 1.04 [95% CI, 1.03-1.06]; P < .001). In contrast, study therapy, prior antibiotic treatment, bacterial resistance, and gram-negative enrollment pathogens were not associated with the mean SOFA score or time to death.

Subgroup Analyses

Unplanned subgroup analyses stratified by prerandomization SOFA score or with patients categorized by site and origin of infection or by enrollment organisms did not show significant differences in survival or mean SOFA score (eFigure). In addition, a predefined analysis excluding all patients treated for less than 4 days with study medication did not reveal significant differences (eFigure).

In this clinical trial of 551 patients with severe sepsis or septic shock, we found no beneficial effect of combination therapy including meropenem and moxifloxacin with regard to the 14-day mean SOFA score, or with regard to any secondary end point. There were no statistical differences in serious adverse events or major adverse event profiles between the 2 study groups.

To our knowledge, this is the first randomized trial of the empirical use of combination therapy compared with monotherapy in patients with severe sepsis or septic shock. However, several randomized trials of combination therapy vs monotherapy in serious infections, including endocarditis, gram-negative bacteremia, and neutropenic sepsis,5,10,21 and animal models,11,22,23 have supported the possibility of clinically relevant antimicrobial synergism with appropriate combinations of antibiotics. Two separate meta-analyses have failed to demonstrate any consistent benefit with combination therapy of β-lactams and aminoglycosides in immunocompetent patients with sepsis, gram-negative bacteremia, or both.24,25

In contrast, a meta-regression study by Kumar et al26 suggested that the beneficial effect of combination therapy may be restricted to critically ill patients with septic shock. Another retrospective, propensity-matched, multicenter cohort study of 4662 patients with culture-positive, bacterial septic shock, also by Kumar et al,27 demonstrated that combination therapy may decrease 28-day mortality (36.3% vs 29.0%; HR, 0.77 [95% CI, 0.67-0.88]; P <.001) and hospital mortality (47.8% vs 37.4%; odds ratio, 0.69 [95% CI, 0.59-0.81]; P <.001). The use of combination therapy also was associated with increased ventilator-free and pressor/inotrope-free days and significant reductions in stay in the ICU. The beneficial effects of combination therapy in the study by Kumar et al27 applied to both gram-positive and gram-negative infections but these findings were restricted to patients treated with β-lactams in combination with aminoglycosides, fluoroquinolones, or macrolides/clindamycin. Carbapenems, extended-spectrum β-lactam or β-lactamase inhibitor combinations, and antipseudomonal cephalosporins, which tend to demonstrate optimal pharmacokinetic indices (with presumably maximal kill rates) for most septic shock pathogens, yielded the weakest evidence of benefit with combination therapy.

The findings from our clinical trial must be interpreted carefully. The specific antibiotic combination used in this trial failed to be superior to monotherapy. The rationale to select moxifloxacin was 3-fold. First, it was thought to increase the antimicrobial coverage to community-acquired infections, particularly gram-positive pathogens such as streptococci and staphylococci as well as atypical pathogens. Second, dual coverage of pathogens typically involved in intra-abdominal infections might be of value. Third, rapid antibacterial killing and anti-inflammatory effects described for moxifloxacin might exert additional beneficial effects. In fact, community-acquired infections comprised about 50% of cases. However, occurrence of Streptococcus pneumoniae was uncommon in our trial (4.5% of pathogens), and we cannot exclude the possibility that a trial including mainly patients with severe sepsis and septic shock due to community-acquired pneumonia would show a benefit from receiving combination treatment including moxifloxacin and meropenem.28 Dual coverage of gram-negative Enterobacteriaceae would not result in superior outcomes due to the low number of such pathogens resistant to meropenem, although combination therapy may still be efficacious in the presence of a high rate of multidrug-resistant pathogens.

The outcome of septic shock (and probably severe sepsis) not only depends on adequate antimicrobial coverage but also on the timing of treatment initiation.29 In our study, the rate of adequate initial antimicrobial treatment with meropenem was 96.8% (94.2% in the monotherapy group and 100% in the combination therapy group) among patients tested. Initiation of antimicrobial treatment occurred predominantly within the first 1½ hours after enrollment. In observational studies, both factors might be less controlled and account for differences in outcomes. Therefore, our results must be interpreted on the background of optimal management of patients within the predefined study setting.

We found a higher rate of carbapenem-resistant pathogens in the monotherapy compared with the combination therapy group after treatment (until ICU discharge or day 21). However, the numbers were small (8 patients vs 1 patient; Table 4). Development of carbapenem resistance during treatment has been described and initial combination with fluoroquinolones may prevent the risk for selection of carbapenem-resistant pathogens during treatment.30

Our data provide evidence for shorter treatment duration for patients with severe sepsis and septic shock. Using a procalcitonin-guided treatment protocol on study days 7 and 10, the median treatment duration was 8 days for monotherapy and 7 days for combination therapy, and the upper IQR for both groups was 10 days. This finding is consistent with recent data using procalcitonin as a guide to limit treatment duration in a similar patient population.31

In conclusion, in this randomized multicenter trial of adult patients with severe sepsis or septic shock, empirical treatment with the combination of meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure.

Corresponding Author: Tobias Welte, MD, Klinik für Pneumologie, Medizinische Hochschule Hannover, Carl Neuberg Str 1, D-30625 Hannover, Germany (welte.tobias@mh-hannover.de).

Published Online: May 21, 2012. doi:10.1001/jama.2012.5833

Author Contributions: Drs Brunkhorst and Reinhart had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Reinhart and Welte contributed equally to the work.

Study concept and design: Brunkhorst, Bloos, Kuhnt, Bogatsch, Engel, Loeffler, Welte.

Acquisition of data: Brunkhorst, Oppert, Marx, Bloos, Ludewig, Putensen, Nierhaus, Jaschinski, Meier-Hellmann, Weyland, Gründling, Moerer, Riessen, Seibel, Ragaller, Büchler, John, Bach, Spies, Reill, Fritz, Kiehntopf, Kollef, Reinhart, Welte.

Analysis and interpretation of data: Brunkhorst, Bloos, Ludewig, Reill, Kiehntopf, Kuhnt, Bogatsch, Engel, Loeffler, Kollef, Reinhart, Welte.

Drafting of the manuscript: Brunkhorst, Kuhnt, Kollef, Welte.

Critical revision of the manuscript for important intellectual content: Brunkhorst, Oppert, Marx, Bloos, Ludewig, Putensen, Nierhaus, Jaschinski, Meier-Hellmann, Weyland, Gründling, Moerer, Riessen, Seibel, Ragaller, Büchler, John, Bach, Spies, Reill, Fritz, Kiehntopf, Kuhnt, Bogatsch, Engel, Loeffler, Kollef, Reinhart, Welte.

Statistical analysis: Kuhnt, Engel, Loeffler.

Obtained funding: Brunkhorst, Reinhart, Welte.

Administrative, technical, or material support: Brunkhorst, Oppert, Marx, Bloos, Ludewig, Putensen, Nierhaus, Jaschinski, Meier-Hellmann, Weyland, Gründling, Moerer, Riessen, Seibel, Ragaller, Büchler, John, Bach, Spies, Reill, Fritz, Kiehntopf, Kuhnt, Bogatsch, Engel, Kollef, Reinhart, Welte.

Study supervision: Brunkhorst, Bloos, Ludewig, Bogatsch, Loeffler, Reinhart.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Brunkhorst reported receiving payment for lectures from Bayer HealthCare AG, AstraZeneca GmbH, Thermo Fisher Scientific, Pfizer Deutschland GmbH, Becton Dickinson and Company, and bioMérieux Deutschland GmbH. Dr Oppert reported receiving payments for lectures Bayer HealthCare AG. Dr Marx reported receiving grants from SIRS-Lab GmbH; and payments for lectures from Thermo Fisher Scientific. Dr Bloos reported receiving grants from Pfizer Deutschland GmbH; payments for lectures from Biosyn GmbH and Roche Diagnostics; and travel expenses from SIRS-Lab GmbH, Roche Diagnostics, and Bayer HealthCare AG. Dr Putensen reported serving as a consultant to Pulsion AG; and receiving payments for lectures from Dräger Medical GmbH. Dr Nierhaus reported receiving grants from Sysmex Europe; and receiving payments for lectures from Thermo Fisher Scientific, Biotest Pharma, and Merck Sharpe and Dohme. Dr Meier-Hellmann reported owning stock options in Fresenius. Dr Weyland reported receiving grants and payments for lectures from Pulsion Medical Systems and Edwards Life Sciences. Dr Gründling reported receiving grants from Pfizer Deutschland GmbH; and payment for lectures from Becton Dickinson Management GmbH&Co KG. Dr Moerer reported receiving payments for lectures from Maquet Critical Care and Carefusion. Dr Ragaller reported receiving grants from Johnson & Johnson. Dr John reported receiving payment for lectures from UpToDate GmbH. Dr Bach reported receiving payments for development of educational presentations from AstraZeneca GmbH, sanofi-aventis GmbH, Roche Diagnostics, Thermo Fisher Scientific, Bayer HeathCare AG, Fresenius Kabi, Baxter Germany, CLS Behring, and GlaxoSmithKline. Dr Spies reported receiving grants from Abbott, Aspect, Baxter, Care Fusion, Deltex, Fresenius, Grünenthal, Hutchinson, Köhler Chemie, Merck Sharpe and Dohme, Medizinische Congressorganisation Nürnberg AG, Novartis, Pajunk, Pulsion, Roche, and Sysmex; payments for lectures from Abbott, Essex Pharma, and GlaxoSmithKline; and travel expenses from Abbott and Aspect. Dr Reill reported receiving payment for lectures from Merck Sharpe and Dohme; and travel expenses from Merck Sharpe and Dohme and Pfizer. Dr Fritz reported receiving payment for employment in the HYPRESS study (NCT00670254). Dr Kiehntopf reported board membership with and payment for lectures from Telematik; and grants from the German Federal Ministry of Education and Research. Dr Kollef reported receiving payments for lectures from Cubist and Hospira. Dr Reinhart reported receiving payments from Brahms GmbH for serving as a consult and for giving lectures. Dr Welte reported board memberships at AstraZeneca, Bayer HealthCare, Novartis, Pfizer Pharma, and Astellas; receiving grants from Novartis and Bayer HealthCare; and receiving payments for lectures from AstraZeneca, Astellas, Bayer HealthCare, GlaxoSmithKline, Novartis, Pfizer, and Merck Sharpe and Dohme. Drs Ludewig, Jaschinski, Riessen, Seibel, Büchler, Bogatsch, Engel, and Loeffler and Ms Kuhnt did not report any disclosures.

Funding/Support: This study was supported by the German Federal Ministry of Education and Research grant 01 KI 0106; the Paul-Martini Clinical Sepsis Research Group, which is funded by the Thuringian Ministry of Education, Science and Culture grant PE 108-2; the publicy funded Thuringian Foundation for Technology, Innovation and Research; and the Jena Center of Sepsis Control and Care, which is funded by the German Ministry of Education and Research grant 01 EO 1002. AstraZeneca and Bayer HealthCare provided the drugs for this study.

Role of the Sponsors: The sponsors 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.

German Study Group Competence Network Sepsis (SepNet) Organization:Clinical Data Collection and Management: Anke Schöler, Holger Bogatsch, Evelyn Kuhnt, Thomas Junge, Martin Beck, Matthias Collier, Madlen Doerschmann, and Andre Rothe (all from the Clinical Trial Centre Leipzig, University of Leipzig); Christoph Engel (Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig); Katrin Ludewig, Frank M. Brunkhorst, Frank Bloos, and Viola Bahr (all from the Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller University of Jena). Study Nurses: Petra Bloos, Almut Noack, Daniela Fergen, Ulrike Redlich, and Anke Braune (all from the Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller University of Jena). Onsite Monitoring: Dagmar Fiedler, Monika Rohwedder, and Angelika Siegmund (all from the Clinical Trial Centre Leipzig, University of Leipzig). Data Trustee: Karsten Komischke (lawyer, Jena). Central Sample Biobank: Michael Kiehntopf and Kay Stötzer (both from Institute for Clinical Chemistry and Laboratory Medicine, Friedrich-Schiller-University Jena). Data and Safety Monitoring Board: Harald Seifert (Department of Microbiology and Infectious Diseases, Cologne University Hospital, Cologne); Waheedullah Karzai (Department of Anesthesiology and Intensive Care Medicine, Zentralklinik Bad Berka); and Herbert Witte (Institute of Medical Statistics, Informatics and Documentation, University of Jena).

SepNet Study Investigators: Michael Oppert (Department of Nephrology and Medical Intensive Care, Charité, Campus Virchow-Klinikum, University Medical Center, Berlin); Konrad Reinhart (Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller University of Jena); Gernot Marx (Department of Anesthesiology and Intensive Care Medicine, University of Aachen); Christian Putensen (Department of Anesthesiology and Intensive Care Medicine, University of Bonn); Axel Nierhaus (Department of Anesthesiology and Intensive Care Medicine, University of Hamburg); Ulrich Jaschinski (Department of Anesthesiology and Critical Care Medicine, Klinikum Augsburg); Andreas Meier-Hellmann (Department of Anesthesiology and Intensive Care Medicine, HELIOS Klinikum, Erfurt); Andreas Weyland (Department of Anesthesiology and Intensive Care Medicine, Klinikum Oldenburg); Matthias Gründling (Department of Anesthesiology and Intensive Care Medicine, Ernst-Moritz-Arndt University, Greifswald); Onnen Moerer (Department of Anesthesiology and Intensive Care Medicine, University of Goettingen); Maximilian Ragaller (Department of Anesthesiology and Intensive Care Medicine, University Hospital of the Technical University of Dresden); Armin Seibel (Department of Anesthesiology and Intensive Care Medicine, Jung-Stilling-Krankenhaus Siegen); Reimer Riessen (Department of Internal Medicine, University of Tübingen); Markus W. Büchler (Department of Surgery, University of Heidelberg); Stefan John (Department of Nephrology and Hypertension, University of Erlangen-Nuremberg); Friedhelm Bach (Department of Anesthesiology and Intensive Care Medicine, Evangelisches Krankenhaus Bielefeld); Claudia Spies (Department of Anesthesiology and Intensive Care Medicine, Charité, Campus Mitte, University Medical Center, Berlin); Lorenz Reill (Department of Cardiology and Intensive Care Medicine, Vivantes Klinikum Neukölln Berlin); Harald Fritz (Department of Anesthesiology and Intensive Care Medicine, Krankenhaus Martha-Maria Halle); Herwig Gerlach (Department of Anesthesiology and Intensive Care Medicine, Vivantes Klinikum Neukölln Berlin); Ursula Hoffmann (Department of Internal Medicine, Klinikum Mannheim); Udo Gottschaldt (Department of Anesthesiology and Intensive Care Medicine, University Hospital Leipzig); Gabriele Nöldge-Schomburg (Department of Anesthesiology and Intensive Care Medicine, University of Rostock); Norbert Weiler (Department of Anesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel); Martin Westphal (Department of Anesthesiology and Intensive Care Medicine, University of Münster); Dirk Pappert (Department of Anesthesiology and Intensive Care Medicine, Klinikum Ernst von Bergmann, Potsdam); Stefan Schröder (Department of Anesthesiology and Intensive Care Medicine, Westküstenklinikum Heide); Claus Peckelsen (Department of Internal Intensive Care Medicine, Klinikum Harlaching München); Martin Welte (Department of Anesthesiology and Intensive Care Medicine, Klinikum Darmstadt); Harry Bromber (Department of Anesthesiology and Intensive Care Medicine, Martin-Luther-University, Halle-Wittenberg); Karl-Friedrich Rothe (Department of Anesthesiology and Intensive Care, Staedtisches Krankenhaus Dresden-Friedrichstadt); Frank Wappler (Department of Anesthesiology and Intensive Care Medicine, Krankenhaus Merheim Köln); Simone Rosseau (Department of Infectiology and Pneumology, Charité, Campus Mitte, University Medical Center, Berlin); Matthias Kochanek (Department of Internal Medicine, University of Cologne); Malte Meesmann (Department of Cardiology and Intensive Care Medicine, Juliusspital Würzburg); Tobias Welte (Department of Pneumology, Medizinische Hochschule Hannover); Sigrun Friesecke (Department of Internal Medicine, University of Greifswald); Hauke Rensing (Department of Anesthesiology and Intensive Care Medicine, University of Homburg); and Roland Gärtner (Medizinische Klinik Innenstadt, Ludwig-Maximilians Universität München).

Bochud PY, Glauser MP, Calandra T,  et al.  Antibiotics in sepsis.  Intensive Care Med. 2001;27:(suppl 1)  S33-S48
PubMed   |  Link to Article
Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A,  et al.  Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis.  Crit Care Med. 2003;31(12):2742-2751
PubMed   |  Link to Article
Harbarth S, Garbino J, Pugin J,  et al.  Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis.  Am J Med. 2003;115(7):529-535
PubMed   |  Link to Article
Dellinger RP, Levy MM, Carlet JM,  et al.  Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008.  Crit Care Med. 2008;36(1):296-327
PubMed   |  Link to Article
EORTC International Antimicrobial Therapy Cooperative Group.  Ceftazidime combined with a short or long course of amikacin for empirical therapy of gram-negative bacteremia in cancer patients with granulocytopenia.  N Engl J Med. 1987;317(27):1692-1698
PubMed   |  Link to Article
Gribble MJ, Chow AW, Naiman SC,  et al.  Prospective randomized trial of piperacillin monotherapy versus carboxypenicillin-aminoglycoside combination regimens in the empirical treatment of serious bacterial infections.  Antimicrob Agents Chemother. 1983;24(3):388-393
PubMed   |  Link to Article
Milatovic D, Braveny I. Development of resistance during antibiotic therapy.  Eur J Clin Microbiol. 1987;6(3):234-244
PubMed   |  Link to Article
Labro MT. Interference of antibacterial agents with phagocyte functions.  Clin Microbiol Rev. 2000;13(4):615-650
PubMed   |  Link to Article
Pasquale TR, Tan JS. Nonantimicrobial effects of antibacterial agents.  Clin Infect Dis. 2005;40(1):127-135
PubMed   |  Link to Article
Anderson ET, Young LS, Hewitt WL. Antimicrobial synergism in the therapy of gram-negative rod bacteremia.  Chemotherapy. 1978;24(1):45-54
PubMed   |  Link to Article
Calandra T, Glauser MP. Immunocompromised animal models for the study of antibiotic combinations.  Am J Med. 1986;80(5C):45-52
PubMed
De Jongh CA, Joshi JH, Newman KA,  et al.  Antibiotic synergism and response in gram-negative bacteremia in granulocytopenic cancer patients.  Am J Med. 1986;80(5C):96-100
PubMed
Giamarellou H. Aminoglycosides plus beta-lactams against gram-negative organisms.  Am J Med. 1986;80(6B):126-137
PubMed   |  Link to Article
Klastersky J, Zinner SH. Synergistic combinations of antibiotics in gram-negative bacillary infections.  Rev Infect Dis. 1982;4(2):294-301
PubMed   |  Link to Article
Brunkhorst FM, Engel C, Bloos F,  et al.  Intensive insulin therapy and pentastarch resuscitation in severe sepsis.  N Engl J Med. 2008;358(2):125-139
PubMed   |  Link to Article
Pocock SJ. Clinical Trials—A Practical Approach. Chichester, NY: John Wiley & Sons; 1983
Reinhart K, Brunkhorst FM, Bone HG,  et al.  Prevention, diagnosis, treatment, and follow-up care of sepsis: first revision of the S2k Guidelines of the German Sepsis Society (DSG) and the German Interdisciplinary Association for Intensive and Emergency Care Medicine (DIVI) [in German].  Anaesthesist. 2010;59(4):347-370
PubMed   |  Link to Article
Moreno R, Vincent JL, Matos R,  et al.  The use of maximum SOFA score to quantify organ dysfunction/failure in intensive care.  Intensive Care Med. 1999;25(7):686-696
PubMed   |  Link to Article
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials.  Biometrika. 1983;70(3):659-663
Link to Article
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials.  Biometrics. 1979;35(3):549-556
PubMed   |  Link to Article
Bouza E, Muñoz P. Monotherapy versus combination therapy for bacterial infections.  Med Clin North Am. 2000;84(6):1357-1389, v
PubMed   |  Link to Article
Darras-Joly C, Bédos JP, Sauve C,  et al.  Synergy between amoxicillin and gentamicin in combination against a highly penicillin-resistant and -tolerant strain of Streptococcus pneumoniae in a mouse pneumonia model.  Antimicrob Agents Chemother. 1996;40(9):2147-2151
PubMed
Kumar A, Mensing J, Zelenitsky S,  et al.  Effect of antibiotic sequence on blood bacterial counts in a rat model of E. coli peritonitis/septic shock.  ICAAC Proceedings. 2004;26, A-1296
Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in gram-negative bacteraemia?  Lancet Infect Dis. 2004;4(8):519-527
PubMed   |  Link to Article
Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients.  BMJ. 2004;328(7441):668
PubMed   |  Link to Article
Kumar A, Safdar N, Kethireddy S, Chateau D. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death.  Crit Care Med. 2010;38(8):1651-1664
PubMed   |  Link to Article
Kumar A, Zarychanski R, Light B,  et al.  Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock.  Crit Care Med. 2010;38(9):1773-1785
PubMed   |  Link to Article
Baddour LM, Yu VL, Klugman KP,  et al.  Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia.   Am J Respir Crit Care Med. 2004;170(4):440-444
PubMed   |  Link to Article
Kumar A, Roberts D, Wood KE,  et al.  Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock.  Crit Care Med. 2006;34(6):1589-1596
PubMed   |  Link to Article
Lister PD, Wolter DJ. Levofloxacin-imipenem combination prevents the emergence of resistance among clinical isolates of Pseudomonas aeruginosa Clin Infect Dis. 2005;40:(suppl 2)  S105-S114
PubMed   |  Link to Article
Bouadma L, Luyt CE, Tubach F,  et al.  Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial).  Lancet. 2010;375(9713):463-474
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Screening and Inclusion Process for Patients in the Study
Graphic Jump Location
Place holder to copy figure label and caption
Figure 2. Daily Sequential Organ Failure Assessment (SOFA) Scores
Graphic Jump Location

The data markers indicate means and the error bars indicate 95% CIs.

Place holder to copy figure label and caption
Figure 3. Overall Survival
Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographics and Baseline Characteristics
Table Graphic Jump LocationTable 2. Site and Source of Infection
Table Graphic Jump LocationTable 3. Gram-Positive, Gram-Negative, and Fungi Pathogens at Enrollment

References

Bochud PY, Glauser MP, Calandra T,  et al.  Antibiotics in sepsis.  Intensive Care Med. 2001;27:(suppl 1)  S33-S48
PubMed   |  Link to Article
Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A,  et al.  Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis.  Crit Care Med. 2003;31(12):2742-2751
PubMed   |  Link to Article
Harbarth S, Garbino J, Pugin J,  et al.  Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis.  Am J Med. 2003;115(7):529-535
PubMed   |  Link to Article
Dellinger RP, Levy MM, Carlet JM,  et al.  Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008.  Crit Care Med. 2008;36(1):296-327
PubMed   |  Link to Article
EORTC International Antimicrobial Therapy Cooperative Group.  Ceftazidime combined with a short or long course of amikacin for empirical therapy of gram-negative bacteremia in cancer patients with granulocytopenia.  N Engl J Med. 1987;317(27):1692-1698
PubMed   |  Link to Article
Gribble MJ, Chow AW, Naiman SC,  et al.  Prospective randomized trial of piperacillin monotherapy versus carboxypenicillin-aminoglycoside combination regimens in the empirical treatment of serious bacterial infections.  Antimicrob Agents Chemother. 1983;24(3):388-393
PubMed   |  Link to Article
Milatovic D, Braveny I. Development of resistance during antibiotic therapy.  Eur J Clin Microbiol. 1987;6(3):234-244
PubMed   |  Link to Article
Labro MT. Interference of antibacterial agents with phagocyte functions.  Clin Microbiol Rev. 2000;13(4):615-650
PubMed   |  Link to Article
Pasquale TR, Tan JS. Nonantimicrobial effects of antibacterial agents.  Clin Infect Dis. 2005;40(1):127-135
PubMed   |  Link to Article
Anderson ET, Young LS, Hewitt WL. Antimicrobial synergism in the therapy of gram-negative rod bacteremia.  Chemotherapy. 1978;24(1):45-54
PubMed   |  Link to Article
Calandra T, Glauser MP. Immunocompromised animal models for the study of antibiotic combinations.  Am J Med. 1986;80(5C):45-52
PubMed
De Jongh CA, Joshi JH, Newman KA,  et al.  Antibiotic synergism and response in gram-negative bacteremia in granulocytopenic cancer patients.  Am J Med. 1986;80(5C):96-100
PubMed
Giamarellou H. Aminoglycosides plus beta-lactams against gram-negative organisms.  Am J Med. 1986;80(6B):126-137
PubMed   |  Link to Article
Klastersky J, Zinner SH. Synergistic combinations of antibiotics in gram-negative bacillary infections.  Rev Infect Dis. 1982;4(2):294-301
PubMed   |  Link to Article
Brunkhorst FM, Engel C, Bloos F,  et al.  Intensive insulin therapy and pentastarch resuscitation in severe sepsis.  N Engl J Med. 2008;358(2):125-139
PubMed   |  Link to Article
Pocock SJ. Clinical Trials—A Practical Approach. Chichester, NY: John Wiley & Sons; 1983
Reinhart K, Brunkhorst FM, Bone HG,  et al.  Prevention, diagnosis, treatment, and follow-up care of sepsis: first revision of the S2k Guidelines of the German Sepsis Society (DSG) and the German Interdisciplinary Association for Intensive and Emergency Care Medicine (DIVI) [in German].  Anaesthesist. 2010;59(4):347-370
PubMed   |  Link to Article
Moreno R, Vincent JL, Matos R,  et al.  The use of maximum SOFA score to quantify organ dysfunction/failure in intensive care.  Intensive Care Med. 1999;25(7):686-696
PubMed   |  Link to Article
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials.  Biometrika. 1983;70(3):659-663
Link to Article
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials.  Biometrics. 1979;35(3):549-556
PubMed   |  Link to Article
Bouza E, Muñoz P. Monotherapy versus combination therapy for bacterial infections.  Med Clin North Am. 2000;84(6):1357-1389, v
PubMed   |  Link to Article
Darras-Joly C, Bédos JP, Sauve C,  et al.  Synergy between amoxicillin and gentamicin in combination against a highly penicillin-resistant and -tolerant strain of Streptococcus pneumoniae in a mouse pneumonia model.  Antimicrob Agents Chemother. 1996;40(9):2147-2151
PubMed
Kumar A, Mensing J, Zelenitsky S,  et al.  Effect of antibiotic sequence on blood bacterial counts in a rat model of E. coli peritonitis/septic shock.  ICAAC Proceedings. 2004;26, A-1296
Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in gram-negative bacteraemia?  Lancet Infect Dis. 2004;4(8):519-527
PubMed   |  Link to Article
Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients.  BMJ. 2004;328(7441):668
PubMed   |  Link to Article
Kumar A, Safdar N, Kethireddy S, Chateau D. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death.  Crit Care Med. 2010;38(8):1651-1664
PubMed   |  Link to Article
Kumar A, Zarychanski R, Light B,  et al.  Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock.  Crit Care Med. 2010;38(9):1773-1785
PubMed   |  Link to Article
Baddour LM, Yu VL, Klugman KP,  et al.  Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia.   Am J Respir Crit Care Med. 2004;170(4):440-444
PubMed   |  Link to Article
Kumar A, Roberts D, Wood KE,  et al.  Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock.  Crit Care Med. 2006;34(6):1589-1596
PubMed   |  Link to Article
Lister PD, Wolter DJ. Levofloxacin-imipenem combination prevents the emergence of resistance among clinical isolates of Pseudomonas aeruginosa Clin Infect Dis. 2005;40:(suppl 2)  S105-S114
PubMed   |  Link to Article
Bouadma L, Luyt CE, Tubach F,  et al.  Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial).  Lancet. 2010;375(9713):463-474
PubMed   |  Link to Article
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Supplemental Content

Brunkhorst FM, Oppert M, Marx G, et al; for the German Study Group Competence Network Sepsis (SepNet). Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial.JAMA. doi:10.1001/jama.2012.5833.

eMethods. Definitions of clinical and microbiological outcomes and protocol violations

eFigure. Treatment effect of combination therapy on clinical outcome within various subgroups

eTable 1. Antibiotics used one week prior to randomization

eTable 2. Susceptibility patterns and numbers of resistant enrollment organisms

eTable 3. Adverse events

eTable 4. Response to therapy, clinical and microbiological cure

eTable 5. Protocol violations

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